Clinical trial NCT05000216
Conditions: Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) Pemphigus Vulgaris Multiple Sclerosis (MS) Systemic Sclerosis (SSc) Pediatric SLE Juvenile Idiopathic Arthritis (JIA) Juvenile Dermatomyositis (JDM) Pediatric-Onset Multiple Sclerosis (POMS)
Keywords: SARS-CoV-2 Infection COVID-19 autoimmune disease non-responders to COVID-19 vaccination suboptimal response to COVID-19 vaccination COVID-19 booster vaccine booster effects with autoimmune treatments
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-08-13; Completion date: 2024-03-28
Enrollment: 258 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multi-site, adaptive, open-label clinical trial comparing the immune response to different additional doses of COVID-19 vaccine in participants with autoimmune disease requiring IS medications. All study participants will have negative serologic or suboptimal responses (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL) or a low immune response (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result \>200 U/ml and ≤2500 U/mL) to their previous doses of COVID-19 vaccine.

The study will focus on 5 autoimmune diseases in adults:

* Systemic Lupus Erythematosus (SLE)
* Rheumatoid Arthritis (RA)
* Multiple Sclerosis (MS)
* Systemic Sclerosis (SSc), and
* Pemphigus.

This study will focus on 4 autoimmune diseases in pediatric participants:

* Systemic Lupus Erythematosus (SLE)
* Juvenile Idiopathic Arthritis (JIA)
* Pediatric-Onset Multiple Sclerosis (POMS)
* Juvenile Dermatomyositis (JDM)

Detailed description:
Adult Population:

Stage 1 of this trial will enroll up to a maximum of 900 adult study participants (up to 60 participants per arm).

Participants will be assigned to one of 3 cohorts based on their IS regimens:

* Cohort A: Receipt of MMF or MPA
* Cohort B: Receipt of MTX
* Cohort C: Receipt of any BCDT within the past 18 months.

Treatment Arms: Participants in Cohorts A, B, and C will be assigned to receive an additional dose of the same COVID-19 vaccine as their original vaccine series. The trial initially enrolled participants who were vaccinated with the Pfizer-BioNTech COVID-19 Vaccine, the Moderna COVID-19 Vaccine, and the Janssen COVID-19 Vaccine. Update: Arms to receive an additional homologous vaccine dose after an initial Janssen COVID 19 Vaccine were closed to enrollment after the CDC updated its recommendations to express a clinical preference for individuals to receive an mRNA COVID-19 vaccine over the Janssen COVID-19 vaccine. All Adult Stage 1 treatment arms were closed to enrollment on 15 August 2022.

Participants in Cohorts A and B will be randomized into 2 IS medication treatment plans as follows:

* Participants continue to take their cohort-defining IS medications without alterations in schedule and dosing.
* Participants withhold their cohort-defining IS medications before and after the additional homologous vaccine dose per protocol instructions.

A participant will be enrolled in the study for a maximum of approximately 13 months.

Stage 2 of this trial will include up to a maximum of 960 adult study participants (up to 80per arm) with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after previous COVID-19 vaccine administration (at least 3 doses of mRNA vaccine(s) or 2 doses of the Janssen COVID-19 Vaccine). Participants will be eligible to receive a dose of an alternative COVID-19 vaccine.

Participants may have received their previous COVID-19 vaccine prior to enrollment in the study ("newly recruited participant"), or they may have received their previous COVID-19 vaccine as a study participant and then (re-) enter into Stage 2 ("rollover participant"). Participants can also roll over into Stage 2 via two pathways:

* Stage 1 participant rolls over to Stage 2
* Stage 2 participant rolls over to a different Stage 2 treatment arm

Participants will be allocated to 1 of 3 cohorts based on their IS regimens:

* Cohort D: Receipt of MMF or MPA
* Cohort E: Receipt of MTX
* Cohort F: Receipt of any BCDT within the past 18 months.

Treatment Arms: Participants in Cohorts D, E, and F will receive a dose of an alternative COVID-19 vaccine compared to their previous COVID-19 vaccine doses. Originally, participants who previously received 3 total doses of a single mRNA vaccine (Moderna COVID-19 Vaccine OR Pfizer- BioNTech COVID-19 Vaccine) received their choice of either the Janssen vector-based COVID-19 vaccine or the other mRNA COVID-19 vaccine, and participants who previously received 2 doses of the Janssen vector based COVID-19 vaccine received the Moderna COVID-19 Vaccine.

Update: Beginning with v4.0 of the protocol, this trial will not utilize the Janssen vector-based COVID-19 vaccine. Participants who previously received 3 total doses of a single mRNA vaccine will receive their choice of an alternative mRNA COVID-19 vaccine or the Sanofi-GSK protein based COVID-19 vaccine. Participants who previously received 4 or more doses of a single mRNA vaccine or 3 or more doses of a mixture mRNA vaccines (Moderna COVID-19 Vaccine AND Pfizer-BioNTech COVID-19 Vaccine, in any order or combination) will receive the Sanofi-GSK protein-based COVID-19 vaccine.

Participants in Cohorts D and E will withhold their cohort-defining IS medications before and after the alternative vaccine dose per protocol instructions. Participants in Cohort F who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications before and after the alternative vaccine dose per protocol instructions.

Visits to assess endpoints will occur at Baseline (Week 0), Week 4 ± 1 week, Week 12 ± 2 weeks, Week 24 ± 2 weeks, Week 36 ± 2 weeks, and Week 48 ± 2 weeks. A participant who is newly recruited to the study for entry into Stage 2 may be on study for up to a maximum of 13 months. A participant who enters Stage 2 after a serologic negative, suboptimal, or low immune response to their Stage 1 vaccine dose may be on study for up to a maximum of 26 months. Rollover participants will discontinue follow-up as part of Stage 1 upon rollover into Stage 2. A participant who rolls over to a different Stage 2 treatment arm 2 after a serologic negative, suboptimal, or low immune response to another Stage 2 vaccine dose may be on study for up to a maximum of 38 months.

Pediatric Population:

Stage 1 in the pediatric portion of this trial will enroll up to a maximum of 800 participants (2-17 years of age) with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after receiving an initial COVID-19 vaccine regimen (up to 80participants per arm). Vaccines will be included in this protocol as they receive EUA or approval by FDA for a given age group. Pediatric participants will have 1 of 4 autoimmune diseases: pediatric SLE, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), or pediatriconset multiple sclerosis (POMS). Participants will be assigned to 1 of 3 cohorts based on their IS regimens:

* Cohort A: Receipt of MMF or MPA
* Cohort B: Receipt of MTX
* Cohort C: Receipt of any BCDT within the past 18 months.

Treatment Arms: Participants in Cohorts A, B, and C will be assigned to receive an additional dose of the same vaccine as their original vaccine series. Based on FDA EUA status, pediatric participants were initially eligible to receive the Pfizer-BioNTech COVID-19 Vaccine only.

Participants in Cohorts A and B will be randomized into 2 IS medication treatment plans as follows):

* Participants continue to take their cohort-defining IS medications without alterations in schedule and dosing.
* Participants withhold their cohort-defining IS medications before and after the additional homologous vaccine dose per protocol instructions.

A participant will be enrolled in the study for a maximum of approximately 13 months.

Stage 2 of the pediatric portion of this trial will include up to a maximum of 480 pediatric study participants (up to 80 per arm) with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after previous COVID-19 vaccine administration (an age-appropriate EUA-authorized or FDA-approved initial COVID-19 vaccine regimen plus 1 additional dose of the same vaccine). All participants (2-17 years of age) who previously received doses of the Pfizer-BioNTech COVID-19 Vaccine are eligible to receive an age-appropriate dose of the Moderna COVID-19 Vaccine. Participants 12 through 17 years of age who previously received doses of the Moderna COVID-19 vaccine are eligible to receive an age-appropriate dose of the Pfizer-BioNTech COVID-19 Vaccine. Participants will be eligible to receive a dose of an alternative COVID-19 vaccine. Participants may have received their previous COVID-19 vaccine as a study participant and then enter into Stage 2 ("rollover participant"), or they may have received their previous COVID-19 vaccine prior to enrollment in the study ("newly recruited participant").

Participants will be allocated to 1 of 3 cohorts based on their IS regimens:

* Cohort D: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics)

  o Participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) will be placed in this cohort.
* Cohort E: Receipt of MTX (± other rheumatic disease medications, including biologics)

  o Participants who are taking MTX (without additional B cell depleting medications or MMF/ MPA) will be placed in this cohort.
* Cohort F: Receipt of B cell depletion therapy within the past 18 months (± other rheumatic disease medications) o Participants taking B cell depletion medications, regardless of whether they are also taking MMF or MTX, will be placed in this cohort.

Treatment Arms: Participants in Cohorts D, E, and F will receive a dose of an alternative COVID-19 vaccine compared to their previous COVID-19 vaccine doses. Participants who previously received age-appropriate doses of a single mRNA vaccine (Moderna COVID-19 Vaccine OR Pfizer-BioNTech COVID-19 Vaccine, as noted above) will receive the other mRNA COVID-19 vaccine.

Beginning with v7.0 of the protocol all vaccines used are bivalent versions replacing original monovalent versions.

Participants in Cohorts D and E will withhold their cohort-defining IS medications before and after the alternative vaccine dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).

Participants in Cohort F who are taking MMF, MPA, or MTX in addition to B cell depletion therapies (BCDTs) will withhold these medications before and after the alternative vaccine dose per protocol instruction.

A participant who enters Stage 2 after a serologic negative, suboptimal, or low immune response to their Stage 1 vaccine dose may be on study for up to a maximum of 26 months. Rollover participants will discontinue follow-up as part of Stage 1 upon rollover into Stage 2. A participant who is newly recruited to the study for entry into Stage 2 may be on study for up to a maximum of 13 months.

Adaptive Design

An adaptive design will be employed such that cohorts and arms defined by additional vaccine doses and IS treatment plans may be added or modified based on emerging data from existing and new FDA Emergency Use Authorization (EUA) or approvals of COVID-19 vaccines:

* New cohorts may be defined based on changes in the medication groups if it becomes obvious that certain medications are highly associated with suboptimal or low immune serologic response to initial COVID-19 vaccine regimen.
* Cohorts may limit or expand the autoimmune diseases that are eligible to be included in the clinical trial and may include expansion cohorts of underrepresented diseases.
* New cohorts may include participants whose antibody response falls to suboptimal or low immune levels over time.
* Based upon timing of the FDA EUA authorization for children of each of the COVID-19 vaccines used in this trial, the age range of the inclusion criteria may be expanded.
* Allocation or randomization to treatment with new COVID-19 vaccines may be incorporated into the design when the products become available.
* Identification of additional strategies to enhance vaccine responsiveness in autoimmune diseases, including a temporary switch of immunomodulatory medications.

Arms: arm 1: Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will receive an additional dose of the Moderna COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 2: Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 3: Arm closed, effective protocol version 3.0. Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will receive the Janssen COVID-19 vaccine booster (1 dose) and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 4: Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 5: Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Pfizer-BioNTech COVID-19 vaccine, per protocol instruction. arm 6: Arm closed, effective protocol version 3.0. Adult participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after the Janssen COVID-19 vaccine booster (1 dose), per protocol instruction. arm 7: Adult participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will receive an additional dose of the Moderna COVID-19 vaccine booster and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 8: Adult participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine booster and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 9: Arm closed, effective protocol version 3.0. Adult participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will receive the Janssen COVID-19 vaccine booster (1 dose) and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 10: Adult Participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 11: Adult participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Pfizer-BioNTech COVID-19 vaccine booster, per protocol instruction. arm 12: Arm closed, effective protocol version 3.0. Adult participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after the Janssen COVID-19 vaccine booster (1 dose), per protocol instruction. arm 13: Adult participants taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will receive an additional dose of the Moderna COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 14: Adult participants taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 15: Arm closed, effective protocol version 3.0. Adult participants taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will receive the Janssen COVID-19 vaccine booster (1 dose) and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 16: Arm closed, effective protocol version 4.0. Adult participants who previously received an mRNA vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Janssen COVID-19 vaccine, per protocol instruction. arm 17: Adult participants who previously received an mRNA vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of an alternative COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 18: Adult participants who previously received the Janssen COVID-19 vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 19: Arm closed, effective protocol version 4.0. Adult participants who previously received an mRNA vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Janssen COVID-19 vaccine, per protocol instruction. arm 20: Adult participants who previously received an mRNA vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of an alternative COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 21: Adult participants who previously received the Janssen COVID-19 vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 22: Arm closed, effective protocol version 4.0. Adult participants who previously received an mRNA vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX ) before and after receiving a dose of the Janssen COVID-19 vaccine, per protocol instruction. arm 23: Adult participants who previously received an mRNA vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX) before and after receiving a dose of the alternative COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 24: Adult participants who previously received the Janssen COVID-19 vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction. Beginning with version 6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original monovalent versions. arm 25: Adult participants who previously received an mRNA vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Sanofi-GSK COVID-19 vaccine, per protocol instruction. arm 26: Adult participants who previously received an mRNA vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Sanofi-GSK COVID-19 vaccine, per protocol instruction. arm 27: Adult participants who previously received an mRNA vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX) before and after receiving a dose of the Sanofi-GSK COVID-19 vaccine, per protocol instruction arm 28: Pediatric participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will receive an additional dose of the Moderna COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 29: Pediatric participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 30: Pediatric participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 31: Pediatric participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Pfizer-BioNTech COVID-19 vaccine, per protocol instruction. arm 32: Pediatric participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will receive an additional dose of the Moderna COVID-19 vaccine booster and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 33: Pediatric participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine booster and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 34: Pediatric participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 35: Pediatric participants who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease will withhold their immunosuppressive medications (IS) before and after receiving an additional dose of the Pfizer-BioNTech COVID-19 vaccine booster, per protocol instruction. arm 36: Pediatric participants taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will receive an additional dose of the Moderna COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 37: Pediatric participants taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will receive an additional dose of the Pfizer-BioNTech COVID-19 vaccine and continue to take their immunosuppressive medications (IS) without alterations in schedule and dosing. arm 38: Pediatric participants who previously received the Moderna COVID-19 vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Pfizer-BioNTech COVID-19 vaccine, per protocol instruction. arm 39: Pediatric participants who previously received the Pfizer-BioNTech COVID-19 vaccine and who are taking MMF or MPA (without additional B cell depleting medications or MTX) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 40: Pediatric participants who previously received the Moderna COVID-19 vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Pfizer-BioNTech COVID-19 vaccine, per protocol instruction. arm 41: Pediatric participants who previously received the Pfizer-BioNTech COVID-19 vaccine and who are taking methotrexate (without additional B cell depleting medications or MMF/ MPA) for management of their underlying autoimmune disease, will withhold their immunosuppressive medications (IS) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction. arm 42: Pediatric participants who previously received the Moderna COVID-19 vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX) before and after receiving a dose of the Pfizer-BioNTech COVID-19 vaccine, per protocol instruction. arm 43: Pediatric participants who previously received the Pfizer-BioNTech COVID-19 vaccine and who are taking B cell depletion medication(s) for management of their underlying autoimmune disease, regardless of whether they are also taking MMF or MTX, will continue to take their prescribed BCDTs without alterations in schedule and dosing. Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX) before and after receiving a dose of the Moderna COVID-19 vaccine, per protocol instruction.
Interventions: intervention 1: Moderna mRNA-1273 intervention 2: BNT162b2 intervention 3: Ad26.COV2.S intervention 4: Continue IS (MMF or MPA) intervention 5: Continue IS (MTX) intervention 6: Continue IS (B cell depletion therapy) intervention 7: Monovalent [B.1.351] CoV2 preS dTM-AS03 intervention 8: Withhold IS (MMF or MPA) intervention 9: Withhold IS (MTX) intervention 10: Withhold IS (B cell depletion therapy) intervention 11: Moderna mRNA-1273, Bivalent intervention 12: BNT162b2, Bivalent
Intervention descriptions: intervention 1: Administration: One dose administered intramuscularly. intervention 2: Administration: One dose administered intramuscularly. intervention 3: Administration: One dose administered intramuscularly. intervention 4: Participants continue to take their immunosuppressive (IS) medications for management of their autoimmune disease without alterations in schedule and dosing. intervention 5: Participants continue to take their immunosuppressive (IS) medications for management of their autoimmune disease without alterations in schedule and dosing. intervention 6: Participants will continue to take their prescribed immunosuppressive (IS) medications without alterations in schedule and dosing. intervention 7: One dose administered intramuscularly intervention 8: Participants withhold their cohort-defining immunosuppressive (IS) medications for management of their autoimmune disease before and after the additional vaccine dose per protocol instructions. intervention 9: Participants withhold their cohort-defining immunosuppressive (IS) medications for management of their autoimmune disease before and after the additional vaccine dose per protocol instructions. intervention 10: Participants who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications (MMF, MPA, or MTX ) before and after the additional vaccine dose per protocol instructions. Participants will continue to take their prescribed BCDTs without alterations in schedule and dosing. intervention 11: Administration: One dose administered intramuscularly. intervention 12: Administration: One dose administered intramuscularly.

Protocol documents:
ICF_000.pdf: 
The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 1 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
Informed Consent Form 
And 
Authorization To Disclose Health Information 
 
Study Treatment Stage 1 and Stage 2 Adult Informed Consent Form 
 
Sponsor / Study Title: 
  
The National Institute of Allergy and Infectious Diseases 
(NIAID)/ “BOOSTER EFFECTS WITH AUTOIMMUNE 
TREATMENTS IN PATIENTS WITH POOR RESPONSE TO 
INITIAL COVID-19 VACCINE” 
 
Protocol Number: 
 
ACV01 
 
Principal Investigator: 
(Study Doctor) 
 
Judith James, MD 
 
Telephone: 
 
(405) 271-7805 
(405) 330-4471 (24 Hours) 
 
Address: 
Oklahoma Medical Research Foundation 
825 NE 13th Street 
Oklahoma City, OK    73104 
 
1. YOUR PARTICIPATION IS VOLUNTARY 
We will explain this research study to you.  You may ask questions.   
• 
Taking part in this study is your decision. 
• 
You may change your mind at any time. 
• 
You will be given a copy of this consent form for your records 
 
2. CONSENT KEY INFORMATION  
This section is a summary of the research study to help you decide whether- or- not to 
participate.  Detailed information is provided after the key information.  
 
Why is this research being done? 
The United States Food and Drug Administration (US FDA) has approved the use of the 
bivalent COVID-19 vaccines for adults. Both the Pfizer and Moderna COVID-19 vaccines used 
in this study and referenced below are the bivalent vaccines. The bivalent COVID-19 vaccines 
include a component of the original virus strain to provide broad protection against COVID-19 
and a component of the Omicron variant to provide better protection against COVID-19 caused 
by the Omicron variant. 
 
Some people with autoimmune diseases who take medications that weaken the immune system 
to control their disease have not had a good response to the COVID-19 vaccines. A positive 
response to the COVID-19 vaccine means that the immune system has made lots of antibodies 
against the COVID-19 virus. Antibodies are proteins made by the immune system that can 
attach to the COVID-19 virus and help to kill and remove it from the body. A strong antibody 
response to COVID-19 vaccine is needed to provide protection from COVID-19 infection. This 
research is being done to see if an additional shot of a COVID-19 vaccine will help these people 
develop a good response to the COVID-19 vaccines. The study is also being done to see if 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 2 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
temporarily stopping the medication you take for your autoimmune disease will help your 
immune system have a positive response to the additional COVID-19 vaccine. 
 
What happens if you take part in this research study? 
If you decide to join this study, you will receive an additional COVID-19 vaccination. This study 
will use COVID-19 vaccines that are authorized under an Emergency Use Authorization by the 
United States Food and Drug Administration (FDA) for initial vaccination and in some situations, 
they are authorized for an additional dose.  This includes the Pfizer, Moderna COVID-19 
vaccines. This study will also use a COVID -19 vaccine that is not currently authorized by the 
FDA. This is the Sanofi-GSK COVID-19 vaccine.  
 
This study has two stages. In Study Treatment Stage 1, you will be asked to come to the clinic 
for up to 8 research visits over 13 months. If you move to Study Treatment Stage 2 because you 
do not respond to the additional dose given as part of Stage 1 and need a fourth vaccine dose 
(Moderna, Pfizer, Sanofi-GSK) you will be asked to come to the clinic for up to 8 additional 
research visits over 13 months. If you still do not develop antibodies (after your Stage 2 study 
vaccine shot), you may be eligible to receive another COVID-19 vaccine. If this happens you will 
start Stage 2 over and will come to the clinic for an additional 8 visits over 13 months. The 
Sanofi-GSK vaccine will only be used in Study Treatment Stage 2 as an option to those who 
have not responded to Moderna or Pfizer. At these research visits you will have the following 
procedures: 
• 
Physical exam, 
• 
Blood work, 
• 
COVID-19 testing to see if you are currently infected, and 
• 
Complete questionnaires and participate in assessments related to the autoimmune 
disease you have. 
 
Is there any way being in this research can hurt me? 
All procedures and vaccinations in this study have some level of risk. You may be asked to hold 
(temporarily stop taking) your autoimmune disease medication around the time you receive the 
COVID-19 vaccine. We do not know if stopping your medications will help your immune system 
develop a positive response to the COVID-19 vaccine. It is possible that stopping your 
medication could cause a flare of your autoimmune disease. 
 
The most common risks associated with the COVID-19 vaccinations are: 
• 
Pain at the injection site 
• 
Fatigue (feeling tired) 
• 
Headache 
• 
Muscle pain 
• 
Chills 
• 
Joint pain 
• 
Fever 
• 
Redness or swelling at the injection site 
• 
Axillary (armpit) swelling/tenderness 
• 
Nausea/vomiting 
 
Will being in this research study help me in any way? 
There might be no direct medical benefit to you for being in this study. The information learned 
from this study may someday benefit people with autoimmune disorders. 
 
 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
 
What other choices do I have besides taking part in this research? 
Before you decide to take part in this study, your study doctor will talk with you about other 
options available to you. Monoclonal antibody administration is available both to prevent 
COVID-19 infection either before or after exposure or as treatment for mild infection. 
Monoclonal antibody treatment is not a substitute for vaccination. There may be other research 
studies that you can choose to join. 
 
Who is sponsoring this study? 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part 
of the National Institutes of Health (NIH). The study is being conducted through the 
Autoimmunity Centers of Excellence (ACE) network. 
 
DETAILED CONSENT INFORMATION 
The rest of the consent document includes detailed information about this study. 
 
3. INTRODUCTION 
An autoimmune disease is a disease where the patient’s immune system incorrectly attacks 
certain parts of their own body (for example, joints, nervous system, kidneys, or skin). There are 
many different types of autoimmune disease, including: 
• 
Systemic Lupus Erythematosus (SLE), 
• 
Rheumatoid Arthritis (RA)  
• 
Multiple Sclerosis (MS)  
• 
Systemic Sclerosis (SSc) 
• 
Pemphigus  
 
Approximately 1 in 12 Americans have an autoimmune disease. Minority populations are 
diagnosed with autoimmune disorders more frequently. These same populations are more 
severely impacted by the COVID-19 pandemic. People with autoimmune disease who become 
infected with SARS-CoV-2 (the virus that causes COVID-19) have worse symptoms and die 
more often than those without autoimmune disease. Early reports are indicating that some 
people with autoimmune disease are not responding to the COVID-19 vaccinations as well as 
expected. Doctors do not know if this is because of the disease itself or because of the 
medications used to treat autoimmune diseases. Doctors also do not know whether another 
dose of the same type of vaccine or another type of vaccine is needed to help these people with 
autoimmune disease respond better.  
 
Some medications seem to have a greater ability to interfere with a proper immune response to 
the COVID-19 vaccine. This study will look at medications that may interfere with a good 
immune response (mycophenolate mofetil [MMF], mycophenolic acid [MPA], methotrexate 
[MTX], and B cell depleting medications like rituximab or ofatumumab).  
 
This study will use two types of vaccines, mRNA (Moderna and Pfizer) and protein-based 
vaccines. mRNA vaccines teach our cells directly how to make a protein—or even just a piece 
of a protein—that triggers an immune response inside our bodies to fight the COVID-19 
infection. Protein-based vaccines include only the parts of a virus that best stimulate your 
immune system. This vaccine contains harmless viral proteins. Once your immune system 
recognizes the proteins, it creates antibodies and defensive white blood cells. If you later 
become infected with the COVID-19 virus, the antibodies and cells will fight the virus. This 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
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Revised 22 Dec 2022 
 
vaccine uses an adjuvant, a compound that helps stimulate an immune response. The adjuvant 
used in the Sanofi-GSK vaccine has been used before in certain influenza vaccines. 
 
Why is this research being done? 
The main reason this research study is being done is to see if additional COVID-19 vaccine 
doses will help people with autoimmune disease who are taking medications that weaken their 
immune system develop a better response to the vaccine. The study doctors also want to see if 
temporarily stopping some medications (such as mycophenolate mofetil, mycophenolic acid, 
and methotrexate) around the time of vaccination will help the immune system respond to the 
COVID-19 vaccination. 
 
You are being asked to join this study because: 
• You have one of the autoimmune diseases listed above,  
• Your immune system did not develop COVID-19 antibodies (immune proteins that fight 
infection) after you received the COVID-19 vaccination,  
• And you take one of the medications that doctors think may prevent a positive (effective) 
immune response (mycophenolate mofetil, mycophenolic acid, methotrexate, and B cell 
depleting medications like rituximab or ofatumumab). 
 
4. STUDY COMPONENTS 
Who is sponsoring this study? 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part 
of the National Institutes of Health (NIH). The study is being conducted through the 
Autoimmunity Centers of Excellence (ACE) network. 
 
How many people will be in the study? How many centers will conduct this study?  
Up to about 2300 subjects (adults and children) could be in this study at about 30 centers in the 
United States. 
 
How long will I be on this study? 
Study Treatment Stage 1 can be up to 13 months. If you move to Study Treatment Stage 2, you 
will be on the study for a maximum of another 13 months. If you still do not develop antibodies 
after your Stage 2 study vaccine dose, you may be eligible to receive another COVID-19 
vaccine. If this happens you will start Stage 2 over and will come to the clinic for an additional 8 
visits over 13 months. Total study duration will depend on if and when you move from Study 
Treatment Stage 1 to Study Treatment Stage 2 and if you require an additional Study Treatment 
Stage 2 vaccine. 
 
What am I being asked to do? 
If you choose to take part in this study, you will need to sign and date this consent form before 
we do any study procedures.  
 
Screening Phase 
Once you have signed and dated this consent form, the screening phase of the study is started. 
The purpose of the screening phase is to find out whether you will be able to participate in the 
study. The screening phase can last for up to 21 days while we wait for the laboratory test 
results and review medical records if necessary.  
 
 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
 
The screening visit will include the following procedures: 
 
Medical History and Physical Exam: During the screening visit, you will be asked about your 
medical history, your autoimmune disease history, any recent vaccines you have had, and any 
medication you may take. You will be given a full physical exam (including vital signs), urine and 
blood tests, and a test for pregnancy (if you are female and able to become pregnant).  This 
includes testing your blood (and sometimes a skin test) for several infections, including HIV (the 
virus that causes AIDS), tuberculosis, hepatitis, and COVID-19. If you test positive for COVID-
19, HIV, or hepatitis, we may have to report this information to the department of health.  
Approximately 2 tablespoons of blood will be needed for these tests.  
 
Oklahoma law requires us to report positive HIV, hepatitis B, C and/or tuberculosis testing to the 
health department.  This reporting will include information that identifies you (for example name, 
date of birth, home address, phone number, etc.) as required by Oklahoma law.  The health 
department may use this information to contact you for further follow up and/or to help conduct 
health surveillance activities aimed at preventing or controlling diseases. 
 
Autoimmune Disease Evaluations: Based on the autoimmune disease that you have, you will 
have a set of evaluations and will be asked to complete questionnaires about your disease and 
its impact on your life.  
 
After all screening tests are complete and you qualify for the study, you will move to the study 
treatment phase of the study. 
 
This study has two study treatment stages. During the first stage you will receive the same type 
of vaccination that you received in the community. If at any point during Study Treatment Stage 
1, the antibodies needed to fight COVID-19 infection drop below a certain level, you can move 
to Study Treatment Stage 2. In Study Treatment Stage 2 you will be able to receive an 
additional dose of vaccine. If antibodies still do not develop, one more vaccine dose may be 
available. Study Treatment Stage 1 and 2 and the vaccine dosing plan are described below in 
detail. 
 
Study Treatment Stage 1 
 
Randomization (Week -1): If you are taking mycophenolate mofetil, mycophenolic acid 
or methotrexate (immune suppression drugs), you will be assigned randomly (like 
flipping a coin, 50/50 chance) to either stop your immune suppression drug for a period 
of time around the booster vaccination or continue taking your medications as usual. If 
you are randomized to stop the immunosuppressive drug for a period of time around the 
time you receive the COVID-19 booster vaccination, the study doctor or coordinator will 
call you to tell you exactly how long the medication will be stopped and will give you 
detailed instructions on when to stop your medication. The medication is being stopped 
to see if this will allow your immune system to develop antibodies and thus be likely to 
have better immunity than you did in response to the primary vaccine series, once you 
receive the COVID-19 booster vaccine. 
 
Baseline Visit (Week 0): The Baseline Visit includes the following evaluations: 
• 
COVID-19 Testing (nasal swab): If this test is positive, you will not be allowed to 
receive the booster vaccination. We encourage you to take precautions to avoid 
COVID-19. Please see Information related to COVID-19 below. 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 6 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
Brief Physical Exam: A brief physical exam will be conducted at each visit to 
monitor your general health and disease activity. During this exam you will be 
asked about any health events since the last visit, and you will review all the 
medication you are currently taking. 
• 
Vital Signs: Weight, temperature, blood pressure, respiration rate, and pulse will 
be obtained at all visits.  
• 
Clinical Labs: Clinical labs include blood work. The table below lists the total 
amount of blood to be collected at each visit for clinical labs. These tests are to 
monitor your general health and disease activity. If you are a woman of 
childbearing potential, urine will be collected for a pregnancy test at the week 0 
visit. If the test is positive, you will not have the booster vaccination. You will be 
given the results of the clinical lab tests. 
• 
Research Labs: The table below lists the total volume of blood to be collected at 
each visit for research testing. These research tests will help us learn more about 
your autoimmune disease, the immune system, and help us learn how your 
autoimmune disease responds to the COVID-19 vaccine. The research testing 
being conducted may look at large chunks of your DNA (whole exome testing) or 
all your DNA at once (whole genome testing). You will not be given the results of 
the research lab tests. 
• 
Mycophenolate Mofetil or Methotrexate Drug Levels: If you take mycophenolate 
mofetil or methotrexate we will draw additional blood to determine what your 
current drug levels are. If you are taking mycophenolate mofetil, you will be 
asked to not take it the morning of the Baseline Visit. 
• 
Autoimmune Disease Assessments: These are described above under 
Screening.  
• 
Questionnaires: You will be asked to complete questionnaires related to how you 
feel physically and emotionally. 
• 
COVID-19 Vaccination: You will receive a booster of the same vaccine as your 
original vaccine series (Moderna COVID-19 vaccine, Pfizer-BioNTech COVID-19 
vaccine, or Janssen-J&J COVID-19 vaccine) 
• 
Diary Completion Using electronic questionnaires: You will receive a link to 
MyOwnMed, where you will complete a daily diary on a mobile device (such as a 
desktop computer, tablet or smartphone) for seven days following your 
vaccination.  There may be instances where your responses may trigger study 
staff to contact you to find out more information. For subjects who do not have 
internet access or a mobile device or do not wish to complete the questionnaires 
electronically, the study staff may provide paper versions of questionnaires to 
complete. Site personnel then will enter questionnaire responses into the system. 
If you would like reminders to complete the daily diary, you will need to provide 
your email address or your mobile phone number. This information will only be 
kept for the time you are completing the diary. Study staff will call you at the end 
of this week to review your diary entries. 
 
Follow-Up Visits at Weeks 4, 12, 24, 36 and 48 
The Follow-up Visits will last approximately 1 hour each and include the following 
evaluations:  
• 
Brief Physical Exam: A brief physical exam will be conducted at each visit to 
monitor your general health and disease activity. During this exam you will be 
asked about any health events since the last visit, and you will review all the 
medication you are currently taking. 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 7 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
Vital Signs: Weight, temperature, blood pressure, respiration rate, and pulse will 
be obtained at all visits.  
• 
Clinical Labs: Clinical labs include blood work. The table below lists the total 
amount of blood to be collected at each visit for clinical labs. These tests are to 
monitor your general health and disease activity. If you are a woman of 
childbearing potential, urine will be collected for a pregnancy test at the week 0 
visit. If the test is positive, you will not have the booster vaccination. We will also 
be testing your immune system’s response to the study vaccination. You will be 
given the results of the clinical lab tests. 
• 
Research Labs: The table below lists the total volume of blood to be collected at 
each visit for research testing. These research tests will help us learn more about 
your autoimmune disease, the immune system, and help us learn how your 
autoimmune disease responds to the COVID-19 vaccine. The research testing 
being conducted may look at large chunks of your DNA (whole exome testing) or 
all your DNA at once (whole genome testing). You will not be given the results of 
the research lab tests. 
• 
Autoimmune Disease Assessments: These are described above under 
Screening.  
• 
Questionnaires: You will be asked to complete questionnaires related to how you 
feel physically and emotionally. 
 
Study Treatment Stage 1 Schedule of Study Procedures and Assessments 
Below is a schedule of the procedures that you will have while in this study. A detailed 
explanation of each of these procedures is given above in the Screening Phase and Study 
Treatment Phase descriptions.  
 
Study Week Number 
-1 0 4 
1
2 
2
4 
3
6 
4
8 
Early 
Terminati
on Visit 
Study Visit Number 
R
* 
1 2 3 
4 
5 6 
ET 
Randomization 
X X  
 
 
 
 
 
Brief Physical Exam 
 
X X X X X X X 
Vital Signs 
 
X X X X X X X 
Autoimmune Disease Assessment 
 
X X X X X X X 
Questionnaires 
 
X X X X X X X 
COVID-19 Vaccination and Diary Completion for 7 
Days 
 
X  
 
 
 
 
 
COVID-19 Testing 
 
X  
 
 
 
 
 
Clinical Labs 
 
X X X X X X X 
Research Labs 
 
X X X X X X X 
Approximate Blood Volume for Clinical Labs 
(Tablespoons) 
 
1 1 1 
1 
1 1 
1 
Approximate Blood Volume for Research Labs 
(Tablespoons) 
 
4 4 4 
4 
4 4 
4 
*R=Randomization 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 8 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
 
Study Treatment Stage 2 
 
If at any point during Study Treatment Stage 1, the antibodies in your blood needed to fight 
COVID-19 infection drop below a certain level, you can move to Study Treatment Stage 2. In 
Study Treatment Stage 2 you will be able to receive an additional dose of study vaccine. If this 
dose of study vaccine does not work to create antibodies, one more study vaccine dose may be 
available. The table below explains what study vaccines would be available to you in Stage 2 
based on the study vaccines you have already received.  
 
Previous Vaccines Received 
Vaccine Option for Study Treatment Stage 
Two: First Dose 
3 doses of the same mRNA COVID-19 
vaccine 
A choice of an alternative mRNA COVID-19 
vaccine OR Sanofi-GSK COVID-19 Vaccine 
2 doses of Janssen COVID-19 vaccine 
Moderna mRNA vaccine 
 
Previous Vaccines Received 
Vaccine Option for Study Treatment Stage 
Two: Second Dose 
3 doses of Moderna mRNA COVID-19 
vaccine followed by 1 dose of Pfizer mRNA 
COVID-19 vaccine 
Sanofi-GSK COVID-19 Vaccine 
3 doses of Pfizer mRNA COVID-19 vaccine 
followed by 1 dose of the Moderna mRNA 
COVID-19 vaccine 
Sanofi-GSK COVID-19 Vaccine 
 
 
Screening: The purpose of the Study Treatment Stage 2 screening phase is to make 
sure you are healthy enough to receive another vaccine dose. The screening phase can 
last for up to 28 days while we wait for the laboratory test results and review medical 
records if necessary. If you have had a recent study visit (within 4 weeks) you may not 
have to have all the laboratory tests completed.  
 
Immune Suppression Drug Stopping: When you begin Study Treatment Stage 2, you 
will be asked to stop the mycophenolate mofetil, mycophenolic acid or methotrexate (if 
you are taking these) you take for a period around the time you receive the Study 
Treatment Stage 2 vaccine COVID-19 vaccination. The study doctor or study coordinator 
will call you to tell you exactly how long the medication will be stopped and will give you 
detailed instructions on when to stop and restart your immune suppressive medication. 
This medication is being stopped to see if this allows your immune system to develop 
antibodies and have better immunity than you did in response to the other vaccine 
doses. 
 
Study Treatment Stage 2 Schedule of Study Procedures and Assessments 
Below is a schedule of the procedures that you will have while in this study. A detailed 
explanation of each of these procedures is given above in the Screening Phase and Study 
Treatment Phase 1 descriptions.  
 
If you receive a second Stage 2 study vaccine, you will start Stage 2 visits from the beginning 
and will come to the clinic for an additional 8 visits over 13 months. 
 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 9 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
Study Week Number 
 
Screening 
S2 
0 
S2 4 
S2 
12 
S2 
24 
S2 
36 
S2 
48 
Early 
Termination 
Visit 
Study Visit Number 
Screening 
S2 
1 
S2 2 
S2 
3 
S2 
4 
S2 
5 
S2 
6 
ET 
Brief Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Autoimmune Disease Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
COVID-19 Vaccination and Diary Completion for 
7 Days 
X 
X 
 
 
 
 
 
 
COVID-19 Testing 
X 
X 
 
 
 
 
 
 
Clinical Labs 
X 
X 
X 
X 
X 
X 
X 
X 
Research Labs 
X 
X 
X 
X 
X 
X 
X 
X 
Approximate Blood Volume for Clinical Labs 
(Tablespoons) 
 
1 
1 
1 
1 
1 
1 
1 
Approximate Blood Volume for Research Labs 
(Tablespoons) 
 
4 
4 
4 
4 
4 
4 
4 
S2 = Study Treatment Stage 2 
 
5.  RISKS ASSOCIATED WITH PROCEDURES AND STUDY TREATMENTS 
This study will use the Pfizer-BioNTech COVID-19 Vaccine, the Moderna COVID-19 Vaccine, 
and the Janssen COVID-19 Vaccine (Commonly referred to as the Johnson & Johnson Covid-
19 Vaccine).  
 
RISKS OF THE PFIZER-BIONTECH COVID-19 VACCINE 
There is a remote chance that the Pfizer-BioNTech COVID-19 Vaccine could cause a severe 
allergic reaction. A severe allergic reaction would usually occur within a few minutes to one hour 
after getting a dose of the Pfizer-BioNTech COVID-19 Vaccine. For this reason, your study 
vaccination provider may ask you to stay at the place where you received your study vaccine for 
monitoring after study vaccination. Signs of a severe allergic reaction can include:  
• 
Difficulty breathing  
• 
Swelling of your face and throat  
• 
A fast heartbeat  
• 
A bad rash all over your body  
• 
Dizziness and weakness  
 
Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining 
outside the heart) have occurred in some people who have received the Pfizer-BioNTech 
COVID-19 Vaccine, more commonly in adolescent males and adult males under 40 years of 
age than among females and older males. In most of these people, symptoms began within a 
few days following receipt of the second dose of vaccine. The chance of having this occur is 
very low. You should seek medical attention right away if you have any of the following 
symptoms after receiving the vaccine:  
• 
Chest pain  
• 
Shortness of breath or difficulty breathing 
• 
Feelings of having a fast-beating, fluttering, or pounding heart.  


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
Fainting 
• 
Unusual and persistent irritability 
• 
Unusual and persistent poor feeding 
• 
Unusual and persistent fatigue or lack of energy 
• 
Persistent vomiting 
• 
Persistent pain in the abdomen 
• 
Unusual and persistent cool, pale skin 
 
Side effects that have been reported with the Pfizer-BioNTech COVID-19 Vaccine include:  
• 
Severe allergic reactions  
• 
Non-severe allergic reactions such as rash, itching, hives, or swelling of the face  
• 
Myocarditis (inflammation of the heart muscle)  
• 
Pericarditis (inflammation of the lining outside the heart)  
• 
Injection site pain  
• 
Tiredness  
• 
Headache  
• 
Muscle pain  
• 
Chills  
• 
Joint pain  
• 
Fever  
• 
Injection site swelling 
• 
Injection site redness  
• 
Nausea  
• 
Feeling unwell  
• 
Swollen lymph nodes (lymphadenopathy)  
• 
Decreased appetite 
• 
Diarrhea  
• 
Vomiting  
• 
Arm pain  
• 
Fainting in association with injection of the study vaccine 
• 
Dizziness 
• 
Irritability 
 
These may not be all the possible side effects of the Pfizer-BioNTech COVID-19 Vaccine. Not 
all adverse events (side effects) of the study vaccine are known and there may be effects of the 
vaccine on you or your unborn baby, including as yet unknown effects related to additional 
doses. Serious and unexpected side effects may occur. The possible side effects of the study 
vaccine are still being studied in clinical trials. 
 
RISKS OF THE MODERNA COVID-19 VACCINE 
There is a remote chance that the Moderna COVID-19 Vaccine could cause a severe allergic 
reaction. A severe allergic reaction would usually occur within a few minutes to one hour after 
getting a dose of the Moderna COVID-19 Vaccine. For this reason, your study vaccination 
provider may ask you to stay at the place where you received your study vaccine for monitoring 
after study vaccination. Signs of a severe allergic reaction can include: 
• 
Difficulty breathing 
• 
Swelling of your face and throat 
• 
A fast heartbeat 
• 
A bad rash all over your body 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 11 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
Dizziness and weakness 
 
Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining 
outside the heart) have occurred in some people who have received the Moderna COVID-19 
Vaccine, more commonly in adolescent males and adult males under 40 years of age than 
among females and older males. In most of these people, symptoms began within a few days 
following receipt of the second dose of vaccine. The chance of having this occur is very low. 
You should seek medical attention right away if you have any of the following symptoms after 
receiving the vaccine: 
• 
Chest pain 
• 
Shortness of breath or difficulty breathing 
• 
Feelings of having a fast-beating, fluttering, or pounding heart 
• 
Fainting 
• 
Unusual and persistent irritability 
• 
Unusual and persistent poor feeding 
• 
Unusual and persistent fatigue or lack of energy 
• 
Persistent vomiting 
• 
Persistent pain in the abdomen 
• 
Unusual and persistent cool, pale skin 
 
Side effects that have been reported in a clinical trial with the Moderna COVID-19 Vaccine 
include: 
• 
Injection site reactions: pain, tenderness and swelling of the lymph nodes in the same 
arm of the injection , swelling (hardness), and redness 
• 
General side effects: fatigue (tiredness), headache, muscle pain, joint pain, chills, 
nausea and vomiting, fever, and rash. 
 
Side effects that have been reported during post-authorization use of the Moderna COVID-19 
Vaccine include: 
• 
Severe allergic reactions 
• 
Urticaria (itchy rash/hives) 
• 
Myocarditis (inflammation of the heart muscle) 
• 
Pericarditis (inflammation of the lining outside the heart) 
• 
Fainting in association with injection of the study vaccine 
 
These may not be all the possible side effects of the Moderna COVID-19 Vaccine. Not all 
adverse events (side effects) of the study vaccine are known and there may be effects of the 
vaccine on you or your unborn baby, including as yet unknown effects related to additional 
doses. Serious and unexpected side effects may occur. The Moderna COVID-19 Vaccine is still 
being studied in clinical trials. 
 
RISKS OF THE Sanofi-GSK COVID-19 VACCINE 
There is a remote chance that the Sanofi-GSK COVID-19 Vaccine could cause a severe allergic 
reaction. A severe allergic reaction would usually occur within a few minutes to one hour after 
getting a dose of the Sanofi-GSK COVID-19 Vaccine. If you have a known allergy to 
polysorbate, you cannot receive the Sanofi vaccine.  For this reason, your study vaccination 
provider may ask you to stay at the place where you received your study vaccine for monitoring 
after study vaccination. Signs of a severe allergic reaction can include:  
• 
Difficulty breathing  
• 
Swelling of your face and throat  


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
A fast heartbeat  
• 
A bad rash all over your body  
• 
Dizziness and weakness  
 
Side effects that have been reported in a clinical trial with the Sanofi-GSK COVID-19 Vaccine 
include: 
• 
Injection site reactions: pain, tenderness and swelling of the lymph nodes in the same 
arm of the injection, swelling (hardness), and redness 
• 
General side effects: fatigue (tiredness), nausea, diarrhea, fever, headache, malaise 
(generally feeling unwell), myalgia (sore and achy muscles), arthralgia (joint pain), and 
chills 
• 
Fainting in association with injection of the study vaccine may also occur. 
• 
Narcolepsy is an illness that affects your brain and causes uncontrollable sleepiness. 
People with narcolepsy sometimes go limp or fall asleep suddenly, such as while talking 
or driving, and it can be a lifelong problem. Narcolepsy has been reported in people who 
received a flu vaccine containing the adjuvant (called Pandemrix) during the H1N1 
pandemic in 2009-2010. A similar risk of narcolepsy was not seen with other vaccines 
that contain the adjuvant. 
• 
No safety concerns have been seen with any of the Sanofi-GSK vaccine studies 
regarding blood clotting, myocarditis (inflammation of the heart muscle), or pericarditis 
(inflammation of the membrane around the heart). However, these side effects are 
included as possible risks from the Sanofi-GSK vaccine because they have been 
reported after getting COVID-19 vaccines from other manufacturers. You should seek 
medical attention right away if you have any of the following symptoms after receiving 
the Sanofi-GSK COVID-19 Vaccine: 
• 
Chest pain 
• 
Shortness of breath 
• 
Feelings of having a fast-beating, fluttering, or pounding heart  
 
The adjuvanted vaccine formulations are not expected to give 100% protection against 
SARS-CoV-2 infection or COVID-19; therefore, SARS-CoV-2 infection or COVID-19 may occur 
even after the completion of the vaccination schedule. 
 
These may not be all the possible side effects of the Sanofi-GSK COVID-19 Vaccine. Not all 
adverse events (side effects) of the study vaccine are known and there may be effects of the 
vaccine on you or your unborn baby, including as yet unknown effects related additional doses. 
Serious and unexpected side effects may occur. The Sanofi-GSK COVID-19 Vaccine is still 
being studied in clinical trials. 
 
The risks associated with the study procedures in this study are described below. 
 
Stopping Immune Suppression Drug: By temporarily stopping your immune suppression drugs 
you risk your autoimmune disease getting worse or flaring. If you notice any sign of this, please 
contact the study doctor right away. The time your medication will be stopped will be short to 
reduce the possibility of a flare. Your study doctor will tell you exactly how long your medication 
will be stopped. During this time, you should contact your doctor immediately if you begin to 
have a flare of your autoimmune disease. 
 


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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
Blood Draw: Having blood drawn can cause temporary pain and bruising in the area where the 
needle was put in your vein. Lightheadedness or rarely fainting due to temporary lowering of the 
blood pressure can occur. 
 
COVID-19 Testing Nasal Swab: You may have some mild or moderate discomfort, and, in rare 
instances, nose bleeds can occur because of nasopharyngeal, nasal swab and/or other 
oronasal samples. You may also experience watery eyes and/or coughing, but only for the short 
duration of the swab. 
 
Autoimmune Disease Assessments: There are no physical risks or discomforts involved with the 
autoimmune disease assessments. Completing testing may cause a feeling of stress or 
embarrassment. These assessments may make you think about unpleasant effects of your 
autoimmune disease on your life and may make you upset or anxious. 
 
Questionnaires: You may find it inconvenient to participate in these surveys.  Being asked to 
think about your health and healthcare related information could make you feel worried or 
anxious. 
 
Study treatment and procedures in this research study may involve risks that are not possible to 
predict.  You will be informed of any new risks that may be identified during the study.  Please 
ask your study doctor or the study staff to explain any procedures or risks that you do not 
understand. 
 
Information related to COVID-19 
 
• 
Measures to protect yourself and others from COVID-19 infection are outlined on the 
Centers for Disease Control website at the following link: 
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. To 
decrease your risk of infection with SARS-CoV-2, we strongly recommend that you 
follow these recommendations, which include wearing a mask, practicing social 
distancing, and frequent handwashing/use of hand sanitizer.  
• 
If you develop COVID-19 infection during your participation in the study or have a close 
contact exposure, notify the study doctor immediately.  
 
6.  POTENTIAL BENEFITS    
If you agree to take part in this study, there may be no direct medical benefit to you. 
 
Information learned from this study may someday benefit people in the future.  
 
7.  ALTERNATIVES TO PARTICIPATION 
The study doctor and/or study staff will talk with you about this study and other options available 
to you. Monoclonal antibody administration may be available both to prevent COVID-19 
infection either before or after exposure or as treatment for mild infection. Monoclonal antibody 
treatment is not a substitute for vaccination. There are also oral treatments available if you test 
positive for COVID-19. Your study doctor will be able to tell you about any additional COVID-19 
prevention or treatments that become available during your study participation. You may choose 
not to be in this research study.     
 
8.  NEW FINDINGS  
The study doctor will tell you about any new information that may affect your willingness to 
continue in this study.  


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Revised 22 Dec 2022 
 
 
9.  VOLUNTARY WITHDRAWAL FROM STUDY 
You may decide not to take part or to leave the study at any time.  If you decide to leave the 
study, there is no penalty or loss of benefits in your routine medical care or any other benefit(s) 
that you would otherwise be entitled to receive. The study staff may ask you to return to the 
clinic for a final visit. 
 
You should talk to your study doctor who will discuss future treatment and procedures for your 
continued care.   
 
10.  REASONS WHY YOU MAY BE TAKEN OFF STUDY WITHOUT YOUR CONSENT 
You may be removed from the study without your consent at any time.  Reasons why you may 
be removed from the study include, but are not limited to, the following:      
• 
The study doctor feels it is not in your best interest to continue in this study.   
• 
You are unable to complete required study treatments and examinations. 
• 
The study is stopped by the Institution, the Sponsor(s), the Food and Drug 
Administration (FDA), or other health authorities. 
 
If you are removed from the study, your study doctor will contact you to discuss stopping 
procedures and your future care.  
 
11.  PREGNANCIES, BREASTFEEDING AND BIRTH CONTROL  
You cannot participate in this study if:   
• 
You are currently pregnant or breast feeding 
• 
You plan to get pregnant during the study  
 
COVID-19 vaccination is recommended for people who are pregnant, breastfeeding, trying to 
get pregnant now, or might become pregnant in the future. Evidence about the safety and 
effectiveness of COVID-19 vaccination during pregnancy has been growing. These data 
suggest that the benefits of receiving a COVID-19 vaccine outweigh any known or potential 
risks of vaccination during pregnancy.  
 
However, treatments for your underlying autoimmune disease and other procedures involved in 
this research study may involve risks to your unborn or nursing child. If you are female, a 
pregnancy test will be performed prior to your enrollment.  
 
To prevent risk to the fetus, it is important that female subjects take care to avoid becoming 
pregnant during this study. Avoiding sexual activity is the only certain method to prevent 
pregnancy. However, if sexually active, female subjects of reproductive potential are 
encouraged to use reliable method(s) of contraception (birth control) unless you are unable to 
become pregnant because of prior surgical sterilization. Acceptable contraceptive methods 
should be used for the duration of the study.     
 
If you should become pregnant while participating in this study, or if you suspect that you have 
become pregnant, you must contact the study doctor immediately. The study staff will collect 
information about the pregnancy, its outcome, and the health of the child after birth. 
 
Because of the known pregnancy risks associated with MMF, the FDA created an education 
program, Mycophenolate REMS (Risk Evaluation and Mitigation Strategy) to prevent unplanned 
pregnancies, reduce fetal exposure to MMF, collect information on pregnancies, and inform 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
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Revised 22 Dec 2022 
 
patients about the risks of MMF. Your study doctor has enrolled, and we strongly encourage you 
to discuss the program with your doctor and to participate in the MMF REMS program as well. A 
description of this program is available at 
https://www.mycophenolaterems.com/PatientOverview.aspx.  
 
12.  COSTS TO YOU 
The costs of all vaccinations, tests and procedures described above that are required by the 
study will be paid for by NIAID through the ACE. This study will not pay for your autoimmune 
disease standard of care medications. You will be responsible for any expenses related to your 
routine clinical care. Please ask your study doctor about any expected added costs that you 
may incur. Check with your health plan or insurance company to find out what they will pay for.  
 
Taking part in this study may lead to added costs to you or your insurance company. 
 
13. PAYMENTS (REIMBURSEMENT) 
You will receive $50 for each study visit to cover travel and other expenses for taking part in this 
study for the following visits: 
 
Screening 
Baseline 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Early Term Visit (if necessary) 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid following each completed visit. 
 
14.  RESEARCH-RELATED INJURY 
If you are injured or get sick while in this study, it is important to tell your study doctor listed on 
page one of this consent form.    
 
Emergency medical treatment will be available to you. The study site will bill you or your 
insurance company in the normal way for the cost of such care. No payment or additional 
compensation is available to you for such injuries. There is no provision for free medical care or 
monetary compensation from the study sponsor, the NIAID, NIH. You do not lose any legal 
rights by signing and dating this form. 
 
A new public health declaration, called the Public Readiness and Emergency Preparedness 
Declaration (PREP), was issued by the Department of Health and Human Services on March 
10, 2020. This declaration limits the legal rights of a subject participating in a COVID-19 clinical 
study that uses a drug, device or vaccine designed to treat, diagnose, cure or prevent COVID-
19. This includes the study vaccines, the Pfizer-BioNTech COVID-19 Vaccine, the Moderna 
COVID-19 Vaccine, or the Janssen-J&J COVID-19 Vaccine used in this study. Subjects using 
the Pfizer-BioNTech COVID-19 Vaccine, the Moderna COVID-19 Vaccine, or the Janssen-J&J 
COVID-19 Vaccine in this study will have limits on their right to sue the manufacturers, the study 
sponsor, healthcare providers and others for significant injuries and adverse reactions. 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
Page 16 of 23   
 
Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
 
15.  HIV POLICY 
You will be tested for HIV as part of the screening visit before you start in the study.  If you are 
found to be HIV positive, you will not be able to participate in the study. Your medical records 
will be kept confidential to the extent permitted by law. However, as mentioned earlier in this 
consent form, the study doctor may be required by law to report the result of this test to the local 
health authority. 
 
16.  CONFIDENTIALITY  
Your medical and research records will be confidential to the extent permitted by law.  Efforts 
will be made to keep your personal information private.  However, we cannot guarantee 
complete confidentiality.   
 
You will be identified by a code, and personal information from your records will not be released 
without your written permission.  A link will be created between your study information and the 
HIPAA compliant MyOwnMed web database. You will not be identified in any publication or in 
the sharing of your data about this study.  After the study is completed, the data may be placed 
in a central storage location.  These data will not include your name or other information that 
can identify you.  The purpose is to make study data available to other researchers.  Information 
from this study may be put into databases along with information from other studies.  There are 
different kinds of databases; some are publicly accessible, and some are restricted.  Anyone on 
the internet can access publicly accessible databases.  Only researchers who apply and are 
approved can access restricted databases.  Traditionally used identifying information about you 
(such as name, phone number, address) will NOT be included or shared with others. 
 
Your privacy is important to us and we will use safety measures to protect your privacy.  Despite 
all the safety measures that we use, we cannot guarantee that your identity will never become 
known.  Although your genetic information is unique to you, you share some genetic information 
with your children, parents, brothers, sisters, and other blood relatives.  Consequently, it may be 
possible that genetic information from them could be used to help identify you.  Similarly, it may 
be possible that genetic information from you could be used to help identify them.    
 
While we will not use information that is traditionally used to identify you, people may develop 
ways in the future that would allow someone to link your genetic or medical information in our 
databases back to you.  For example, someone could compare information in our databases 
with information from you (or a blood relative) in another database and be able to identify you 
(or your blood relative).  It is also possible there could be violations to the security of the 
computer systems used to store the codes linking your genetic and medical information to you.  
There may also be other privacy risks that we have not foreseen. 
 
As a NIH funded study, you are further protected through a policy that prevents the study 
doctor from releasing any sensitive information about you that may identify you.  This does not 
prevent you or a family member from voluntarily releasing information about this research. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance 
and data analysis include:   


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• 
The National Institute of Allergy and Infectious Diseases, (NIAID) sponsor of the 
research,  
• 
NIAID representatives, agents, employees, contractors, and other persons assisting in 
conducting, monitoring, or analyzing the study, 
• 
The U.S. Food and Drug Administration,  
• 
Other State and Local health authorities, and  
• 
Pharmaceutical companies(s) and their commercial partners may review your medical 
and research records for regulatory purposes.    
 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. 
The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (see below); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research subjects. 
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the agency which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA).  You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If you want 
your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law of, for instance, child abuse or neglect, harm to self or others, and 
communicable diseases.  
 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. 
 
17.   WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• 
By mail: 
Study Subject Adviser 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00055883. 
 
18.   FUTURE USE OF YOUR DATA/BIOLOGIC MATERIALS 
Information about you, including your biospecimens, collected for this study may be shared with 
other researchers. It may also be used for other research studies. We will make sure that your 
identity cannot be linked to the information we share. We will not ask you for additional 
permission before sharing the information.  
  
We are asking your permission to store samples of blood and urine collected during the study to 
be used in the future for tests that aren’t yet planned.     
 
Your stored samples will be used to obtain knowledge about genetic information in relation to 
the immune system. Genetic tests study an individual’s inherited characteristics, found in DNA, 
which is present in each of the cells of your body. DNA contains information needed to construct 
and operate the human body. Whole genome sequencing may be performed.    
 
The results of tests performed on stored samples or reports resulting from the analysis of your 
samples will not be given to you or your doctor and they will not be put in your medical record.  
They will not identify you and will not affect your routine medical care. 
 
There is no benefit to you from the storage of samples and information. However, the use of 
your samples and information may help researchers learn more about your disease or the 
genetics related to a specific condition. The purpose of storage and sharing data is to make 
information available for use in health research and to share what is stored with other 
researchers. Collecting, storing, sharing information, and making it available for other studies 
may help people in the future. Coded information put into databases together with other stored 
information from many studies conducted in different places allow researchers to study the 
combined information and learn even more about health and many different diseases.    
 
Samples will be stored at the ACV01 Central Repository. If you decide to allow storage, your 
samples and information may be stored for an unknown length of time. 
 
Although your stored research samples will not be sold, the information obtained from the 
research performed on your samples may in the future lead to the development of commercial 
products.  You will not receive any money from research using your stored samples and 
information. 
 
There may be unknown risks associated with the storage of samples and information. For 
example, if the future research involves genetic testing it is possible that it could be traced back 
to you because your genes are specific to you. We will make every attempt to protect your 
confidentiality and to make sure that your personal identity does not become known.    
 
You can change your mind at any time and ask to have your samples destroyed. This request 
should be made in writing to the study doctor. If you make this request, all remaining stored 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
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Revised 22 Dec 2022 
 
samples will be destroyed. However, the results of any previous tests using your stored samples 
will be used. Your decision regarding the storage of samples or the information resulting from 
the analysis of your samples will not affect your ability to participate in this study. The future use 
of your samples and information may contribute to learning more about disease or help to study 
the genetics related to a specific condition.  
 
Please indicate your response below:    
I agree to the storage and sharing of samples (urine, blood and/or tissue) for genetic tests not 
currently planned.   
 
   Yes       
  No   
_______________________ 
 
 
     
Initials of Research Subject 
 
I agree to the storage and sharing of samples (urine, blood and/or tissue) and information 
resulting from the analysis of my samples for other tests not currently planned.  
 
   Yes       
  No     
 
                                   _______________________ 
 
 
       
Initials of Research Subject 
 
19.  FUTURE CONTACT 
May we contact you by phone to find out if you are interested in hearing about new research 
studies or to ask you about how current health is?  Contact would be made by the study doctor 
or study staff. If you decide at any time that you no longer want to be contacted, please tell us, 
and we will stop calling you. 
 
Would you like us to contact you about future research studies or to ask you about how current 
health is? 
 
   Yes       
  No    _______________________ 
 
 
       
Initials of Research Subject 
 
If you say “no” to this question, this will not affect your participation in this study. 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
20. SIGNATURE PAGE 
Please sign and date below if you agree to take part in this study.  
  
• 
You have read the informed consent and/or had it explained to you 
• 
You were given the opportunity to ask questions about the information, and 
• 
You voluntarily agree to take part in the study 
 
_________________          _____________________      
_________________ 
Research Subject’s Name 
Research Subject’s Signature 
Date 
(Typed or printed) 
 
 
Signature and date of person explaining and obtaining the consent: 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title 
 
Signature 
 
 
 
Date 
(Typed or printed)   
 
 
Signature and date of subject’s legally authorized representative (if applicable): 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title 
 
Signature 
 
 
 
Date 
(Typed or printed)   
 
 
____________________________________________________________ 
Authority of Legally Authorized Representative to act on behalf of Subject 
 
(NOTE:  This consent form with the original signatures MUST be retained on file by the study 
doctor.  A copy must be given to the research subject.  A copy should be placed in the research 
subject’s medical record, if applicable.)      
 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and study staff will use 
and share health data about you to conduct the study. Health data may 
include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records 
kept by your doctor or other health care workers.  
 
For this study, the study staff may share health data about you with 
authorized users. Authorized users may include: 
• Representatives of the National Institute of Allergy and Infectious 
Diseases (NIAID). 
• Representatives of Advarra IRB (an Institutional Review Board that 
reviews this study). 
• The Food and Drug Administration (FDA) and other US federal and 
state agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, 
and STDs) must be reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data 
storage companies, that work with the researchers and sponsor and 
need to access your information to conduct this study. 
• Other research doctors and medical centers participating in this 
study, if applicable.  
• A data safety monitoring board which oversees this study, if 
applicable. 
 
Your health data will be used to conduct and oversee the research, 
including for instance: 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
• For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no 
longer be protected by federal privacy law (HIPAA) and could possibly be 
used or disclosed in ways other than those listed here.  
 
Your permission to use and share health data about you will end in 50 
years unless you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data 
about you at any time by writing to the study doctor at the address listed on 
the first page of this form. If you do this, you will not be able to stay in this 
study. No new health data that identifies you will be gathered after your 
written request is received. However, health data about you that has 
already been gathered may still be used and given to others as described 
in this form.  
 
Your right to access your health data in the study records will be 
suspended during the study to keep from changing the study results. When 
the study is over, you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part 
in the study. 
 
 
 


The National Institute of Allergy and Infectious Diseases (NIAID) / Protocol Number ACV01 
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Judith James, MD 
Advarra IRB Approved Version 22 Dec 2022 
Revised 22 Dec 2022 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have 
been answered. I voluntarily agree to allow study staff to collect, use and 
share my health data as specified in this form. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal 
rights by signing and dating this form.  
 
_____________________________________ 
Printed Name of Subject 
 
____________________________ 
 
 
 
_________ 
Signature of Subject 
 
 
 
 
 
 
Date 
 
____________________________________________ 
 
_________ 
Printed Name of the Person Obtaining the Authorization  
Date 
 
__________________________________________ 
 
_________ 
Signature of the Person Obtaining the Authorization  
 
Date 
 
 
____________________________________________ 
 
 
Signature and date of subject’s legally authorized representative (if 
applicable): 
 
_________________________________________ 
Printed Name of Legally Authorized Representative 
 
______________________________________ 
 
 
_________ 
Signature of Legally Authorized Representative 
 
 
Date 
 
____________________________________________________________ 
Authority of Legally Authorized Representative to act on behalf of Subject 
 

SAP_002.pdf: 
T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
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Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
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S T A TI S TI C A L A N A L Y SI S P L A N  
 
S T U D Y TI T L E:  B O O S T E R E F F E C T S WI T H A U T OI M M U N E T R E A T M E N T S 
I N P A R TI CI P A N T S WI T H P O O R R E S P O N S E T O I NI TI A L C O VI D-1 9 
V A C CI N E  
 
P R O T O C O L N U M B E R:  A C V 0 1  
 
 
S H O R T TI T L E:   
C O VI D -1 9 B O O S T E R V A C CI N E I N A U T OI M M U N E DI S E A S E 
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N C T #:  
N C T 0 5 0 0 0 2 1 6  
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T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
R E G U L A T O R Y 
A G E N C Y 
I D E N TI FI E R 
N U M B E R( S):  
 
I N D # 2 7 5 2 8 
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T his d oc u me nt is c o nfi de ntial a n d pr o prietar y t o NI AI D . T his st u d y is bei n g c o n d ucte d i n c o m plia nce wit h g o o d 
cli nical practice, i ncl u di n g t he arc hi vi n g of esse ntial d oc u me nts.  Acce pta nce of t his d oc u me nt c o nstit utes 
a gree me nt b y t he reci pie nt t hat n o u n p u blis he d i nf or mati o n c o ntai ne d herei n will be re pr o d uce d, p u blis he d, or 
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Pri nci pal Statistical Scie ntist  
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T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
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Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
N at as h a Mc k err a n R ut h, M D  
Pr ot oc ol C o -C h air  
Tr ac e y Wri g ht, M D  
Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
V E R SI O N  HI S T O R Y  
 
S A P Versi o n   
Versi o n D ate   
C h a n ge(s)  
R ati o n ale  
0. 1  
0 2 Mar 2 0 2 2   
I nitial Draft 
 
1. 0  
1 6 Mar 2 0 2 2   
Fi nal Draft  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
T A B L E O F C O N T E N T S  
1.  
LI S T O F A B B R E VI A TI O N S .......................................................................................8  
2.  
P U R P O S E O F T H E A N A L Y S E S  ..............................................................................1 0  
3.  
P R O T O C O L S U M M A R Y  ..........................................................................................1 1  
4.  
G E N E R A L A N A L Y SI S A N D R E P O R TI N G C O N V E N TI O N S  ..............................3 0  
5.  
A N A L Y SI S S A M P L E S ..............................................................................................3 1  
6.  
S T U D Y S U BJ E C T S  ...................................................................................................3 2  
6. 1.  
Dis p ositi o n of S u bjects  ...............................................................................................3 2  
6. 2.  
De m o gra p hic a n d Ot her Baseli ne C haracteristics  ......................................................3 2  
6. 3.  
Pri or a n d C o nc o mita nt Me dicati o ns  ...........................................................................3 3  
6. 4.  
Me dical Hist or y  ..........................................................................................................3 3  
7.  
S T U D Y O P E R A TI O N S  .............................................................................................3 4  
7. 1.  
Pr ot oc ol De viati o ns  ....................................................................................................3 4  
7. 2.  
Ra n d o mizati o n a n d All ocati o n  ...................................................................................3 4  
7. 2. 1.  
A d ult Sta ge 1  ..............................................................................................................3 4  
7. 2. 2.  
A d ult Sta ge 2  ..............................................................................................................3 4  
7. 2. 3.  
Pe diatric P o p ulati o n  ....................................................................................................3 5  
7. 3.  
Meas ures of Treat me nt C o m plia nce  ...........................................................................3 5  
8.  
E N D P OI N T E V A L U A TI O N  .....................................................................................3 6  
8. 1.  
O ver vie w of Efficac y A nal ysis Met h o ds  ....................................................................3 6  
8. 1. 1.  
M ultice nter St u dies  .....................................................................................................3 6  
8. 1. 2.  
Assess me nt Ti me Wi n d o ws  ........................................................................................3 6  
8. 1. 3.  
Ti mi n g of A nal yses  .....................................................................................................3 6  
8. 1. 4.  
M ulti ple C o m paris o ns/ M ulti plicit y  ............................................................................3 6  
8. 2.  
Pri mar y E n d p oi nt  ........................................................................................................3 6  
8. 2. 1.  
C o m p utati o n of t he Pri mar y E n d p oi nt  ........................................................................3 6  
8. 2. 2.  
Pri mar y A nal ysis of t he Pri mar y E n d p oi nt  .................................................................3 7  
8. 2. 3.  
Se nsiti vit y A nal yses of t he Pri mar y A nal ysis  ............................................................3 7  
8. 2. 4.  
Sec o n dar y A n al yses of t he Pri mar y E n d p oi nt  ............................................................3 7  
8. 3.  
Sec o n dar y E n d p oi nts  ..................................................................................................3 8  
8. 3. 1.  
Ser oc o n versi o n at Wee k 4  ..........................................................................................3 8  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 6  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
8. 3. 2.  
F ol d I ncrease i n a nti -C O VI D -1 9 A nti b o d y Le v els at Wee k 4  ...................................3 9  
8. 3. 3.  
L o n git u di nal C ha n ges i n a nti -C O VI D -1 9 A nti b o d y Res p o nses  ................................3 9  
8. 3. 4.  
L o n git u di nal C ha n ges i n Ne u tralizati o n a n d Pse u d o Ne utralizati o n Assa ys .............3 9  
8. 3. 5.  
C ha n ges i n Diseases A cti vit y usi n g C GI -C  ................................................................4 0  
8. 3. 6.  
C ha n ges i n Diseases A cti vit y usi n g P G A  ...................................................................4 0  
8. 3. 7.  
C ha n ges i n Disease Acti vit y as Meas ure d b y Dis ease -S pecifi c Assess me nts  ...........4 0  
8. 3. 8.  
C ha n ges i n Patie nt -re p ort e d O utc o mes ......................................................................4 1  
8. 4.  
Ot her E n d p oi nts  ..........................................................................................................4 2  
8. 5.  
E xa mi nati o n of S u b gr o u ps  .........................................................................................4 2  
9.  
S A F E T Y E V A L U A TI O N  ..........................................................................................4 3  
9. 1.  
O ver vie w of Safet y A n al ysis Met h o ds  .......................................................................4 3  
9. 2.  
A d verse E v e nts  ...........................................................................................................4 3  
9. 2. 1.  
S olicit e d A d verse E ve nts  ............................................................................................4 5  
9. 3.  
Deat hs, Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt A d verse E ve nts  ..................4 5  
9. 4.  
Cli nical La b orat or y E val uati o n  ...................................................................................4 6  
9. 5.  
Vital Si g ns, P h ysical Fi n di n gs, a n d Ot her O bser vati o ns Relate d t o Safet y  ...............4 6  
9. 5. 1.  
Vital Si g ns  ..................................................................................................................4 6  
9. 5. 2.  
P h ysical E xa mi nati o ns  ................................................................................................4 6  
9. 5. 3.  
Ot her Safet y M eas ures  ................................................................................................4 6  
1 0.  
O T H E R A N A L Y S E S  .................................................................................................4 7  
1 1.  
I N T E RI M A N A L Y S E S A N D D A T A M O NI T O RI N G .............................................4 8  
1 2.  
C H A N G E S T O T H E A N A L Y S E S P L A N N E D I N T H E P R O T O C O L  .....................4 9  
1 3.  
R E F E R E N C E S  ...........................................................................................................5 0  
1 4.  
A P P E N DI X .................................................................................................................5 1  
1 4. 1.  
St u d y Fl o w C hart  ........................................................................................................5 1  
1 4. 2.  
Sc he d ule of E ve nts  .....................................................................................................5 4  
1 5.  
A T T A C H M E N T S  .......................................................................................................5 5  
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 7  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
LI S T O F T A B L E S  
Ta ble  1:  
List of A b bre viati o ns  ....................................................................................................8  
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 8  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1.   
LI S T O F A B B R E VI A TI O N S  
T a ble  1 :  
List of A b bre vi ati o ns  
A b bre vi ati o n   
Ter m  
A C E  
A ut oi m m u nit y Ce nters of E xcelle nce  
A E  
A d verse e ve nt  
C R F  
Case re p ort f or ms  
C S R  
Cli nical St u d y Re p ort  
C V  
C oefficie nt of variati o n  
D AI T  
Di visi o n of Aller g y, I m m u n ol o g y, a n d Tra ns pla ntati o n  
D A S  
Disease Acti vit y Sc ore  
D A S 2 8 -C R P   
Disease Acti vit y Sc ore 2 8 usi n g C -reacti ve pr otei n 
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
E D S S  
E x pa n de d Disa bilit y Stat us Scale  
H -S L E D AI   
H y bri d S yste mic L u p us Er yt he mat os us Disease Acti vit y I n de x  
I S 
I m m u n os u p pressi ve me dicati o ns 
J A D A S  
J u ve nile Art hritis Disease Acti vit y Sc ore 
J D M 
j u ve nile der mat o m y ositis 
JI A 
j u ve nile i di o pat hic art hritis 
L L O D  
L o wer Li mit of Detecti o n  
M A A E  
me dicall y atte n de d a d verse e ve nt  
M C A R  
Missi n g -c o m pletel y -at-ra n d o m 
Me d D R A   
Me dical Dicti o nar y f or Re g ulat or y Acti vitie s 
M M F  
M yc o p he n olate m ofetil  
M P A  
M yc o p he n olic aci d  
M S  
M ulti ple scler osis  
M T X  
Met h otre xate  
N CI  
Nati o nal Ca ncer I nstit ute  
NI AI D  
T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases  
NI H  
Nati o nal I nstit utes of Healt h  
N O C M C   
Ne w o nset c hr o nic me dical c o n diti o n  
P A SI  
Ps oriasis Area a n d Se verit y I n de x  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 9  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
P D AI  
Pe m p hi g us Disease Area I n de x  
Pe ds Q L   
Pe diatric Q ualit y of Life I n ve nt or y ™ 
P GI -C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
Pt G A  
Patie nt’s Gl o bal Assess me nt  
P G A  
P h ysicia n Gl o bal Assess me nt  
P O M S  
Pe diatric -o nset m ulti ple scler osis  
P R O MI S   
Partici pa nt -Re p orte d O utc o mes Meas ure me nt I nf or mati o n S yste m  
P T  
P referre d ter m 
R A  
R he u mat oi d art hritis  
R B D  
Rece pt or bi n di n g d o mai n  
S A C C C   
Statistical a n d Cli nical C o or di nati n g Ce nter  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical a nal ysis pla n  
S A R S -C O V -2   
Se vere Ac ute Res pirat or y S y n dr o me C or o na vir us -2  
S D  
Sta n dar d de viati o n  
S A R S -C O V -2   
Se vere Ac ute Res pirat or y S y n dr o me C or o na vir us -2  
S E L E N A -
S L E D AI  
Safet y of Estr o ge ns i n L u p us Er yt he mat os us: Nati o nal Assess me nt –  S yste mic 
L u p us Er yt he mat os us Disease Acti vit y I n de x  
S L E  
S yste mic l u p us er yt he mat os us  
S O C  
S yste m or ga n class  
S Sc  
S yste mic scler osis  
V R C  
Vacci ne Researc h Ce nter  
W H O  
W orl d Healt h Or ga nizati o n  
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 0  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
2.   
P U R P O S E O F T H E A N A L Y S E S  
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pla n ne d a nal yses a n d d ata 
dis pla ys t o be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R)  f or Pr ot oc ol A C V 0 1. T his d oc u me nt 
pr o vi des details o n st u d y p o p ulati o ns, h o w t he varia bles will be deri ve d, h o w missi n g data will 
be ha n dle d a n d d etails o n statistical met h o ds t o be use d t o a nal yze t h e safet y a n d effi cac y d ata.  
T he S A P is base d o n I C H g ui deli nes E 3 a n d E 9 ( Statistical Pri nci ples f or Cli nical Trials).  
T he d oc u me nt w ill be u p date d o ver ti me t o reflect t he re q uire m e nts of t he a da pti ve st u d y desi g n, 
pr ot oc ol a me n d me nts a n d a n y  re g ulat or y re q uests. H o we ver, t he fi nal S A P m ust be fi nalize d, 
a p pr o ve d b y t he Clie nt, a n d place d o n file b ef ore data base is l oc k e d. If differe nc es occ ur 
bet wee n a nal yses des cri b e d i n t he S A P a n d t he c urre nt pr ot oc ol, t h ose f o u n d i n t his S A P will 
ass u me pri mac y. De viati o ns fr o m t he fi nal a p pr o v e d pla n will be n ote d i n t he cli nical st u d y 
re p ort. 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 1  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
3.   
P R O T O C O L S U M M A R Y  
Versi o n 1. 0 of t he pr ot oc ol was fi nal ize d J ul y 9, 2 0 2 1; t he pr ot oc ol is c urre ntl y u n der Versi o n 3. 0 w hic h  
i ncl u des se veral of t he pla n ne d a da pti ve ele me nts t o A C V 0 1, a n d is s u m marize d bel o w.  
Title  
B o oster effects wit h a ut oi m m u ne treat me nts i n patie nts wit h p o or res p o nse t o i nitial C O VI D -
1 9 v acci ne  
S h ort Title  
C O V I D -1 9 B O O S T E R V A C C I N E I N A U T O I M M U N E D I S E A S E N O N -
R E S P O N D E R S  
Cli nic al P h ase   
II 
N u m ber of Sites  
A d ult p o p ul ati o n: 1 5 –  2 0 sites i n t he U nite d States ( U S) t hat are acti ve Nati o nal I nstit ute of 
Aller g y a n d I nfecti o us Diseases ( NI AI D) A ut oi m m u nit y Ce nters of E xcelle nce ( A C E) or 
acti ve s u ba war d reci pie nts of t he NI AI D A C E Net w or k  
Pe di atric p o p ul ati o n: 1 5 –  2 0 sites i n t he U S.  
I N D S p o ns or/ N u m ber   T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D) / I N D # 2 7 5 2 8      
St u d y O bjecti ves  
H y p ot heses  
•   
We h y p ot hesize t hat a d ult a n d pe diatric partici pa nts wit h a ut oi m m u ne diseases 
re q uiri n g i m m u n os u p pressi ve (I S) me dicati o ns w h o ha ve ha d a s u b-o pti mal res p o nse 
t o a n i nitial C O VI D-1 9 vacci ne re gi me n ma y de m o nstrate e n ha nce d i m m u ne 
res p o nse after recei vi n g a n a d diti o nal h o m ol o g o us d ose of a n m R N A or vect or-base d 
vacci ne.  
•   
We h y p ot hesize t hat a d ult a n d pe diatric partici pa nts wit h tra nsie nt cessati o n  of 
m yc o p he n olate m ofetil ( M M F)/ m yc o p he n olic aci d ( M P A) or met h otre xate ( M T X) 
bef ore a n d after vacci nati o n will ha ve a n e n ha nce d i m m u ne res p o nse . 
•   
We f urt her h y p ot hesize t hat a d ult partici pa nts wit h a ut oi m m u ne diseases re q uiri n g 
I S me dicati o ns w h o c o nti n ue t o ha ve a s u b-o pti mal res p o nse after a n i nitial C O VI D -
1 9 vacci ne re gi me n pl us a n a d diti o nal h o m ol o g o us vacci ne d ose ma y de m o nstrate 
e n ha nce d i m m u ne res p o nse after recei vi n g a n a d diti o nal d ose of a n alter nati ve 
C O VI D -1 9 vacci ne.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o deter mi ne t he pr o p orti o ns of a d ult a n d pe diatric partici pa nts w h o 
ha ve a pr otecti ve a nti b o d y res p o nse at 4 wee ks after a n a d diti o nal h o m ol o g o us d ose of a 
C O VI D -1 9 vacci ne usi n g t he NI AI D Vacci ne Researc h Ce nter ( NI AI D -V R C) M S D 3 ple x 
( W u-1 f ull -le n gt h s pi ke, R B D, a n d N pr otei ns) assa y wit hi n ar ms defi ne d b y t he i nitial 
C O VI D -1 9 vacci ne re gi me n recei ve d, I S re gi me ns, a n d treat me nt pla ns t o eit her wit h h ol d or 
c o nti n ue me dicati o ns ar o u n d t he ti me of vacci nati o n.  
Sec o n d ar y O bjecti ves  
Sta ge 1 Sec o n dar y O bjecti ves (a d ult & pe diatric):  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•   
T o deter mi ne t he i nci de nce of ser oc o n versi o n f oll o wi n g a n a d diti o nal h o m ol o g o us 
C O VI D -1 9 vacci ne d ose i n t he s u b gr o u p of partici pa nts t hat are a nti -C O VI D -1 9 
a nti b o d y ne gati ve at Baseli ne.  
•   
T o deter mi ne t he i nci de nce of a d verse e ve nts ( A Es), i ncl u di n g me dicall y atte n de d 
a d verse e ve nts ( M A A Es), ne w o nset c hr o nic me dical c o n diti o ns ( N O C M Cs), a n d 
seri o us a d verse e ve nts ( S A Es) f oll o wi n g a n a d diti o nal h o m ol o g o us C O VI D -1 9 
vacci ne d ose.  
•   
T o assess w het her res p o nses t o a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose 
differ wit h te m p orar y cessati o n of I S me dicati o ns ar o u n d t he ti me of vacci ne.  
•   
T o assess w het her res p o nses t o a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose 
differ b y t y pe of vacci ne a d mi nistere d.  
•   
T o assess w het her res p o nses t o a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose 
differ b y t y pe of c o h ort -defi ni n g I S me dicati o ns a n d b y disease t y pe.  
•   
T o assess w het her res p o nse t o a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose is 
ass ociate d wit h c ortic oster oi d d ose at  t he ti me of vacci nati o n.  
•   
T o assess w het her res p o nse t o a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose is 
ass ociate d wit h cli nical para meters i ncl u di n g disease acti vit y, c o -m or bi d ill ness, a ge, 
a n d se x. 
•   
T o deter mi ne w het her disease acti vit y is i ncrease d f oll o wi n g a n a d diti o nal 
h o m ol o g o us C O VI D -1 9 vacci ne d ose, a n d if s o, w het her Baseli ne or i n d uce d 
i m m u n ol o gic varia bles are ass ociate d wit h i ncrease d disease acti vit y a n d/ or 
vacci nati o n res p o nse.  
Sta ge 2 Sec o n dar y O bjecti ves (a d ult):  
•   
T o deter mi ne t he pr o p ort i o ns of partici pa nts wit h a ne gati ve ser ol o gic or s u b-o pti mal 
res p o nse t o a n a d diti o nal h o m ol o g o us C O VI D-1 9 vacci ne d ose w h o de vel o p a 
pr otecti ve a nti b o d y res p o nse after recei vi n g a s u bse q ue nt alter nati ve vacci ne d ose, 
e val uate d usi n g t he NI AI D -V R C M S D 3 p le x ( W u-1 f ull -le n gt h s pi ke, R B D, a n d N 
pr otei ns) assa y.  
•   
T o deter mi ne t he i nci de nce of ser oc o n versi o n f oll o wi n g a s u bse q ue nt alter nati ve 
vacci ne d ose i n t he s u b gr o u p of partici pa nts t hat are a nti -C O VI D -1 9 a nti b o d y 
ne gati ve f oll o wi n g a n a d diti o nal h o m ol o g o u s C O VI D-1 9 vacci ne d ose.  
•   
T o deter mi ne t he i nci de nce of A Es, i ncl u di n g M A A Es, N O C M Cs, a n d S A Es 
f oll o wi n g a s u bse q ue nt alter nati ve C O VI D-1 9 vacci ne d ose.  
•   
T o assess w het her res p o nses t o a s u bse q ue nt alter nati ve C O VI D -1 9 vacci ne d ose 
differ b y t y pe of vacci ne a d mi nistere d.  
•   
T o assess w het her res p o nses t o a s u bse q ue nt alter nati ve C O VI D -1 9 vacci ne d ose 
differ b y t y pe of c o h ort -defi ni n g I S me dicati o ns a n d b y disease t y pe.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•   
T o assess w het her res p o nse t o a s u bse q ue nt alter nati ve C O VI D -1 9 vacci ne d ose is 
ass ociate d wi t h c ortic oster oi d d ose at t he ti me of vacci nati o n.  
•   
T o assess w het her res p o nse t o a s u bse q ue nt alter nati ve C O VI D -1 9 vacci ne d ose is 
ass ociate d wit h cli nical para meters i ncl u di n g disease acti vit y, c o -m or bi d ill ness, a ge, 
a n d se x. 
•   
T o deter mi ne w het her disease acti vit y is i ncrease d f oll o wi n g a s u bse q ue nt 
alter nati ve C O VI D -1 9 vacci ne d ose, a n d if s o, w het her i m m u n ol o gic varia bles are 
ass ociate d wit h i ncrease d disease acti vit y a n d/ or vacci nati o n res p o nse.  
E x pl or at or y O bjecti ves:  
•   
T o e val uate w het her Baseli n e C D 1 9 p ositi ve B cell n u m bers ass ociate wit h res p o nse 
t o a n a d diti o nal st u d y C O VI D-1 9 vacci ne d ose i n t he c o h ort t hat ha ve recei ve d B 
cell de pleti o n t hera p y.  
•   
T o e val uate t he ass ociati o n bet wee n i m m u ne res p o nse a n d le vels of S A R S -C o V -2 
a nti b o dies at Basel i ne. 
•   
T o e val uate t he le vels of Baseli ne i nterfer o n si g nal or i nterfer o n ga m ma -i n d uci ble 
pr otei n 1 0 (I P -1 0) ser u m le vels t hat ass ociate wit h a n effecti ve vacci ne res p o nse.  
•   
T o e val uate t he le vels of Baseli ne i nfla m mat or y si g nals t hat ass ociate wit h a n 
effecti ve vacci ne i m m u ne res p o nse. 
•   
T o e val uate t he ass ociati o n bet wee n i m m u ne res p o nse t o a n a d diti o nal st u d y 
C O VI D -1 9 vacci ne d ose a n d cell ular a n d mec ha nistic e n d p oi nts.  
St u d y Desi g n  
T his is a ra n d o mize d, m ulti -site, a da pti ve, o pe n-la bel cli nical trial c o m pari n g t he i m m u ne 
res p o nse t o differe nt a d diti o nal d oses of C O VI D-1 9 vacci ne i n partici pa nts wit h a ut oi m m u ne 
disease re q uiri n g I S me dicati o ns. All st u d y partici pa nts will ha ve ne gati v e ser ol o gic or s u b -
o pti mal res p o nses ( defi ne d as a R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L) t o 
i nitial C O VI D-1 9 vacci ne re gi me n wit h M o der na C O VI D -1 9 Vacci ne, Pfizer -Bi o N Tec h 
C O VI D -1 9 Vacci ne, or Ja nsse n C O VI D -1 9 Vacci ne.  
A d ult P o p ul ati o n:  
A d ult  St a ge 1:  
Sta ge 1 of t his trial will e nr oll u p t o a ma xi m u m of 9 0 0 a d ult st u d y partici pa nts ( u p t o 6 0 
partici pa nts per ar m). T he trial i nitiall y f oc use d o n a d ults wit h at least 1 of 5 a ut oi m m u ne 
diseases: s yste mic l u p us er yt he mat os us ( S L E), r he u mat oi d art hritis ( R A), m ulti ple scler osis 
( M S), s yste mic scler osis ( S Sc), a n d pe m p hi g us.   
Partici pa nts will be assi g ne d t o o ne of 3 c o h orts base d o n t heir I S re gi me ns:  
•   
C o h ort A: Recei pt of M M F or M P A  
•   
C o h ort B: Recei pt of M T X  
•   
C o h ort C:  Recei pt of a n y B cell de plet i o n t hera p y wit hi n t he past 1 8 m o nt hs. 
Tre at me nt Ar ms:   Partici pa nts i n C o h orts A, B, a n d C will be assi g ne d t o recei ve a n 
a d diti o nal d ose of t he sa me vacci ne as t heir ori gi nal vacci ne series.  
Partici pa nts i n C o h orts A a n d B will be ra n d o mize d i nt o t w o I S me dicati o n treat me nt pla ns as 
f oll o ws 
•   
Partici pa nts c o nti n ue t o ta ke t heir c o h ort -defi ni n g I S me dicati o ns wit h o ut alterati o ns 
i n sc he d ule a n d d osi n g.   
•   
Partici pa nts wit h h ol d t heir c o h ort -defi ni n g I S me dicati o ns bef ore a n d after t he 
a d diti o nal h o m ol o g o us vac ci ne d ose per pr ot oc ol i nstr ucti o ns.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
Sc he d ule of Eve nts:   Visits t o assess e n d p oi nts will occ ur at Baseli ne ( Wee k 0), Wee k 4 ± 1 
wee k, Wee k 1 2 ± 2 wee ks, Wee k 2 4 ± 2 wee ks, Wee k 3 6 ± 2 wee ks, a n d Wee k 4 8 ± 2 wee ks. 
A partici pa nt will be e nr olle d i n t he st u d y f or a ma xi m u m of a p pr o xi matel y 1 3 m o nt hs.  
A d ult St a ge 2:  
Sta ge 2 of t his trial will i ncl u de u p t o a ma xi m u m of 5 4 0 a d ult st u d y partici pa nts ( u p t o 6 0 per 
ar m). Partici pa nts will be eli gi ble t o recei ve a d ose of a n alter nati ve C O VI D -1 9 vacci ne. 
Partici pa nts ma y ha ve recei ve d t heir a d diti o nal h o m ol o g o us vacci n e d ose as a Sta ge 1 st u d y 
partici pa nt a n d t he n e nter i nt o Sta ge 2 (“r oll o ver partici pa nt”), or t he y ma y ha ve recei ve d 
t heir a d diti o nal h o m ol o g o us d ose pri or t o e nr oll me nt i n t he st u d y (“ ne wl y recr uite d 
partici pa nt”).  
Partici pa nts will be all ocate d t o 1 of 3 c o h orts base d o n t heir I S re gi me ns:  
•   
C o h ort D: Recei pt of M M F or M P A  
•   
C o h ort E: Recei pt of M T X  
•   
C o h ort F:  Recei pt of a n y B cell de pleti o n t hera p y wit hi n t he past 1 8 m o nt hs.  
Tre at me nt Ar ms:   Partici pa nts i n C o h orts D, E, a n d F will recei ve a d ose of a n alt er nati ve 
C O VI D -1 9 vacci ne c o m pare d t o t heir pre vi o us C O VI D -1 9 vacci ne d oses. Partici pa nts w h o 
pre vi o usl y recei ve d 3 t otal d oses of a n m R N A vacci ne ( M o der na C O VI D -1 9 Vacci ne O R 
Pfizer -Bi o N Tec h C O VI D -1 9 Vacci ne) will recei ve t heir c h oice of eit her t he Ja nsse n vect or -
base d C O VI D 1 9 vacci ne or t he ot her m R N A C O VI D -1 9 vacci ne, a n d partici pa nts w h o 
pre vi o usl y recei ve d 2 d oses of t he Ja nsse n vect or -base d C O VI D -1 9 vacci ne will recei ve t he 
M o der na C O VI D -1 9 Vacci ne.  
Partici pa nts i n C o h orts D a n d E will wit h h ol d t heir  c o h ort-defi ni n g I S me dicati o ns bef ore a n d 
after t he alter nati ve vacci ne d ose per pr ot oc ol i nstr ucti o ns. Partici pa nts i n C o h ort F w h o are 
ta ki n g M M F, M P A, or M T X i n a d diti o n t o B cell de pleti o n t hera pies ( B C D Ts) will wit h h ol d 
t hese me dicati o ns bef ore a n d after t he alter nati ve vacci ne d ose per pr ot oc ol i nstr ucti o ns. 
Sc he d ule of Eve nts:   Visits t o assess e n d p oi nts will occ ur at Baseli ne ( Wee k 0), Wee k 4 ± 1 
wee k, Wee k 1 2 ± 2 wee ks, Wee k 2 4 ± 2 wee ks, Wee k 3 6 ± 2 wee ks, a n d Wee k 4 8 ± 2 wee ks. 
A partici pa nt w h o  e nters Sta ge 2 after a ser ol o gic ne gati ve or s u b -o pti mal res p o nse t o t heir 
Sta ge 1 vacci ne d ose ma y be o n st u d y f or u p t o a ma xi m u m of 2 6 m o nt hs. A partici pa nt w h o 
is ne wl y recr uite d t o t he st u d y f or e ntr y i nt o Sta ge 2 ma y be o n st u d y f or u p t o a ma xi m u m of 
1 3 m o nt hs.  
Pe di atric P o p ul ati o n:  
T he pe diatric p orti o n of t his trial will e nr oll u p t o a ma xi m u m of 9 0 0 partici pa nts ( 5 -1 7 years 
of a ge) wit h a R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L after recei vi n g a n 
i nitial C O VI D-1 9 vacci ne re gi me n ( u p t o 6 0 partici pa nts per ar m). Vacci nes w ill be i ncl u de d 
i n t his pr ot oc ol as t he y recei ve E U A or a p pr o val b y F D A f or a gi ve n a ge gr o u p.  Pe diatric 
partici pa nts will ha ve 1 of 4 a ut oi m m u ne diseases: pe diatric S L E, j u ve nile i di o pat hic art hritis 
(JI A), j u ve nile der mat o m y ositis (J D M), or pe diatric-o n set m ulti ple scler osis ( P O M S). 
Partici pa nts will be assi g ne d t o o ne of 3 c o h orts base d o n t heir I S re gi me ns:  
•   
C o h ort A: Recei pt of M M F or M P A  
•   
C o h ort B: Recei pt of M T X  
•   
C o h ort C:  Recei pt of a n y B cell de pleti o n t hera p y wit hi n t he past 1 8 m o nt hs.  
Tre at me nt A r ms:  Partici pa nts i n C o h orts A, B, a n d C will be assi g ne d t o recei ve a n 
a d diti o nal d ose of t he sa me vacci ne as t heir ori gi nal vacci ne series.  
Partici pa nts i n C o h orts A a n d B will be ra n d o mize d i nt o t w o I S me dicati o n treat me nt pla ns as 
f oll o ws):  
•   
Partici pa nts c o nti n ue t o ta ke t heir c o h ort -defi ni n g I S me dicati o ns wit h o ut alterati o ns 
i n sc he d ule a n d d osi n g.   


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•   
Partici pa nts wit h h ol d t heir c o h ort -defi ni n g I S me dicati o ns bef ore a n d after t he 
a d diti o nal h o m ol o g o us vacci ne d ose per pr ot oc ol i nstr ucti o ns.  
Sc he d ule o f Eve nts:  Visits t o assess e n d p oi nts will occ ur at Baseli ne ( Wee k 0), Wee k 4 ± 1 
wee k, Wee k 1 2 ± 2 wee ks, Wee k 2 4 ± 2 wee ks, Wee k 3 6 ± 2 wee ks, a n d Wee k 4 8 ± 2 wee ks. 
A partici pa nt will be e nr olle d i n t he st u d y f or a ma xi m u m of a p pr o xi matel y 1 3 m o nt hs.  
A d a pti ve Desi g n:  
A n a da pti ve desi g n will be e m pl o ye d s uc h t hat c o h orts a n d ar ms defi ne d b y a d diti o nal 
vacci ne d oses a n d I S treat me nt pla ns ma y be a d de d or m o difie d base d o n e mer gi n g data fr o m 
e xisti n g a n d ne w F D A E mer ge nc y Use A ut h orizati o n ( E U A) or a p pr o va ls of C O VI D-1 9 
vacci nes:  
•   
Ne w c o h orts ma y be defi ne d base d o n c ha n ges i n t he me dicati o n gr o u ps if it 
bec o mes o b vi o us t hat certai n me dicati o ns are hi g hl y ass ociate d wit h s u b -o pti mal 
ser ol o gic res p o nse t o i nitial C O VI D-1 9 vacci ne re gi me n.  
•   
C o h orts ma y li mit or  e x pa n d t he a ut oi m m u ne diseases t hat are eli gi ble t o be 
i ncl u de d i n t he cli nical trial, a n d ma y i ncl u de e x pa nsi o n c o h orts of u n derre prese nte d 
diseases.  
•   
Ne w c o h orts ma y i ncl u de partici pa nts w h ose a nti b o d y res p o nse falls t o s u b -o pti mal 
le vels o ver ti me. 
•   
Bas e d u p o n ti mi n g of t he F D A E U A a ut h orizati o n f or c hil dre n of eac h of t he 
C O VI D -1 9 vacci nes use d i n t his trial, t he a ge ra n ge of t he i ncl usi o n criteria ma y be 
e x pa n de d. 
•   
All ocati o n or ra n d o mizati o n t o treat me nt wit h ne w vacci nes desi g ne d f or C O VI D 
varia nts or  wit h a pr otei n -base d vacci ne ma y be i nc or p orate d i nt o t he desi g n w he n 
t he pr o d ucts bec o me a vaila ble. 
•   
I de ntificati o n of a d diti o nal strate gies t o e n ha nce vacci ne res p o nsi ve ness i n 
a ut oi m m u ne diseases, i ncl u di n g a te m p orar y s witc h of i m m u n o m o d ulat or y 
me dicati o ns.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt i n t he a d ult a n d pe diatric p o p ulati o ns of a pr otecti ve a nti b o d y res p o nse 
at Wee k 4 will be assesse d b y t he NI AI D -V R C M S D 3 ple x ( W u -1 f ull -le n gt h s pi ke, R B D, 
a n d N pr otei ns) assa y . 
Sec o n d ar y a n d 
E x pl or at or y 
E n d p oi nts  
Sec o n d ar y E n d p oi nts  
Sec o n dar y e n d p oi nts relate d t o a nti b o d y res p o nse will pri maril y be assesse d b y t he NI AI D -
V R C M S D 3 ple x ( W u -1 f ull -le n gt h s pi ke, R B D, a n d N pr otei ns) assa y; w here a p plica ble, 
t he y will als o be assesse d b y t he R oc he Elecs ys ® A nti-S A R S -C o V -2 S 
electr oc he mil u mi nesce nce i m m u n oassa y.  
T he sec o n dar y e n d p oi nts are a p plica ble t o b ot h t he a d ult a n d pe diatric p o p ulati o ns.  
•   
Ser oc o n versi o n at Wee k 4 f oll o wi n g a d diti o nal d oses of C O VI D -1 9 vacci ne i n t he 
s u b gr o u p of partici pa nts t hat are a nti-C O VI D -1 9 a nti b o d y ne gati ve at Wee k 0.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 6  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•   
F ol d i ncrease i n a nti -C O VI D -1 9 a nti b o d y le vels at Wee k 4 f oll o wi n g a n a d diti o nal 
d ose of C O VI D -1 9 vacci ne i n t he s u b gr o u p of partici pa nts w h o are a nti -C O VI D -1 9 
a nti b o d y p ositi ve at Wee k 0.  
•   
L o n git u di nal c ha n ges i n a nti -C O VI D -1 9 a nti b o d y res p o nses fr o m Wee k 0 t o Wee ks 
4, 1 2, 2 4, 3 6, a n d 4 8.  
•   
L o n git u di nal c ha n ges i n ne utralizati o n a n d pse u d o ne utralizati o n assa ys fr o m Wee k 
0 t o Wee ks 4, 1 2, 2 4, 3 6, a n d 4 8.  
•   
C ha n ges i n disease acti vit y after recei pt of a d diti o nal d oses of C O VI D -1 9 vacci ne as 
meas ure d b y t he Cli nical Gl o bal I m pressi o n of C ha n ge ( C GI -C).  
•   
C ha n ges i n disease acti vit y after recei pt of a d diti o nal d oses of C O VI D -1 9 vacci ne as 
meas ure d b y t he P h ysicia n Gl o bal Assess me nt ( P G A).  
•   
C ha n ges i n disease acti vit y after recei pt of a d diti o nal d o ses of C O VI D-1 9 vacci ne as 
meas ure d b y t he f oll o wi n g disease -s pecific assess me nts: 
o  
A d ult p o p ulati o n disease assess me nts:  
o  
H y bri d S yste mic L u p us Er yt he mat os us Disease Acti vit y I n de x ( H -
S L E D AI) a n d T ha n o u m o difie d Safet y of Estr o ge ns i n L u p us 
Er yt he mat os us: N ati o nal Assess me nt –  S yste mic L u p us 
Er yt he mat os us Disease Acti vit y I n de x ( S E L E N A -S L E D AI) Flare 
I n de x f or S L E 
o  
Disease Acti vit y Sc ore 2 8 usi n g C -reacti ve pr otei n ( D A S 2 8-C R P) 
f or R A   
o  
Flare assess me nt f or S Sc (i ncl u di n g patie nt re p orte d flare 
assess me nt)  
o  
Pe m p h i g us Disease Area I n de x ( P D AI) f or pe m p hi g us 
o  
P h ysicia n -assesse d rela pse f or M S  
o  
Pe diatric p o p ulati o n disease assess me nts:  
o  
JI A: 
▪  J A D A S 1 0 f or p ol yart hritis, e nt hesitis relate d t o JI A, 
oli g oart hritis, a n d ps oriatic art hritis  
▪  Ps oriasis Area a n d Se verit y I n de x ( P A SI) f or ps oriatic 
art hritis 
o  
S L E D AI -2 K a n d C hil d h o o d -o nset S L E Criteria f or Gl o bal Flare 
[ 1] f or pe diatric S L E 
o  
C hil d h o o d M y ositis Assess me nt Scale ( C M A S) a n d J D M Disease 
Acti vit y Sc ore ( D A S) f or J D M  
o  
P h ysicia n -assesse d rela pse f or M S f or P O M S  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 7  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•   
C ha n ges i n patie nt -re p orte d o utc o mes as meas ure d b y:  
o  
Partici pa nt -Re p orte d O utc o mes Meas ure me nt I nf or mati o n S yste m 
( P R O MI S) 2 9 (a d ults o nl y) 
o  
Pe diatric Q ualit y of Life I n ve nt or y ™ ( Pe ds Q L) ( pe diatrics o nl y)  
o  
Patie nt Gl o bal Assess me nt ( Pt G A)  
o  
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C)  
•   
T he pr o p orti o n of partici pa nts w h o e x perie nce t he f oll o wi n g safet y e ve nts:  
o  
A n y Gra de 1 or hi g her A Es relate d t o t he a d diti o nal d oses of C O VI D -1 9 
vacci ne  
o  
A n y S A Es, M A A Es, N O C M Cs  
o  
A n y S A R S -C o V -2 i nfecti o n  
E x pl or at or y E n d p oi nts  
•   
C ha n ges i n a ut oa nti b o d y le vels after C O VI D -1 9 vacci nati o n bet wee n Wee k 0, a n d 
Wee ks 4, 1 2, 2 4, 3 6, a n d 4 8.  
•   
Assess me nts of cell ular a n d mec ha nistic res p o nse, i ncl u di n g  
o  
I m m u ne cell p o p ulati o n pr ofili n g o ver ti me 
o  
A nti ge n -s pecific T cell res p o nses 
o  
A nti ge n -s pecific me m or y B cell res p o nses 
o  
T o tal I g G res p o nses  
o  
B cell a n d T cell re pert oire  
o  
C ha n ges i n ge ne e x pressi o n pr ofile m o d ules  
o  
Plas ma le vels of s ol u ble me diat ors  
Accr u al O bjecti ve   
A d ult P o p ul ati o n:   
I n Sta ge 1, 1 5 ar ms are pla n ne d wit hi n c o h orts defi ne d b y cate g ories of I S me dicati o ns s uc h 
t hat a ma xi m u m of 9 0 0 partici pa nts are t o be ra n d o mize d/all ocate d. I n A d ult Sta ge 2, 9  ar ms 
are pla n ne d t o e val uate t he i m m u ne res p o nse t o a s u bse q ue nt alter nati ve C O VI D -1 9 vacci ne 
d ose s uc h t hat a ma xi m u m of 5 4 0 partici pa nts (eit her r oll o ver or ne wl y recr uite d) are t o be 
all ocate d.  
Pe di atric P o p ul ati o n:   
A t otal of 1 5 ar ms are pla n ne d wit hi n c o h orts defi ne d b y cate g ories of I S me dicati o ns s uc h 
t hat a ma xi m u m of 9 0 0 partici pa nts are t o be ra n d o mize d/all ocate d ( u p t o 3 0 0  partici pa nts f or 
each vacci ne t o recei ve F D A E U A i n pe diatric partici pa nts).  
 
I n all p o p ulati o ns a n d sta ges, 4 0 partici pa nts wit h a R oc he Elecs ys ® A nti -S A R S -C o V -2 S 
res ult ≤5 0 U/ m L will be tar gete d f or eac h ar m, wit h a t otal of 6 0 partici pa nts wit h a R oc he 
Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L ra n d o mize d or all ocate d t o eac h ar m. I n 
eac h ar m, t he n u m ber of partici pa nts wit h R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ults ≤5 0 
U/ m L will be ca p pe d at 4 0 partici pa nts, a n d t he n u m ber of partici pa nts wit h R oc he Elecs ys ® 
A nti -S A R S -C o V -2 S res ults > 5 0 U/ m L a n d ≤2 0 0 U/ m L will be ca p pe d at 4 0  partici pa nts.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 8  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
St u d y D ur ati o n  
St u d y d urati o n f or A d ult Sta ge 1, A d ult Sta ge 2 ne wl y recr uite d, or pe diatric partici pa nt: 
1 3  m o nt hs  
St u d y d urati o n f or A d ult 2 partici pa nt r olli n g o ver fr o m Sta ge 1: ma xi m u m of 2 6 m o nt hs  
Tre at m e nt 
Descri pti o n  
All partici pa nts will recei ve o ne d ose of t he f oll o wi n g:  
•   
m R N A C O VI D -1 9 vacci ne : M o der na O R  
•   
m R N A C O VI D -1 9 vacci ne :  Pfizer -Bi o N Tec h O R  
•   
vect or -base d C O VI D -1 9 vacci ne : Ja nsse n  
I ncl usi o n/ E xcl usi o n 
Criteri a –  A d ult St a ge 
1  
I ncl usi o n Criteri a: 
I n di vi d uals w h o meet all of t he f oll o wi n g criteria are eli gi ble f or ra n d o mizati o n/all ocati o n as 
st u d y partici pa nts i n A d ult Sta ge 1:  
1.  I n di vi d uals 1 8 years of a ge or ol der t hat meet classificati o n criteria f or S L E, S Sc, R A, 
M S, or pe m p hi g us.  
2.  Partici pa nts m ust meet t he 2 0 1 9 A C R/ E U L A R [ 2] or 2 0 1 2 S LI C C classificati o n criteria 
f or S L E [ 3], t he 2 0 1 0 A C R/ E U L A R classificati o n criteria f or R A [ 4],  t he 2 0 1 3 
E U L A R/ A C R classificati o n criteria f or S Sc [ 5], t he 2 0 1 7 Mc D o nal d [ 6] criteria f or M S, 
a n d t he i nter nati o nal c o nse ns us criteria f or pe m p hi g us [ 7]. 
a. 
If a partici pa nt has bee n dia g n ose d wit h m ore t ha n o ne a ut oi m m u ne disease, t he 
partici pa nt will be assesse d base d o n t he disease t hat is selecte d f or st u d y e ntr y.  
3.  Willi n g a n d a ble t o si g n i nf or me d c o nse nt.  
4.  D oc u me nte d f ull C O VI D -1 9 vacci nati o n ( Ce nters f or Disease C o ntr ol a n d Pre ve nti o n 
[ C D C] car d or d oc u me ntati o n i n me dical rec or ds) t hat was c o m plete d at least 4 wee ks 
pri or a n d n o m ore t ha n 5 2 wee ks pri or t o t he Scree ni n g  visit.  
5.  Ne g ati ve or s u b o pti mal ser ol o gic res p o nse t o i nitial C O VI D -1 9 vacci ne re gi me n, defi ne d 
as a n Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L - at Scree ni n g visit.  
a. 
I nitial C O VI D-1 9 vacci ne re gi me n is defi ne d as eit her:  
i. 2 d oses of t he Pfizer -Bi o N Tec h C O V I D-1 9 Vacci ne  
ii. 2 d oses of t he M o der na C O VI D -1 9 Vacci ne  
6.  M ust be c urre ntl y ta ki n g o ne of t he f oll o wi n g I S me dicati o ns wit h or wit h o ut a d diti o nal 
disease -relate d me dicati o ns: M M F ( mi ni m u m of 1 0 0 0 m g per da y)/ M P A ( mi ni m u m of 
7 2 0 m g per da y), M T X ( mi ni m u m of 7. 5 m g per wee k), or B cell de pleti n g a ge nts wit hi n 
t he past 1 8 m o nt hs (s uc h as rit u xi ma b, ocreliz u ma b, ofat u m u ma b).  
a. 
If ta ki n g M M F/ M P A or M T X, t he partici pa nt m ust ha ve i nitiate d t hera p y at 
least 8 wee ks pri or t o ra n d o mizati o n a n d be ta ki n g t he sa me me dicati ons 
(re gar dless of d ose) as at t he ti me of t he i nitial C O VI D-1 9 vacci ne re gi me n.  
N ote: Partici pa nts w h o wit h hel d t heir I S me dicati o ns ar o u n d t heir i nitial 
vacci nati o ns are eli gi ble t o partici pate.   
b.  If e nr olli n g i n t he B cell de pleti n g t hera p y c o h ort, t he partici pa nt  m ust  ha ve 
recei ve d a n a nti-C D 2 0 or a n a nti -C D 1 9 B cell de pleti n g t hera p y i n t he past 1 8 
m o nt hs.    


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 1 9  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
7.  N o c ha n ges i n bac k gr o u n d I S me dicati o ns, i ncl u di n g M M F/ M P A or M T X, i n t he 8 
wee ks pri or t o Scree ni n g, e xcl u di n g t he f oll o wi n g:  
a. 
H C Q,  
b.  I ntraartic ular ster oi ds,   
c. 
T he a d diti o n of pre d nis o ne at ≤1 0 m g per da y or pre d nis o ne at a n y d ose w he n 
gi ve n f or ≤3 da ys, a n d   
d.  C ortic oster oi d b ursts f or n o n -a ut oi m m u ne disease -relate d c o n diti o ns, s uc h as 
ast h ma or C O P D, are per mitte d.  
E xcl usi o n Criteri a:  
I n di vi d uals w h o meet a n y of t hese criteria are n ot eli gi ble f or ra n d o mizati o n/all ocati o n as 
st u d y partici pa nts i n A d ult Stage 1 :  
1.  I na bilit y or u n willi n g ness of a partici pa nt t o gi ve writte n i nf or me d c o nse nt or 
c o m pl y wit h st u d y pr ot oc ol.  
2.  Hist or y of se vere aller gic reacti o n t o t he i nitial C O VI D -1 9 vacci ne re gi me n, t o a n y 
c o m p o ne nt of a n y of t he C O VI D -1 9 vacci nes, or t o p ol yet h yle ne gl yc ol ( P E G).  
3.  Ne w dia g n osis of mali g na nc y t hat will re q uire c he m ot hera p y or i m m u n ot hera p y, or 
o n g oi n g treat me nt f or a mali g na nc y wit h c he m ot hera p y or i m m u n ot hera p y.  
4.  Acti ve disease ( per t he I n vesti gat or’s decisi o n) res ulti n g i n i na bilit y t o h ol d t he I S 
t hera p y i n t he M M F/ M P A or M T X ar ms of t he st u d y.  
a. 
T he p ote ntial i m pact of te m p oraril y h ol di n g me dicati o n f or part ici pa nts 
wit h a rece nt mil d disease flare wit hi n 4 wee ks s h o ul d be caref ull y 
c o nsi dere d.  
5.  Acti ve disease d uri n g t he Scree ni n g peri o d res ulti n g i n:  
a. 
A n i ncrease/a d diti o n of I S me dicati o ns, or  
b.  A s u g gesti o n of M S rela pse per t he i n vesti gat or  
6.  Rece nt or c urre nt S A R S -C o V -2 i nfecti o n defi ne d as:  
a. 
D oc u me nte d S A R S -C o V -2 i nfecti o n i n t he past 3 0 da ys (fr o m t he da y t he 
partici pa nt is dia g n ose d b y p ositi ve test t o Scree ni n g).  
b.  P ositi ve res ult o n a m olec ular C O VI D -1 9 test at Scree ni n g.  
7.  Recei pt of a C O VI D -1 9 vacci n e b o oster pri or t o Scree ni n g wit h t he M o der na 
C O VI D -1 9 Vacci ne, Pfizer -Bi o N Tec h C O VI D -1 9 Vacci ne, or Ja nsse n C O VI D -1 9 
Vacci ne.  
8.   I nfla m mat or y m y ocar ditis/ pericar ditis f oll o wi n g i nitial C O VI D-1 9 vacci ne 
re gi me n.  
9.  Partici pa nts wit h acti ve, o n g oi n g c hr o nic i nf ecti o ns, i ncl u di n g partici pa nts wit h 
e vi de nce of:  
a. 
H u ma n I m m u n o deficie nc y Vir us ( HI V)  
b.  He patitis B as i n dicate d b y s urface a nti ge n  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 0  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
c. 
He p atitis C as i n dicate d b y a nti -he patitis C a nti b o d y p ositi vit y; if a 
partici pa nt is He patitis C a nti b o d y p ositi ve, t he y wil l be eli gi ble t o 
partici pate i n t he st u d y if he/s he is ne gati ve f or viral l oa d at Scree ni n g.  
N ote: P artici p a nts are per mitte d t o be o n c hr o nic pr o p hyl actic a nti micr o bi al 
t her a py.   
1 0.  Partici pa nts wit h c o m m o n varia ble i m m u n o deficie nc y disease, as well as a n y 
partici pa nts c urre ntl y recei vi n g i m m u ne gl o b uli n re place me nt t hera p y.  
1 1.  Partici pa nts w h o recei ve d lice nse d or i n vesti gati o nal m o n ocl o nal a nti b o dies or 
plas ma pr o d ucts directe d a gai nst S A R S -C o V -2 wit hi n 3 0 da ys of Scree ni n g.  
1 2.  Partici pa nts w h o ha ve recei ve d a n y  li ve vacci nes wit hi n 2 m o nt hs of t he a ntici pate d 
st u d y vacci ne d ose or w h o will ha ve nee d of a li ve vacci ne at a n y ti me d uri n g t he 
st u d y. 
1 3.  C urre ntl y pre g na nt or breastfee di n g.  
1 4.  Partici pa nts w h o are pla n ni n g a pre g na nc y d uri n g t he c o urse of t he trial.  
1 5.  He m o gl o bi n ( H g b) < 8. 0 g/ d L ( 8 0 g/ L)  
1 6.  Past or c urre nt me dical pr o ble ms or fi n di n gs fr o m p h ysical e xa mi nati o n or 
la b orat or y testi n g t hat are n ot liste d a b o ve, w hic h, i n t he o pi ni o n of t he i n vesti gat or, 
ma y p ose a d diti o nal ris ks fr o m partici pati o n i n t he st u d y, ma y i nterfere wit h t he 
partici pa nt’s a bilit y t o c o m pl y wit h st u d y re q uire me nts or t hat ma y i m pact t he 
q ualit y or i nter pretati o n of t he data o btai ne d fr o m t he st u d y.  
1 7.  Ot her i n vesti g ati o nal c he mical a ge nt wit hi n 3 0 da ys or ot her i n vesti gati o nal bi ol o gic 
a ge nt wit hi n 8 wee ks or 5  half -li ves ( w hic he ver is l o n ger) of Scree ni n g.  
1 8.  C o nc urre nt treat me nt wit h c ycl o p h os p ha mi de, cla dri bi ne, ale mt uz u ma b, or 
mit o xa ntr o ne.  
1 9.  Partici pa nts c urre ntl y o n a n y t y pe of dial ysis, or w h o ha ve recei ve d a s oli d or ga n 
tra ns pla nt.  
2 0.  Pris o ners or partici pa nts w h o are c o m p uls oril y detai ne d (i n v ol u ntaril y i ncarcerate d) 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e. g., i nfecti o us disease) ill ness. 
2 1.  Ta ki n g b ot h M M F/ M P A a n d M T X.  
2 2.  Recei vi n g ot her i n vesti gati o nal B cell de pleti n g t hera p y as part of a cli nical trial 
wit hi n 1 8 m o nt hs of Scree ni n g, u nless dr u g assi g n me nt is k n o w n a n d t he partici pa nt 
recei ve d a n a nti-C D 2 0 or C D 1 9 dr u g.  
2 3.  Partici pa nts wit h acti ve s yste mic i n fecti o ns w h o ha ve recei ve d s yste mic 
a nti micr o bials wit hi n t he 1 4 da ys pri or t o Scree ni n g.  
I ncl usi o n/ E xcl usi o n 
Criteri a –  A d ult St a ge 
2 Ne wl y Recr uite d 
P artici p a nts  
I ncl usi o n Criteri a: 
I n di vi d uals w h o meet all of t he f oll o wi n g criteria are eli gi ble f or e nr oll me nt as partici pa nts i n 
Sta ge 2:  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 1  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1.  I n di vi d uals 1 8 years of a ge or ol der t hat meet classificati o n criteria [ 1-6] f or S L E, 
S Sc, R A, M S, or pe m p hi g us If a partici pa nt has bee n dia g n ose d wit h m ore t ha n o ne 
a ut oi m m u n e disease, t he partici pa nt will be assesse d base d o n t he disease t hat is 
selecte d f or st u d y e ntr y. 
2.  Willi n g a n d a ble t o si g n i nf or me d c o nse nt.  
3.  D oc u me nte d f ull C O VI D -1 9 vacci nati o n ( C D C car d or d oc u me ntati o n i n me dical 
rec or ds). 
4.  Recei ve d a n a d diti o nal h o m ol o g o us C O VI D -1 9 vacci ne d ose ( d oc u me nte d b y C D C 
car d or i n me dical rec or ds) t hat was c o m plete d at least 4 wee ks pri or a n d n o m ore 
t ha n 4 8 wee ks pri or t o t he Sta ge 2 Scree ni n g visit.  
5.  Ne g ati ve or s u b o pti mal ser ol o gic res p o nse t o t he a d diti o nal h o m ol o g o us C O VI D -1 9 
vacci ne i n o ne of t he q ualif yi n g re gi me ns, defi ne d as a n Elecs ys ® A nti -S A R S -C o V -
2 S ( R B D) ne gati ve res ult or p ositi ve res ult of ≤2 0 0  U/ m L wit hi n 4  wee ks of t he 
Sta ge 2 Baseli ne/ Wee k 0 visit.  
T he re gi me ns of C O VI D -1 9 vacci nati o n t hat q ualif y are as f ol l o ws: 
a. 
3 f ull d oses of t he Pfizer -Bi o N Tec h C O VI D -1 9 Vacci ne  
b.  3 f ull d oses of t he M o der na C O VI D -1 9 Vacci ne  
c. 
2 f ull d oses of t he Ja nsse n C O VI D -1 9 Vacci ne  
6.  M ust be c urre ntl y ta ki n g o ne of t he f oll o wi n g I S me dicati o ns wit h or wit h o ut 
a d diti o nal disease -relate d me dicati o ns: M M F ( mi ni m u m of 1 0 0 0 m g per da y)/ M P A 
( mi ni m u m of 7 2 0 m g per da y), M T X ( mi ni m u m of 7. 5 m g per wee k), or B cell 
de pleti n g a ge nts wit hi n t he past 1 8 m o nt hs (s uc h as rit u xi ma b, ocreliz u ma b, or 
ofat u m u ma b).  
a. 
If ta ki n g M M F/ M P A or M T X, t he partici pa nt m ust ha ve i nitiate d t hera p y at 
least 8 wee ks pri or t o all ocati o n a n d be ta ki n g t he sa me me dicati o ns 
(re gar dless of d ose) as at t he ti me of t he i nitial C O VI D-1 9 vacci ne re gi me n. 
N ote: Partici pa nts w h o wit h hel d t heir  I S me dicati o ns ar o u n d t heir i nitial 
vacci nati o ns are eli gi ble t o partici pate.  
b.  If e nr olli n g i n t he B cell de pleti n g t hera p y c o h ort, t he partici pa nt m ust  ha ve 
recei ve d a n a nti-C D 2 0 or a n a nti -C D 1 9 B cell de pleti n g t hera p y i n t he past 
1 8 m o nt hs.  
7.  N o c ha n ges  i n bac k gr o u n d I S me dicati o ns, i ncl u di n g M M F/ M P A or M T X, i n t he 4 
wee ks pri or t o Sta ge 2 Scree ni n g, e xcl u di n g t he f oll o wi n g:  
a. 
H C Q,  
b.  I ntraartic ular ster oi ds,   
c. 
T he a d diti o n of pre d nis o ne at ≤1 0 m g per da y or pre d nis o ne at a n y d ose 
w he n gi ve n f or ≤3 da ys, a n d    


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
d.  C ortic oster oi d b ursts f or n o n -a ut oi m m u ne disease -relate d c o n diti o ns, s uc h 
as ast h ma or C O P D, are per mitte d.  
E xcl usi o n Criteri a:  
I n di vi d uals w h o meet a n y of t hese criteria are n ot eli gi ble f or ra n d o mizati o n/all ocati o n as 
st u d y partici pa nts i n Sta ge 2:  
1.  I na bilit y or u n willi n g ness of a partici pa nt t o gi ve writte n i nf or me d c o nse nt or 
c o m pl y wit h st u d y pr ot oc ol.  
2.  Hist or y of se vere aller gic reacti o n t o a n y pre vi o us C O VI D -1 9 vacci nes, t o a n y 
c o m p o ne nt of a n y of t he C O VI D -1 9 vacci nes, or t o P E G.  
3.  Ne w dia g n osis o f mali g na nc y t hat will re q uire c he m ot hera p y or i m m u n ot hera p y, or 
o n g oi n g treat me nt f or a mali g na nc y wit h c he m ot hera p y or i m m u n ot hera p y.  
4.  Acti ve disease ( per t he I n vesti gat or’s decisi o n) res ulti n g i n i na bilit y t o h ol d t he I S 
t hera p y i n t he M M F/ M P A or M T X ar ms of t he st u d y.  
a. 
T he p ote ntial i m pact of te m p oraril y h ol di n g me dicati o n f or partici pa nts 
wit h a rece nt mil d disease flare wit hi n 4 wee ks s h o ul d be caref ull y 
c o nsi dere d.  
5.  Acti ve disease d uri n g t he Sta ge 2 Scree ni n g peri o d res ulti n g i n:  
a. 
A n i ncrease/a d diti o n of a n y I S me dicat i o ns, or  
b.  A s u g gesti o n of M S rela pse per t he i n vesti gat or.  
6.  Rece nt or c urre nt S A R S -C o V -2 i nfecti o n defi ne d as:  
a. 
D oc u me nte d S A R S -C o V -2 i nfecti o n i n t he past 3 0 da ys (fr o m t he da y t he 
partici pa nt is dia g n ose d b y p ositi ve test t o Sta ge 2 Scree ni n g).  
b.  P ositi ve r es ult o n a m olec ular C O VI D -1 9 test at Sta ge 2 Scree ni n g.  
7.  Recei pt of a n a d diti o nal heter ol o g o us C O VI D -1 9 vacci ne d ose pri or t o Sta ge 2 
Scree ni n g, i.e., a partici pa nt ca n n ot ha ve recei ve d a mi xt ure of m R N A vacci nes or 
b ot h m R N A a n d Ja nsse n C O VI D -1 9 vacci nes i n a n y or der or c o m bi nati o n. 
8.   I nfla m mat or y m y ocar ditis/ pericar ditis f oll o wi n g a n y C O VI D-1 9 vacci ne d oses.   
9.  Partici pa nts wit h acti ve, o n g oi n g c hr o nic i nfecti o ns i ncl u di n g partici pa nts wit h 
e vi de nce of:  
a. 
HI V.  
b.  He patitis B as i n dicate d b y s urface a nti ge n.  
c. 
He p atitis C as i n dicate d b y a nti -he patitis C a nti b o d y p ositi vit y; if a 
partici pa nt is He patitis C a nti b o d y p ositi ve, t he y will be eli gi ble t o 
partici pate i n t he st u d y if he/s he is ne gati ve f or viral l oa d at Sta ge 2 
Scree ni n g.   


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
N ote: P artici pa nts are per mitte d t o be o n c hr o nic pr o p hyl actic a nti micr o bi al 
t her a py. 
1 0.  Partici pa nts wit h c o m m o n varia ble i m m u n o deficie nc y disease, as well as a n y 
partici pa nts c urre ntl y recei vi n g i m m u ne gl o b uli n re place me nt t hera p y.  
1 1.  Partici pa nts w h o recei ve d lice ns e d or i n vesti gati o nal m o n ocl o nal a nti b o dies or 
plas ma pr o d ucts directe d a gai nst S A R S -C o V -2 wit hi n 3 0 da ys of Sta ge 2 Scree ni n g.  
1 2.  Partici pa nts w h o ha ve recei ve d a n y li ve vacci nes wit hi n 2 m o nt hs of t he a ntici pate d 
st u d y vacci ne d ose or w h o will ha ve nee d of a li ve vacci ne at a n y ti me d uri n g t he 
st u d y. 
1 3.  C urre ntl y pre g na nt or breastfee di n g.  
1 4.  Fe male partici pa nts w h o are pla n ni n g a pre g na nc y d uri n g t he c o urse of t he trial.  
1 5.  He m o gl o bi n ( H g b) < 8. 0 g/ d L ( 8 0 g/ L)  
1 6.  Past or c urre nt me dical pr o ble ms or fi n di n gs fr o m p h ysi cal e xa mi nati o n or 
la b orat or y testi n g t hat are n ot liste d a b o ve, w hic h, i n t he o pi ni o n of t he i n vesti gat or, 
ma y p ose a d diti o nal ris ks fr o m partici pati o n i n t he st u d y, ma y i nterfere wit h t he 
partici pa nt’s a bilit y t o c o m pl y wit h st u d y re q uire me nts or t hat ma y i m pact t he 
q ualit y or i nter pretati o n of t he data o btai ne d fr o m t he st u d y.  
1 7.  Ot her i n vesti gati o nal c he mical a ge nt wit hi n 3 0 da ys or ot her i n vesti gati o nal bi ol o gic 
a ge nt wit hi n 8  wee ks or 5 half -li ves ( w hic he ver is l o n ger) of Sta ge 2 Scree ni n g.  
1 8.  C o nc urre nt t reat me nt wit h c ycl o p h os p ha mi de, cla dri bi ne, ale mt uz u ma b, or 
mit o xa ntr o ne.  
1 9.  Partici pa nts c urre ntl y o n a n y t y pe of dial ysis, or w h o ha ve recei ve d a s oli d or ga n 
tra ns pla nt. 
2 0.  Pris o ners or partici pa nts w h o are c o m p uls oril y detai ne d (i n v ol u ntaril y i ncarcerate d) 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e. g., i nfecti o us disease) ill ness. 
2 1.  Ta ki n g b ot h M M F/ M P A a n d M T X.  
2 2.  Recei vi n g ot her i n vesti gati o nal B cell de pleti n g t hera p y as part of a cli nical trial 
wit hi n 1 8 m o nt hs of Scree ni n g, u nless dr u g assi g n me nt is k n o w n a n d t he partici pa nt 
recei ve d a n a nti-C D 2 0 or C D 1 9 dr u g.  
2 3.  Partici pa nts wit h acti ve s yste mic i nfecti o ns w h o ha ve recei ve d s yste mic 
a nti micr o bials wit hi n t he 1 4 da ys pri or t o Sta ge 2 Scree ni n g.  
I ncl usi o n/ E xcl usi o n 
Criteri a –  A d ult St a ge 
2 R oll o ver 
P artici p a nts  
I ncl usi o n Criteri a: 
I n di vi d uals w h o meet all of t he f oll o wi n g criteria are eli gi ble t o c o nti n ue as partici pa nts i n 
Sta ge 2:  
5.  Ne g ati ve or s u b o pti mal ser ol o gic res p o nse t o t he a d diti o nal h o m ol o g o us C O VI D -1 9 
vacci ne i n o ne of t he q ualif y i n g re gi me ns, defi ne d as a n Elecs ys ® A nti-S A R S -C o V -


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
2 S ( R B D) ne gati ve res ult or p ositi ve res ult of ≤2 0 0  U/ m L wit hi n 4 wee ks of t he 
Sta ge 2 Baseli ne/ Wee k 0 visit.  
T he re gi me ns of C O VI D -1 9 vacci nati o n t hat q ualif y are as f oll o ws:  
a. 
3 f ull d oses of t he Pfizer -Bi o N Tec h C O VI D -1 9 Vacci ne  
b.  3 f ull d oses of t he M o der na C O VI D -1 9 Vacci ne  
c. 
2 f ull d oses of t he Ja nsse n C O VI D -1 9 Vacci ne  
6.  M ust be c urre ntl y ta ki n g o ne of t he f oll o wi n g I S me dicati o ns wit h or wit h o ut 
a d diti o nal disease -relate d me dicati o ns: M M F ( mi ni m u m of 1 0 0 0 m g per da y)/ M P A 
( mi ni m u m of 7 2 0 m g per da y), M T X ( mi ni m u m of 7. 5 m g per wee k), or B cell 
de pleti n g a ge nts wit hi n t he past 1 8 m o nt hs (s uc h as rit u xi ma b, ocreliz u ma b, 
ofat u m u ma b).  
a. 
If ta ki n g M M F/ M P A or M T X, t he partici pa nt m ust ha ve i nitiate d t hera p y at 
least 8 wee ks pri or t o all ocati o n a n d be ta ki n g t he sa me me dicati o ns 
(re gar dless of d ose) as at t he ti me of t he i nitial C O VI D-1 9 vacci ne re gi me n. 
N ote: Partici pa nts w h o wit h hel d t heir I S me dicati o ns ar o u n d t heir i nitial 
vacci nati o ns are eli gi ble t o partici pate.  
b.  If e nr olli n g i n t he B cell de pleti n g t hera p y c o h ort, t he partici pa nt m ust  ha ve 
recei ve d a n a nti-C D 2 0 or a n a nti -C D 1 9 B cell de pleti n g t hera p y i n t he past 
1 8 m o nt hs.  
7.  N o c ha n ges i n bac k gr o u n d I S me dicati o ns, i ncl u di n g M M F/ M P A or M T X, i n t he 4 
wee ks pri or t o Sta ge 2 Baseli ne/ Wee k 0 visit, e xcl u di n g t he f oll o wi n g:  
a. 
H C Q,  
b.  I ntraarticular ster oi ds,   
c. 
T he a d diti o n of pre d nis o ne at ≤1 0 m g per da y or pre d nis o ne at a n y d ose 
w he n gi ve n f or ≤3 da ys, a n d   
d.  C ortic oster oi d b ursts f or n o n -a ut oi m m u ne disease -relate d c o n diti o ns, s uc h 
as ast h ma or C O P D, are per mitte d.  
E xcl usi o n Criteri a:  
I n di vi d uals w h o meet a n y of t hese criteria are n ot eli gi ble t o c o nti n ue as partici pa nts i n Sta ge 
2 :  
2.  Hist or y of se vere aller gic reacti o n t o a n y pre vi o us C O VI D -1 9 vacci nes, t o a n y 
c o m p o ne nt of a n y of t he C O VI D -1 9 vacci nes, or t o P E G.  
3.  Ne w dia g n osis of mali g na nc y t hat will re q uire c he m ot hera p y or i m m u n ot hera p y, or 
o n g oi n g treat me nt f or a mali g na nc y wit h c he m ot hera p y or i m m u n ot hera p y.  
4.  Acti ve disease ( per t he I n vesti gat or’s decisi o n) res ulti n g i n i na bilit y t o h ol d t he I S 
t hera p y i n t he M M F/ M P A or M T X ar ms of t he st u d y.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
a. 
T he p ote ntial i m pact of te m p oraril y h ol di n g me dicati o n f or partici pa nts 
wit h a rece nt mil d disease flare wit hi n 4  wee ks s h o ul d be caref ull y 
c o nsi dere d.  
5.  Acti ve disease d uri n g t he Sta ge 2 Scree ni n g peri o d res ulti n g i n:  
a. 
A n i ncrease/a d diti o n of a n y I S me dicati o ns, or  
b.  A s u g gesti o n of M S rela pse per t he i n vesti gat or.  
6.  Rece nt or c urre nt S A R S -C o V -2 i nfecti o n defi ne d as:  
a. 
D oc u me nte d S A R S -C o V -2 i nfecti o n i n t he past 3 0 da ys (fr o m t he da y t he 
partici pa nt is dia g n ose d b y p ositi ve test t o Sta ge 2 Scree ni n g).  
b.  P ositi ve res ult o n a m olec ular C O VI D -1 9 test at Sta ge 2 Scree ni n g or Sta ge 
2 Baseli ne/ Wee k 0.  
8.  I nfla m mat or y m y ocar ditis/ pericar ditis f oll o wi n g a n y C O VI D-1 9 vacci ne d oses.   
1 1.  Partici pa nts w h o recei ve d lice nse d or i n vesti gati o nal m o n ocl o nal a nti b o dies or 
plas ma pr o d ucts directe d a gai nst S A R S -C o V -2 wit hi n 3 0 da ys of Sta ge 2 Scree ni n g.  
1 3.  C urre ntl y pre g na nt or breastfee di n g.  
1 4.  Fe male partici pa nts w h o are pla n ni n g a pre g na nc y d uri n g t he c o urse of t he trial.  
1 5.  He m o gl o bi n ( H g b) < 8. 0 g/ d L ( 8 0 g/ L)  
1 6.  Past or c urre nt me d ical pr o ble ms or fi n di n gs fr o m p h ysical e xa mi nati o n or 
la b orat or y testi n g t hat are n ot liste d a b o ve, w hic h, i n t he o pi ni o n of t he i n vesti gat or, 
ma y p ose a d diti o nal ris ks fr o m partici pati o n i n t he st u d y, ma y i nterfere wit h t he 
partici pa nt’s a bilit y t o c o m pl y wit h st u d y re q uire me nts or t hat ma y i m pact t he 
q ualit y or i nter pretati o n of t he data o btai ne d fr o m t he st u d y.  
1 7.  Ot her i n vesti gati o nal c he mical a ge nt wit hi n 3 0 da ys or ot her i n vesti gati o nal bi ol o gic 
a ge nt wit hi n 8  wee ks or 5 half -li ves ( w hic he ver is l o n ger) of Sta ge 2 Scree ni n g.  
1 8.  C o nc urre nt treat me nt wit h c ycl o p h os p ha mi de, cla dri bi ne, ale mt uz u ma b, or 
mit o xa ntr o ne.  
1 9.  Partici pa nts c urre ntl y o n a n y t y pe of dial ysis, or w h o ha ve recei ve d a s oli d or ga n 
tra ns pla nt. 
2 0.  Pris o ners or partici pa nts w h o are c o m p uls oril y deta i ne d (i n v ol u ntaril y i ncarcerate d) 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e. g., i nfecti o us disease) ill ness. 
2 3.  Partici pa nts wit h acti ve s yste mic i nfecti o ns w h o ha ve recei ve d s yste mic 
a nti micr o bials wit hi n t he 1 4 da ys pri or t o Sta ge 2 Baseli ne/ Wee k  0.  
I ncl usi o n/ E xcl usi o n 
Criteri a –   Pe di atric 
P artici p a nts  
I ncl usi o n Criteri a: 
I n di vi d uals w h o meet all of t he f oll o wi n g criteria are eli gi ble f or e nr oll me nt 
ra n d o mizati o n/all ocati o n as partici pa nts i n t he pe diatric p orti o n of t he st u d y: 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 6  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
. 
 
 
1.  I n di vi d uals 5-1 7 years of a ge t hat meet classificati o n criteria f or S L E, JI A, P O M S, 
or J D M. N ote: J u ve nile i di o pat hic art hri tis i ncl u des t he f oll o wi n g c o n diti o ns: 
p ol yartic ular JI A ( b ot h R F + a n d -), oli g oartic ular persiste nt a n d oli g oartic ular 
e xte n de d JI A, ps oriatic art hritis, a n d e nt hesitis relate d JI A.  
a. 
Partici pa nts m ust meet t he 2 0 1 7 E U L A R/ A C R classificati o n criteria f or 
a d ult a n d j u ve nile i di o pat hic i nfla m mat or y m y o pat hies a n d t heir maj or 
s u b gr o u ps [ 8], t he I nter nati o nal Lea g ue of Ass ociati o ns f or R he u mat ol o g y 
(I L A R) classificati o n f or JI A [ 4], t he 2 0 1 7 Mc D o nal d [ 6] criteria f or M S, or 
t he B o ha n a n d Peter criteria or t he 2 0 1 7 E U L A R/ A C R classificati o n criteria 
f or J D M.  
b.  If a partici pa nt has bee n dia g n ose d wit h m ore t ha n o ne a ut oi m m u ne 
disease, t he partici pa nt will be assesse d base d o n t he disease t hat is selecte d 
f or st u d y e ntr y.  
2.  Pare nts/ g uar dia ns of pe diatric partici pa nts m ust be willi n g a n d a ble t o si g n i nf or me d 
c o nse n t. Partici pa nts, a ges 7-1 7, m ust be willi n g a n d a ble t o si g n asse nt.  
3.  D oc u me nte d f ull C O VI D -1 9 vacci nati o n ( C D C car d or d oc u me ntati o n i n me dical 
rec or ds) t hat was c o m plete d at least 4 wee ks pri or a n d n o m ore t ha n 5 2 wee ks pri or 
t o t he Scree ni n g visit. 
4.  Ne g at i ve or s u b o pti mal ser ol o gic res p o nse t o i nitial C O VI D-1 9 vacci ne re gi me n, 
defi ne d as a n Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L at Scree ni n g visit.  
a. 
I nitial C O VI D-1 9 vacci ne re gi me n is defi ne d as:  
i. 2 d oses (as a p pr o priate t o a ge) of t he Pfizer -Bi o N Tec h C O VI D -1 9 
Vacci ne  
T he f oll o wi n g vacci nes ha ve yet t o recei ve E U A i n pe diatric 
p o p ulati o ns. If E U A occ urs f or y o u n ger a ges, t he partici pa nts 
recei vi n g a ge-a p pr o priate re gi me ns of t he f oll o wi n g C O VI D -1 9 
vacci nes ma y be e nr olle d i nt o t he st u d y:  
ii. M o der na C O VI D -1 9  Vacci ne  
iii. Ja nsse n C O VI D-1 9 Vacci ne  
5.  M ust be c urre ntl y ta ki n g o ne of t he f oll o wi n g I S me dicati o ns wit h or wit h o ut 
a d diti o nal disease -relate d me dicati o ns: M M F ( mi ni m u m of 2 5 0 m g per da y)/ M P A 
( mi ni m u m of 3 6 0 m g per da y), M T X ( mi ni m u m of 5 m g per wee k), or B cell 
de pleti n g a ge nts wit hi n t he past 1 8 m o nt hs (s uc h as rit u xi ma b, ocreliz u ma b, or 
ofat u m u ma b).  
a. 
If ta ki n g M M F/ M P A or M T X, t he partici pa nt m ust ha ve i nitiate d t hera p y at 
least 8 wee ks pri or t o ra n d o mizati o n a n d be ta ki n g t he sa me me dicati o ns 
(re gar dless of d ose) as at t he ti me of t he i nitial C O VI D-1 9 vacci ne re gi me n. 
N ote: Partici pa nts w h o wit h hel d t h eir I S me dicati o ns ar o u n d t heir i nitial 
vacci nati o ns are eli gi ble t o partici pate.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 7  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
b.  If e nr olli n g i n t he B cell de pleti n g t hera p y c o h ort, partici pa nt m ust ha ve 
recei ve d a n a nti-C D 2 0 or a n a nti -C D 1 9 B cell de pleti n g t hera p y i n t he past 
1 8 m o nt hs.  
6.  N o c ha n ges i n bac k gr o u n d I S me dicati o ns, i ncl u di n g M M F/ M P A or M T X, i n t he 8 
wee ks pri or t o Scree ni n g, e xcl u di n g t he f oll o wi n g:  
a. 
H C Q,  
b.  I ntraartic ular ster oi ds,   
c. 
T he a d diti o n of pre d nis o ne at ≤1 0 m g per da y or pre d nis o ne at a n y d ose 
w he n gi ve n f or ≤3 da ys, a n d   
d.  C ortic oster oi d b ursts f or n o n -a ut oi m m u ne disease -relate d c o n diti o ns, s uc h 
as ast h ma or C O P D, are per mitte d  
E xcl usi o n Criteri a:  
I n di vi d uals w h o meet  a n y of t hese criteria are n ot eli gi ble f or ra n d o mizati o n/all ocati o n as 
st u d y partici pa nts:  
1.  I na bilit y or u n willi n g ness of a partici pa nt t o gi ve asse nt or of a pare nt/ g uar dia n t o 
gi ve writte n i nf or me d c o nse nt, or of eit her t o c o m pl y wit h st u d y pr ot oc ol.  
2.  Hi st or y of se vere aller gic reacti o n t o t he i nitial C O VI D-1 9 vacci ne re gi me n, or a n y 
c o m p o ne nt of a n y of t he C O VI D -1 9 vacci nes, or t o P E G.  
3.  Ne w dia g n osis of mali g na nc y t hat will re q uire c he m ot hera p y or i m m u n ot hera p y, or 
o n g oi n g treat me nt f or a mali g na nc y wit h c he m ot hera p y or i m m u n ot hera p y.  
4.  Acti ve disease ( per t he I n vesti gat or’s decisi o n) res ulti n g i n i na bilit y t o h ol d t he I S 
t hera p y i n t he M M F/ M P A or M T X ar ms of t he st u d y.  
a. 
T he p ote ntial i m pact of te m p oraril y h ol di n g me dicati o n f or partici pa nts 
wit h a rece nt mil d disease flare wit hi n 4 wee ks s h o ul d be caref ull y 
c o nsi dere d.  
5.  Acti ve disease d uri n g t he Scree ni n g peri o d res ulti n g i n:  
a. 
 a n i ncrease/a d diti o n of a n y I S me dicati o ns, or  
b.  a s u g gesti o n of M S rela pse per t he i n vesti gat or  
6.  Rece nt or c urre nt S A R S -C o V -2 i nfecti o n defi ne d as:  
a. 
D oc u me nte d S A R S -C o V -2 i nfecti o n i n t he past 3 0 da ys (fr o m t he da y t he 
partici pa nt is dia g n ose d b y p ositi ve test t o Scree ni n g).  
b.  P ositi ve res ult o n a m olec ular C O VI D -1 9 test at Scree ni n g.  
7.  Recei pt of a C O VI D -1 9 vacci ne b o oster p ri or t o Scree ni n g. 
8.   I nfla m mat or y m y ocar ditis/ pericar ditis f oll o wi n g i nitial C O VI D-1 9 vacci ne 
re gi me n.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 8  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
9.  Partici pa nts wit h acti ve, o n g oi n g c hr o nic i nfecti o ns, i ncl u di n g partici pa nts wit h 
e vi de nce of:  
a. 
HI V.  
b.  He patitis  B as i n dicate d b y s urface a nti ge n.  
c. 
He p atitis C as i n dicate d b y a nti -he patitis C a nti b o d y p ositi vit y; if a 
partici pa nt is He patitis C a nti b o d y p ositi ve, t he y will be eli gi ble t o 
partici pate i n t he st u d y if he/s he is ne gati ve f or viral l oa d at Scree ni n g.   
N ote: Partici pa nts  are per mitte d t o be o n c hr o nic pr o p hyl actic a nti micr o bi al 
t her a py.  
1 0.  Partici pa nts wit h c o m m o n varia ble i m m u n o deficie nc y disease, as well as a n y 
partici pa nts c urre ntl y recei vi n g i m m u ne gl o b uli n re place me nt t hera p y.  
1 1.  Partici pa nts w h o recei ve d lice nse d or i n vesti gati o nal m o n ocl o nal a nti b o dies or 
plas ma pr o d ucts directe d a gai nst S A R S -C o V -2 wit hi n 3 0 da ys of Scree ni n g.  
1 2.  Partici pa nts w h o ha ve recei ve d a n y li ve vacci nes wit hi n 2 m o nt hs of t he a ntici pate d 
st u d y vacci ne d ose or w h o will ha ve nee d of a li ve vacci ne at a n y ti me d uri n g t he 
st u d y. 
1 3.  C urre ntl y pre g na nt or breastfee di n g ( p ost me narc hal fe males m ust ha ve a ne gati ve 
uri ne pre g na nc y test at Scree ni n g)  
1 4.  He m o gl o bi n ( H g b) < 8. 0 g/ d L ( 8 0 g/ L)  
1 5.  Past or c urre nt me dical pr o ble ms or fi n di n gs fr o m p h ysical e xa mi nati o n or 
la b orat or y testi n g t hat are n ot liste d a b o ve, w hic h, i n t he o pi ni o n of t he i n vesti gat or, 
ma y p ose a d diti o nal ris ks fr o m partici pati o n i n t he st u d y, ma y i nterfere wit h t he 
partici pa nt’s a bilit y t o c o m pl y wit h st u d y re q uire me nts or t hat ma y i m p act t he 
q ualit y or i nter pretati o n of t he data o btai ne d fr o m t he st u d y.  
1 6.  Ot her i n vesti gati o nal c he mical a ge nt wit hi n 3 0 da ys or ot her i n vesti gati o nal bi ol o gic 
a ge nt wit hi n 8 wee ks or 5 half -li ves ( w hic he ver is l o n ger) of Scree ni n g.  
1 7.  C o nc urre nt treat me nt wit h  c ycl o p h os p ha mi de.  
1 8.  Partici pa nts c urre ntl y o n a n y t y pe of dial ysis, or w h o ha ve recei ve d a s oli d or ga n 
tra ns pla nt.  
1 9.  Pris o ners or partici pa nts w h o are c o m p uls oril y detai ne d (i n v ol u ntaril y i ncarcerate d) 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e. g., i nfecti o us disease) ill ness m ust 
n ot be all o we d t o partici pa nt i n t his st u d y.  
2 0.  Ta ki n g b ot h M M F/ M P A a n d M T X.  
2 1.  Ot her i n vesti gati o nal B cell de pleti n g t hera p y as part of a cli nical trial wit hi n 1 8 
m o nt hs of Scree ni n g, u nless dr u g assi g n me nt is k n o w n a n d t he pa rtici pa nt recei ve d 
a n a nti-C D 2 0 or C D 1 9 dr u g.  
2 2.  Partici pa nts wit h acti ve s yste mic i nfecti o ns w h o ha ve recei ve d s yste mic 
a nti micr o bials wit hi n t he 1 4 da ys pri or t o Scree ni n g.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2 9  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
St u d y St o p pi n g R ules  
0 B If a n y of t he e ve nts liste d bel o w occ ur, t he D S M B c hair will be n otifie d, a n d a re vie w of 
safet y data will be perf or me d t o deter mi ne if e nr oll me nt i n t he st u d y, 
ra n d o mizati o n/all ocati o n, a n d/ or a d mi nistrati o n of i n vesti gati o nal st u d y me dicati o n s h o ul d be 
h alte d. If t w o wee ks has ela pse d a n d t he D S M B has n ot met, t he n n o ne w partici pa nts will be 
c o nse nte d, all ocate d or ra n d o mize d u ntil after t he D S M B c o m pletes re vie w of t he safet y data.  
A d ult P artici p a nts:  
A n y of t he f oll o wi n g a d verse e ve nts i n a d ult partici pa nts attri b uta ble t o t he vacci ne will 
tri g ger a n a d h oc  D S M B Safet y Re vie w:  
•   
Deat h relate d t o vacci ne.  
•   
Life -t hreati n g a d verse e ve nt ( Gra de 4) relate d t o vacci ne. 
•   
Per ma ne nt or se vere disa bilit y relate d t o vacci ne.  
•   
Occ urre nce of a Gra de 3 or hi g her, vacci ne -relate d S A E of t he sa me t y pe i n 3 or 
m ore of t he st u d y partici pa nts w h o ha ve recei ve d a st u d y treat me nt. N ote: O nly S A Es 
occ urri n g bet wee n D ay 1 a n d t he Week 2 4 st u dy visit will be c o u nte d.  
•   
Occ urre nce of  se vere flare or rela pse after a n a d diti o nal h o m ol o g o us C O VI D -1 9 
vacci ne d ose gi ve n at Sta ge 1, defi ne d as wit hi n 1 2 wee ks of t he Sta ge 
Baseli ne/ Wee k 0 visit ( vacci nati o n), i n 3 of t he first 1 0 partici pa nts or 3 0 % 
t hereafter, defi ne d as f oll o ws. 
•   
Occ urre nce of se vere flare or rela pse after a s u bse q ue nt alter nati ve C O VI D -1 9 
vacci ne d ose gi ve n at Sta ge 2, defi ne d as wit hi n 1 2 wee ks of t he Sta ge 2 
Baseli ne/ Wee k 0 visit ( vacci nati o n), i n 3 of t he first 1 0 partici pa nts or 3 0 % 
t hereafter. 
Pe di atric P arti ci p a nts:  
A n y of t he f oll o wi n g a d verse e ve nts i n pe diatric partici pa nts attri b uta ble t o t he vacci ne will 
tri g ger a n a d h oc  D S M B Safet y Re vie w:  
•   
Deat h relate d t o vacci ne  
•   
Life -t hreate ni n g A E ( Gra de 4) relate d t o vacci ne 
•   
Per ma ne nt or se vere disa bilit y relate d t o vacci ne  
•   
Occ urre nce of a Gra de 3 or hi g her, vacci ne -relate d S A E of t he sa me t y pe i n 3 or 
m ore of t he st u d y partici pa nts w h o ha ve recei ve d a st u d y treat me nt. N ote: O nl y 
S A Es occ urri n g bet wee n Da y 1 a n d t he Wee k 2 4 st u d y visit will be c o u nte d.  
•   
Occ urre nce o f se vere flare or rela pse, bet wee n Baseli ne/ Wee k 0 ( vacci nati o n) a n d 
t he Wee k 1 2 visit, i n 3 of t he first 1 0 partici pa nts or 3 0 % t hereafter. 
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 0  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
4.   
G E N E R A L A N A L Y SI S A N D R E P O R TI N G C O N V E N TI O N S  
T he f oll o wi n g is a list of ge neral a nal ysis a n d re p orti n g c o n ve nti o ns t o be a p plie d f or t his st u d y:  
•  Cate g orical varia bles will be s u m marize d usi n g c o u nts ( n) a n d perce nts  ( %) a n d will be 
prese nte d i n t he f or m n ( %).  
•  M o me nt statistics i ncl u di n g mea n will be re p orte d at 1 m ore si g nifica nt di git t ha n t he 
precisi o n of t he ori gi nal data. T he sta n dar d de viati o n will be re p orte d at 2 m ore 
si g nifica nt di gits t ha n t he precisi o n of t he ori gi nal data. T he le vel of precisi o n ma y be 
m o difie d o n s pecific dis pla ys base d o n cli nical j u d ge me nt.  
•  Or der statistics i ncl u di n g me dia n , mi n, a n d ma x will be re p orte d t o t he sa m e le vel of 
precisi o n as t he ori gi nal o bser vati o ns. If a n y val u es are calc ul ate d t o ha ve m ore 
si g nifica nt di gits, t he n t he val ue s h o ul d be r o u n d e d s o t hat it is t he sa me le vel of 
precisi o n as t he ori gi nal data.  
•  F oll o wi n g S A S defa ult r ules, t he me dia n will be re p orte d as t he a vera ge of t he t w o 
mi d dle n u m bers if t he dataset c o ntai ns a n e v e n n u m ber of o bser vati o ns.  
•  Test statistics i ncl u di n g t a n d z test statistics will be re p orte d t o t w o deci mal places.  
•  P -val ues will b e re p ort e d t o 3 deci mal places if greater t ha n 0. 0 0 1 ; if less t ha n 0. 0 0 1, t he n 
t he y will be re p orte d as ‘ < 0. 0 0 1’. P -val ues a n d si g nifica nt le vels will be re p orte d as 0. 0 5 
rat her t ha n . 0 5. A p-val u e will  be re p orte d as “ 1. 0 0 0” o nl y if it is e xactl y 1. 0 0 0 wit h o ut 
r o u n di n g. A p-val ue will  be re p orte d as “ 0. 0 0 0 ” o nl y if it is e xactl y 0. 0 0 0 wit h o ut 
r o u n di n g. 
•  N o preli mi nar y r o u n di n g s h o ul d be perf or me d; r o u n di n g s h o ul d o nl y occ ur after a nal ysis. 
T o r o u n d, c o nsi der t he di git t o t he ri g ht of last si g nifica nt di git; if <5 t he n r o u n d d o w n, 
a n d if ≥5 t he n r o u n d u p.  
•  I n g e neral, listi n gs will be dis pla ye d b y treat me nt ar m a n d s u bject a n d will be s orte d i n 
t he or der t hat c ol u m ns are dis pla ye d, starti n g wit h t he first c ol u m n o n t he left.  
•  All a nal yses will be perf or me d usi n g t he S A S S yste m versi o n 9. 4  or hi g her . 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 1  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
5.   
A N A L Y SI S S A M P L E S  
A nal ysis sa m ples f or A C V 0 1 f or eac h st u d y sta ge ( Sta ge 1, Sta ge 2 ) a n d a g e gr o u p ( A d ult, 
Pe diatric) will be defi n e d as f oll o ws:  
•  V acci n ate d p o p ul ati o n : will be defi ne d as all partici pa nts w h o are ra n d o mi ze d or 
all ocate d a n d recei ve st u d y vacci ne i n t he st u d y. F or all e n d p oi nts, partici pa nts will be 
e val uate d b y t he act ual v acci ne recei ve d. I n C o h orts A a n d B, partici pa nts will be 
a nal yze d i n s u b gr o u ps d efi ne d b y ra n d o mize d assi g n me nt t o c o nti n ue or wit h h ol d I S 
me dicati o ns i n t he pri mar y a nal ysis .  
•  Per pr ot oc ol p o p ul ati o ns : will be defi ne d as t he s u b gr o u p of partici pa nts i n t he 
vacci nat e d p o p ulati o n w h o a d here t o t he treat me nt pla n f or I S me dicati o ns defi ne d i n 
Secti o n 7. 1. 1 Pr ot oc ol -ma n date d Me dicati o ns a n d ha ve n o maj or pr ot oc ol de viati o ns or 
i neli gi ble e ntr y criteria t h at w o ul d i m pact t he vacci ne res p o nse ass ess me nt at Wee k 4. 
•  S afet y p o p ul ati o n : will be defi ne d as all partici p a nts w h o i nitiate t he treat me nt pla n f or 
I S me dicati o ns or recei ve a n a d diti o nal d ose of vacci ne. 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
6.   
S T U D Y S U B J E C T S  
6. 1.   
Dis p ositi o n of S u bjects  
T he dis p ositi o n of partici pa nts will be s u m marize d i n ta bles a n d liste d  f or eac h st u d y sta ge 
(Sta ge 1, Sta ge 2 ) a n d a g e gr o u p ( A d ult, Pe diatric). A C O N S O R T dia gra m o utli ni n g t he fl o w of 
partici pa nts i n t he st u d y will als o be create d.  T he n u m bers a n d perce nta ges of partici pa nts  
ra n d o mize d/all ocate d, i n eac h a nal ysis sa m ple, a n d recei vi n g vacci ne, as well as reas o ns f or 
earl y ter mi nati o n fr o m t he st u d y , will be prese nte d. F or partici pa nts w h o were 
ra n d o mize d/all ocate d b ut di d n ot recei ve a n a d diti o nal d ose of vacci ne , t he reas o ns f or n ot 
recei vi n g vacci ne will als o be prese nt e d.  F or Sta ge 2 of t he st u d y, t he n u m ber s a n d perce nt a ges 
of partici pa nts  w h o are n e wl y recr uite d vs . r oll o vers fr o m Sta ge 1 will be s u m marized.  St u d y 
dis p ositi o n will als o be s u m marize d b y site.  
6. 2.   
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics  
S u m mar y descri pti ve statistics f or baseli ne a n d d e m o gra p hic c haracteristics will be re p orte d f or 
all a nal ysis  sa m ples b y st u d y ar m . C haracteristics t o be s u m marize d i ncl u d e : 
•  A ge, race, et h nicit y, se x, b o d y wei g ht at scree ni n g, hei g ht  
•  Disease t y pe  a n d d urati o n  
•  R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult at scree ni n g; b ot h as a c o nti n u o us varia ble 
a n d cate g orical: ne g ati ve ( ≤0. 7 9 U/ m L) vs. p ositi ve ( > 0. 7 9 U/ m L); a d diti o n all y, 
cate g orize d as ≤0. 7 9 U/ m L, > 0. 7 9  U/ m L  t hr o u g h 5 0 U/ m L, > 5 0 U/ m L t hr o u g h 
2 0 0  U/ m L, > 2 0 0 U/ m L  
•  Hist or y of pri or S A R S -C o V -2  i nfecti o n at Scree ni n g  
•  Ti me  (i n wee ks) fr o m pre vi o us vacci ne series   
•  A d di ti o nal I S me dicati o ns  
•  Ster oi d d ose  
•  F or Sta ge 2: pr e vi o us vacci ne series  
•  Me dicati o n d ose f or or C o h ort A: M M F or M P A  a n d C o h ort B: M T X   
•  F or C o h ort C a n d C o h ort F: B cell de pleti o n t hera p y :  
o  T y pe  of B cell de pleti o n t hera p y  
o  Ti me (i n wee ks) fr o m last d ose of b cell de pleti o n t hera p y t o vacci ne.  
o  C D 1 9 +  B cells   


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
6. 3.   
Pri or a n d C o nc o mit a nt Me dic ati o ns  
Me dicati o ns will be c o de d acc or di n g t o t he W orl d Healt h Or ga ni zati o n ( W H O) Dr u g Dicti o nar y : 
W H O -Dr u g Gl o bal v 2 0 2 1 -Marc h . M e dicati o ns will be re p orte d o n b ot h t he I m m u n os u p pressive 
Me dic ati o n  a n d C o nc o mit a nt Me dic ati o ns  case re p ort f or ms ( C R Fs ).  
T he n u m ber a n d p erce nta ge of partici p a nts recei vi n g I S me dicati o ns will be prese nte d o verall 
a n d b y me dicati o n  class. Im m u n os u p pressi ve  me dicati o ns will als o be s u m marize d b y disease 
t y pe. W he n re p orti n g t he n u m ber of s u bjects r ecei vi n g t he me dicati o n, a s u bject will o nl y be 
c o u nte d o nce if t h e y e ver recei v e d t h e me dicati o n wit hi n t he me dicati o n class . Perce nta ges will 
be base d o n t he n u m ber of s u bjects i n t he a nal ysis p o p ulati o n.  Me dicati o ns will als o be liste d.  
T he n u m ber s a n d p erce nt a ge s of partici pa nts recei vi n g t he f oll o wi n g c o nc o mita nt me dicati o ns 
wi ll be prese nte d o verall a n d b y me dicati o n class: 
•  S A R S -C o V -2 vacci nes or li ve vacci n es ( of a n y ki n d) a d mi nistere d o utsi de of t he st u d y . 
•  M o n ocl o nal a nti b o dies a d mi nistere d f or (a) pre -e x p os ure pre v e nti o n of C O VI D -1 9 , ( b) 
p ost -e x p os ure pre ve nti o n of C O VI D -1 9 , or (c) treat me nt of C O VI D-1 9 i nfecti o n. 
6. 4.   
Me dic al Hist or y  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
7.   
S T U D Y O P E R A TI O N S  
7. 1.   
Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns will be liste d b y site wit h i nf or mat i o n s uc h as date of de viati o n, cate g or y, 
descri pti o n a n d reas o n f or de viati o n, a n d c orrecti ve acti o n ta ke n . Pr ot oc ol d e viati o ns will be 
s u m marize d o verall a n d b y site  i n ta b ular f or mat b y t y pe of de viati o n. 
7. 2.   
R a n d o miz ati o n  a n d All oc ati o n  
W he n e m pl o ye d i n a n y  p o p ulati o n, ra n d o mizati o n will be acc o m plis he d t hr o u g h a pass w or d -
pr otecte d, we b -bas e d ra n d o mizati o n s yste m. T he i n vesti gat ors, cli nic pers o n nel, a n d partici pa nts 
will n ot be bli n de d t o ra n d o mize d treat me nt assi g n me nts. Statistical a n d pr oject staff at t h e 
Statistical a n d Cli nical C o or di nati n g Ce nter ( S A C C C) a n d t he D AI T Me di cal M o nit or a n d 
Pr oject Ma na ger will be u n bli n de d t o i n di vi d ual treat me nt assi g n me nts as well. La b orat ori es 
perf or mi n g ass a ys f or t his pr ot oc ol will be bli n de d t o t he i de ntit y a n d gr o u p assi g n me nt of 
bi ol o gical materials t o be st u die d.  
7. 2. 1.   
A d ult St a ge 1  
Partici pa nts w h o si g n t he i nf or me d c o nse nt f or m a n d meet all eli gi bilit y criteria f or Sta ge 1 will 
be assi g ne d t o c o h orts defi ne d b y I S me dicati o n a n d b y t he i nitial C O VI D -1 9 vacci ne re gi me n  
recei v e d. Partici pa nts i n C o h ort C will be all ocate d t o c o nti n ui n g t o ta ke  t heir prescri be d I S 
me dicati o ns t hr o u g h o ut t he trial. Partici pa nts i n C o h orts A a n d B will be ra n d o mize d i n a 
bala nce d fas hi o n ( 1: 1), wit hi n t he c o h orts defi ne d b y I S me dicati o n a n d i nitial C O VI D -1 9 
vacci ne re gi me n, t o o ne of t he a vaila ble I S m e dicati o n tr eat me nt pla ns (c o nti n ue c o h ort -defi ni n g 
I S vs. wit h h ol d c o h ort-d efi ni n g I S). Ra n d o mizati o n will be perf or me d usi n g a per m ute d bl oc k 
desi g n stratifie d b y disease t y pe.  
A t otal of 6 0 partici pa nts wit h a R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L will be 
ra n d o mize d or all ocate d t o eac h ar m. I n eac h ar m, t he n u m ber of partici pa nts wit h R oc he 
Elecs ys ® A nti -S A R S -C o V -2 S res ults ≤5 0 U/ m L will be ca p pe d at 4 0 parti ci pa nts, a n d t he 
n u m ber of partici p a nts wit h R oc he El ecs ys ® A nti -S A R S -C o V -2 S res ults > 5 0 U/ m L a n d 
≤2 0 0  U/ m L will be ca p p e d at 4 0 partici pa nts . 
7. 2. 2.   
A d ult St a ge 2  
Partici pa nts w h o ha ve si g ne d t he i nf or me d c o nse nt f or m a n d meet all eli gi bilit y criteria f or 
Sta ge  2 will be all ocate d t o c o h orts defi ne d b y I S me dic ati o n a n d b y t he i nitial C O VI D -1 9 
vacci ne re gi me n recei v e d. Partici pa nts w h o recei v e d eit her t he M o d er na C O VI D -1 9 Vacci ne or 
Pfizer -Bi o N Tec h C O VI D -1 9 Vacci ne will be all ocate d t o t he Sta ge 2 Ar m t hat c orres p o n ds t o 
t heir c h oice of eit her t he Ja nsse n vect or-base d C O VI D -1 9 vacci ne or t he ot her m R N A 
C O VI D -1 9 vacci ne. Partici pa nts w h o recei ve d t he Ja nsse n C O VI D -1 9 Vacci ne will be all ocate d 
t o t he Sta ge 2 Ar m t hat c orres p o n ds t o t he M o der na C O VI D-1 9 Vacci ne. Partici pa nts i n C o h ort 
D will wit h h ol d t heir M M F/ M P A,  partici pa nts i n C o h ort E will wit h h ol d t heir M T X, a n d a n y 
partici pa nts i n C o h ort F ( B cell de pleti o n t hera p y) w h o are als o ta ki n g M M F/ M P A or M T X will 
wit h h ol d t hese me dicati o ns. N o ra n d o mizati o n will be e m pl o ye d.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
A t otal of 6 0 partici pa nts wit h a R oc he E lecs ys ® A nti-S A R S -C o V -2 S res ult ≤2 0 0 U/ m L will be 
all ocate d t o eac h ar m. I n eac h ar m, t he n u m ber of partici pa nts wit h R oc he Elecs ys ® A nti -S A R S -
C o V -2 S res ults ≤5 0 U/ m L will be ca p pe d at 4 0 partici pa nts, a n d t he n u m ber of partici pa nts wit h 
R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ults > 5 0 U/ m L a n d ≤2 0 0 U/ m L will be ca p pe d at 
4 0  partici pa nts.  
7. 2. 3.   
Pe di atric P o p ul ati o n  
Partici pa nts a n d t heir le gal g uar dia n(s) w h o si g n t he c o nse nt a n d asse nt f or ms, as a p pr o priate t o 
a ge, a n d meet all eli gi bilit y criteria f or t he pe d iatric p orti o n of t he trial will be assi g ne d t o 
c o h orts defi ne d b y I S me dicati o n a n d b y t he i nitial C O VI D -1 9 vacci ne re gi me n recei ve d. 
Partici pa nts i n C o h ort C will be all ocate d t o c o nti n ui n g t o ta ke t heir prescri be d I S me dicati o ns 
t hr o u g h o ut t he trial. Partici pa nts i n C o h orts A a n d B will be ra n d o mize d i n a bala nce d fas hi o n 
( 1: 1), wit hi n t he c o h orts defi ne d b y I S me dicati o n a n d i nitial C O VI D-1 9 vacci ne re gi me n, t o o ne 
of t he a vaila ble I S m e dicati o n treat me nt pla ns (c o nti n ue I S vs. wit h h ol d I S). Ra n d o mizati o n will 
be perf or me d usi n g a per m ute d bl oc k desi g n stratifie d b y disease t y pe.  
A t otal of 6 0 partici pa nts wit h a R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L will be 
ra n d o mize d or all ocate d t o eac h ar m. I n eac h ar m, t he n u m ber of partici pa nts wit h R oche 
Elecs ys ® A nti -S A R S -C o V -2 S res ults ≤5 0 U/ m L will be ca p pe d at 4 0 parti ci pa nts, a n d t he 
n u m ber of partici p a nts wit h R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ults > 5 0 U/ m L a n d 
≤2 0 0  U/ m L will be ca p p e d at 4 0 partici pa nts.  
7. 3.   
Me as ures of Tre at me nt C o m pli a nce  
T he n u m ber of partici pa nts w h o recei v e st u d y vacci ne will be s u m marize d b y ar m.  
I n st u d y ar ms t hat wit h h ol d I S me dicati o ns ar o u n d t he ti me of vacci n ati o n, t he t otal n u m ber of 
da ys, t he n u m ber of da ys pri or t o vacci n e, a n d t he n u m ber of da ys p os t-v acci ne t hat I S 
me dicati o ns are wit h hel d will be s u m marize d.  
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 6  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
8.   
E N D P OI N T E V A L U A TI O N  
8. 1.   
O ver vie w of Effic ac y A n al ysis Met h o ds  
8. 1. 1.   
M ultice nter St u dies  
St u d y partici pa nts  will be recr uite d fr o m 1 5 -2 0  st u d y sites f or eac h of  t he a d ult a n d pe diatric 
gr o u ps . S t u d y data will be a nal yze d as a w h ole, a n d n o f or mal acc o m m o dati o n f or site -t o-site 
variati o n will be ma de.  
8. 1. 2.   
Assess m e nt Ti m e Wi n d o ws  
A d diti o nal details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P . 
8. 1. 3.   
Ti mi n g of A n al yses  
T he pri mar y a n al ysis will be e val uate d i n d e pe n de ntl y wit hi n eac h ar m ( d efi ne d b y a ge, c o h ort, 
vacci ne, a n d I S treat me nt pla n) i n t he vacci nate d p o p ulati o n , a n d will be c o n d ucte d o verall, i n all 
partici pa nts wit h a R oc he El ecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L at t he Scree ni n g 
visit , a n d i n t he s u b gr o u p of partici pa nts wit h a R o c he Elecs ys ® A nti -S A R S -C o V -2 S res ult 
≤5 0  U/ m L at t he Scree ni n g visit . Eac h a nal ysis will occ ur after t he e v al ua bl e partici pa nts 
assi g ne d t o t hat ar m ha ve c o m plete d t he Wee k 4 st u d y visit or are wit h dra w n fr o m t he st u d y.  
8. 1. 4.   
M ulti ple C o m p aris o ns/ M ulti plicit y  
T he pri mar y a n al ysis will be e val uate d i n d e pe n de ntl y wit hi n eac h ar m , a n d p-val ues will n ot be 
a dj uste d f or m ulti ple c o m paris o ns.  
All sec o n dar y a nal yses will be c o n d ucte d i n a n e x pl orat or y fas hi o n , wit h a n y p -val ues a n d 
c o nfi de nce i nter vals pr es e nte d as des cri pti ve statistics wit h n o a dj ust me nts f or m ulti ple 
c o m paris o ns . 
8. 2.   
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of a pr otecti ve a nti b o d y res p o nse will be t he pr o p orti o n of partici pa nts 
w h o reac h t he la b orat or y-defi ne d t hr es h ol d f or t he NI AI D -V R C M S D 3 ple x ( W u -1 f ull -le n gt h 
s pi ke, R B D, a n d N pr otei ns) assa y at Wee k 4.  T he W u -1 f ull -le n gt h s pi ke pr otei n will be use d  i n 
deter mi ni n g a pr otecti ve a nti b o d y res p o nse  i n t he pri mar y a nal ysis; t he R B D pr otei n will be use d 
i n sec o n dar y a nal yses of a nti b o d y res p o nse; a n d N pr otei ns will be use d i n s u p p orti ve a nal yses 
as e vi de nce of C O VI D i nfecti o n.   
8. 2. 1.   
C o m p ut ati o n of t he Pri m ar y E n d p oi nt  
T he pr o p orti o n of partici pa nts w h o reac h t he la b orat or y-defi ne d t hres h ol d f or t he NI AI D -V R C 
M S D 3 ple x  assay  at Wee k 4 will be s u m marize d b y ar m  o verall, i n all partici pa nts wit h a R oc he 
El ecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 U/ m L at t he Scree ni n g visit , a n d i n t he s u b gr o u p of 
partici pa nts wit h a R oc he El ecs ys ® A nti -S A R S -C o V -2 S res ult ≤5 0 U/ m L at t he Scree ni n g visit . 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3 7  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
F or c o n ce ntr ati o ns t hat are bel o w t he L o wer Li mit of Detecti o n ( L L O D ), n u meric val ues 
e q ui vale nt t o L L O D / 2 are assi g ne d before a n d f or all descri pti ve re p orti n g. C o nce ntrati o ns t hat 
are a b o v e t he U p p er Li mit of Q ua ntificati o n  are re p orte d wit h o ut a dj ust me nts.  
Partici pa nts wit h missi n g Wee k 4 a nti -C O VI D -1 9 a nti b o d y res p o nse data wit h a d oc u me nte d 
C O VI D i nfecti o n pri or t o We e k 4 will be c o nsi dere d as n ot ha vi n g a pr ot ecti ve a nti b o d y 
res p o nse. All ot her partici pa nts missi n g Wee k 4 a nti-C O VI D -1 9 a nti b o d y res p o nse data will be 
c o nsi dere d t o be missi n g -c o m pletel y -at-ra n d o m ( M C A R). 
8. 2. 2.   
Pri m ar y A n al ysis of t he Pri m ar y E n d p oi nt  
T h e pri mar y a n al ysis will be e val uate d i n d e pe n de ntl y wit hi n eac h ar m ( d efi ne d b y sta ge, a ge, 
c o h ort, vacci ne, a n d I S tr eat me nt pla n) i n t he vacci nate d p o p ulati o n. T he pr o p orti o n of 
partici pa nts meeti n g a pr otecti ve a nti b o d y res p o ns e criteria will be  re p orte d i n eac h ar m wit h 
9 0 % Cl o p per -Pears o n c o nfi de nce i nter vals a n d a n al yze d usi n g a o ne -si de d e xact test wit h 
al p ha =  0. 0 5 a g ai nst t he n ull h y p ot hesis t hat t he pr o ba bilit y of ac hie vi n g a pr otecti ve i m m u ne 
res p o nse is ≤0. 2 5. P -val u es will n ot be a dj uste d f or m ulti ple c o m paris o ns.  
T he pri mar y a n al ysis will be c o n d ucte d i n all partici pa nts wit h a R oc he El ecs ys ® A nti -S A R S -
C o V -2 S res ult ≤2 0 0 U/ m L at t he Scree ni n g visit , a n d i n t he s u b gr o u p of partici pa nts wit h a 
R oc he El ecs ys ® A nti -S A R S -C o V -2 S res ult ≤5 0 U/ m L at t he Scree ni n g visit . Eac h a nal ysis will 
occ ur after t he e val ua bl e partici pa nts assi g ne d t o t hat ar m ha ve c o m plete d  t he Wee k 4 st u d y visit 
or are wit h dra w n fr o m t he st u d y.  
8. 2. 3.   
Se nsiti vit y A n al yses of t he Pri m ar y A n al ysis  
A se nsiti vit y a nal ysis will be  perf or me d  o n t h e per pr ot oc ol p o p ulati o n.  
8. 2. 4.   
Sec o n d ar y A n al yses of t he Pri m ar y E n d p oi nt  
Descri pti ve statistics will be use d t o s u m marize a nti b o d y res p o nse t o t he a d diti o nal h o m ol o g o us 
vacci ne d os e o n a c o nti n u o us scale , i ncl u di n g me dia n, mi ni m u m, a n d ma xi m u m, i nterq uartile 
ra n ge, ge o m etric mea n, C V of t he ge o metric mea n, a n d 9 5 % c o nfi de nce i nter vals.  S u m mar y 
statistics, i ncl u di n g 2 5t h perce ntile, mea n, me dia n, a n d 7 5t h perce ntile, will be pl otte d f or eac h 
visit b y treat me nt ar m.  Ge o metric mea n  a n d C V of t he ge o metric m ea n will be c o m p ute d as 
f oll o ws:  
Ge o metric mea n = e x p( mea n o n l o g e scale). 
% C V ge o metric m ea n = √e x p ((𝑆𝐷𝑜𝑛𝑙𝑜𝑔𝑒𝑠𝑐𝑎𝑙𝑒) 2 ) −1 𝑥1 0 0  
P ri mar y a n d sec o n d ar y a nal yses will be re peate d f or t he R B D pr otei ns  t o s u m marize a nti b o d y 
res p o nse t o t he a d diti o nal h o m ol o g o us vacci ne d ose o n a c o nti n u o us scale.  Su p p orti ve a nal yses 
will use descri pti v e statistics t o s u m marize N pr ot ei n le vels a s e vi de nce of C O VI D i nfecti o n .   
I n t he fi nal a nal ysis, su p p orti ve a nal yses will als o use a m ulti varia ble re gressi o n m o del o n t he 
e ntire vacci nate d p o p ulati o n i n or der t o esti mate t he rates of v acci ne res p o nse wit hi n a n d acr oss 
ar ms (a ge gr o u p, c o h ort, vacci ne, a n d I S treat me nt pla n gr o u p) usi n g t he l o gistic li n k f u ncti o n, 
a n d i ncl u di n g baseli ne c o variates f or disease t y p e ( S L E, R A, M S, S Sc, a n d pe m p hi g us i n a d ults 






T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 0  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
8. 3. 5.   
C h a n ges i n Dise ases Acti vit y usi n g C GI -C  
C ha n ges i n disease acti vit y after recei pt of a d diti o nal d oses of C O VI D -1 9 vacci ne will be 
assesse d as me as ure d b y t he C GI -C . I n preli mi nar y a nal yses, t he c h a n ge i n C GI-C fr o m Wee k 0 
t o Wee k 4 will be s u m marize d i n eac h st u d y p o p ulati o n usi n g descri pti ve statistics. A nal ysis 
details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 6.   
C h a n ges i n Dise ases Acti vit y usi n g P G A  
C ha n ges i n disease acti vit y after recei pt of a d diti o nal d oses of C O VI D -1 9 vacci ne will be 
assesse d as me as ure d b y t he P G A . T his e n d p oi nt will n ot be e val uate d i n preli mi nar y a nal yses . 
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 7.   
C h a n ges in Dise ase Acti vit y a s Me as ure d b y Dise ase -S pecific Assess me nts  
L o n git u di nal c ha n ges in d isease acti vit y will n ot be e val uat e d i n preli mi nar y a nal yses. T he 
pr o p orti o n of partici pa nts w h o meet  t he defi niti o n f or disease -s pecifi c flares b y Wee k 4 will be 
s u m marize d i n preli mi nar y a nal yses. 
8. 3. 7. 1.  
H -S L E D AI a n d S E L E N A -S L E D AI  Fl are I n de x  
Disease acti vit y f or S L E partici pa nts will be meas ure d b y t he ( H-S L E D AI  a n d S E L E N A -
S L E D AI  Flare I n d e x  f or S L E. A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he 
S A P.  
8. 3. 7. 2.  
D A S 2 8 -C R P  
Disease acti vit y f or R A  partici pa nts will be meas ure d  b y t he D A S 2 8 -C R P  f or R A. A nal ysis 
details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 7. 3.  
Fl are assess me nt f or S Sc  
Disease acti vit y f or S Sc partici pa nts will be meas ure d usi n g t he f lare assess me nt f or S Sc 
(i ncl u di n g patie nt-re p orte d flare assess me nt). A nal ysis details will be pr o vi de d i n s u bse q ue nt 
versi o ns of t he S A P.  
8. 3. 7. 4.  
P D AI  
Disease acti vit y f or pe m p hi g us partici pa nts will be meas ure d usi n g t he P D AI  f or p e m p hi g us. 
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 7. 5.  
P h ysici a n -assesse d rel a pse f or M S  
Disease acti vit y f or M S partic i pa nts will be meas ure d usi n g t he ph ysicia n -assesse d rela pse f or 
M S.  A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 1  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
. 
 
 
8. 3. 7. 6.  
J A D A S -1 0  
Disease acti vit y f or  JI A partici pa nts will be meas ure d usi n g t he J A D A S-1 0 f or p ol yart hritis, 
e nt hesitis relat e d t o JI A, oli g oart hritis, a n d ps oriatic art hritis.  A nal ysis details will be pr o vi de d i n 
s u bse q ue nt versi o ns of t h e S A P. 
8. 3. 7. 7.  
P A SI  
Disease acti vit y f or JI A partici pa nts will als o be meas ure d usi n g t he P A SI  f or ps oriatic art hritis. 
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 7. 8.  
S L E D AI -2 K a n d C hil d h o o d -o nset S L E Criteri a f or Gl o b al Fl are  
Disease acti vit y f or pe diatric S L E will be meas ure d usi n g t he S L E D AI -2 K a n d C hil d h o o d -o nset 
S L E Criteria f or Gl o bal Flare [ 1] f or pe diatri c S L E. A nal ysis details will be pr o vi de d i n 
s u bse q ue nt versi o ns of t h e S A P. 
8. 3. 7. 9.  
C M A S  
Disease acti vit y f or J D M will be meas ure d usi n g t he C M A S  f or J D M. A nal ysis details will be 
pr o vi de d i n s u bse q ue nt v ersi o ns of t he S A P.  
8. 3. 7. 1 0.  J D M D A S  
Disease acti vit y f or J D M will be meas ure d usi n g t he J D M D A S  f or J D M. A nal ysis details will 
be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 7. 1 1.  P h ysic i a n-assesse d rel a pse f or P O M S  
Disease acti vit y f or P O M S will be meas ure d usi n g t he p h ysicia n -assess e d rela pse f or M S f or 
P O M S.  A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 3. 8.   
C h a n ges i n P atie nt -re p orte d O utc o mes  
8. 3. 8. 1.  
P R O MI S 2 9  
C ha n ges i n t h e P R O MI S  2 9 will be assesse d i n t he a d ult p o p ulati o n. A nal ysis details will be 
pr o vi de d i n s u bse q ue nt v ersi o ns of t he S A P . 
8. 3. 8. 2.  
Pe ds Q L  
C ha n ges i n t he Pe ds Q L  will be assesse d i n t he pe diatric p o p ulati o n. A nal ysis details will be 
pr o vi de d i n s u bse q ue nt v ersi o ns of t he S A P.  
8. 3. 8. 3.  
Pt G A  
C ha n ges i n t he Pt G A  will be assesse d i n t he a d ult a n d pe diatric p o p ulati o ns. A nal ysis details will 
be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
8. 3. 8. 4.  
P GI -C  
C ha n ges i n t he P GI -C  will be assesse d i n t he a d ult a n d pe diatric p o p ulati o ns . A nal ysi s details 
will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
 
8. 4.   
Ot her  E n d p oi nts  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
8. 5.   
E x a mi n ati o n of S u b gr o u ps  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
9.   
S A F E T Y E V A L U A TI O N  
9. 1.   
O ver vie w of S afet y A n al ysis Met h o ds  
All safet y a nal yses will be carrie d o ut usi n g t he safet y sa m ple defi ne d i n Secti o n 5  u nless 
ot her wise n ote d. Missi n g safet y i nf or mati o n will n ot be i m p ute d. T hese a n al yses will n ot be 
stratifie d b y site. 
9. 2.   
A d verse E ve nts  
F or t his st u d y , solicite d A Es  are pre defi ne d l ocal a n d s yste mic e ve nts f or w hic h t he partici pa nts 
will be s pecificall y q uesti o ne d, a n d w hic h will be n ote d b y t hese partici p a nts.  A n A E  is 
c o nsi dere d “ u ns olicite d” w he n it is c ollecte d t hr o u g h a n o pe n -e n de d q uesti o n a n d  is n ot s pecifie d 
as a s olicite d A E.  A n M A A E  is defi ne d as a h os pitalizati o n, e mer ge n c y r o o m visit , or a n 
ot her wise u nsc h e d ule d visit t o or fr o m me dical pers o n nel f or a n y reas o n; a n d c o nsi dere d relate d 
t o st u d y vacci ne . A N O C M C  is defi ne d as a n y ne w I C D dia g n osis ( per c urre nt I nter n ati o nal 
Statistical Classificati o n of Diseases a n d Relate d Healt h Pr o ble ms) t hat is a p plie d t o t he st u d y 
partici pa nt d uri n g t he c o urse of t he st u d y, after re cei pt of t he vacci ne, t hat is e x pecte d t o 
c o nti n ue f or at least 3 m o nt hs a n d re q uires c o nti n ue d healt h care i nter ve nti o n.  A n A E  is 
c o nsi dere d “seri o us” if, i n t he vie w of eit her t he i n vesti gat or or S p o ns or ( D AI T/ NI AI D), it 
res ults i n a n y of t he f oll o wi n g outc o mes: deat h, life -t hreate ni n g, h os pitalizati o n, persiste nt or 
si g nifica nt i nca pacit y, c o n ge nital a n o mal y or birt h defect, or is c o nsi dere d a n i m p orta nt me dical 
e ve nt. See pr ot oc ol Secti o n 1 2. 2 f or m ore d etails o n A E defi niti o ns.  
T he c ollecti o n peri o ds a n d re p orti n g f or A Es are as f oll o ws : 
•  S olicite d A Es (all gra des) will be c ollecte d fr o m Da y 1 ( vacci ne a d mi nistrati o n) t hr o u g h 
7 da ys p ost st u d y vacci nati o n usi n g t he M y O w n Me d vacci ne reacti o n diar y.  
o  I n v esti gat ors are res p o nsi ble f or re p orti n g s olicite d A Es i n t he electr o nic d at a 
ca pt ure s yste m (E D C ) i n t he f oll o wi n g s pecial cases:  
▪ If a s olicite d A E is als o a n S A E or M A A E m ust be e ntere d i n E D C t o 
ca pt ure a d diti o nal i nf or mati o n a b o ut t he e ve nt.  
▪ If a s olicite d A E, pre vi o usl y re p orte d i n M y O w n Me d, is f o u n d t o be 
o n g oi n g at Da y 7 ( p ost v acci nati o n), t he s olicite d A E m ust be e ntere d i n 
E D C s o it ca n be f oll o we d t o res ol uti o n, wit h or wit h o ut se q uelae.  
▪ U ns olicite d A Es ( u nrelat e d t o react o ge nicit y) t hat are e nt ere d i nt o t he 
Vacci n e Reacti o n Diar y a n d a re als o i de ntifie d d uri n g t he Wee k 1 visit are 
t o be re p orte d i n E D C 
•  U ns olicite d A Es will be c ollecte d as f oll o ws a n d re p orte d i n E D C:   
o  A n y u ns olicite d A Es t hat are Gra de 3 or hi g her will be c ollecte d fr o m 
ra n d o mizati o n/all ocati o n t hr o u g h vacci nati o n a d mi nistrati o n.  
o  All u ns olicite d A Es (all gra des) will be c ollecte d fr o m Da y 1 t hr o u g h Da y 2 8.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
. 
 
 
o  A n y flares of a sec o n dar y a ut oi m m u ne disease will be re p orte d as a n u ns olicite d 
A E (all gra d es) a n d will be c ollecte d fr o m Da y 1 t hr o u g h t he e n d of t h e 
partici pa nt’s st u d y partici pati o n.  
•  S A Es , M A A Es , a n d N O C M Cs  will be c ollecte d fr o m Da y 1 t hr o u g h t he e n d of t he 
partici pa nt’s st u d y partici pati o n, re gar dless of t he Nati o nal Ca ncer I nstit ute’s ( N CI’s) 
C o m m o n T o xicit y Criteria f or A d verse E ve nts ( C T C A E)  gra de , a n d re p orte d i n E D C.  
•  C O VI D -1 9 dia g n oses (all gra des) c o nfir me d b y m olec ular C O VI D -1 9 testi n g will be 
c ollecte d fr o m Da y 1 t hr o u g h t he e n d of t he partici pa nt’s st u d y partici pati o n  a n d re p orte d 
i n E D C. 
All A Es will be classifie d b y s yste m or ga n class ( S O C) a n d preferre d ter m, acc or di n g t o a 
sta n dar dize d t h esa ur us ( Me dical Dicti o nar y f or R e g ulat or y Acti vities [ Me d D R A] versi o n 2 4. 0).  
Gra di n g criteria are defi ne d as f oll o ws:  
•  S olicite d A Es : Partici pa nts will gra de s olicite d A Es usi n g a 0 -3 ( n o s y m pt o m, mil d, 
m o derate, a n d s e vere) partici pa nt s y m pt o m rati n g scale as o utli ne d i n t he Vacci ne 
Reacti o n Diar y i nstr ucti o ns.  
•  Aller gic reacti o ns: T he  i n vesti gat or will gra de se verit y of s yste mic aller gic reacti o ns o n a 
scale of 1 t o 5 acc or di n g t o criteria set f ort h i n t he C o ns orti u m of F o o d Aller g y Researc h 
( C o F A R) Gra di n g Scale m o difie d f or use i n a d ults o nl y ( See Pr ot oc ol Secti o n 2 0. 2 
C o F A R Gra di n g Scal e f or S yste mic Aller gic Reacti o ns Versi o n 3. 0).  
•  Li ver F u n cti o n A b n or mali ties: Li ver f u ncti o n a b n or malities will be gra de d usi n g 
alter nati ve criteria, w hi c h are bas e d o n t he N CI -C T C A E versi o n 4. 0, a n d are defi ne d 
relati ve t o t he u p per li mit of n or mal (U L N) as defi ne d i n Pr ot oc ol Secti o n 1 2. 3. 1 Gr a di n g 
Criteri a . 
•  All ot her e ve nts: T he st u d y site will gra de t he se v erit y of all ot her A Es e x p erie nce d b y 
t he st u d y partici pa nts acc or di n g t o t he criteria s et f ort h i n t he N CI -C T C A E versi o n 5. 0 as 
dee me d a p pr o priate f or t he 5 a d ult a ut oi m m u ne diseases a n d 4 p e diatric a ut oi m m u ne 
diseases, a n d use of bac k gr o u n d I S me dicati o ns of i nterest i n t his trial.  
If t he start dat e of a n A E is i nc o m plete or missi n g, it will be ass u me d t o ha ve occ urre d o n or 
after t he first d ose of i n v esti gati o nal pr o d uct, e xce pt if a n i nc o m plete dat e (e. g., m o nt h a n d year) 
clearl y i n dicat es t hat t he e ve nt starte d pri or t o treat me nt  
If a s u bject e x peri e nces t he sa me A E o n m ulti ple occasi o ns, t he e v e nt will be c o u nte d o nce f or 
eac h o cc urre nce w he n re p orti n g t he n u m ber of A Es. W he n re p orti n g t he n u m ber of s u bjects 
e x perie n ci n g t he e ve nts, a s u bject will o nl y be c o u nte d o nce if t he y e x perie nce at least o ne e v e n t 
wit hi n t he partic ular S O C or preferre d t er m. Perce nta ges will be bas e d o n t he n u m ber of s u bjects 
i n t he safet y p o p ulati o n. T he ta b ular s u m mari es will be s orte d b y desce n di n g fre q ue n c y b y S O C 
a n d preferre d ter m  ( P T) i n t he treat me nt gr o u p ar m. 
S u m mar y ta bles will be re p orte d f or treat me nt e m er ge nt a d verse e ve nts u nl ess ot her wise 
i n dicate d. A n o verall s u m mar y ta ble will i ncl u de:  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
o  T otal n u m ber of e v e nts, a n d n u m ber a n d p erce nta ge of s u bjects  e x p erie n ci n g at 
least o ne e ve nt f or t he f oll o wi n g cate g ories: 
•   
A Es  
•   
S A Es  
•   
A Es relate d t o st u d y vacci ne  
•   
A E lea di n g t o st u d y vacci ne  disc o nti n uati o n  
•   
A E lea di n g t o deat h  
•   
M A A E s 
•   
N O C M C s 
•   
S A R S -C o V -2 i nfecti o n s 
•   
S olicite d A d verse E ve nts  
•   
A Es b y se verit y  
A Es classifie d b y Me d D R A S O C a n d preferre d ter m will be s u m marize d f or eac h treat me nt 
gr o u p f or eac h of t h e f oll o wi n g:  
o  All A Es  
o  All Relate d A Es  
o  All S A Es  
o  All A Es lea di n g t o st u d y dr u g disc o nti n uati o n  
o  A Es b y se verit y  
o  A Es b y relati o ns hi p t o st u d y dr u g  
Listi n gs of all A Es, M A A Es, a n d N O C M Cs will be pr o vi de d f or t he safet y p o p ulati o n.  
9. 2. 1.   
S olicite d A d verse E ve nts  
Partici pa nts are pr o vi de d access t o a n electr o nic 7 -da y diar y t o ai d i n rec or di n g s olicite d l ocal 
a n d s yste mic reacti o ns t o t he vacci n e, as well as s y m pt o ms of a p ote ntial aller gic reacti o n, 
u ns olicite d A Es, a n d c o n c o mita nt me dicati o ns, i ncl u di n g start a n d st o p dates. T he diar y i ncl u d es 
i nstr ucti o ns f or partici pa nts o n h o w t o ta ke a n oral te m perat ure a n d h o w t o meas ure i njecti o n site 
reacti o ns. A p a per c o py of t he diar y ma y be pr o vi de d f or partici pa nts w h o d o n ot ha ve a de vi ce 
t o access t he electr o ni c diar y or as a b ac k u p c ollecti o n t o ol. A me m ber of t he st u d y tea m will 
re vie w t he i nf or mati o n i n t he diar y wit h t he partici pa nt, i ncl u di n g h o w t o use a n d access t he 
electr o nic diar y, a n d will rec or d a d verse e v e nts o n t he C R F pa ge as a p pr o priate base d o n re vie w 
of t he diar y . 
S u m mar y dis pla ys base d o n t he ma xi m u m se verit y of s olicite d s y m pt o ms re p orte d o ver t he 7-
da y peri o d will be prese nte d  i n ta bles a n d gra p hi call y b y st u d y ar m. Su m maries  of t he  diar y 
e ntries o ver t he 7 -da y p eri o d will als o be prese nte d b y st u d y ar m.  
9. 3.   
De at hs, Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt A d verse 
E ve nts  
 
Seri o us A Es classifie d b y Me d D R A S O C a n d P T will be s u m marize d f or eac h treat me nt gr o u p 
a n d o verall f or eac h of t h e f oll o wi n g:  
•  All seri o us A Es  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 6  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
•  Seri o us A Es b y se verit y  
•  Seri o us A Es b y relati o ns hi p t o st u d y dr u g  
R ules f or c o u nti n g S A Es i n s u m mar y ta bles are t h e sa me as t h ose a p plie d t o A Es re p orte d i n 
Secti o n 9. 3.  
All S A Es a n d S A Es res ulti n g i n deat h will be pres e nte d i n data listi n gs f or s u bjects i n t he safet y 
p o p ulati o n. A se parat e dis pla y listi n g will be create d f or all deat hs s u m marizi n g t he ti me t o deat h 
a n d ca use of deat h.  
9. 4.   
Cli nic al L a b or at or y E v al u ati o n  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
9. 5.   
Vit al Si g ns, P h ysic al Fi n di n gs, a n d Ot her O bser v ati o ns Rel ate d t o 
S afet y  
9. 5. 1.   
Vit al Si g ns  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
9. 5. 2.   
P h ysic al E x a mi n a ti o ns 
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  
9. 5. 3.   
Ot her S afet y Me as ures  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 7  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 0.   
O T H E R A N A L Y S E S  
A nal ysis details will be pr o vi de d i n s u bse q ue nt versi o ns of t he S A P.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 8  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 1.   
I N T E RIM A N A L Y S E S  A N D D A T A M O NI T O RI N G  
T he pr o gress of t he st u d y will be m o nit ore d b y t he NI AI D D S M B. T he NI AI D A ut oi m m u ne 
D S M B is c hartere d t o r e vie w safet y d ata a n d t o ma ke rec o m me n dati o ns t o NI AI D re gar di n g 
c o nti n uati o n, ter mi nati o n, or m o dificati o n of t he st u d y. T he D S M B will re vie w t he safet y data 
wit hi n 6 m o nt hs after t he first partici pa nt is treate d, a n d a n i nitial re vie w s h o ul d occ ur n o later 
t ha n after t his first ar m has cl ose d t o e nr oll me nt a n d all partici pa nts c o m plete d 4 wee ks of f oll o w 
u p. F oll o wi n g t he i nitial re vie w, t he D S M B will re vie w t he safet y data a p pr o xi matel y e ver y 
6  m o nt hs d uri n g pla n ne d D S M B Data Re vie w Meeti n gs. Data f or t he pl a n n e d safet y re vie ws will 
i ncl u de, at a mi ni m u m, a listi n g of all re p orte d A Es, S A Es, M A A Es, N O C M Cs, a n d i ncreas es i n 
a ut oi m m u ne disease acti vit y (flares/rel a pses).  
T he D S M B c hair will be i nf or me d of a n y I N D Safet y Re p orts i n a ti mel y ma n ner i n or d er t o 
ma ke a rec o m me n dati o n f or a n a d h o c f ull b oar d re vie w a n d / or pr ot oc ol s us pe nsi o n. I n a d diti o n, 
safet y data will be re vie we d b y t he D S M B w he n a n e ve nt occ urs t hat is of s ufficie nt c o ncer n t o 
t he NI AI D m e dical m o nit or or pr ot oc ol c o-c hairs t o warra nt re vie w, or w he n a n e ve nt occ urs t hat 
c o ul d c o ntri b ute t o a st o p pi n g r ule.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 4 9  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 2.   
C H A N G E S T O T H E A N A L Y S E S P L A N N E D I N T H E P R O T O C O L  
1.  T he pr ot oc ol s pecifies t hat t he a nal ysis of pri mar y a n d sec o n dar y e n d p oi nt s will be e val uate d 
i n de pe n de ntl y wit hi n eac h ar m ( defi ne d b y a ge, c o h ort, vacci ne, a n d I S treat me nt pla n) a n d 
c o n d ucte d i n ( 1) all parti ci pa nts wit h a R oc he Elecs ys ® A nti -S A R S -C o V -2 S res ult ≤2 0 0 
U/ m L at t he Scree ni n g visit, a n d ( 2) i n t he s u b gr o u p of partici pa nts wit h a R oc he Elecs ys ® 
A nti -S A R S -C o V -2 S res ult ≤5 0 U/ m L at t he Scree ni n g visit . Eac h a nal ysis of t he pri mar y 
e n d p oi nt will occ ur aft er t he e val ua ble p artici pa nts assi g ne d t o t hat ar m a n d s u b gr o u p ha ve 
c o m plete d t he Wee k 4 st u d y visit or are wit h dra w n fr o m t he st u d y.   F or t he p ur p oses of t his 
d oc u me nt, we refer t o a n al yses at t his ti me p oi nt as preli mi nar y, a n d a fi nal a nal ysis will 
occ ur o nce all partici pa nts ha ve c o m plete d or wit h dra w n fr o m t he st u d y.   
If at t he p oi nt of eac h preli mi nar y a nal ysis, a defi niti o n of a pr otecti ve a nti b o d y res p o nse 
usi n g a la b orat or y -d efi ne d t hres h ol d f or res p o nses wit hi n t he NI AI D -V R C M S D 3  ple x assay  
is u na vaila ble, t he pri mar y a nal ysis of pri mar y a n d sec o n dar y e n d p oi nts will n ot be 
perf or me d, a n d o nl y t he sec o n dar y a nal ysis t o  s u m marize a nti b o d y res p o nse o n a c o nti n u o us 
scale usi n g descri pti ve statistics will be perf or me d. 
2.  Pr ot oc ol Secti o n 1 3. 4. 4, A n alyses of Sec o n d ary a n d Ot her E n d p oi nt(s) , n otes “T he i nci de n ce 
of ser oc o n v ersi o n f oll o wi n g a d diti o nal vacci ne d oses of C O VI D -1 9 vacci ne will be 
e val uate d i n t he s u b gr o u ps of partici pa nts t hat are a nti -C O VI D -1 9 a nti b o d y ne gati ve at 
baseli ne usi n g se paratel y, (a) NI AI D -V R C M S D 3 ple x ( W u -1 f ull -le n gt h s pi ke, R B D, a n d 
N ) assa y  wit h t hres h ol ds < 1 2 0 4. 7  a n d 5 1 7. 9  pr otei ns  A U/ m L, res pecti vel y, a n d ( b) t he 
R oc he Elecs ys ® A nti -S A R S -C o V -2 S electr oc h e mil u mi nesce nce  i m m u n oassa y wit h a 
t hres h ol d < 0. 8 0 U/ m L.” Ser oc o n versi o n will n ot be assesse d usi n g t he N pr otei ns test as it is 
a meas ure of nat ur al i nfecti o n rat her t ha n vacci n e res p o nse.  
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 0  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 3.   
R E F E R E N C E S  
N A.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 1  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 4.   
A P P E N DI X  
1 4. 1.   
St u d y Fl o w C h art  
Fi g ure 1 . P artici p a nt Fl o w Di a gr a m f or A d ult St a ge 1 
 
I S = i m m u n os u p pressi v e me dicati o ns; M M F = m yc o p he n olate m ofetil; M P A = m yc o p he n olic aci d; M S = m ulti ple scler osis; 
M T X =  met h otre xate; R A  = r he u mat oi d art hritis; S L E = s yste mic l u p us er yt h e mat os us; S Sc = s yste mic scler osis  
Fi g ure 2 .  Stu d y Fl o w f or A d ult St a ge 1  
 
I S = i m m u n os u p pressi v e me dicati o n 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
Fi g ure 3.  P artici p a nt Fl o w Di a gr a m f or A d ult St a ge 2  
 
I S = i m m u n os u p pressi v e me dicati o ns; M M F = m yc o p he n olate m ofetil; M P A = m yc o p he n olic aci d; M S = m ulti ple scler osis; 
M T X =  met h otre xate; R A  = r he u mat oi d art hritis; S L E = s yste mic l u p us er yt h e mat os us; S Sc = s yste mic scler osis  
Fi g ure 4.  St u d y Fl o w f or A d ult St a ge 2  
 
I S = i m m u n os u p pressi v e; M M F = m yc o p he n olate m ofetil; M P A = m yc o p he n olic aci d 
* A d diti o nal h o m ol o g o us vacci n e d os e is defi n e d as a t hir d d ose of t h e Pfizer -Bi o N Tec h C O VI D -1 9 Vacci n e or M o der na 
C O VI D -1 9 Vacci n e, or a sec o n d d ose of t h e Ja nsse n C O VI D -1 9 Vacci n e.  
¥ Pfizer -Bi o N Tec h C O VI D -1 9 Vacci n e or M o der na C O VI D -1 9 Vacci n e, w hic he ver was n ot recei ve d f or t he i nitial r e gi me n a n d 
a d diti o nal h o m ol o g o us d ose.  
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
Fi g ure 5. P artici p a nt Fl o w Di a gr a m f or Pe di atric P artici p a nts  
I S = i m m u n os u p pressi v e me dicati o ns; J D M = j u ve nile der mat o m y ositis; JI A = j u ve nile i di o pat hic art hritis; P O M S = pe diatric-
o nset m ulti ple scler osis; M M F =  m yc o p he n olate m ofetil; M P A = m yc o p he n olic aci d; M T X =  met h otre xate; S L E = s yste mic 
l u p us er yt he mat os us 
Fi g ure 6. St u d y Fl o w Di a gr a m f or Pe di atric P artici p a nts  
 
I S = i m m u n os u p pressi v e me dicati o n 
* Treat me nt ar m will be o pe ne d f or e nr oll me nt w he n a ut h orizati o n or a p pr o val of t hese vacci n es is gra nte d f or t he pe diatric 
p o p ulati o n(s).  
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 4  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 4. 2.   
Sc he d ule of E ve nts  
See pr ot oc ol Secti o n 2 0. 1, Sc he d ules of Eve nts , f or m ore details.  


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 5 5  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
1 5.   
A T T A C H M E N T S  
N A.  




T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
Di nes h K ha n na, M B B S, M S C  
Pr ot oc ol C o -C hair  
A mit Bar -Or, M D, F R C P C  
Pr ot oc ol C o -C hair  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
Vir gi ni a P asc u al, M D  
Pr ot oc ol C o -C h air  
St ac y Ar d oi n, M D  
Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
N at as h a Mc k err a n R ut h, M D  
Pr ot oc ol C o -C h air  
Tr ac e y Wri g ht, M D  
Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 






Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
J u dit h J a m e s
J u dit h- J a m e s @ o mrf. or g
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
0 1 C 3 1 3 7 1- 4 8 0 8- 4 E 7 1- A 4 2 C- A 9 A 2 B 9 E 2 A 8 0 2
U si n g I P A d dr e s s: 1 5 6. 1 1 0. 1 4 5. 2 4 6
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 4 P M
Vi e w e d: 3/ 1 6/ 2 0 2 2 2: 1 3: 0 4 P M 
Si g n e d: 3/ 1 6/ 2 0 2 2 2: 1 4: 2 4 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 3/ 1 6/ 2 0 2 2 2: 1 3: 0 4 P M
      I D: 8 e 4 5 6 8 ef- 9 0 b 4- 4 6 2 d- 8 c c 7- 0 0 c 5 b 9 3 a d 4f 8
M e g g a n M a c k a y
m m a c k a y @ n ort h w ell. e d u
M D
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
2 4 6 4 E 5 A F- B C 9 5- 4 4 2 3- A 6 8 E- 6 3 3 7 D 9 4 6 8 9 E 5
U si n g I P A d dr e s s: 6 9. 2 7. 2 2 9. 1 3 0
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 4 P M
R e s e nt: 3/ 1 7/ 2 0 2 2 1 2: 3 5: 0 7 P M
Vi e w e d: 3/ 1 7/ 2 0 2 2 1 2: 4 5: 0 0 P M 
Si g n e d: 3/ 1 7/ 2 0 2 2 1 2: 4 5: 4 5 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 1 2/ 3/ 2 0 2 1 1 0: 2 8: 5 5 A M
      I D: a 9f 3ff 0 3- 0 3 1 d- 4ff 7- 9 3 0 e- d 6 3 9 2 7 8 d 3 0 1f
N at a s h a M c k err a n R ut h
r ut h n @ m u s c. e d u
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
C D E 7 1 C E B- 7 6 7 6- 4 A B 4- B D 2 3- A F 4 4 0 A 9 C E C 2 E
U si n g I P A d dr e s s: 7 6. 2 3. 1 2 5. 2 3 6
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 5 P M
Vi e w e d: 3/ 1 6/ 2 0 2 2 1: 4 2: 2 0 P M 
Si g n e d: 3/ 1 6/ 2 0 2 2 1: 4 3: 0 2 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 3/ 1 6/ 2 0 2 2 1: 4 2: 2 0 P M
      I D: e 7 9 9f 9 0 7- e d c 7- 4f b 5- a 1 2 3- 9 d 9 7 4 d 4 c 4 6 8 c


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
St a c y Ar d oi n
st a c y. ar d oi n @ n ati o n wi d e c hil dr e n s. or g
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
6 6 9 5 E 7 A 3- F 9 2 C- 4 B 1 6- 9 4 D A- 1 B F C 1 4 F 9 8 F 6 8
U si n g I P A d dr e s s: 6 9. 2 4. 1 4 4. 1 8
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 5 P M
R e s e nt: 3/ 1 7/ 2 0 2 2 1 2: 3 5: 0 7 P M
Vi e w e d: 3/ 2 0/ 2 0 2 2 1 2: 2 4: 0 2 P M 
Si g n e d: 3/ 2 0/ 2 0 2 2 1 2: 2 4: 5 0 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 3/ 2 0/ 2 0 2 2 1 2: 2 4: 0 2 P M
      I D: 1 e 8 1 a c 1 d- 6 9 6 5- 4 b 2 1- a 9 9 7- a 3 3 0 0 d 5 a 3f 9 d
Tr a c e y B. Wri g ht, M D
tr a c e y. wri g ht @ ut s o ut h w e st er n. e d u
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
7 E F C 6 8 2 3- A 1 3 9- 4 1 D C- A 7 9 C- 3 4 B 2 4 E 6 2 E F E 5
U si n g I P A d dr e s s: 1 2 9. 1 1 2. 1 0 9. 5 3
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 6 P M
Vi e w e d: 3/ 1 6/ 2 0 2 2 1: 1 2: 0 8 P M 
Si g n e d: 3/ 1 6/ 2 0 2 2 1: 1 3: 4 5 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 3/ 1 6/ 2 0 2 2 1: 1 2: 0 8 P M
      I D: d 9 1 b 8 6 2 2- a 0 8f- 4f 7 6- 9 2 8 0- e 7 8 d 8 d 6 4 2f 2 8
Vir gi ni a P a s c u al
vi p 2 0 2 1 @ m e d. c or n ell. e d u
M D
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
6 0 0 7 4 5 2 4- 1 B 5 9- 4 6 7 B- 8 2 E D- 5 E D 4 7 F 2 1 4 D 2 D
U si n g I P A d dr e s s: 9 6. 2 2 4. 2 4 4. 1 2 4
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 6 P M
Vi e w e d: 3/ 1 6/ 2 0 2 2 1 2: 2 3: 0 0 P M 
Si g n e d: 3/ 1 6/ 2 0 2 2 1 2: 2 3: 5 6 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 3/ 1 6/ 2 0 2 2 1 2: 2 3: 0 0 P M
      I D: e e 9 9 b 2 af- 8 9 7 7- 4 2f 1- 8 2 2 8- a d eff b 1 c a 9 5 e
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p


I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
3/ 1 6/ 2 0 2 2 1 2: 2 1: 1 6 P M
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
3/ 1 6/ 2 0 2 2 1 2: 2 3: 0 0 P M
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
3/ 1 6/ 2 0 2 2 1 2: 2 3: 5 6 P M
C o m pl et e d
S e c urit y C h e c k e d
9/ 2 3/ 2 0 2 2 3: 4 5: 2 6 P M
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e


E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, R h o, I n c. ( we, us or C o m pa n y) ma y b e re q uire d b y la w t o pr o vi de t o y o u 
certai n writte n n otices or discl os ures. Descri be d bel o w are t he ter ms a n d c o n diti o ns f or pr o vi di n g 
t o y o u s uc h n otices a n d discl os ures electr o ni call y t hr o u g h t h e D oc uSi g n s yste m. Please rea d t he 
i nf or mati o n bel o w caref ull y a n d t h or o u g hl y, a n d if y o u ca n access t his i nf or mati o n electr o nicall y 
t o y o ur satisfacti o n a n d a gree t o t his Electr o nic Rec or d a n d Si g nat ure Discl os ure ( E R S D), pleas e 
c o nfir m y o ur a gree m e nt b y select i n g t h e c hec k-b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d 
si g nat ur es’ bef ore clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yste m.  
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of a n y rec or d pr o vi de d or ma de a v aila ble 
electr o nic all y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n acc o u nt, y o u ma y access t he d oc u me nts f or a li mi te d peri o d of ti me 
( us uall y 3 0 d a ys) after s uc h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fr o m o ur office t o y o u, y o u will be c har ge d a 
$ 0. 0 0  per -pa ge fee. Y o u ma y re q uest deli ver y o f s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w.  
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t hat t hereafter y o u wa nt t o recei v e  re q uire d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nicall y is des cri be d bel o w.  
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u elect t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tra nsacti o ns wit h y o u a n d deli veri n g s er vices t o 
y o u beca use we will nee d first t o  se n d t he re q uire d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u Si g n s yste m t o 
receiv e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   


U nless y o u tell us ot her wise i n acc or da nce wit h t he pr oce d ures des cri be d h erei n, we will p r o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d uri n g t he c o urse of o ur relati o ns hi p wit h y o u. T o r e d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei ve all t he discl os ur es a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he para gra p h i m me diatel y a b o ve t hat des cri bes t he 
c o nse q ue nces of y o ur e lecti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us.  
 
H o w t o c o nt act  
  
 ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fr o m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges 
 
 
T o a d vise   
. of y o ur ne w e m ail a d dress   
T o let us k n o w of a c h a n ge i n y o ur e ma il a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa ge t o us at  
 a n d i n t he 
b o d y of s uc h re q u est y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail a d dress.  We 
d o n ot re q u ire a n y ot h er i nf or mati o n fr o m y o u t o c ha n ge y o ur e m ail a d dress.  
If y o u create d a D oc u Si g n acc o u nt, y o u ma y u p d ate it wit h y o ur ne w e mail a d dress t hr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest p a per c o pies fr o m 
  
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u electr o nicall y, y o u m ust se n d us a n e mail t o
 a n d i n t he b o d y 
of s uc h re q u est y o u m ust state y o ur e mail a d dress, f ull na me, maili n g a d dress, a n d tele p h o ne 
n u m ber . We will bill y o u f or a n y fees at t hat ti me, if a n y.  
 
T o wit h dr a w y o ur c o nse nt wit h  
  
T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 


i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k-b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y;  
ii. se n d us a n e mail t o
 a n d i n t he b o d y of s uc h re q uest y o u m ust state 
y o ur e mail, f ull na me, m aili n g a d dress, a n d tele p h o ne n u m ber. We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h dra w c o nse nt..  T he c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr ocess..  
 
Re q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s yste m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me. T he 
c urre nt s yste m re q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui des/si g ner -g ui de -
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will be si milar t o 
ot her electr o nic n otices  a n d discl os ures t hat we will pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve 
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t hat y o u are a ble t o e mail t his E R S D t o a n  e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o ur f ut ure refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k -b o x ne xt t o ‘I  a gree t o use electr o ni c rec or ds a n d si g nat ures’ bef ore 
clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yst e m.  
B y selecti n g t he c hec k -b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ures’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d  
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y   
. as descri be d a b o ve, y o u c o ns e nt t o recei ve 
e x cl usi vel y t hr o u g h electr o nic mea ns all n otices, discl os ures, a ut h orizati o ns, 
ac k n o wle d ge me nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u b y   
 d uri n g t he c o urse of y o ur relati o ns hi p wit h 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 2  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
 
 
A C K N O W L E D G E M E N T  A N D SI G N A T U R E S H E E T  
 
 
A p pr o ve d:  
A p pr o ve d:  
 
 
 
 
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
A p pr o ve d:  
A p pr o ve d:  
  
 
   
 
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
A p pr o ve d:  
A p pr o ve d:  
J u dit h Ja mes, M D, P h D 
Pr ot oc ol C o -C hair  
Me g ga n Mac k a y, M D, M S  
Pr ot oc ol C o -C hair  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
 


T he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases ( NI AI D)  
Statistical A nal ysis Pla n - Pr ot oc ol A C V 0 1  
Pa ge 3  of 5 5  
Versi o n Date: 2 0 2 2 -0 3 -1 6  
Versi o n: 1. 0   
D oc u m e nt C o ntr ol N o.: T M P -S A -0 0 8 -0 1  
T e m pl at e Eff ectiv e D at e: 2 3 M ar 2 0 2 1  
 
 
 
A p pr o ve d:  
A p pr o ve d:  
Di nes h K ha n na, M B B S, M S C  
Pr ot oc ol C o -C hair  
A mit Bar -Or, M D, F R C P C  
Pr ot oc ol C o -C hair  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
Vir gi ni a P asc u al, M D  
Pr ot oc ol C o -C h air  
St ac y Ar d oi n, M D  
Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
A p pr o ve d:  
A p pr o ve d:  
N at as h a Mc k err a n R ut h, M D  
Pr ot oc ol C o -C h air  
Tr ac e y Wri g ht, M D  
Pr ot oc ol C o -C h air  
Si g nat ure a n d Date  
Si g nat ure a n d Date  
 
 
 
 
M ar c h 1 6 2 0 2 2 

Prot_001.pdf: 




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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the 
Division of Allergy, Immunology, and Transplantation, National Insitutute of Allergy and Infectious Diseases, National 
Institutes of Health. 
 
 
 
 




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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Version History 
Protocol 
Version 
Protocol 
Date 
Summary of Revisions 
1.0 
09Jul2021 
Initial version 
2.0 
06Dec2021 
• 
Administrative updates, expansion of Elecsys® Anti-SARS-CoV-2 S specimen collection to Weeks 12 – 
48/Early Termination.  
• 
Extension of entry criteria time limits to account for expanded enrollment period. 
• 
Vaccine risks updated to match current EUA factsheets for healthcare providers.  
• 
Additional information added regarding the collection of solicited adverse events.  
3.0 
04Jan2022 
• 
Addition of adult Stage 2 (with heterologous additional vaccine dose) and pediatric population (with 
homologous additional vaccine dose).  
• 
Elecsys® Anti-SARS-CoV-2 S entry criterion increased from a result ≤ 50 U/mL to 200 U/mL for adult 
stage 1, adult Stage 2, and pediatric study eligibility. Treatment arm sample size increased to 
60/treatment arm in response to this change.  
• 
Vaccine risks updated to match current EUA factsheets for healthcare providers.  
• 
Closure of Janssen COVID-19 vaccine treatment arms in adult Stage 1.  
• 
Prohibited medications section updated to include guidance for use of monoclonal antibodies for 
pre-exposure prophylaxis.  
4.0 
29Jul2022 
• 
Administrative updates 
• 
Pediatric Updates 
o 
Removal of MMT8 from pediatric schedule of events and Section 8. 
o 
Note added to Exclusion #10:  
 
 Note: Participants on IVIG therapeutically may enter the study provided they 
have sufficiently quiet disease that they can withhold their IVIG from 8 weeks 
prior to the Screening visit through 4 weeks after vaccination. 
• 
Expansion of adult Stage 2 criteria to allow participants who have received more than 3 doses of the 
same mRNA vaccine and a mixture of mRNA vaccine doses to enter the study. 
• 
Addition of the Sanofi-GSK protein-based COVID-19 Vaccine to the list of available vaccine options 
for adult Stage 2 (with associated background, risks, investigational agent, and safety information). 
• 
Removal of Janssen as an alternative dose option for adult Stage 2.  
• 
Study design revised to allow participants who received an alternative mRNA vaccine dose and have 
a Roche Elecsys result ≤200 U/mL at a post-Baseline visit to re-enter Stage 2 and restart the Stage 2 
schedule of events. 
• 
Vaccine formulation information updated to reflect the current EUA factsheets and FDA Approvals. 
• 
Section 7.3, Prohibited Medications, updated to separate COVID-19 vaccine and other vaccine 
guidance.  
5.0 
19Aug2022 
• 
Administrative updates 
• 
Updates to both pediatric and adult populations: 
o 
Revisions to entry criteria, study risks, vaccine eligibility criteria, safety events, and study 
stopping rules, and related to pericarditis/myocarditis. 
o 
Revisions to vaccine formulation information to match current EUAs/FDA approvals. 
• 
Pediatric Updates 
o 
Addition of pediatric Stage 2 (with heterologous additional vaccine dose) 
o 
Expansion of entry criteria to allow enrollment of 2-4 year olds.  
o 
Addition of Moderna COVID-19 vaccine investigational agent information for 2 -17 year 
olds and Pfizer COVID-19 vaccine investigational agent information for 2-4 year olds.  
o 
Removal of infectious disease testing (HIV, Hepatitis B, and Hepatitis C).  
6.0 
11Nov2022 
• 
Administrative updates 
• 
Protocol updated to note the closure of all Adult Stage 1 treatment arms on 15 August 2022.  
• 
Addition of Omicron bivalent vaccines for use as additional doses and discontinuation of use of 
monovalent vaccines where applicable. 
• 
Revisions to vaccine formulation information to match current EUAs/FDA approval. 
• 
Extension of Roche Elecsys entry criterion to include participants with a low vaccine response. 
• 
Extension of treatment arm sample size from 60 participants per treatment arm to 80 participants 
per treatment arm.  
7.0 
13Dec2022 
• 
Addition of Omicron bivalent vaccine for use in young pediatric participants and discontinuation of 
use of monovalent vaccines.  


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Protocol Synopsis 
Title 
Booster effects with autoimmune treatments in patients with poor response 
to initial COVID-19 vaccine  
Short Title 
COVID-19 BOOSTER VACCINE IN AUTOIMMUNE DISEASE NON-
RESPONDERS 
Clinical Phase 
II 
Number of Sites 
Adult population: 15 – 20 sites in the United States (US). 
Pediatric population: 15 – 20 sites in the US. 
IND Sponsor/Number   
The National Institute of Allergy and Infectious Diseases (NIAID) / IND #27528      
Study Objectives 
Hypotheses 
• 
We hypothesize that adult and pediatric participants with 
autoimmune diseases requiring immunosuppressive (IS) medications 
who have had a suboptimal response (defined as a Roche Elecsys® 
Anti-SARS-CoV-2 S result ≤200 U/mL) to an initial COVID-19 vaccine 
regimen may demonstrate enhanced immune response after receiving 
an additional homologous dose of an mRNA or vector-based vaccine.  
• 
We hypothesize that pediatric participants with autoimmune diseases 
requiring IS medications who have a low immune response (defined as 
a Roche Elecsys® Anti-SARS-CoV-2 S result >200 U/ml and ≤2500 
U/mL) after an initial COVID-19 vaccine regimen may demonstrate 
enhanced immune response after receiving an additional dose of an 
additional homologous COVID-19 vaccine.  
• 
We hypothesize that adult and pediatric participants with transient 
cessation of mycophenolate mofetil (MMF)/ mycophenolic acid (MPA) 
or methotrexate (MTX) before and after vaccination will have an 
enhanced immune response. 
• 
We hypothesize that adult and pediatric participants with 
autoimmune diseases requiring IS medications who continue to have a 
suboptimal response after an initial COVID-19 vaccine regimen plus 
additional vaccine doses may demonstrate enhanced immune 
response after receiving an additional dose of an alternative COVID-19 
vaccine. 
• 
We hypothesize that adult and pediatric participants with 
autoimmune diseases requiring IS medications who have a low 
immune response after an initial COVID-19 vaccine regimen plus 
additional vaccine doses may demonstrate enhanced immune 
response after receiving an additional dose of an alternative COVID-19 
vaccine. 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Primary Objective 
The primary objective is to determine the proportions of adult and pediatric 
participants who have a protective antibody response at 4 weeks after an 
additional homologous dose of a COVID-19 vaccine using the NIAID Vaccine 
Research Center (NIAID-VRC) MSD 3 plex (Wu-1 full-length spike, RBD, and N 
proteins) assay within arms defined by the initial COVID-19 vaccine regimen 
received, IS regimens, and treatment plans to either withhold or continue 
medications around the time of vaccination. 
Secondary Objectives 
Stage 1 Secondary Objectives (adult and pediatric):  
• 
To determine the incidence of seroconversion following an additional 
homologous COVID-19 vaccine dose in the subgroup of participants 
that are anti-COVID-19 antibody negative at Baseline. 
• 
To assess the immune response following an additional homologous 
COVID-19 vaccine dose in the subgroup of participants that had a low 
immune response following a previous COVID-19 vaccine dose. 
• 
To determine the incidence of adverse events (AEs), including 
medically attended adverse events (MAAEs), new onset chronic 
medical conditions (NOCMCs), and serious adverse events (SAEs) 
following an additional homologous COVID-19 vaccine dose. 
• 
To assess whether responses to an additional homologous COVID-19 
vaccine dose differ with temporary cessation of IS medications around 
the time of vaccine. 
• 
To assess whether responses to an additional homologous COVID-19 
vaccine dose differ by type of vaccine administered.  
• 
To assess whether responses to an additional homologous COVID-19 
vaccine dose differ by type of cohort-defining IS medications and by 
disease type. 
• 
To assess whether response to an additional homologous COVID-19 
vaccine dose is associated with corticosteroid dose at the time of 
vaccination.  
• 
To assess whether response to an additional homologous COVID-19 
vaccine dose is associated with clinical parameters including disease 
activity, co-morbid illness, age, and sex. 
• 
To determine whether disease activity is increased following an 
additional homologous COVID-19 vaccine dose, and if so, whether 
Baseline or induced immunologic variables are associated with 
increased disease activity and/or vaccination response. 
Stage 2 Secondary Objectives (adult and pediatric): 
• 
To determine the proportions of participants with a negative serologic 
or suboptimal response to a previous COVID-19 vaccine administration 
who develop a protective antibody response after receiving a 
subsequent alternative vaccine dose, evaluated using the NIAID-VRC 
MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay. 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
• 
To assess the immune response following a subsequent alternative 
vaccine dose in the subgroup of participants that had a low immune 
response following a previous COVID-19 vaccine dose. 
• 
To determine the incidence of seroconversion following a subsequent 
alternative vaccine dose in the subgroup of participants that are anti-
COVID-19 antibody negative following a previous COVID-19 vaccine 
dose. 
• 
To determine the incidence of AEs, including MAAEs, NOCMCs, and 
SAEs following a subsequent alternative COVID-19 vaccine dose. 
• 
To assess whether responses to a subsequent alternative COVID-19 
vaccine dose differ by type of vaccine administered.  
• 
To assess whether responses to a subsequent alternative COVID-19 
vaccine dose differ by type of cohort-defining IS medications and by 
disease type. 
• 
To assess whether response to a subsequent alternative COVID-19 
vaccine dose is associated with corticosteroid dose at the time of 
vaccination.  
• 
To assess whether response to a subsequent alternative COVID-19 
vaccine dose is associated with clinical parameters including disease 
activity, co-morbid illness, age, and sex. 
• 
To determine whether disease activity is increased following a 
subsequent alternative COVID-19 vaccine dose, and if so, whether 
immunologic variables are associated with increased disease activity 
and/or vaccination response. 
Exploratory Objectives (adult and pediatric) 
• 
To evaluate whether Baseline CD19 positive B cell numbers associate 
with response to an additional study COVID-19 vaccine dose in the 
cohort that have received B cell depletion therapy (BCDT).  
• 
To evaluate the association between immune response and levels of 
SARS-CoV-2 antibodies at Baseline. 
• 
To evaluate the levels of Baseline interferon signal or interferon 
gamma-inducible protein 10 (IP-10) serum levels that associate with 
an effective vaccine response. 
• 
To evaluate the levels of Baseline inflammatory signals that associate 
with an effective vaccine immune response. 
• 
To evaluate the association between immune response to an 
additional study COVID-19 vaccine dose and cellular and mechanistic 
endpoints. 
Study Design 
This is a randomized, multi-site, adaptive, open-label clinical trial comparing 
the immune response to different additional doses of COVID-19 vaccine in 
participants with autoimmune disease requiring IS medications. All study 
participants will have negative serologic or suboptimal responses (defined as a 
Roche Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL) or a low immune 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
response (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result >200 U/ml and 
≤2500 U/mL) to their previous doses of COVID-19 vaccine.  
Adult Population 
Adult Stage 1: 
Stage 1 of this trial will enroll up to a maximum of 900 adult study participants 
(up to 60 participants per arm). The trial initially focused on adults with at 
least 1 of 5 autoimmune diseases: systemic lupus erythematosus (SLE), 
rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc), and 
pemphigus.  
Participants will be assigned to one of 3 cohorts based on their IS regimens: 
• 
Cohort A: Receipt of MMF or MPA  
• 
Cohort B: Receipt of MTX 
• 
Cohort C:  Receipt of any BCDT within the past 18 months. 
Treatment Arms:  Participants in Cohorts A, B, and C will be assigned to receive 
an additional dose of the same COVID-19 vaccine as their original vaccine 
series. The trial initially enrolled participants who were vaccinated with the 
Pfizer-BioNTech COVID-19 Vaccine, the Moderna COVID-19 Vaccine, and the 
Janssen COVID-19 Vaccine.  
Update:  Arms to receive an additional homologous vaccine dose after an 
initial Janssen COVID 19 Vaccine were closed to enrollment after the CDC 
updated its recommendations to express a clinical preference for individuals 
to receive an mRNA COVID-19 vaccine over the Janssen COVID-19 vaccine. All 
Adult Stage 1 treatment arms were closed to enrollment on 15 August 2022. 
Participants in Cohorts A and B will be randomized into 2 IS medication 
treatment plans as follows: 
• 
Participants continue to take their cohort-defining IS medications 
without alterations in schedule and dosing.  
• 
Participants withhold their cohort-defining IS medications before and 
after the additional homologous vaccine dose per protocol 
instructions. 
Schedule of Events:   Visits to assess endpoints will occur at Baseline (Week 0), 
Week 4 ± 1 week, Week 12 ± 2 weeks, Week 24 ± 2 weeks, Week 36 ± 2 weeks, 
and Week 48 ± 2 weeks. A participant will be enrolled in the study for a 
maximum of approximately 13 months. 
Adult Stage 2:  
Stage 2 of this trial will include up to a maximum of 960 adult study 
participants (up to 80 per arm) with a Roche Elecsys® Anti-SARS-CoV-2 S result 
≤2500 U/mL after previous COVID-19 vaccine administration (at least 3 doses 
of mRNA vaccine(s) or 2 doses of the Janssen COVID-19 Vaccine). Participants 
will be eligible to receive a dose of an alternative COVID-19 vaccine.  
Participants may have received their previous COVID-19 vaccine prior to 
enrollment in the study (“newly recruited participant”), or they may have 
received their previous COVID-19 vaccine as a study participant and then (re-) 
enter into Stage 2 (“rollover participant”). 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Participants can also roll over into Stage 2 via two pathways: 
• 
Stage 1 participant rolls over to Stage 2 
• 
Stage 2 participant rolls over to a different Stage 2 treatment arm 
Participants will be allocated to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort D: Receipt of MMF or MPA  
• 
Cohort E: Receipt of MTX 
• 
Cohort F:  Receipt of any BCDT within the past 18 months. 
Treatment Arms:  Participants in Cohorts D, E, and F will receive a dose of an 
alternative COVID-19 vaccine compared to their previous COVID-19 vaccine 
doses. Originally, participants who previously received 3 total doses of a single 
mRNA vaccine (Moderna COVID-19 Vaccine OR Pfizer-BioNTech COVID-19 
Vaccine) received their choice of either the Janssen vector-based COVID-19 
vaccine or the other mRNA COVID-19 vaccine, and participants who previously 
received 2 doses of the Janssen vector-based COVID-19 vaccine received the 
Moderna COVID-19 Vaccine.  
Update: Beginning with v4.0 of the protocol, this trial will not utilize the 
Janssen vector-based COVID-19 vaccine. Participants who previously received 
3 total doses of a single mRNA vaccine will receive their choice of an 
alternative mRNA COVID-19 vaccine or the Sanofi-GSK protein-based COVID-
19 vaccine. Participants who previously received 4 or more doses of a single 
mRNA vaccine or 3 or more doses of a mixture mRNA vaccines (Moderna 
COVID-19 Vaccine AND Pfizer-BioNTech COVID-19 Vaccine, in any order or 
combination) will receive the Sanofi-GSK protein-based COVID-19 vaccine. 
Beginning with v6.0 of the protocol, bivalent versions of the mRNA vaccines, 
Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original 
monovalent versions.  
Participants in Cohorts D and E will withhold their cohort-defining IS 
medications before and after the alternative vaccine dose per protocol 
instructions. Participants in Cohort F who are taking MMF, MPA, or MTX in 
addition to BCDTs will withhold these medications before and after the 
alternative vaccine dose per protocol instructions. 
Schedule of Events:  Visits to assess endpoints will occur at Baseline (Week 0), 
Week 4 ± 1 week, Week 12 ± 2 weeks, Week 24 ± 2 weeks, Week 36 ± 2 weeks, 
and Week 48 ± 2 weeks. A participant who is newly recruited to the study for 
entry into Stage 2 may be on study for up to a maximum of 13 months. A 
participant who enters Stage 2 after a serologic negative, suboptimal, or low 
immune response to their Stage 1 vaccine dose may be on study for up to a 
maximum of 26 months. Rollover participants will discontinue follow-up as 
part of Stage 1 upon rollover into Stage 2. A participant who rolls over to a 
different Stage 2 treatment arm 2 after a serologic negative, suboptimal, or 
low immune response to another Stage 2 vaccine dose may be on study for up 
to a maximum of 38 months. 
Pediatric Population 
Pediatric Stage 1: 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
The pediatric portion of this trial will enroll up to a maximum of 800 
participants (2-17 years of age) with a Roche Elecsys® Anti-SARS-CoV-2 S result 
≤2500 U/mL after receiving an initial COVID-19 vaccine regimen (up to 80 
participants per arm). Vaccines will be included in this protocol as they receive 
EUA or approval by FDA for a given age group. Pediatric participants will have 
1 of 4 autoimmune diseases: pediatric SLE, juvenile idiopathic arthritis (JIA), 
juvenile dermatomyositis (JDM), or pediatric-onset multiple sclerosis (POMS). 
Participants will be assigned to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort A: Receipt of MMF or MPA  
• 
Cohort B: Receipt of MTX 
• 
Cohort C:  Receipt of any BCDT within the past 18 months. 
Treatment Arms:  Participants in Cohorts A, B, and C will be assigned to receive 
an additional dose of the same vaccine as their original vaccine series. Based 
on FDA EUA status, pediatric participants were initially eligible to receive the 
Pfizer-BioNTech COVID-19 Vaccine only. 
Update:  Beginning with v6.0 of the protocol, bivalent versions of the mRNA 
vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original 
monovalent versions. 
Participants in Cohorts A and B will be randomized into 2 IS medication 
treatment plans as follows):  
• 
Participants continue to take their cohort-defining IS medications 
without alterations in schedule and dosing.  
• 
Participants withhold their cohort-defining IS medications before and 
after the additional homologous vaccine dose per protocol 
instructions. 
Schedule of Events:  Visits to assess endpoints will occur at Baseline (Week 0), 
Week 4 ± 1 week, Week 12 ± 2 weeks, Week 24 ± 2 weeks, Week 36 ± 2 weeks, 
and Week 48 ± 2 weeks. A participant will be enrolled in the study for a 
maximum of approximately 13 months.  
Pediatric Stage 2: 
Stage 2 of this trial will include up to a maximum of 480 pediatric study 
participants (up to 80 per arm) with a Roche Elecsys® Anti-SARS-CoV-2 S result 
≤2500 U/mL after previous COVID-19 vaccine administration (an age-
appropriate EUA-authorized or FDA-approved initial COVID-19 vaccine 
regimen plus 1 additional dose of the same vaccine as shown in Table 8). All 
participants (2-17 years of age) who previously received doses of the Pfizer-
BioNTech COVID-19 Vaccine are eligible to receive an age-appropriate dose of 
the Moderna COVID-19 Vaccine. Participants 12 through 17 years of age who 
previously received doses of the Moderna COVID-19 vaccine are eligible to 
receive an age-appropriate dose of the Pfizer-BioNTech COVID-19 Vaccine.  
Participants will be eligible to receive a dose of an alternative COVID-19 
vaccine. Participants may have received their previous COVID-19 vaccine as a 
study participant and then enter into Stage 2 (“rollover participant”), or they 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
may have received their previous COVID-19 vaccine prior to enrollment in the 
study (“newly recruited participant”). 
Participants will be allocated to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort D: Receipt of MMF or MPA (± other rheumatic disease 
medications, including biologics) 
o Participants who are taking MMF or MPA (without additional 
B cell depleting medications or MTX) will be placed in this 
cohort.  
• 
Cohort E: Receipt of MTX (± other rheumatic disease medications, 
including biologics) 
o Participants who are taking MTX (without additional B cell 
depleting medications or MMF/ MPA) will be placed in this 
cohort.  
• 
Cohort F: Receipt of B cell depletion therapy within the past 18 
months (± other rheumatic disease medications) 
o Participants taking B cell depletion medications, regardless of 
whether they are also taking MMF or MTX, will be placed in 
this cohort. 
Treatment Arms: Participants in Cohorts D, E, and F will receive a dose of an 
alternative COVID-19 vaccine compared to their previous COVID-19 vaccine 
doses. Participants who previously received age-appropriate doses of a single 
mRNA vaccine (Moderna COVID-19 Vaccine OR Pfizer-BioNTech COVID-19 
Vaccine, as noted above) will receive the other mRNA COVID-19 vaccine. Table 
8 describes the age-appropriate qualifying COVID-19 vaccine regimen for 
participation in Pediatric Stage 2. 
Update:  Beginning with v6.0 of the protocol, bivalent versions of the mRNA 
vaccines, Moderna and Pfizer-BioNTech COVID-19 vaccines, replaced original 
monovalent versions. 
Participants in Cohorts D and E will withhold their cohort-defining IS 
medications before and after the alternative vaccine dose per protocol 
instructions (see Section 7.1.1 Protocol-mandated Medications).  
Participants in Cohort F who are taking MMF, MPA, or MTX in addition to B cell 
depletion therapies (BCDTs) will withhold these medications before and after 
the alternative vaccine dose per protocol instruction (see Section 7.1.1 
Protocol-mandated Medications).  
All potential treatment arms for Pediatric Stage 2 are detailed in Table 9. 
Schedule of Events: Visits to assess endpoints will occur at Baseline (Week 0), 
Week 4 ± 1 week, Week 12 ± 2 weeks, Week 24 ± 2 weeks, Week 36 ± 2 weeks, 
and Week 48 ± 2 weeks. Participant and study flow diagrams for Stage 2 are 
provided in Figure 7 and Figure 8, respectively.  
A participant who enters Stage 2 after a serologic negative, suboptimal, or low 
immune response to their Stage 1 vaccine dose may be on study for up to a 
maximum of 26 months. Rollover participants will discontinue follow-up as 
part of Stage 1 upon rollover into Stage 2. A participant who is newly recruited 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
to the study for entry into Stage 2 may be on study for up to a maximum of 13 
months. 
Adaptive Design 
An adaptive design will be employed such that cohorts and arms defined by 
additional vaccine doses and IS treatment plans may be added or modified 
based on emerging data from existing and new FDA Emergency Use 
Authorization (EUA) or approvals of COVID-19 vaccines: 
• 
New cohorts may be defined based on changes in the medication 
groups if it becomes obvious that certain medications are highly 
associated with suboptimal or low immune response to initial COVID-
19 vaccine regimen. 
• 
Cohorts may limit or expand the autoimmune diseases that are eligible 
to be included in the clinical trial, and may include expansion cohorts 
of underrepresented diseases.  
• 
New cohorts may include participants whose antibody response falls 
to suboptimal or low immune response levels over time. 
• 
Based upon timing of the FDA EUA authorization for children of each 
of the COVID-19 vaccines used in this trial, the age range of the 
inclusion criteria may be expanded. 
• 
Allocation or randomization to treatment with new COVID-19 vaccines 
may be incorporated into the design when the products become 
available. 
• 
Identification of additional strategies to enhance vaccine 
responsiveness in autoimmune diseases, including a temporary switch 
of immunomodulatory medications. 
Primary Endpoint 
The primary endpoint in the adult and pediatric populations of a protective 
antibody response at Week 4 will be assessed by the NIAID-VRC MSD 3 plex 
(Wu-1 full-length spike, RBD, and N proteins) assay. 
Secondary and Exploratory 
Endpoints  
Secondary Endpoints 
Secondary endpoints related to antibody response will primarily be assessed 
by the NIAID-VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) 
assay; where applicable, they will also be assessed by the Roche Elecsys® Anti-
SARS-CoV-2 S electrochemiluminescence immunoassay. 
The secondary endpoints are applicable to both the adult and pediatric 
populations. 
• 
Seroconversion at Week 4 following additional doses of COVID-19 
vaccine in the subgroup of participants that are anti-COVID-19 
antibody negative at Week 0. 
• 
Fold increase in anti-COVID-19 antibody levels at Week 4 following an 
additional dose of COVID-19 vaccine in the subgroup of participants 
who are anti-COVID-19 antibody positive at Week 0. 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
• 
Longitudinal changes in anti-COVID-19 antibody responses from Week 
0 to Weeks 4, 12, 24, 36, and 48.  
• 
Longitudinal changes in neutralization and pseudo neutralization 
assays from Week 0 to Weeks 4, 12, 24, 36, and 48. 
• 
Changes in disease activity after receipt of additional doses of COVID-
19 vaccine as measured by the Clinical Global Impression of Change 
(CGI-C). 
• 
Changes in disease activity after receipt of additional doses of COVID-
19 vaccine as measured by the Physician Global Assessment (PGA). 
• 
Changes in disease activity after receipt of additional doses of COVID-
19 vaccine as measured by the following disease-specific assessments: 
o Adult population disease assessments: 
o Hybrid Systemic Lupus Erythematosus Disease Activity 
Index (H-SLEDAI) and Thanou modified Safety of 
Estrogens in Lupus Erythematosus: National 
Assessment– Systemic Lupus Erythematosus Disease 
Activity Index (SELENA-SLEDAI) Flare Index for SLE 
o Disease Activity Score 28 using C-reactive protein 
(DAS28-CRP) for RA   
o Flare assessment for SSc (including patient reported 
flare assessment) 
o Pemphigus Disease Area Index (PDAI) for pemphigus 
o Physician-assessed relapse for MS 
o Pediatric population disease assessments: 
o JIA: 
 
JADAS10 for polyarthritis, enthesitis related to 
JIA, oligoarthritis, and psoriatic arthritis 
 
Psoriasis Area and Severity Index (PASI) for 
psoriatic arthritis 
o SLEDAI-2K and Childhood-onset SLE Criteria for Global 
Flare [1] for pediatric SLE 
o Childhood Myositis Assessment Scale (CMAS) and JDM 
Disease Activity Score (DAS) for JDM 
o Physician-assessed relapse for MS for POMS 
• 
Changes in patient-reported outcomes as measured by: 
o Participant-Reported Outcomes Measurement Information 
System (PROMIS) 29 (adults only) 
o Pediatric Quality of Life Inventory™ (PedsQL) (pediatrics only) 
o Patient Global Assessment (PtGA) 
o Patient Global Impression of Change (PGI-C) 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
• 
The proportion of participants who experience the following safety 
events: 
o Any Grade 1 or higher AEs related to the additional doses of 
COVID-19 vaccine  
o Any SAEs, MAAEs, NOCMCs 
o Any SARS-CoV-2 infection  
Exploratory Endpoints 
• 
Changes in autoantibody levels after COVID-19 vaccination between 
Week 0 and Weeks 4, 12, 24, 36, and 48. 
• 
Assessments of cellular and mechanistic response, including 
o Immune cell population profiling over time 
o Antigen-specific T cell responses 
o Antigen-specific memory B cell responses 
o Total IgG responses  
o B cell and T cell repertoire 
o Changes in gene expression profile modules  
o Plasma levels of soluble mediators  
Accrual Objective 
The Adult Stage 1 portion of this trial will enroll up to a maximum of 900 
participants. The Pediatric Stage 1 portion will enroll up to a maximum of 800 
participants. The Adult Stage 2 portion of the trial will enroll up to a maximum 
of 960 participants. The Pediatric Stage 2 portion will enroll up to a maximum 
of 480 participants.  
In Adult Stage 2 and Pediatric Stages 1 and 2, a total of 80 participants with a 
Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL randomized or allocated 
to each arm. In each arm, the number of participants with Roche Elecsys® 
Anti-SARS-CoV-2 S results ≤200 U/mL will be capped at 40 participants, and 
the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results 
>200 U/mL and ≤2500 U/mL will be capped at 40 participants. 
Study Duration 
Study duration for Adult Stage 1, Adult Stage 2 newly recruited, Pediatric Stage 
1, or Pediatric Stage 2 newly recruited participant: 13 months 
Study duration for Adult Stage 2 or Pediatric Stage 2 participant rolling over 
from Stage 1: maximum of 26 months 
Study duration for Adult Stage 2 participant re-entering Stage 2: maximum of 
38 months   
Treatment Description  
All participants will receive at least 1 dose of the following: 
• 
mRNA COVID-19 vaccine: Moderna OR 
• 
mRNA COVID-19 vaccine: Pfizer-BioNTech OR 
• 
vector-based COVID-19 vaccine: Janssen (Protocol v1.0-v3.0) 
• 
protein-based COVID-19 vaccine: Sanofi-GSK (Adult Stage 2 only) 


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Participants who qualify may rollover from Stage 1 to Stage 2 to receive an 
alternative vaccine dose. Adult participants who qualify may re-enter Stage 2 
to receive the protein-based COVID-19 vaccine (Sanofi-GSK). 
Inclusion/Exclusion Criteria 
– Adult Stage 1 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible for 
randomization/allocation as study participants in Adult Stage 1:  
1. Individuals 18 years of age or older that meet classification criteria for SLE, 
SSc, RA, MS, or pemphigus. 
2. Participants must meet the 2019 ACR/EULAR[2] or 2012 SLICC 
classification criteria for SLE [3], the 2010 ACR/EULAR classification criteria 
for RA [4],  the 2013 EULAR/ACR classification criteria for SSc [5], the 2017 
McDonald [6] criteria for MS, and the international consensus criteria for 
pemphigus [7]. 
a. If a participant has been diagnosed with more than one 
autoimmune disease, the participant will be assessed based on the 
disease that is selected for study entry.  
3. Willing and able to sign informed consent. 
4. Documented full COVID-19 vaccination (Centers for Disease Control and 
Prevention [CDC] card or documentation in medical records) that was 
completed at least 4 weeks prior and no more than 52 weeks prior to the 
Screening visit. 
5. Negative or suboptimal serologic response to initial COVID-19 vaccine 
regimen, defined as an Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL, at 
Screening visit. 
a. Initial COVID-19 vaccine regimen is defined as either: 
i. 2 doses of the Pfizer-BioNTech COVID-19 Vaccine 
ii. 2 doses of the Moderna COVID-19 Vaccine 
6. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 1000 
mg per day)/MPA (minimum of 720 mg per day), MTX (minimum of 7.5mg 
per week), or B cell depleting agents within the past 18 months (such as 
rituximab, ocrelizumab, ofatumumab).  
a. If taking MMF/MPA or MTX, the participant must have initiated 
therapy at least 8 weeks prior to randomization and be taking the 
same medications (regardless of dose) as at the time of the initial 
COVID-19 vaccine regimen. Note: Participants who withheld their 
IS medications around their initial vaccinations are eligible to 
participate.  
b. If enrolling in the BCDT cohort, the participant must have received 
an anti-CD20 or an anti-CD19 BCDT in the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or MTX, in 
the 4 weeks prior to Screening, excluding the following:  
a. HCQ,  


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b. Intraarticular steroids,   
c. The addition of prednisone at ≤10mg per day or prednisone at any 
dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted. 
Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible for 
randomization/allocation as study participants in Adult Stage 1:  
1. Inability or unwillingness of a participant to give written informed 
consent or comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine 
regimen, to any component of any of the COVID-19 vaccines, or to 
polyethylene glycol (PEG).  
3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Screening period resulting in: 
a. An increase/addition of IS medications, or  
b. A suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to 
Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of a COVID-19 vaccine booster prior to Screening with the 
Moderna COVID-19 Vaccine, Pfizer-BioNTech COVID-19 Vaccine, or 
Janssen COVID-19 Vaccine. 
8.  Inflammatory myocarditis/pericarditis following initial COVID-19 
vaccine regimen.  
9. Participants with active, ongoing chronic infections, including 
participants with evidence of: 
a. Human Immunodeficiency Virus (HIV)  
b. Hepatitis B as indicated by surface antigen  
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; 
if a participant is Hepatitis C antibody positive, they will be 


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eligible to participate in the study if he/she is negative for viral 
load at Screening. 
Note: Participants are permitted to be on chronic prophylactic 
antimicrobial therapy.  
10. Participants with common variable immunodeficiency disease, as well 
as any participants currently receiving immune globulin replacement 
therapy. 
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Screening. 
12. Participants who have received any live vaccines within 2 months of 
the anticipated study vaccine dose or who will have need of a live 
vaccine at any time during the study. 
13. Currently pregnant or breastfeeding.  
14. Participants who are planning a pregnancy during the course of the 
trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Screening.  
18. Concurrent treatment with cyclophosphamide, cladribine, 
alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a 
solid organ transplant.  
20. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
21. Taking both MMF/MPA and MTX. 
22. Receiving other investigational BCDT as part of a clinical trial within 18 
months of Screening, unless drug assignment is known and the 
participant received an anti-CD20 or CD19 drug. 
23. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Screening. 
Inclusion/Exclusion Criteria 
– Adult Stage 2 Newly 
Recruited Participants 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible for enrollment as 
participants in Adult Stage 2: 


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1. Individuals 18 years of age or older that meet classification criteria [1-
6] for SLE, SSc, RA, MS, or pemphigus. If a participant has been 
diagnosed with more than one autoimmune disease, the participant 
will be assessed based on the disease that is selected for study entry. 
2. Willing and able to sign informed consent. 
3. Documented full COVID-19 vaccination (CDC card or documentation in 
medical records). 
4. Received an additional COVID-19 vaccine dose (documented by CDC 
card or in medical records) that was completed at least 4 weeks prior 
and no more than 48 weeks prior to the Stage 2 Screening visit.  
5. Negative or suboptimal serologic response to a previous COVID-19 
vaccine administration in one of the qualifying regimens, defined as an 
Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response defined as an Elecsys® Anti-
SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 weeks of the Stage 
2 Baseline/Week 0 visit. 
The regimens of COVID-19 vaccination that qualify are as follows: 
a. 3 doses of the Pfizer-BioNTech COVID-19 Vaccine 
b. 3 doses of the Moderna COVID-19 Vaccine 
c. 2 doses of the Janssen COVID-19 Vaccine 
d. 4 or more doses of a single mRNA vaccine (Pfizer-BioNTech 
COVID-19 Vaccine OR Moderna COVID-19 Vaccine) 
e. 3 or more doses of a mixture of mRNA vaccines (Pfizer-
BioNTech COVID-19 Vaccine OR Moderna COVID-19 Vaccine) 
6. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 
1000 mg per day)/MPA (minimum of 720 mg per day), MTX (minimum 
of 7.5mg per week), or B cell depleting agents within the past 18 
months (such as rituximab, ocrelizumab, or ofatumumab).  
a. If taking MMF/MPA or MTX, the participant must have 
initiated therapy at least 8 weeks prior to allocation and be 
taking the same medications (regardless of dose) as at the 
time of the initial COVID-19 vaccine regimen. Note: 
Participants who withheld their IS medications around their 
initial vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, the participant must have 
received an anti-CD20 or an anti-CD19 BCDT in the past 18 
months.  
7. No changes in background IS medications, including MMF/MPA or 
MTX, in the 4 weeks prior to Stage 2 Screening, excluding the 
following:  
a. HCQ,  
b. Intraarticular steroids,   


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c. The addition of prednisone at ≤10mg per day or prednisone at 
any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted. 
Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible for 
randomization/allocation as study participants in Adult Stage 2:  
1. Inability or unwillingness of a participant to give written informed 
consent or comply with study protocol. 
2. History of severe allergic reaction to the COVID-19 vaccine, or to any 
component of the COVID-19 vaccine, that is to be administered in 
Stage 2, including polysorbate for participants receiving the Sanofi-GSK 
COVID-19 Vaccine, or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a. An increase/addition of any IS medications, or  
b. A suggestion of MS relapse per the investigator. 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to Stage 2 
Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 
Screening. 
7. Receipt of a mixture of Janssen COVID-19 vaccines and mRNA COVID-
19 vaccines (in any order or combination) prior to Stage 2 Screening. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 
vaccine doses.  
9. Participants with active, ongoing chronic infections including 
participants with evidence of: 
a. HIV. 
b. Hepatitis B as indicated by surface antigen.  
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; 
if a participant is Hepatitis C antibody positive, they will be 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
eligible to participate in the study if he/she is negative for viral 
load at Stage 2 Screening.  
Note: Participants are permitted to be on chronic prophylactic 
antimicrobial therapy. 
10. Participants with common variable immunodeficiency disease, as well 
as any participants currently receiving immune globulin replacement 
therapy. 
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Stage 2 Screening. 
12. Participants who have received any live vaccines within 2 months of 
the anticipated study vaccine dose or who will have need of a live 
vaccine at any time during the study. 
13. Currently pregnant or breastfeeding.  
14. Female participants who are planning a pregnancy during the course 
of the trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Stage 2 Screening.  
18. Concurrent treatment with cyclophosphamide, cladribine, 
alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a 
solid organ transplant. 
20. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
21. Taking both MMF/MPA and MTX. 
22. Receiving other investigational BCDT as part of a clinical trial within 18 
months of Screening, unless drug assignment is known and the 
participant received an anti-CD20 or CD19 drug. 
23. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Stage 2 Screening. 
Inclusion/Exclusion Criteria 
– Adult Stage 2 Rollover 
Participants 
Inclusion Criteria: 
Individuals who were previously enrolled in Adult Stage 1 or Adult Stage 2 will 
have met some inclusion and exclusion criteria at that time. Only a subset of 


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the criteria for (re-)entering Adult Stage 2 will be assessed in rollover 
participants at the time of screening for Stage 2. 
Individuals who meet all of the following criteria are eligible to (re-)enter Adult 
Stage 2:  
4. Received an additional COVID-19 vaccine dose that was completed at 
least 4 weeks prior and no more than 48 weeks prior to the Stage 2 
vaccination. 
5. Negative or suboptimal serologic response to a previous COVID-19 
vaccine administration in one of the qualifying regimens, defined as an 
Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response defined as an Elecsys® Anti-
SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 weeks of the Stage 
2 Baseline/Week 0 visit. 
The regimens of COVID-19 vaccination that qualify are as follows: 
a. 3 doses of the Pfizer-BioNTech COVID-19 Vaccine 
b. 3 doses of the Moderna COVID-19 Vaccine 
c. 2 doses of the Janssen COVID-19 Vaccine 
d.  4 doses of a combination of mRNA vaccines (i.e., Pfizer-
BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine) 
6. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 
1000 mg per day)/MPA (minimum of 720 mg per day), MTX (minimum 
of 7.5 mg per week), or B cell depleting agents within the past 18 
months (such as rituximab, ocrelizumab, ofatumumab).  
a. If taking MMF/MPA or MTX, the participant must have 
initiated therapy at least 8 weeks prior to allocation and be 
taking the same medications (regardless of dose) as at the 
time of the initial COVID-19 vaccine regimen. Note: 
Participants who withheld their IS medications around their 
initial vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, the participant must have 
received an anti-CD20 or an anti-CD19 BCDT in the past 18 
months.  
7. No changes in background IS medications, including MMF/MPA or 
MTX, in the 4 weeks prior to Stage 2 Baseline/Week 0 visit, excluding 
the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at ≤10mg per day or prednisone at 
any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted. 


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Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible to (re-)enter Adult 
Stage 2:  
2. History of severe allergic reaction to the COVID-19 vaccine, or to any 
component of the COVID-19 vaccine, that is to be administered in 
Stage 2, including polysorbate for participants receiving the Sanofi-GSK 
COVID-19 Vaccine, or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a. An increase/addition of any IS medications, or  
b. A suggestion of MS relapse per the investigator. 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to Stage 2 
Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 
Screening or Stage 2 Baseline/Week 0. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 
vaccine doses.  
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Stage 2 Screening. 
13. Currently pregnant or breastfeeding.  
14. Female participants who are planning a pregnancy during the course 
of the trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Stage 2 Screening.  


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18. Concurrent treatment with cyclophosphamide, cladribine, 
alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a 
solid organ transplant. 
20. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
23. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Stage 2 
Baseline/Week 0. 
Inclusion/Exclusion Criteria 
for Pediatric Stage 1 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible for enrollment 
randomization/allocation as participants in the pediatric portion of the study: 
1. Individuals 2-17 years of age that meet classification criteria for SLE, 
JIA, POMS, or JDM. Note: Juvenile idiopathic arthritis includes the 
following conditions: polyarticular JIA (both RF + and -), oligoarticular 
persistent and oligoarticular extended JIA, psoriatic arthritis, and 
enthesitis related JIA. 
a. Participants must meet the 2017 EULAR/ACR classification 
criteria for adult and juvenile idiopathic inflammatory 
myopathies and their major subgroups [8], the International 
League of Associations for Rheumatology (ILAR) classification 
for JIA [4], the 2017 McDonald [6] criteria for MS, or the 
Bohan and Peter criteria or the 2017 EULAR/ACR classification 
criteria for JDM.  
b. If a participant has been diagnosed with more than one 
autoimmune disease, the participant will be assessed based 
on the disease that is selected for study entry.  
2. Parents/guardians of pediatric participants and participants ages 14 – 
17 must be willing and able to sign informed consent. Participants, 
ages 7-13, must be willing and able to sign assent. 
3. Documented EUA-authorized or FDA-approved COVID-19 doses (CDC 
card or documentation in medical records) that was completed at 
least 4 weeks prior and no more than 52 weeks prior to the Screening 
visit. 
4. Negative or suboptimal serologic response to initial EUA-authorized or 
FDA-approved COVID-19 vaccine doses, defined as an Elecsys® Anti-
SARS-CoV-2 S result ≤200 U/mL, or a low immune response defined as 
an Elecsys® Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 
weeks of the Stage 1 Baseline/Week 0 visit  
Initial COVID-19 vaccine regimen is defined as: 
i. Pfizer-BioNTech COVID-19 Vaccine (2 through 4 years 
of age): 3 age-appropriate doses  


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ii. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years 
of age): 2 age-appropriate doses  
iii. Moderna COVID-19 Vaccine (2 through 17 years of 
age): 2 age-appropriate doses. 
5. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 
250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum 
of 5 mg per week), or B cell depleting agents within the past 18 
months (such as rituximab, ocrelizumab, or ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have 
initiated therapy at least 8 weeks prior to randomization and 
be taking the same medications (regardless of dose) as at the 
time of the initial COVID-19 vaccine regimen. Note: 
Participants who withheld their IS medications around their 
initial vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, participant must have received 
an anti-CD20 or an anti-CD19 BCDT in the past 18 months.  
6. No changes in background IS medications, including MMF/MPA or 
MTX, in the 8 weeks prior to Screening, excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or 
prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted 
Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible for 
randomization/allocation as participants in the pediatric portion of the study:  
1. Inability or unwillingness of a participant to give assent or of a 
parent/guardian to give written informed consent, or of either to 
comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine 
regimen, or any component of any of the COVID-19 vaccines, or to 
PEG.  
3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Screening period resulting in: 


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a.  an increase/addition of any IS medications, or  
b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to 
Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of a COVID-19 vaccine booster prior to Screening. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 
vaccine doses.  
9. Participants with active, ongoing chronic infections. 
Note: Participants are permitted to be on chronic prophylactic 
antimicrobial therapy.  
10. Participants with common variable immunodeficiency disease, as well 
as any participants currently receiving immune globulin replacement 
therapy. 
Note: Participants on IVIG therapeutically may enter the study 
provided they have sufficiently quiet disease that they can withhold 
their IVIG from 8 weeks prior to the Screening visit through 4 weeks 
after vaccination.  
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Screening. 
12. Participants who have received any live vaccines within 2 months of 
the anticipated study vaccine dose or who will have need of a live 
vaccine at any time during the study. 
13. Currently pregnant or breastfeeding (postmenarchal females must 
have a negative urine pregnancy test at Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a 
solid organ transplant.  


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
19. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness must not be allowed to participant in this 
study. 
20. Taking both MMF/MPA and MTX. 
21. Other investigational BCDT as part of a clinical trial within 18 months 
of Screening, unless drug assignment is known and the participant 
received an anti-CD20 or CD19 drug. 
22. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Screening. 
Inclusion/Exclusion Criteria 
– Pediatric Stage 2 Newly 
Recruited Participants 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible for enrollment as 
participants in Pediatric Stage 2: 
1. Individuals 2-17 years of age that meet classification criteria for SLE, 
JIA, POMS, or JDM. Note: Juvenile idiopathic arthritis includes the 
following conditions: polyarticular JIA (both RF + and -), oligoarticular 
persistent and oligoarticular extended JIA, psoriatic arthritis, and 
enthesitis related JIA. 
a. Participants must meet the 2017 EULAR/ACR classification 
criteria for adult and juvenile idiopathic inflammatory 
myopathies and their major subgroups [8], the International 
League of Associations for Rheumatology (ILAR) classification 
for JIA [4], the 2017 McDonald [6] criteria for MS, or the 
Bohan and Peter criteria or the 2017 EULAR/ACR classification 
criteria for JDM.  
b. If a participant has been diagnosed with more than one 
autoimmune disease, the participant will be assessed based 
on the disease that is selected for study entry.  
2. Parents/guardians of all pediatric participants and participants ages 14 
– 17 must be willing and able to sign informed consent. Participants 
ages 7-13 must be willing and able to sign assent. 
3. Documented full COVID-19 vaccination (CDC card or documentation in 
medical records). 
4. Received an additional COVID-19 vaccine dose (documented by CDC 
card or in medical records) that was completed at least 4 weeks prior 
and no more than 48 weeks prior to the Stage 2 Screening visit. 
5. Negative or suboptimal serologic response to homologous doses of 
COVID-19 vaccine in one of the qualifying regimens, defined as an 
Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response defined as an Elecsys® Anti-
SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 weeks of the Stage 
2 Baseline/Week 0 visit. Initial COVID-19 vaccine regimen is defined as: 


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a. Pfizer-BioNTech COVID-19 Vaccine (2 through 5 years of age): 
4 full, age-appropriate doses of the Pfizer-BioNTech COVID-19 
Vaccine 
b. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years old): 3 
full, age-appropriate doses of the Pfizer-BioNTech COVID-19 
Vaccine 
Note: Participants who are 5 years old and previously 
received the Pfizer-BioNTech COVID-19 Vaccine may 
have received either age-appropriate regimen. See 
Section 3.1.2.2, Pediatric Stage 2, for additional 
details.  
c. Moderna COVID-19 Vaccine (12 through 17 years of age): 3 
full, age-appropriate doses of the Moderna COVID-19 Vaccine  
6. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 
250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum 
of 5 mg per week), or B cell depleting agents within the past 18 
months (such as rituximab, ocrelizumab, or ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have 
initiated therapy at least 8 weeks prior to allocation and be 
taking the same medications (regardless of dose) as at the 
time of the initial COVID-19 vaccine regimen. Note: 
Participants who withheld their IS medications around their 
initial vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, participant must have received 
an anti-CD20 or an anti-CD19 BCDT in the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or 
MTX, in the 4 weeks prior to Screening, excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or 
prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted 
Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible for enrollment as 
participants in Pediatric Stage 2:  
1. Inability or unwillingness of a participant to give assent or consent; or 
of a parent/guardian to give written informed consent, or of either to 
comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine 
regimen, or any component of any of the COVID-19 vaccine, that is to 
be administered in Stage 2, or to PEG.  


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3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Screening period resulting in: 
a.  an increase/addition of any IS medications, or  
b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to 
Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of an additional heterologous COVID-19 vaccine dose prior to 
Stage 2 Screening, i.e., a participant cannot have received a mixture of 
mRNA vaccines. 
8.  Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-
19 vaccine doses.  
9. Participants with active, ongoing chronic infections. 
Note: Participants are permitted to be on chronic prophylactic 
antimicrobial therapy.  
10. Participants with common variable immunodeficiency disease, as well 
as any participants currently receiving immune globulin replacement 
therapy. 
Note: Participants on IVIG therapeutically may enter the study 
provided they have sufficiently quiet disease that they can withhold 
their IVIG from 8 weeks prior to the Screening visit through 4 weeks 
after vaccination.  
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Screening. 
12. Participants who have received any live vaccines within 2 months of 
the anticipated study vaccine dose or who will have need of a live 
vaccine at any time during the study. 
13. Currently pregnant or breastfeeding (postmenarchal females must 
have a negative urine pregnancy test at Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 


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the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a 
solid organ transplant.  
19. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness must not be allowed to participant in this 
study. 
20. Taking both MMF/MPA and MTX. 
21. Other investigational BCDT as part of a clinical trial within 18 months 
of Screening, unless drug assignment is known and the participant 
received an anti-CD20 or CD19 drug. 
22. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Screening. 
 
Inclusion/Exclusion Criteria 
– Pediatric Stage 2 Rollover 
Participants 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible for enrollment as 
participants in Pediatric Stage 2: 
4. Received an additional COVID-19 vaccine dose that was completed at 
least 4 weeks prior and no more than 48 weeks prior to the Stage 2 
vaccination. 
5. Negative or suboptimal serologic response to a previous COVID-19 
vaccine administration in one of the qualifying regimens, defined as an 
Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response defined as an Elecsys® Anti-
SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 weeks of the Stage 
2 Baseline/Week 0 visit. 
The regimens of COVID-19 vaccination that qualify are as follows: 
a. Pfizer-BioNTech COVID-19 Vaccine (2 through 5 years of age): 
4 full, age-appropriate doses of the Pfizer-BioNTech COVID-19 
Vaccine 
b. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years old): 3 
full, age-appropriate doses of the Pfizer-BioNTech COVID-19 
Vaccine 
Note: Participants who are 5 years old and previously 
received the Pfizer-BioNTech COVID-19 Vaccine may 
have received either age-appropriate regimen. See 


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Section 3.1.2.2, Pediatric Stage 2, for additional 
details.  
c. Moderna COVID-19 Vaccine (12 through 17 years of age): 3 
full, age-appropriate doses of the Moderna COVID-19 Vaccine  
6. Must be currently taking one of the following IS medications with or 
without additional disease-related medications: MMF (minimum of 
250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum 
of 5 mg per week), or B cell depleting agents within the past 18 
months (such as rituximab, ocrelizumab, or ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have 
initiated therapy at least 8 weeks prior to allocation and be 
taking the same medications (regardless of dose) as at the 
time of the initial COVID-19 vaccine regimen. Note: 
Participants who withheld their IS medications around their 
initial vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, participant must have received 
an anti-CD20 or an anti-CD19 BCDT in the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or 
MTX, in the 4 weeks prior to Stage 2 Baseline/Week 0, excluding the 
following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or 
prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related 
conditions, such as asthma or COPD, are permitted 
Exclusion Criteria: 
Individuals who meet any of these criteria are not eligible for enrollment as 
participants in Pediatric Stage 2:  
2. History of severe allergic reaction to the initial COVID-19 vaccine 
regimen, or any component of any of the COVID-19 vaccine, that is to 
be administered in Stage 2, or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or 
immunotherapy, or ongoing treatment for a malignancy with 
chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to 
hold the IS therapy in the MMF/MPA or MTX arms of the study.  
a. The potential impact of temporarily holding medication for 
participants with a recent mild disease flare within 4 weeks 
should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a.  an increase/addition of any IS medications, or  


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b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from 
the day the participant is diagnosed by positive test to Stage 2 
Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 
Screening or Stage 2 Baseline/Week 0. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 
vaccine doses.  
11. Participants who received licensed or investigational monoclonal 
antibodies or plasma products directed against SARS-CoV-2 within 30 
days of Screening. 
13. Currently pregnant or breastfeeding (postmenarchal females must 
have a negative urine pregnancy test at Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other 
investigational biologic agent within 8 weeks or 5 half-lives (whichever 
is longer) of Stage 2 Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a 
solid organ transplant.  
19. Prisoners or participants who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness must not be allowed to participant in this 
study. 
22. Participants with active systemic infections who have received 
systemic antimicrobials within the 14 days prior to Stage 2 
Baseline/Week 0. 
 


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Study Stopping Rules 
If any of the events listed below occur, other than myocarditis/pericarditis, the 
DSMB chair will be notified, and a review of safety data will be performed to 
determine if enrollment in the study, randomization/allocation, and/or 
administration of investigational study medication should be halted. If two 
weeks has elapsed and the DSMB has not met, then no new participants will 
be consented, allocated or randomized until after the DSMB completes review 
of the safety data.  
For any NCI-CTCAE Grade 2 or higher myocarditis or pericarditis that occurs 
within 6 weeks of vaccine administration, the DSMB chair be notified of the 
event within 3 business days from when the AESI was reported to DAIT/NIAID 
(see Section 12.5.2). The DSMB chair will adjudicate whether an expedited, ad 
hoc safety review by the full DSMB is required. 
Adult Participants: 
Any of the following adverse events in adult participants attributable to the 
vaccine will trigger an ad hoc DSMB Safety Review: 
• 
Death related to vaccine. 
• 
Life-threating adverse event (Grade 4) related to vaccine. 
• 
Permanent or severe disability related to vaccine. 
• 
Occurrence of a Grade 3 or higher, vaccine-related SAE of the same 
type in 3 or more of the study participants who have received a study 
treatment. Note: Only SAEs occurring within 24 weeks of a Day 1 visit 
will be counted.  
• 
Occurrence of a Grade 2 or higher myocarditis or pericarditis within 6 
weeks of vaccine administration. Note: the DSMB chair will be notified 
within 3 business from when the AESI is reported to DAIT/NIAID. 
• 
Occurrence of severe flare or relapse after an additional homologous 
COVID-19 vaccine dose given at Stage 1, defined as within 12 weeks of 
the Stage Baseline/Week 0 visit (vaccination), in 3 of the first 10 
participants or 30% thereafter. 
• 
Occurrence of severe flare or relapse after a subsequent alternative 
COVID-19 vaccine dose given at Stage 2, defined as within 12 weeks of 
the Stage 2 Baseline/Week 0 visit (vaccination), in 3 of the first 10 
participants or 30% thereafter. 
Pediatric Participants: 
Any of the following adverse events in pediatric participants attributable to 
the vaccine will trigger an ad hoc DSMB Safety Review: 
• 
Death related to vaccine 
• 
Life-threatening AE (Grade 4) related to vaccine 
• 
Permanent or severe disability related to vaccine 
• 
Occurrence of a Grade 3 or higher, vaccine-related SAE of the same 
type in 3 or more of the study participants who have received a study 


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treatment. Note: Only SAEs occurring between Day 1 and the Week 24 
study visit will be counted.  
• 
Occurrence of a Grade 2 or higher myocarditis or pericarditis within 6 
weeks of vaccine administration. Note: the DSMB chair will be notified 
within 3 business days from when the AESI is reported to DAIT/NIAID. 
• 
Occurrence of severe flare or relapse after an additional homologous 
COVID-19 vaccine dose given at Stage 1, defined as within 12 weeks of 
the Stage Baseline/Week 0 visit (vaccination), in 3 of the first 10 
participants or 30% thereafter, defined as follows. 
• 
Occurrence of severe flare or relapse after a subsequent alternative 
COVID-19 vaccine dose given at Stage 2, defined as within 12 weeks of 
the Stage 2 Baseline/Week 0 visit (vaccination), in 3 of the first 10 
participants or 30% thereafter. 


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Table of Contents 
 
Version History ........................................................................................................................................................................ 5 
Protocol Synopsis .................................................................................................................................................................... 6 
Glossary of Abbreviations ..................................................................................................................................................... 41 
1. 
Background and Rationale ............................................................................................................................................ 45 
1.1 
Background and Scientific Rationale ..................................................................................................................... 45 
1.2 
Clinical Trial Design and Rationale ........................................................................................................................ 46 
1.2.1 
Initial Trial Design - Additional Homologous Vaccine Dose .......................................................................... 46 
1.2.2 
Alternative Vaccine Dose Adaptation ........................................................................................................... 47 
1.2.3 
Pediatric Adaptation ..................................................................................................................................... 48 
1.3 
Rationale for Selection of Investigational Product ............................................................................................... 49 
1.4 
Clinical Studies ...................................................................................................................................................... 50 
2. 
Study Hypotheses/Objectives ....................................................................................................................................... 52 
2.1 
Primary Objective .................................................................................................................................................. 53 
2.2 
Secondary Objectives ............................................................................................................................................ 53 
2.2.1 
Stage 1 Secondary Objectives ....................................................................................................................... 53 
2.2.2 
Stage 2 Secondary Objectives ....................................................................................................................... 53 
2.3 
Exploratory Objectives .......................................................................................................................................... 54 
3. 
Study Design .................................................................................................................................................................. 54 
3.1 
Description of Study Design .................................................................................................................................. 54 
3.1.1 
Adult Population ........................................................................................................................................... 54 
3.1.2 
Pediatric Population ...................................................................................................................................... 62 
3.1.3 
Adaptive Design ............................................................................................................................................ 70 
3.2 
Primary Endpoint .................................................................................................................................................. 70 
3.3 
Secondary Endpoints ............................................................................................................................................ 70 
3.4 
Exploratory Endpoints ........................................................................................................................................... 71 
3.5 
Stratification, Randomization, and Blinding ......................................................................................................... 72 
3.5.1 
Adult Population ........................................................................................................................................... 72 
3.5.2 
Pediatric Population ...................................................................................................................................... 72 
4. 
Selection of Participants and Clinical Sites ................................................................................................................... 73 
4.1 
Rationale for Study Population ............................................................................................................................. 73 
4.2 
Inclusion and Exclusion Criteria ............................................................................................................................ 74 


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4.2.1 
Inclusion and Exclusion Criteria for Adult Participants ................................................................................. 74 
4.2.2 
Inclusion and Exclusion Criteria for Pediatric Participants ........................................................................... 80 
5. 
Known and Potential Risks and Benefits to Participants .............................................................................................. 87 
5.1 
Risks of Investigational Products .......................................................................................................................... 87 
5.1.1 
Risks of COVID vaccine based on the mRNA vaccines (Moderna COVID-19 Vaccine and Pfizer-BioNTech 
COVID-19 Vaccine) ........................................................................................................................................................ 87 
5.1.2 
Risks of COVID vaccine based on the Janssen COVID-19 Vaccine ................................................................. 88 
5.1.3 
Risks of COVID vaccine based on the Sanofi-GSK COVID-19 Vaccine ........................................................... 89 
5.2 
Risks of Other Protocol-specified Medications ..................................................................................................... 90 
5.3 
Risks of Study Procedures ..................................................................................................................................... 90 
5.3.1 
Risks Associated with Withdrawal of IS Medications ................................................................................... 90 
5.3.2 
Risks Associated with Blood Collection ......................................................................................................... 90 
5.3.3 
Risks Associated with Physical Exam ............................................................................................................. 90 
5.3.4 
Risks Associated with Medical History or Participant Diary.......................................................................... 90 
5.3.5 
Risks Associated with Urine Collection ......................................................................................................... 90 
5.3.6 
Risks Associated with Nasal Swab Collection ................................................................................................ 90 
5.4 
Potential Benefits .................................................................................................................................................. 90 
6. 
Investigational Agents ................................................................................................................................................... 91 
6.1 
Investigational Agent #1: Moderna COVID-19 Vaccine ........................................................................................ 91 
6.2 
Investigational Agent #2: Pfizer-BioNTech COVID-19 Vaccine.............................................................................. 93 
6.3 
Investigational Agent #3: Janssen COVID-19 Vaccine ........................................................................................... 96 
6.4 
Investigational Agent #4: Sanofi-GSK COVID-19 Vaccine ...................................................................................... 97 
6.5 
Drug Accountability ............................................................................................................................................... 97 
6.6 
Assessment of Participant Compliance with Investigational Agent ..................................................................... 98 
6.7 
Toxicity Prevention and Management .................................................................................................................. 98 
7. 
Other Medications ........................................................................................................................................................ 98 
7.1 
Concomitant Medications ..................................................................................................................................... 98 
7.1.1 
Protocol-mandated Medications .................................................................................................................. 98 
7.1.2 
Other permitted concomitant medications .................................................................................................. 99 
7.2 
Prophylactic Medications ...................................................................................................................................... 99 
7.3 
Prohibited Medications ......................................................................................................................................... 99 
7.4 
Rescue Medications .............................................................................................................................................. 99 
8. 
Study Procedures ........................................................................................................................................................ 100 
8.1 
Adult Stage 1 Study Procedures .......................................................................................................................... 100 


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8.1.1 
Visit Windows.............................................................................................................................................. 100 
8.1.2 
Screening and Randomization/Allocation ................................................................................................... 100 
8.1.3 
Baseline (Week 0/Day 1) Visit ..................................................................................................................... 103 
8.1.4 
Study Procedures and Assessments ............................................................................................................ 104 
8.1.5 
Unscheduled Visits ...................................................................................................................................... 106 
8.1.6 
Early Termination ........................................................................................................................................ 106 
8.2 
Adult Stage 2 Study Procedures .......................................................................................................................... 106 
8.2.1 
Visit Windows.............................................................................................................................................. 106 
8.2.2 
Screening and Allocation............................................................................................................................. 107 
8.2.3 
Evaluation of Eligibility and Allocation ........................................................................................................ 111 
8.2.4 
Baseline (Week 0/Day 1) Visit ..................................................................................................................... 112 
8.2.5 
Study Procedures and Assessments ............................................................................................................ 112 
8.2.6 
Unscheduled Visits ...................................................................................................................................... 112 
8.2.7 
Early Termination ........................................................................................................................................ 112 
8.3 
Pediatric Stage 1 Study Procedures .................................................................................................................... 113 
8.3.1 
Visit Windows.............................................................................................................................................. 113 
8.3.2 
Screening and Randomization/Allocation ................................................................................................... 113 
8.3.3 
Baseline (Week 0/Day 1) Visit ..................................................................................................................... 115 
8.3.4 
Study Procedures and Assessments ............................................................................................................ 115 
8.3.5 
Unscheduled Visits ...................................................................................................................................... 117 
8.3.6 
Early Termination ........................................................................................................................................ 117 
8.4 
Pediatric Stage 2 Study Procedures .................................................................................................................... 117 
8.4.1 
Visit Windows.............................................................................................................................................. 117 
8.4.2 
Screening and Allocation............................................................................................................................. 118 
8.4.3 
Evaluation of Eligibility and Allocation ........................................................................................................ 122 
8.4.4 
Baseline (Week 0/Day 1) Visit ..................................................................................................................... 122 
8.4.5 
Study Procedures and Assessments ............................................................................................................ 123 
8.4.6 
Unscheduled Visits ...................................................................................................................................... 123 
8.4.7 
Early Termination ........................................................................................................................................ 123 
9. 
Mechanistic Assays ..................................................................................................................................................... 123 
10. Biospecimen Storage................................................................................................................................................... 125 
11. Criteria for Participant and Study Completion and Premature Study Termination.................................................... 126 
11.1 
Participant Completion ....................................................................................................................................... 126 
11.2 
Participant Stopping Rules and Withdrawal Criteria .......................................................................................... 126 


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11.3 
Participant Replacement ..................................................................................................................................... 126 
11.4 
Follow-up after Early Study Withdrawal ............................................................................................................. 126 
11.5 
Study Stopping Guidance .................................................................................................................................... 126 
12. Safety Monitoring and Reporting ............................................................................................................................... 127 
12.1 
Overview ............................................................................................................................................................. 127 
12.2 
Definitions ........................................................................................................................................................... 127 
12.2.1 
Adverse Event (AE) ...................................................................................................................................... 127 
12.2.2 
Unsolicited Adverse Event .......................................................................................................................... 128 
12.2.3 
New-onset Chronic Medical Condition (NOCMC) ....................................................................................... 128 
12.2.4 
Medically Attended Adverse Event ............................................................................................................. 128 
12.2.5 
Adverse Events of Special Interest .............................................................................................................. 128 
12.2.6 
Serious Adverse Event (SAE) ....................................................................................................................... 128 
12.3 
Grading and Attribution of Adverse Events ........................................................................................................ 129 
12.3.1 
Grading Criteria ........................................................................................................................................... 129 
12.3.2 
Attribution Definitions ................................................................................................................................ 131 
12.4 
Collection and Recording of Adverse Events ...................................................................................................... 131 
12.4.1 
Collection Period For All Cohorts ................................................................................................................ 131 
12.4.2 
Increase in Autoimmune Disease Activity ................................................................................................... 132 
12.4.3 
Collecting Adverse Events ........................................................................................................................... 132 
12.4.4 
Recording Adverse Events ........................................................................................................................... 132 
12.5 
Reporting Adverse Events and Serious Adverse Events to Sponsor (DAIT/NIAID) ............................................. 132 
12.5.1 
Reporting Adverse Events ........................................................................................................................... 132 
12.5.2 
Reporting Serious Adverse Events .............................................................................................................. 133 
12.5.3 
Reporting to Health Authority .................................................................................................................... 134 
12.5.4 
Mandatory reporting to Vaccine Adverse Event Reporting System ........................................................... 134 
12.5.5 
Reporting of Adverse Events to Institutional Review Boards (IRBs)/Institutional Ethics Committees (IECs)
 
135 
12.6 
Pregnancy Reporting ........................................................................................................................................... 135 
12.7 
Reporting of Other Safety Information ............................................................................................................... 135 
12.8 
Review of Safety Information ............................................................................................................................. 135 
12.8.1 
Medical Monitor Review ............................................................................................................................. 135 
12.8.2 
DSMB Review .............................................................................................................................................. 136 
13. Statistical Considerations and Analytical Plan ............................................................................................................ 138 
13.1 
Overview ............................................................................................................................................................. 138 


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13.2 
Endpoints ............................................................................................................................................................ 139 
13.3 
Measures to Minimize Bias ................................................................................................................................. 139 
13.4 
Analysis Plan ........................................................................................................................................................ 139 
13.4.1 
Analysis Populations ................................................................................................................................... 139 
13.4.2 
Primary Analysis of Primary Endpoint ......................................................................................................... 139 
13.4.3 
Supportive Analyses of the Primary Endpoint ............................................................................................ 140 
13.4.4 
Analyses of Secondary and Other Endpoint(s)............................................................................................ 140 
13.4.5 
Descriptive Analyses ................................................................................................................................... 141 
13.5 
Interim Analysis ................................................................................................................................................... 141 
13.5.1 
Interim Analysis of Efficacy Data ................................................................................................................. 141 
13.5.2 
Interim Analysis of Safety Data ................................................................................................................... 141 
13.5.3 
Futility Analysis ........................................................................................................................................... 141 
13.6 
Statistical Hypotheses ......................................................................................................................................... 141 
13.7 
Sample Size Considerations ................................................................................................................................ 142 
14. Identification and Access to Source Data ................................................................................................................... 142 
14.1 
Source Data ......................................................................................................................................................... 142 
14.2 
Access to Source Data ......................................................................................................................................... 143 
15. Quality Assurance and Quality Control ....................................................................................................................... 143 
16. Protocol Deviations ..................................................................................................................................................... 144 
16.1 
Protocol Deviation Definitions ............................................................................................................................ 144 
16.2 
Reporting and Managing Protocol Deviations .................................................................................................... 144 
17. Ethical Considerations and Compliance with Good Clinical Practice .......................................................................... 144 
17.1 
Statement of Compliance ................................................................................................................................... 144 
17.2 
Informed Consent Process .................................................................................................................................. 144 
17.3 
Privacy and Confidentiality ................................................................................................................................. 145 
18. Publication Policy ........................................................................................................................................................ 145 
19. References .................................................................................................................................................................. 146 
20. Appendices .................................................................................................................................................................. 150 
20.1 
Schedules of Events ............................................................................................................................................ 150 
20.2 
CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0 ...................................................................... 168 
20.3 
Adult Vaccine Reaction Diary .............................................................................................................................. 170 
20.4 
Pediatric Vaccine Reaction Diary (2 year old) ..................................................................................................... 175 
20.5 
Pediatric Vaccine Reaction Diary (3 – 4 year old) ............................................................................................... 180 
20.6 
Pediatric Vaccine Reaction Diary (5 – 17 year old) ............................................................................................. 185 


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20.7 
List of potential immune-mediated diseases (version: January-2022) ............................................................... 190 
20.8 
Case definitions of probable and confirmed myocarditis, pericarditis, and myopericarditis............................. 193 
 


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Glossary of Abbreviations 
ACE 
Autoimmunity Centers of Excellence 
ACR/EULAR 
American College of Rheumatology/European League Against Rheumatism 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BCDT 
B-cell depletion therapy 
CAP 
College of American Pathologists 
CAPA 
Corrective and Preventative Action  
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change 
CI 
confidence interval 
CK 
creatine kinase 
CMAS 
Childhood Myositis Assessment Scale 
CMP 
comprehensive metabolic panel 
CoFAR 
Consortium of Food Allergy Research 
COPD 
chronic obstructive pulmonary disease 
CRP 
C-reactive protein 
CSVT 
cerebral sinus venous thrombosis 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DAS 
Disease Activity Score 
DAS28-CRP 
Disease Activity Score 28 using C-reactive protein 
DMG 
dimyristoyl glycerol 
DSMB 
Data and Safety Monitoring Board 
DSPC 
1,2,-distearoyl-sn-glycero-3-phosphocholine 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
ESR 
erythrocyte sedimentation rate 


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EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FSS 
Functional Systems Score 
GBS 
Guillain Barré Syndrome 
GCP 
Good Clinical Practice 
H-SLEDAI 
Hybrid Systemic Lupus Erythematosus Disease Activity Index 
HCQ 
hydroxycholoroquine 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IBD 
inflammatory bowel disease 
ICD 
International Statistical Classification of Diseases and Related Health Problems 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IgG 
immunoglobulin G 
ILAR 
International League of Associations for Rheumatology 
IND 
Investigational New Drug 
IP-10 
interferon gamma-inducible protein 10 
IRB 
Institutional Review Board 
IS 
immunosuppressive  
JADAS 
Juvenile Arthritis Disease Activity Score 
JAK 
Janus kinase 
JDM 
juvenile dermatomyositis 
JIA 
juvenile idiopathic arthritis 
MAAE 
medically attended adverse event 
MMF 
mycophenolate mofetil 
MOP 
Manual of Procedures 
MPA 
mycophenolic acid 
mRNA 
messenger ribonucleic acid 
modRNA 
nucleoside-modified messenger RNA 
MS 
multiple sclerosis 
MTX 
methotrexate 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 


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NOCMC 
new onset chronic medical condition 
OMRF 
Oklahoma Medical Research Foundation 
PASI 
Psoriasis Area and Severity Index 
PBMC 
peripheral blood mononuclear cell 
PBS 
phosphate-buffered saline 
PDAI 
Pemphigus Disease Area Index 
PedsQL 
Pediatric Quality of Life Inventory™ 
PEG 
polyethylene glycol 
PGI-C 
Patient Global Impression of Change 
PtGA 
Patient’s Global Assessment 
PGA 
Physician Global Assessment  
PI 
[Site] Principal Investigator 
pIMD 
potential immune-mediated diseases 
POMS 
pediatric-onset multiple sclerosis 
PROMIS 
Participant-Reported Outcomes Measurement Information System 
RA 
rheumatoid arthritis 
RBD 
receptor binding domain 
S 
pre-fusion stabilized spike glycoprotein 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SARS-COV-2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SELENA-SLEDAI 
Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus Erythematosus 
Disease Activity Index 
SLE 
systemic lupus erythematosus 
SLICC 
Systemic Lupus International Collaborating Clinics 
SSc 
systemic sclerosis 
SUSAR 
serious unexpected suspected adverse reaction 
TNF 
tumor necrosis factor 
TTS 
thrombosis with thrombocytopenia syndrome 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VAERS 
Vaccine Adverse Event Reporting System  
VP 
viral particles 


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VRC 
Vaccine Research Center 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 


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1. 
Background and Rationale  
1.1 
Background and Scientific Rationale 
Autoimmune disease afflicts up to 1 in 12 Americans and disproportionately afflicts the minority communities most 
severely impacted by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. For example, 
systemic lupus erythematosus (SLE) is a top 10 medical cause of death in African American and Hispanic women 
between the ages of 15 and 45 [9]. Many of these autoimmune diseases have higher rates of co-morbidities associated 
with increased severe COVID-19 disease and death, such as obesity, hypertension, and cardiovascular disease. These co-
morbidities may result from underlying disease processes or a requirement for immunosuppressive (IS) medications 
including prednisone, anti-metabolite drugs, or B-cell targeting therapies [10, 11]. Increased disease severity and death 
rates from COVID-19 in systemic autoimmune disease patients have been reported [12]. Whether this increased risk of 
severe SARS-CoV-2 infection is attributable to underlying autoimmune disease, background IS medication, or both is 
unknown. Data is scarce but some studies have associated mycophenolate mofetil (MMF), rituximab, and corticosteroid 
use with increased risk of poor outcomes [13]. For example, in a French cohort of 1,090 rheumatic and autoimmune 
disease patients, severe disease was more frequent after adjusting for potential confounding factors (effect size 3.26; 
95% confidence interval [CI] 1.66-6.40, p = 0.0006) with rituximab use. Furthermore, more patients died in the rituximab 
group (21%) than in the patients not taking rituximab (7%) [14], although it may be that patients on rituximab have more 
severe autoimmune disease with underlying organ damage. Autoimmune disease patients on IS medications harbor 
higher viral loads of SARS-CoV-2 and have prolonged viral shedding, potentially serving as ongoing sources of community 
infection. Unfortunately, based upon their underlying medical conditions, immunomodulatory medications, and co-
morbid health conditions, very few autoimmune disease patients were studied in the COVID-19 vaccine trials even 
though they may be some of the patients who most need protection (category 1b for vaccines based upon the National 
Academy of Medicine report [15]).  
Early case reports show that a significant number of individuals taking IS medications respond poorly or not at all to 
COVID-19 vaccination. Approximately 26% of 123 chronic inflammatory rheumatic disease patients had undetectable 
SARS-CoV-2 receptor binding domain (RBD) antibody response (Roche Elecsys® enzyme immunoassay) 3 weeks after 
their first messenger ribonucleic acid (mRNA) vaccine dose. Following the second dose of an mRNA vaccine in this 
cohort, significant improvement was seen with only 6% of 404 patients having persistent undetectable SARS-CoV-2 RBD 
antibody [16]. However, those taking MMF or rituximab were at much higher risk of not mounting a detectable response 
or having a very low SARS-CoV-2 RBD antibody response [17]. Another report has demonstrated diminished overall 
serologic response in 133 adults with chronic inflammatory diseases particularly in those treated with B-cell depletion, 
glucocorticoids, or antimetabolites including methotrexate [18]. In another preliminary study of 113 autoimmune 
disease patients after receiving both doses of mRNA vaccine, a 3-fold lesser response in anti-S immunoglobulin G (IgG) 
titers (p = 0.009) and COVID-19 neutralization (p <0.0001) was observed in patients compared to immunocompetent 
controls. Again, diminished responses were most pronounced in patients taking B cell depletion therapies (BCDTs), 
corticosteroids, Janus kinase (JAK) inhibitors, and methotrexate (MTX) [18]. A smaller study of autoimmune disease 
patients (which excluded patients on rituximab or MMF based upon concerns about non-response) [19], showed that all 
26 patients made antibodies after vaccination; however, on average, antibody levels were less than half of levels in 
healthy control patients. Particular IS medications that may impact autoimmune disease patient immune responses to 
vaccination (including B cell depletion, MMF, and calcineurin inhibitors) are also commonly used in transplant recipients, 
other inflammatory diseases, and specific malignancies and have been associated with poor vaccine response. A study of 
SARS-CoV-2 vaccination in Multiple Sclerosis (MS) patients undergoing treatment with anti-CD20 confirmed that 
serologic responses were substantially attenuated (or undetectable), while T-cell responses (including spike-protein 
antigen-specific T-cell responses) were relatively intact [20]. Among 436 transplant recipients, only 76 (17%) mounted a 
detectable antibody response 3 weeks after receiving the first dose of mRNA vaccine, and poor response was associated 
with use of anti-metabolite therapy (mycophenolate and azathioprine, p = 0.001) [21] as well as older age.  
Recent studies have indicated that administration of a vaccine booster dose increases antibody response in solid organ 
transplant recipients. A recent report describes the humoral response in a group of 101 solid organ transplant recipients 
who were given three doses of the Pfizer–BioNTech COVID-19 Vaccine [22]. Among the patients who were seronegative 
before the third dose, 44% were seropositive at 4 weeks after the third dose, and no serious adverse events (SAEs) or 


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acute rejection episodes were reported. A case series has also been reported describing antibody responses and vaccine 
reactions in recipients of solid organ transplants who had a suboptimal response to standard COVID-19 vaccination and 
subsequently received a third dose of vaccine (Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, or 
Janssen COVID-19 Vaccine). The antibody titers increased after the third dose in one third of patients who had negative 
antibody titers and in all patients who had low-positive antibody titers [23]. These data suggest that administration of a 
third dose of COVID-19 vaccine to immunocompromised individuals improves the immunogenicity of the vaccine with no 
safety signals identified.  
Vaccination of autoimmune disease patients may also present efficacy challenges relative to non-autoimmune patients 
for disease-intrinsic reasons. Autoimmune disease patients are more likely to have pre-existing antibodies against RNA, 
RNA-binding proteins, DNA, and adenovirus strains, several of which could potentially limit the effectiveness of the 
related vaccines. In addition, based upon their underlying immune dysregulation, autoimmune disease patients may be 
stimulated to enhanced autoreactivity instead of toward protective vaccine responses. 
In addition, recently published data, consistent with the investigators experience, show that many autoimmune disease 
patients have significant vaccine hesitancy, based upon concerns regarding efficacy and perceived unknown safety in 
patients like them. In a survey of 1,531 participants, including 1,266 autoimmune disease patients enriched in SLE and 
rheumatoid arthritis (RA) patients, only 53% of patients reported being vaccinated or reported they would be vaccinated 
[24]. Within the autoimmune disease communities and patient groups, concerns are raised regarding whether a mRNA-
based vaccine will be safe in those autoimmune diseases where RNA-protein complexes drive autoimmune disease 
pathogenesis, and whether the early infrequent autoimmune/autoinflammatory and thrombotic adverse events (AEs) 
that paused adenoviral-based vaccines could be harbingers of heightened concerns about autoimmune disease SAEs in 
individuals genetically pre-disposed to autoimmune disorders.  
Vaccines using more established technologies, such as adjuvanted protein-based vaccines, may be more palatable to 
vaccine-hesitant individuals. Sanofi-GlaxoSmithKline (GSK) has an AS03-adjuvanted COVID-19 vaccine currently under 
development. While this vaccine has not been used in patients with autoimmune disease, the safety of protein or 
polysaccharide subunit vaccines with adjuvant, including commonly used vaccines for Hepatitis B, Pneumococcus, 
meningococcus, Haemophilus influenzae, and varicella zoster is well-established in this population [25]. Of note, an 
increased risk of narcolepsy, particularly in Sweden, was observed after an influenza vaccination campaign with 
Pandemrix (an AS03-adjuvanted H1N1 pandemic influenza vaccine) in 2009-2010. A similar risk of narcolepsy was not 
identified in other countries with AS03- or MF59-adjuvanted H1N1 pandemic influenza vaccines except for Taiwan 
where the incidence increased after wild-type H1N1 virus circulated in the country [26]. An EMA report in 2016 
concluded that: “Based on the evidence generated so far, a hypothesis that takes into account the potential role of 
antigen is more likely to explain the increased risk of narcolepsy observed with Pandemrix than hypotheses that are 
based on a direct role for the AS03 adjuvant” [27].  
Additional knowledge about vaccination approaches to optimize efficacy and minimize AEs is critical to understand and 
to communicate to autoimmune disease patients, as they could greatly benefit from COVID-19 vaccination.  
1.2 
Clinical Trial Design and Rationale 
1.2.1 Initial Trial Design - Additional Homologous Vaccine Dose 
This clinical trial was initially designed to assess antibody responses to an additional homologous COVID-19 vaccine dose 
and identify methods for improving COVID-19 vaccine responses in patients with 1 of 5 autoimmune diseases. The 
diseases included in the trial (SLE, RA, MS, pemphigus, and systemic sclerosis [SSc]) were chosen based on prevalence 
rates, use of background medications of interest, and/or availability of pre-existing cohorts among the current 
Autoimmune Centers of Excellence (ACE) associated institutions. The medications of interest, MMF/ mycophenolic acid 
(MPA), MTX, and B cell depleting drugs, are used commonly in these patient populations and have been associated with 
poor vaccine response as described above. Only autoimmune disease patients with a negative or suboptimal serologic 
response to the initial COVID-19 vaccine regimen will be included in this clinical trial. Using the Roche Elecsys anti-SARS-
CoV-2 S enzyme immunoassay, Ruddy et al [17]  demonstrated that while many patients with autoimmune diseases 
have apparently robust antibody to COVID-19 vaccines (median response >250 U/ml) that some, particularly in that 
study those treated with mycophenolate and B cell depletion, have poor responses (8 U/ml and <0.4 U/ml, respectively). 


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Data observations presented in the paper suggest that using 50 U/ml is a reasonable threshold for defining a subgroup 
of patients who may benefit the most from an additional dose. This threshold is the same as chosen for the companion 
National Institute of Allergy and Infectious Disease (NIAID)-supported study in solid organ transplantation (COVID19-TB-
02). Additional studies in healthy populations have shown average responses to primary vaccination ranging from 
2,079 U/ml to 4,435 U/ml, and the reported ranges of immune response were all >250 U/ml [28-30]. Only autoimmune 
disease patients with a negative or suboptimal serologic response to initial COVID-19 vaccine regimen, defined as an 
Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL at the Screening visit will be eligible to be included in this trial. The trial will 
also investigate whether transiently withholding IS therapies has an impact on vaccine response. The study will address 
important public health issues by determining which patients with autoimmune diseases are at increased risk for 
suboptimal responses to COVID-19 vaccines and identifying safe and effective strategies to enhance their immune 
response to COVID-19 vaccines. The planned mechanistic studies will provide critical information about the efficacy of 
an additional homologous vaccine dose in autoimmune patients on other components of immune response such as B 
and T cell responses, and whether baseline molecular signatures may predict response.  
The NIAID ACE Network includes nine institutions with large autoimmune disease patient cohorts, strong infrastructures 
for autoimmune disease vaccine clinical trials, talented basic immunologists at the forefront of understanding vaccine 
immune responses, cutting-edge immune-based technologies, and a history of collaborating on projects that transcend 
the expertise and capabilities of any single center.  
1.2.2 Alternative Vaccine Dose Adaptation 
Some immunocompromised individuals will not develop a robust immune response to an additional full dose of 
homologous vaccine and therefore remain at risk to develop severe COVID-19. Early data suggest an additional vaccine 
dose may be effective in eliciting an immune response in kidney transplant recipients on IS medications [31]. In a study 
of 92 kidney transplant recipients with suboptimal immune responses after the third vaccine dose, 54.3% of participants 
reached a threshold of 143 BAU/mL on anti-spike IgG titers after a fourth dose was administered. As autoimmune 
patients on IS therapies have a similar risk of suboptimal immune responses, an additional dose of vaccine may be an 
effective method of eliciting a robust immune response. The Centers for Disease Control and Prevention (CDC) has 
recently endorsed the use of an additional dose of a COVID-19 vaccine in immunocompromised individuals [32].  
Recent data suggest that a heterologous vaccine dose following the initial vaccine series is both safe and efficacious in 
healthy individuals. Heterologous boosters of all vaccines were found to be immunogenic and the “fold increases from 
baseline in both binding and neutralizing antibody titers were similar or greater after heterologous boosts compared to 
homologous boosts.” Reactogenicity did not differ from prior evaluations of the Moderna, Pfizer-BioNTech, and Janssen 
COVID-19 vaccines and did not differ between patients receiving the heterologous and homologous boosts [33].  
Per the Sanofi-GSK vaccine press release (February 23, 2022), in participants who had received a primary series of an 
already authorized mRNA or adenovirus vaccine (i.e., different platforms), the Sanofi-GSK booster vaccine (prototype 
CoV2 preS dTM [D614] vaccine [5 mcg] with AS03) induced a significant increase in neutralizing antibodies of 18- to 30-
fold across vaccine platforms and age groups. When the Sanofi-GSK vaccines were used as a 2-dose primary series 
followed by a booster dose, neutralizing antibodies increased 84- to 153-fold compared to pre-boost levels [34]. Under 
the alternative vaccine adaptation, participants who agree to receive a fourth dose of vaccine will receive an alternative 
vaccine dose.  
Originally, participants who previously received 3 total doses of a single mRNA vaccine (Moderna COVID-19 Vaccine OR 
Pfizer-BioNTech COVID-19 Vaccine) received their choice of either the Janssen vector-based COVID-19 vaccine or the 
other mRNA COVID-19 vaccine.  
Beginning with v4.0 of the protocol, this trial will not utilize the Janssen vector-based COVID-19 vaccine. Participants 
who previously received 3 total doses of a single mRNA vaccine will receive a choice of an alternative mRNA COVID-19 
vaccine or the Sanofi-GSK protein-based COVID-19 vaccine. Participants who previously received 4 or more doses of a 
single mRNA vaccine or 3 or more doses of a mixture mRNA vaccines (Moderna COVID-19 Vaccine AND Pfizer-BioNTech 
COVID-19 Vaccine) will receive the Sanofi-GSK protein-based COVID-19 vaccine. 


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Participants who previously received 2 doses of the Janssen vector-based COVID-19 vaccine will receive the Moderna 
COVID-19 Vaccine. This alternative Moderna dose will be a full vaccine dose, not a reduced vaccine booster dose.  
Beginning with v6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech COVID-19 
vaccines, replaced original monovalent versions. In addition, autoimmune disease patients with a negative or 
suboptimal serologic response to the initial COVID-19 vaccine regimen (defined as an Elecsys® Anti-SARS-CoV-2 S result 
≤200 U/mL at the Screening visit), or with a low immune response (defined as an Elecsys® Anti-SARS-CoV-2 S result >200 
U/ml and ≤2500 U/mL at the Screening visit) are eligible to receive an additional or homologous or alternative vaccine 
dose.  The threshold of Roche Elecsys® anti-RBD assay ≤2500 U/ml SARS-CoV-2 S antibody concentration has been 
chosen based on a study of immunosuppressed organ transplant candidates, which showed that low anti‐RBD titers 
after the third dose of mRNA‐1273 was associated with low prevalence of Omicron BA.1 neutralizing antibodies [35]. In 
addition, a recent study using a cohort of health-care workers estimated that subsequent Omicron BA.4/5 neutralizing 
titers may be as much as 5-fold lower [36].  
Cohort-defining IS medications (MMF/MPA and MTX) will be held by all participants around the time of vaccination, as 
appropriate, in an effort to improve the likelihood of a robust response to the alternative vaccine.  
1.2.3 Pediatric Adaptation 
While children have more often experienced mild disease from SARS-CoV-2 infection, severe disease occurs resulting in 
admission to the intensive care unit and death [37].COVID-NET data revealed a significant increase in hospitalization 
during the recent Delta variant surge, with approximately 10 times higher rates of admission of unvaccinated 
adolescents compared to those who were vaccinated [38].   
There are limited reports of the impact of SARS-CoV-2 infection in children with rheumatic disease. A recent study 
described SARS-CoV-2 infection and related outcomes in a large cohort of children with rheumatic disease on 
immunomodulatory medications [39].  In the cohort of 262 subjects in which juvenile idiopathic arthritis (JIA) and 
SLE/other connective tissue diseases were the most common diagnoses, there was an estimated 13% rate of SARS-CoV-2 
infection. Half of the IgG-positive subjects had no symptoms, and those taking immunomodulatory medications were 
not more likely to be IgG positive. Infected subjects had mild disease with no deaths or no one requiring hospitalization. 
Sengler et al. evaluated the clinical features and outcomes in children with rheumatic disease from the National 
Paediatric Rheumatology Database from Germany [40]. A diagnosis of JIA was the most common in their cohort of 
76 children, and 76% were treated with IS medications. The majority of subjects had testing due to COVID exposure, 
while only approximately one third experienced any symptoms. A total of 76% of subjects developed symptoms of SARS-
CoV-2, and the majority (96%) had mild symptoms. Two children were hospitalized, one of whom died from 
cardiorespiratory failure. Further study of the deceased patient suggested a possible underlying immunodeficiency and 
not a rheumatic disease as the correct diagnosis. Most (78%) patients with symptoms reported full recovery by 
approximately 4 weeks. The authors were not able to comment on the impact of medication exposure and co-
morbidities on manifestations of SARS-CoV-2 infections in this population. 
In adolescents 12 to 18 years of age, vaccination has been found very effective in preventing COVID-19 hospitalization, 
with an effectiveness estimate of 93% [41]. This effectiveness rate was determined during the period of time when the 
Delta variant was pervasive and having a significant impact on the pediatric population. Of the 464 hospitalized 
adolescents studied, 72% were reported to have at least one underlying condition, and of those, a small proportion (2%) 
had a non-oncologic IS disorder. Most hospitalized patients (97%) were unvaccinated, and all of those who were 
admitted to the intensive care unit or died were unvaccinated.  
COVID-19 vaccination is recommended for all individuals with autoimmune and inflammatory rheumatic disease 
consistent with the age restrictions of the vaccine Emergency Use Authorizations (EUAs) or FDA approvals [42]. Rigorous 
studies of the impact of IS therapy on COVID-19 vaccination response in children with rheumatic disease are needed to 
guide the clinician in effective counsel and management of this population. There is one published study of the clinical 
impact of COVID-19 vaccination in adolescent patients with JIA treated with tumor necrosis factor (TNF) inhibitors [43]. 
This study enrolled 21 patients with inactive JIA between 16 and 21 years of age. Following vaccination, patients were 
monitored for AEs and changes in disease activity, as measured by the Juvenile Arthritis Disease Activity Score-27 
(JADAS-27). Most patients (74%) experienced localized reactions, but systemic reactions did occur rarely (19% of 






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years were presented to the Vaccines and Related Biological Products Advisory Committee in June 2022 [49, 52]. 
Immune responses in subsets of each age group were generally comparable to those seen in adult participants. Among 
approximately 5,400 children, the vaccine was 50.6% effective in preventing COVID-19 in participants 6 through 23 
months of age 36.8% effective in preventing COVID-19 in participants 2 through 5 years of age. No severe cases of 
COVID-19 were observed. Across all pediatric age cohorts, adverse reactions included pain, redness and swelling at the 
injection site, fever and axillary swelling/tenderness. In participants 6 through 36 months of age, side effects also 
included irritability/crying, sleepiness, and loss of appetite. In participants 37 months through 5 years of age, side effects 
also included fatigue, headache, muscle ache, chills, nausea/vomiting and joint stiffness. The safety of the bivalent form 
of the Moderna COVID-19 Vaccine is based on a clinical study that evaluated a booster dose of Moderna’s bivalent 
COVID-19 vaccine (Original and Omicron BA.1). Adverse reactions following a booster dose included pain at the injection 
site, fatigue, headache, myalgia, arthralgia, chills, axillary swelling/tenderness, nausea/vomiting, erythema at the 
injection site, swelling at the injection site, and fever [48].  
The safety and efficacy of the Pfizer-BioNTech COVID-19 Vaccine has been evaluated in 2 clinical studies  [53, 54]. The 
BNT162-01 study (NCT04380701) was a phase 1/2 trial that enrolled 60 participants, 18 through 55 years of age. Study 
C459001 (Study 2) is an ongoing phase 1/2/3 study that has enrolled approximately 44,000 participants, 12 years of age 
or older that were randomized equally and received 2 doses of Pfizer-BioNTech COVID-19 Vaccine or placebo separated 
by 21 days. The population for the analysis of the primary efficacy endpoint included 36,621 participants 12 years of age 
and older (18,242 in the Pfizer-BioNTech COVID-19 Vaccine group and 18,379 in the placebo group) who did not have 
evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. At the time of the analysis of Study 2 
for the EUA, 37,586 participants 16 years of age or older (18,801 Pfizer-BioNTech COVID-19 Vaccine and 18,785 placebo) 
have been followed for a median of 2 months after the second dose of Pfizer-BioNTech COVID-19 Vaccine. Overall, there 
were 8 COVID-19 cases in the Pfizer-BioNTech COVID-19 Vaccine group and 162 cases in the placebo group, with a 
vaccine efficacy of 95% (95% CI 90.3-97.6). Adverse reactions following the Pfizer-BioNTech COVID-19 Vaccine that have 
been reported in clinical trials include injection site pain, fatigue, headache, muscle pain, chills, joint pain, fever, 
injection site swelling, injection site redness, nausea, malaise, and lymphadenopathy[55]. Data were presented to the 
Vaccines and Related Biological Products Advisory Committee for children 5 through 11 years in October 2021 [56, 57], 
and for children 6 months through 4 years in June 2022 [49, 52].  In both age groups, immune responses were generally 
comparable to those seen in adult participants. In a preliminary analysis of approximately 2,000 participants ages 5 
through 11 years, the vaccine was 90.7% effective in preventing COVID-19. No cases of severe COVID-19 were observed. 
Among 860 participants ages 2 through 4 years, the vaccine was 82.4% effective in preventing COVID-19. One 
hospitalization for severe COVID-19 was observed. Adverse reactions following the Pfizer-BioNTech COVID-19 Vaccine 
that have been reported in participants ages 5 through 17 years include injection site pain, redness and swelling, fatigue, 
headache, muscle and/or joint pain, chills, fever, swollen lymph nodes, nausea, and decreased appetite. For participants 
6 months through 4 years of age included irritability, decreased appetite, fever, headache, chills and pain, tenderness, 
redness and swelling at the injection site. The safety of the bivalent form of the Pfizer-BioNTech COVID-19 Vaccine is 
based on a clinical study which evaluated a booster dose of Pfizer-BioNTech’s bivalent COVID-19 vaccine (Original and 
Omicron BA.1). Adverse reactions following a booster dose included injection site pain, fatigue, headache, muscle pain, 
chills, joint pain, injection site swelling, fever, injection site redness, lymphadenopathy, nausea, malaise, pain in 
extremity, rash, and decreased appetite [58]. 
In an ongoing, global, multicenter, randomized trial, 44,325 participants (age 18 and older) were randomized to receive 
a single dose of the Janssen COVID-19 Vaccine or a saline placebo (NCT04505722). The primary efficacy analysis 
population of 39,321 individuals (19,630 in the Janssen COVID-19 Vaccine group and 19,691 in the placebo group) 
included 38,059 SARSCoV-2 seronegative individuals at Baseline and 1,262 individuals with an unknown serostatus. The 
median length of follow up for efficacy for individuals in the study was 8 weeks post vaccination. Vaccine efficacy for the 
co-primary endpoints against moderate to severe/critical COVID-19 in individuals who were seronegative or who had an 
unknown serostatus at Baseline was 66.9% (95% CI 59.0-73.4) at least 14 days after vaccination and 66.1% (95% CI 55.0-
74.8) at least 28 days after vaccination. Vaccine efficacy against severe/critical COVID-19 at least 14 days after 
vaccination was 76.7% (95% CI 54.6-89.1) and 85.4% (95% CI 54.2-96.9) at least 28 days after vaccination. As of the 
primary analysis cut-off date of January 22, 2021, there were no COVID-19-related deaths reported in Janssen COVID-19 
Vaccine recipients compared to 5 COVID-19-related deaths reported in placebo recipients, who were SARS-CoV-2 PCR 


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negative at Baseline. Adverse reactions reported in a clinical trial following administration of the Janssen COVID-19 
Vaccine include injection site pain, headache, fatigue, nausea, fever, injection site erythema, and injection site swelling. 
In clinical studies, severe allergic reactions, including anaphylaxis, have been reported following the administration of 
the Janssen COVID-19 Vaccine [59].  
The Phase 3 trial VAT00008 (NCT04904549), sponsored by Sanofi, is evaluating a 10 µg antigen formulation of a SARS-
CoV-2 adjuvanted, recombinant, protein-based vaccine for efficacy, immunogenicity, and safety compared to a placebo. 
Stage One of the trial is assessing the efficacy of a vaccine formulation containing the spike protein from the original 
D614 (parent) virus in more than 10,000 participants aged 18 years and older who are randomized to receive 2 doses of 
10 µg vaccine or placebo at Day 1 and Day 22 across sites in the US, Asia, Africa, and Latin America. Enrollment recently 
completed for a second stage in the trial evaluating a bivalent formulation that contains the spike protein of both the 
original virus and the B.1.351 (Beta) variant. The Phase 3 trial follows positive initial results from a Phase 2 clinical trial 
(VAT00002; NCT04762680) [60]. In that trial, the COVID-19 vaccine candidate was administered to 722 adults to assess 
the safety, reactogenicity, and immunogenicity of 2 doses and to identify an optimal dosing for use as a booster. Results 
showed strong rates of neutralizing antibody response with 95% to 100% seroconversion following a second injection in 
all adult age groups (18 to 95 years old) across all doses. In the Supplemental Booster Cohort 2 of the VAT00002 trial, 
the safety and immunogenicity of the B.1.351 monovalent booster vaccine has been evaluated in over 1300 individuals 
previously primed with mRNA or adenovirus-vectored COVID-19 vaccines. In a randomized, blinded clinical study 
sponsored by Assistance Publique – Hôpitaux de Paris, evaluating the safety and immunogenicity of heterologous 
boosting with the Sanofi-GSK monovalent CoV2 preS dTM (Beta) and monovalent (D614) vaccines following a 2-dose 
primary series of BNT162b2 compared to a homologous BNT162b2 third dose (NCT05124171), the Sanofi-GSK Beta 
vaccine elicited a higher neutralizing antibody response against the SARS-CoV-2 D614G, Beta, Delta, and Omicron BA.1 
variants compared  with boosting with the BNT162b2 vaccine or the Sanofi-GSK D614 vaccine. This study, which included 
223 participants in the per-protocol population, also found that all 3 boosters were well tolerated and not associated 
with any safety concerns.  
Supplemental cohorts are currently being studied by Sanofi and GSK to address the safety and efficacy of various prime-
boost options. Individuals who were initially vaccinated with other vaccine platforms are being given different 
formulations of the of the CoV2 preS dTM-AS03 vaccine, including monovalent (D614 or B.1.351) and bivalent (D614 + 
B.1.351) forms, for use as a universal late booster. ACV01 will evaluate the safety and immunogenicity of a boost with 
the Beta (B.1.351) variant-containing vaccine formulation (CoV2 preS dTM-AS03 [B.1.351]) in individuals with 
autoimmune diseases on IS medications who have had an inadequate response to previous COVID-19 vaccines.  
2. 
Study Hypotheses/Objectives 
• 
We hypothesize that adult and pediatric participants with autoimmune diseases requiring IS medications who 
have had a suboptimal response (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL) to an initial 
COVID-19 vaccine regimen may demonstrate enhanced immune response after receiving an additional 
homologous dose of an mRNA or vector-based vaccine.  
• 
We hypothesize that pediatric participants with autoimmune diseases requiring IS medications who have a low 
immune response (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result >200 U/ml and ≤2500 U/mL) after an 
initial COVID-19 vaccine regimen may demonstrate enhanced immune response after receiving an additional 
dose of an additional homologous COVID-19 vaccine.  
• 
We hypothesize that adult and pediatric participants with transient cessation of MMF/MPA or MTX before and 
after vaccination will have an enhanced immune response. 
• 
We hypothesize that adult and pediatric participants with autoimmune diseases requiring IS medications who 
continue to have a suboptimal response after an initial COVID-19 vaccine regimen plus additional vaccine doses 
may demonstrate enhanced immune response after receiving an additional dose of an alternative COVID-19 
vaccine.  


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• 
We hypothesize that adult and pediatric participants with autoimmune diseases requiring IS medications who 
have a low immune response after an initial COVID-19 vaccine regimen plus additional vaccine doses may 
demonstrate enhanced immune response after receiving an additional dose of an alternative COVID-19 vaccine. 
 
 
2.1 
Primary Objective 
The primary objective is to determine the proportions of adult and pediatric participants who have a protective antibody 
response at 4 weeks after an additional homologous dose of a COVID-19 vaccine using the NIAID Vaccine Research 
Center (NIAID-VRC) MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay within arms defined by the initial 
COVID-19 vaccine regimen received, IS regimens, and treatment plans to either withhold or continue medications 
around the time of vaccination. 
2.2 
Secondary Objectives 
2.2.1 Stage 1 Secondary Objectives 
These secondary objectives are applicable to both the adult and pediatric populations. 
• 
To determine the incidence of seroconversion following an additional homologous COVID-19 vaccine dose in the 
subgroup of participants that are anti-COVID-19 antibody negative at Baseline. 
• 
To assess the immune response following an additional homologous COVID-19 vaccine dose in the subgroup of 
participants that had a low immune response following a previous COVID-19 vaccine dose. 
• 
To determine the incidence of AEs, including medically attended adverse events (MAAEs), new onset chronic 
medical conditions (NOCMCs), and SAEs following an additional homologous COVID-19 vaccine dose. 
• 
To assess whether responses to an additional homologous COVID-19 vaccine dose differ with temporary 
cessation of IS medications around the time of vaccine. 
• 
To assess whether responses to an additional homologous COVID-19 vaccine dose differ by type of vaccine 
administered.  
• 
To assess whether responses to an additional homologous COVID-19 vaccine dose differ by type of cohort-
defining IS medications and by disease type. 
• 
To assess whether response to an additional homologous COVID-19 vaccine dose is associated with 
corticosteroid dose at the time of vaccination.  
• 
To assess whether response to an additional homologous COVID-19 vaccine dose is associated with clinical 
parameters including disease activity, co-morbid illness, age, and sex. 
• 
To determine whether disease activity is increased following an additional homologous COVID-19 vaccine dose, 
and if so, whether Baseline or induced immunologic variables are associated with increased disease activity 
and/or vaccination response. 
2.2.2 Stage 2 Secondary Objectives 
These secondary objectives are applicable to both the adult and pediatric populations. 
• 
To determine the proportions of participants with a negative serologic or suboptimal response to a previous 
COVID-19 vaccine administration who develop a protective antibody response after receiving a subsequent 
alternative vaccine dose, evaluated using the NIAID-VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N 
proteins) assay. 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
• 
To assess the immune response following a subsequent alternative vaccine dose in the subgroup of participants 
that had a low immune response following a previous COVID-19 vaccine dose. 
• 
To determine the incidence of seroconversion following a subsequent alternative vaccine dose in the subgroup 
of participants that are anti-COVID-19 antibody negative following a previous COVID-19 vaccine dose. 
• 
To determine the incidence of AEs, including MAAEs, NOCMCs, and SAEs following a subsequent alternative 
COVID-19 vaccine dose. 
• 
To assess whether responses to a subsequent alternative COVID-19 vaccine dose differ by type of vaccine 
administered.  
• 
To assess whether responses to a subsequent alternative COVID-19 vaccine dose differ by type of cohort-
defining IS medications and by disease type. 
• 
To assess whether response to a subsequent alternative COVID-19 vaccine dose is associated with corticosteroid 
dose at the time of vaccination.  
• 
To assess whether response to a subsequent alternative COVID-19 vaccine dose is associated with clinical 
parameters including disease activity, co-morbid illness, age, and sex. 
 
• 
To determine whether disease activity is increased following a subsequent alternative COVID-19 vaccine dose, 
and if so, whether immunologic variables are associated with increased disease activity and/or vaccination 
response. 
2.3 
Exploratory Objectives 
The exploratory objectives are applicable to both the adult and pediatric populations. 
• 
To evaluate whether Baseline CD19 positive B cell numbers associate with response to an additional study 
COVID-19 vaccine dose in the cohort that have received BCDT. 
• 
To evaluate the association between immune response and levels of SARS-CoV-2 antibodies at Baseline. 
• 
To evaluate the levels of Baseline interferon signal or interferon gamma-inducible protein (IP-10) serum levels 
that associate with an effective vaccine immune response. 
• 
To evaluate the levels of Baseline inflammatory signals that associate with an effective vaccine immune 
response. 
• 
To evaluate the association between immune response to an additional study COVID-19 vaccine dose and 
cellular and mechanistic endpoints. 
3. 
Study Design 
3.1 
Description of Study Design  
This is a randomized, multi-site, adaptive, open-label clinical trial comparing the immune response to different 
additional doses of COVID-19 vaccine in participants with autoimmune disease requiring IS medications. All study 
participants will have negative serologic or suboptimal responses (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result 
≤200 U/mL) or a low immune response (defined as a Roche Elecsys® Anti-SARS-CoV-2 S result >200 U/ml and ≤2500 
U/mL) to their previous doses of COVID-19 vaccine.  
3.1.1 Adult Population 
3.1.1.1 
Adult Stage 1 
Stage 1 of this trial will enroll up to a maximum of 900 adult study participants (up to 60 participants per arm). The trial 
initially focused on adults with at least 1 of 5 autoimmune diseases: SLE, RA, MS, SSc, and pemphigus. 


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Participants will be assigned to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort A: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) will 
be placed in this cohort.  
• 
Cohort B: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX (without additional B cell depleting medications or MMF/ MPA) will be 
placed in this cohort.  
• 
Cohort C: Receipt of BCDT within the past 18 months (± other rheumatic disease medications) 
o Participants taking B cell depletion medications, regardless of whether they are also taking MMF or 
MTX, will be placed in this cohort. 
Treatment Arms: Participants in Cohorts A, B, and C will be assigned to receive an additional dose of the same COVID-19 
vaccine as their original vaccine series. 
Participants in Cohorts A and B will be randomized into 2 IS medication treatment plans as follows:  
• 
Participants continue to take their IS medications without alterations in schedule and dosing.  
• 
Participants withhold their cohort-defining IS medications before and after the additional homologous vaccine 
dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).  
All potential treatment arms for Adult Stage 1 are detailed in Table 2.  
Update:  Arms to receive an additional homologous vaccine dose after an initial Janssen COVID 19 Vaccine were closed 
to enrollment after the CDC updated its recommendations to express a clinical preference for individuals to receive an 
mRNA COVID-19 vaccine over the Janssen COVID-19 vaccine. All Adult Stage 1 treatment arms were closed to 
enrollment on 15 August 2022.  
Schedule of Events: Visits to assess endpoints will occur at Baseline (Week 0), Week 4 ± 1 week, Week 12 ± 2 weeks, 
Week 24 ± 2 weeks, Week 36 ± 2 weeks, and Week 48 ± 2 weeks. Participant and study flow diagrams are provided in 
Figure 1 and Figure 2, respectively.  
An Adult Stage 1 participant will be enrolled in the study for a maximum of approximately 13 months.  
 
 




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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Figure 1. Participant Flow Diagram for Adult Stage 1 (Closed) 
 
IS = immunosuppressive medications; MMF = mycophenolate mofetil; MPA = mycophenolic acid; MS = multiple sclerosis; MTX = methotrexate; 
RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SSc = systemic sclerosis 
 
Figure 2. Study Flow for Adult Stage 1 (Closed) 
 
IS = immunosuppressive medication 
 


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3.1.1.2 
Adult Stage 2 
Stage 2 of this trial will include up to a maximum of 960 adult study participants (up to 80 per arm) with a Roche 
Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after previous COVID-19 vaccine administration (at least 3 doses of mRNA 
vaccine(s) or 2 doses of the Janssen COVID-19 Vaccine). Participants will be eligible to receive a dose of an alternative 
COVID-19 vaccine.  
Participants may have received their previous COVID-19 vaccine prior to enrollment in the study (“newly recruited 
participant”), or they may have received their previous COVID-19 vaccine as a study participant and then (re-) enter into 
Stage 2 (“rollover participant”).  
Newly recruited Stage 2 participants will be evaluated for eligibility per Section 4.2.1.2.1 Inclusion and Exclusion Criteria 
for Adult Stage 2 Newly Recruited Participants. 
Participants can also roll over into Stage 2 via two pathways: 
• 
Stage 1 participant rolls over to Stage 2 
o A Stage 1 participant who has a Roche Elecsys result ≤2500 U/mL at a post-Baseline visit may elect to roll 
over into Stage 2, starting the Stage 2 schedule of events for rollovers.  
• 
Stage 2 participant rolls over to a different Stage 2 treatment arm 
o A Stage 2 participant who received an alternative mRNA vaccine dose and has a Roche Elecsys result 
≤2500 U/mL at a post-Baseline visit may elect to re-enter Stage 2, restarting the Stage 2 schedule of 
events for rollovers.  
Rollover participants will be evaluated for Stage 2 eligibility per Section 4.2.1.2.2 Inclusion and Exclusion Criteria for 
Adult Stage 2 Rollover Participants. 
Participants will be allocated to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort D: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) will 
be placed in this cohort.  
• 
Cohort E: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX (without additional B cell depleting medications or MMF/ MPA) will be 
placed in this cohort.  
• 
Cohort F: Receipt of BCDT within the past 18 months (± other rheumatic disease medications) 
o Participants taking B cell depletion medications, regardless of whether they are also taking MMF or 
MTX, will be placed in this cohort. 
Treatment Arms: Table 3 describes the vaccines available to newly recruited participants and Table 4 describes the 
vaccines available to rollover participants depending on the previous COVID-19 vaccines they received. Participants in 
Cohorts D, E, and F will receive a dose of an alternative COVID-19 vaccine compared to their previous COVID-19 vaccine 
doses. Originally, participants who previously received 3 total doses of a single mRNA vaccine (Moderna COVID-19 
Vaccine OR Pfizer-BioNTech COVID-19 Vaccine) received their choice of either the Janssen vector-based COVID-19 
vaccine or the other mRNA COVID-19 vaccine, and participants who previously received 2 doses of the Janssen vector-
based COVID-19 vaccine received the Moderna COVID-19 Vaccine.  
Update:  Beginning with v4.0 of the protocol, this trial will not utilize the Janssen vector-based COVID-19 vaccine. 
Participants who previously received 3 total doses of a single mRNA vaccine will receive their choice of an alternative 
mRNA COVID-19 vaccine or the Sanofi-GSK protein-based COVID-19 vaccine. Participants who previously received 4 or 
more doses of a single mRNA vaccine or 3 or more doses of a mixture mRNA vaccines (Moderna COVID-19 Vaccine AND 
Pfizer-BioNTech COVID-19 Vaccine, in any order or combination) will receive the Sanofi-GSK protein-based COVID-19 


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vaccine. Beginning with v6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech 
COVID-19 vaccines, replaced original monovalent versions.  
Participants in Cohorts D and E will withhold their cohort-defining IS medications before and after the alternative 
vaccine dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).  
Participants in Cohort F who are taking MMF, MPA, or MTX in addition to BCDTs will withhold these medications before 
and after the alternative vaccine dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).  
All potential treatment arms for Adult Stage 2 are detailed in Table 5. 
Schedule of Events: Visits to assess endpoints will occur at Baseline (Week 0), Week 4 ± 1 week, Week 12 ± 2 weeks, 
Week 24 ± 2 weeks, Week 36 ± 2 weeks, and Week 48 ± 2 weeks. Participant and study flow diagrams for Stage 2 are 
provided in Figure 3 and Figure 4, respectively.  
A participant who is newly recruited to the study for entry into Stage 2 may be on study for up to a maximum of 13 
months. A participant who enters Stage 2 after a serologic negative, suboptimal, or low immune response to their Stage 
1 vaccine dose may be on study for up to a maximum of 26 months. Rollover participants will discontinue follow-up as 
part of Stage 1 upon rollover into Stage 2. A participant who rolls over to a different Stage 2 treatment arm after a 
serologic negative,  suboptimal, or low immune response to another Stage 2 vaccine dose may be on study for up to a 
maximum of 38 months. 
Table 3. Vaccines Available to Adult Stage 2 Newly Recruited Participants 
Previous Vaccines Received 
Vaccine Option for Study Treatment Stage Two: 
First Dose 
3 doses of the same mRNA COVID-19 vaccine 
A choice of an alternative mRNA COVID-19 
bivalent vaccine OR Sanofi-GSK COVID-19 
Vaccine 
4 or more doses of the same mRNA COVID-19 
vaccine 
Sanofi-GSK COVID-19 Vaccine 
3 or more doses of a mixture of Moderna mRNA 
and Pfizer mRNA COVID-19 vaccines 
Sanofi-GSK COVID-19 Vaccine 
2 doses of Janssen COVID-19 
Moderna COVID-19 Vaccine, bivalent  
 
Table 4. Vaccines Available to Adult Stage 2 Rollover Participants 
Previous Vaccines Received 
Vaccine Option for Study Treatment Stage Two: 
First Dose 
3 doses of the same mRNA COVID-19 vaccine 
A choice of an alternative mRNA COVID-19 
bivalent vaccine OR Sanofi-GSK COVID-19 
Vaccine 
2 doses of Janssen COVID-19 vaccine 
Moderna COVID-19 Vaccine, bivalent  
 
Previous Vaccines Received 
Vaccine Option for Study Treatment Stage Two: 
Second Dose 
3 doses of Moderna mRNA COVID-19 vaccine 
followed by 1 dose of Pfizer mRNA COVID-19 
vaccine 
Sanofi-GSK COVID-19 Vaccine 
3 doses of Pfizer mRNA COVID-19 vaccine 
followed by 1 dose of the Moderna mRNA COVID-
19 vaccine 
Sanofi-GSK COVID-19 Vaccine 
 




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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Figure 3. Participant Flow Diagram for Adult Stage 2 
 
IS = immunosuppressive medications; MMF = mycophenolate mofetil; MPA = mycophenolic acid; MS = multiple sclerosis; MTX = methotrexate; 
RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SSc = systemic sclerosis 
 
Figure 4. Study Flow for Adult Stage 2 
 
 
IS = immunosuppressive; MMF = mycophenolate mofetil; MPA = mycophenolic acid 
 


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3.1.2 Pediatric Population 
3.1.2.1 
Pediatric Stage 1  
The pediatric portion of this trial will enroll up to a maximum of 800 participants (2 through 17 years of age) with a 
Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after receiving an age-appropriate EUA-authorized initial COVID-19 
vaccine regimen as shown in Table 6 (up to 80 participants per arm). Vaccines will be included in this protocol as they 
receive EUA or approval by FDA for a given age group. Pediatric participants will have 1 of 4 autoimmune diseases: 
pediatric SLE, JIA, JDM, or POMS. 
Participants will be assigned to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort A: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) will 
be placed in this cohort.  
• 
Cohort B: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX (without additional B cell depleting medications or MMF/ MPA) will be 
placed in this cohort.  
• 
Cohort C: Receipt of BCDT within the past 18 months (± other rheumatic disease medications) 
o Participants taking B cell depletion medications, regardless of whether they are also taking MMF or 
MTX, will be placed in this cohort. 
Treatment Arms: Participants in Cohorts A, B, and C will be assigned to receive an additional dose of the same COVID-19 
vaccine as their original vaccine series. Table 6 describes the age-appropriate qualifying initial COVID-19 vaccine regimen 
for participation in Pediatric Stage 1. 
Update:  Beginning with v6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech 
COVID-19 vaccines, replaced original monovalent versions. 
Participants in Cohorts A and B will be randomized into 2 IS medication treatment plans as follows:  
• 
Participants continue to take their cohort-defining IS medications without alterations in schedule and dosing.  
• 
Participants withhold their cohort-defining IS medications before and after the additional homologous vaccine 
dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).  
All potential treatment arms for the pediatric population are detailed in Table 7. As of the date of Protocol Version 5.0, 
the Pfizer-BioNTech and Moderna COVID-19 vaccines have been authorized for use in children (ages 6 months through 
17 years) in addition to adults. 
Schedule of Events: Visits to assess endpoints will occur at Baseline (Week 0), Week 4 ± 1 week, Week 12 ± 2 weeks, 
Week 24 ± 2 weeks, Week 36 ± 2 weeks, and Week 48 ± 2 weeks. Participant and study flow diagrams are provided in 
Figure 5 and Figure 6, respectively.  
A pediatric participant will be enrolled in the study for a maximum of approximately 13 months.  
 
 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Table 6. Initial COVID-19 Vaccine Regimens Qualifying Participants for Pediatric Stage 1 and ACV01 Stage 1 Study Doses 
Pfizer-BioNTech COVID-19 Vaccine 
Age of Participant 
Qualifying Regimen 
ACV01 Stage 1 Study Dose 
2 years through 4 years 
3 doses of 3 mcg 
3 mcg bivalent 
5 years through 11 years *  
2 doses of 10 mcg 
10 mcg bivalent 
12 years through 17 years ** 
2 doses of 30 mcg 
30 mcg bivalent 
* Individuals who turned from 4 years to 5 years of age between any doses in the primary series may also have received one or two doses of 3 mcg 
as part of the qualifying regimen. Individuals who turned from 4 years to 5 years of age after completion of the primary series may also have 
received three doses of 3 mcg as the qualifying regimen. 
 
**Individuals who turned from 11 years to 12 years of age between doses in the primary regimen may also have received one or two doses of 
10 mcg as part of the qualifying regimen. Individuals who turned from 11 years to 12 years of age after completion of the primary series may also 
have received two doses of 10 mcg as the qualifying regimen. 
 
Moderna COVID-19 Vaccine 
Age of Participant 
Qualifying Regimen 
ACV01 Stage 1 Study Dose 
2 years through 5 years 
2 doses of 25 mcg  
25 mcg bivalent 
6 years through 11 years * 
2 doses of 50 mcg  
50 mcg bivalent 
12 years through 17 years ** 
2 doses of 100 mcg  
100 mcg bivalent 
* Individuals who turned from 5 years to 6 years of age between any doses in the primary series may also have received one or two doses of 
25 mcg as part of the qualifying regimen. Individuals who turned from 5 years to 6 years of age after completion of the primary series may also 
have received two doses of 25 mcg as the qualifying regimen. 
 
**Individuals who turned from 11 years to 12 years of age between doses in the primary regimen may also have received one or two doses of 
50 mcg as part of the qualifying regimen. Individuals who turned from 11 years to 12 years of age after completion of the primary series may have 
received two doses of 50 mcg as the qualifying regimen. 
 
 


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Table 7. Treatment Arm Assignments in Pediatric Stage 1 
 
  
Additional Homologous Vaccine 
Dose* 
Randomized Treatment 
Plan 
Cohort A: MMF or MPA  
 
ARM A1P 
Moderna COVID-19 Vaccine 
Continue MMF/MPA 
ARM A2P 
Pfizer-BioNTech COVID-19 Vaccine 
Continue MMF/MPA 
ARM A4P 
Moderna COVID-19 Vaccine  
Withhold MMF/MPA 
ARM A5P 
Pfizer-BioNTech COVID-19 Vaccine 
Withhold MMF/MPA 
Cohort B: Methotrexate  
 
ARM B1P 
Moderna COVID-19 Vaccine 
Continue MTX 
ARM B2P 
Pfizer-BioNTech COVID-19 Vaccine 
Continue MTX 
ARM B4P 
Moderna COVID-19 Vaccine  
Withhold MTX 
ARM B5P 
Pfizer-BioNTech COVID-19 Vaccine 
Withhold MTX 
Cohort C: B cell depletion therapy  
 
ARM C1P 
Moderna COVID-19 Vaccine 
N/A 
ARM C2P 
Pfizer-BioNTech COVID-19 Vaccine 
N/A 
IS = immunosuppressive; MMF = mycophenolate mofetil; MPA = mycophenolic acid 
*Bivalent vaccines will be administered per Section 6, Investigational Agents 
 
 
 
  


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Figure 5. Participant Flow Diagram for Pediatric Stage 1
 
IS = immunosuppressive medications; JDM = juvenile dermatomyositis; JIA = juvenile idiopathic arthritis; POMS = pediatric-onset multiple sclerosis; 
MMF = mycophenolate mofetil; MPA = mycophenolic acid; MTX = methotrexate; SLE = systemic lupus erythematosus 
Figure 6. Study Flow Diagram for Pediatric Stage 1 
 
IS = immunosuppressive medication 
 


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3.1.2.2 
Pediatric Stage 2 
Stage 2 of this trial will include up to a maximum of 480 pediatric study participants (up to 80 per arm) with a Roche 
Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL after previous COVID-19 vaccine administration (an age-appropriate EUA-
authorized or FDA-approved initial COVID-19 vaccine regimen plus 1 additional dose of the same vaccine as shown in 
Table 8). All participants (2-17 years of age) who previously received doses of the Pfizer-BioNTech COVID-19 Vaccine are 
eligible to receive an age-appropriate dose of the Moderna COVID-19 Vaccine. Participants 12 through 17 years of age 
who previously received doses of the Moderna COVID-19 vaccine are eligible to receive an age-appropriate dose of the 
Pfizer-BioNTech COVID-19 Vaccine.  
Participants will be eligible to receive a dose of an alternative COVID-19 vaccine. Participants may have received their 
previous COVID-19 vaccine as a study participant and then enter into Stage 2 (“rollover participant”), or they may have 
received their previous COVID-19 vaccine prior to enrollment in the study (“newly recruited participant”). 
Participants will be allocated to 1 of 3 cohorts based on their IS regimens: 
• 
Cohort D: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA (without additional B cell depleting medications or MTX) will 
be placed in this cohort.  
• 
Cohort E: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX (without additional B cell depleting medications or MMF/ MPA) will be 
placed in this cohort.  
• 
Cohort F: Receipt of B cell depletion therapy within the past 18 months (± other rheumatic disease medications) 
o Participants taking B cell depletion medications, regardless of whether they are also taking MMF or 
MTX, will be placed in this cohort. 
Treatment Arms: Participants in Cohorts D, E, and F will receive a dose of an alternative COVID-19 vaccine compared to 
their previous COVID-19 vaccine doses. Participants who previously received age-appropriate doses of a single mRNA 
vaccine (Moderna COVID-19 Vaccine OR Pfizer-BioNTech COVID-19 Vaccine, as noted above) will receive the other 
mRNA COVID-19 vaccine. Table 8 describes the age-appropriate qualifying COVID-19 vaccine regimen for participation in 
Pediatric Stage 2. 
Update:  Beginning with v6.0 of the protocol, bivalent versions of the mRNA vaccines, Moderna and Pfizer-BioNTech 
COVID-19 vaccines, replaced original monovalent versions. 
Participants in Cohorts D and E will withhold their cohort-defining IS medications before and after the alternative 
vaccine dose per protocol instructions (see Section 7.1.1 Protocol-mandated Medications).  
Participants in Cohort F who are taking MMF, MPA, or MTX in addition to B cell depletion therapies (BCDTs) will 
withhold these medications before and after the alternative vaccine dose per protocol instruction (see Section 7.1.1 
Protocol-mandated Medications).  
All potential treatment arms for Pediatric Stage 2 are detailed in Table 9. 
Schedule of Events: Visits to assess endpoints will occur at Baseline (Week 0), Week 4 ± 1 week, Week 12 ± 2 weeks, 
Week 24 ± 2 weeks, Week 36 ± 2 weeks, and Week 48 ± 2 weeks. Participant and study flow diagrams for Stage 2 are 
provided in Figure 7 and Figure 8, respectively.  
A participant who enters Stage 2 after a serologic negative, suboptimal, or low immune response to their Stage 1 vaccine 
dose may be on study for up to a maximum of 26 months. Rollover participants will discontinue follow-up as part of 
Stage 1 upon rollover into Stage 2. A participant who is newly recruited to the study for entry into Stage 2 may be on 
study for up to a maximum of 13 months. 


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ACV01                                                                                         Version 7.0                                                          13DEC2022 
Table 8. Qualifying COVID-19 Vaccine Regimens and Study Doses for Pediatric Stage 2 Participants 
Pfizer-BioNTech COVID-19 Vaccine 
Age of Participant 
Qualifying Regimen 
ACV01 Stage 2 Study Dose of Moderna 
2 years through 4 years 
4 doses of 3 mcg 
25 mcg bivalent  
5 years * 
4 doses of 3 mcg OR 
3 doses of 10 mcg 
25 mcg bivalent  
6 years through 11 years  
3 doses of 10 mcg 
50 mcg bivalent 
12 years through 17 years ** 
3 doses of 30 mcg 
100 mcg bivalent 
* Individuals who turned from 4 years to 5 years of age between any doses in the previous vaccine series may also have received one, two or three 
doses of 3 mcg as part of the qualifying regimen. Individuals who turned from 4 years to 5 years of age after completion of the previous vaccine 
series may also have received four doses of 3 mcg as the qualifying regimen. 
 
**Individuals who turned from 11 years to 12 years of age between doses in the primary regimen may also have received one or two doses of 
10 mcg as part of the qualifying regimen. Individuals who turned from 11 years to 12 years of age after completion of the primary series may also 
have received three doses of 10 mcg as the qualifying regimen. 
 
Moderna COVID-19 Vaccine 
Age of Participant 
Qualifying Regimen 
ACV01 Stage 2 Study Dose of Pfizer-BioNTech 
12 years through 17 years * 
3 doses of 100 mcg 
30 mcg bivalent 
**Individuals who turned from 11 years to 12 years of age between doses in their primary vaccine series may also have received one or two doses 
of 50 mcg as part of the qualifying regimen. Individuals who turned from 11 years to 12 years of age after completion of the previous vaccine series 
primary series may have also received three doses of 50 mcg as the qualifying regimen. 
 
 


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Table 9. Treatment Arm Assignments in Pediatric Stage 2 
  
Previous 
Vaccine Doses 
Stage 2 Arm 
Stage 2 Alternative 
Vaccine Dose* 
Cohort D: MMF or 
MPA  
  
Moderna COVID-19 vaccine 
(from Arms A1P or A4P, or newly 
recruited) Ages 12-17 only 
ARM D1P 
Pfizer-BioNTech COVID-19 Vaccine 
Pfizer-BioNTech COVID-19 vaccine 
(from Arms A2P or A5P, or newly 
recruited)  Ages 2-17 
ARM D2P 
Moderna COVID-19 Vaccine 
Cohort E: 
Methotrexate  
  
Moderna COVID-19 vaccine 
(from Arms B1P or B4P, or newly 
recruited) Ages 12-17 only 
ARM E1P 
Pfizer-BioNTech COVID-19 Vaccine 
Pfizer-BioNTech COVID-19 vaccine 
(from Arms B2P or B5P, or newly 
recruited) Ages 2-17 
ARM E2P 
Moderna COVID-19 Vaccine 
Cohort F: B cell 
depletion therapy  
  
Moderna COVID-19 vaccine 
(from Arms C1P, or newly recruited) 
Ages 12-17 only 
ARM F1P 
Pfizer-BioNTech COVID-19 Vaccine 
Pfizer-BioNTech COVID-19 vaccine 
(from Arms C2P or newly recruited) 
Ages 2-17 
ARM F2P 
Moderna COVID-19 Vaccine 
*Bivalent vaccines will be administered per Section 6, Investigational Agents 
 


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Figure 7. Participant Flow Diagram for Pediatric Stage 2 
 
Figure 8. Study Flow Diagram for Pediatric Stage 2 
 


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3.1.3 Adaptive Design 
An adaptive design will be employed in this trial such that cohorts and arms defined by additional vaccine doses and IS 
treatment plans may be added or modified based on emerging data from existing and new FDA EUA authorizations or 
approvals of COVID-19 vaccines: 
• 
New cohorts may be defined based on changes in the medication groups if it becomes obvious that certain 
medications are highly associated with suboptimal or low immune  response to initial COVID-19 vaccine 
regimen. 
• 
Cohorts may limit or expand the autoimmune diseases that are eligible to be included in the clinical trial, and 
may include expansion cohorts of underrepresented diseases.  
• 
New cohorts may include participants whose antibody response falls to suboptimal or low immune response 
levels over time. 
• 
Based upon timing of the FDA EUA authorization for children of each of the COVID-19 vaccines used in this trial, 
the age range of the inclusion criteria may be expanded. 
• 
Allocation or randomization to treatment with new COVID-19 vaccines may be incorporated into the design 
when the products become available. 
• 
Identification of additional strategies to enhance vaccine responsiveness in autoimmune diseases, including a 
temporary switch of immunomodulatory medications. 
3.2 
Primary Endpoint 
The primary endpoint in the adult and pediatric populations of a protective antibody response at Week 4 will be 
assessed by the NIAID-VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay. 
3.3 
Secondary Endpoints 
Secondary endpoints related to antibody response will primarily be assessed by the NIAID-VRC MSD 3 plex (Wu-1 full-
length spike, RBD, and N proteins) assay; where applicable, they will also be assessed by the Roche Elecsys® Anti-SARS-
CoV-2 S electrochemiluminescence immunoassay. 
The secondary endpoints are applicable to both the adult and pediatric populations. 
• 
Seroconversion at Week 4 following additional doses of COVID-19 vaccine in the subgroup of participants that 
are anti-COVID-19 antibody negative at Week 0. 
• 
Fold increase in anti-COVID-19 antibody levels at Week 4 following an additional dose of COVID-19 vaccine in 
the subgroup of participants who are anti-COVID-19 antibody positive at Week 0. 
• 
Longitudinal changes in anti-COVID-19 antibody responses from Week 0 to Weeks 4, 12, 24, 36, and 48.  
• 
Longitudinal changes in neutralization and pseudo neutralization assays from Week 0 to Weeks 4, 12, 24, 36, 
and 48. 
• 
Changes in disease activity after receipt of additional doses of COVID-19 vaccine as measured by the Clinical 
Global Impression of Change (CGI-C). 
• 
Changes in disease activity after receipt of additional doses of COVID-19 vaccine as measured by the Physician 
Global Assessment (PGA). 
• 
Changes in disease activity after receipt of additional doses of COVID-19 vaccine as measured by the following 
disease-specific assessments: 
o Adult population disease assessments: 


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o Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-SLEDAI) and Thanou modified 
Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus 
Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index for SLE 
o Disease Activity Score 28 using C-reactive protein (DAS28-CRP) for RA   
o Flare assessment for SSc (including patient reported flare assessment) 
o Pemphigus Disease Area Index (PDAI) for pemphigus 
o Physician-assessed relapse for MS 
o Pediatric population disease assessments: 
o JIA: 
 
JADAS10 for polyarthritis, enthesitis related to JIA, oligoarthritis, and psoriatic arthritis 
 
Psoriasis Area and Severity Index (PASI) for psoriatic arthritis 
o SLEDAI-2K and Childhood-onset SLE Criteria for Global Flare [1] for pediatric SLE 
o Childhood Myositis Assessment Scale (CMAS) and Flare Assessment for JDM (Disease Activity 
Score [DAS]) for JDM 
o Physician-assessed relapse for MS for POMS 
• 
Changes in patient-reported outcomes as measured by: 
o Participant-Reported Outcomes Measurement Information System (PROMIS) 29 (adults only) 
o Pediatric Quality of Life Inventory™ (PedsQL) (pediatrics only) 
o Patient Global Assessment (PtGA) 
o Patient Global Impression of Change (PGI-C) 
• 
The proportion of participants who experience the following safety events: 
o Any Grade 1 or higher AEs related to the additional doses of COVID-19 vaccine  
o Any SAEs, MAAEs, NOCMCs 
o Any SARS-CoV-2 infection  
3.4 
Exploratory Endpoints 
The exploratory endpoints are applicable to both the adult and pediatric populations. 
• 
Changes in autoantibody levels after COVID-19 vaccination between Week 0 and Weeks 4, 12, 24, 36, and 48. 
• 
Assessments of cellular and mechanistic response, including 
o Immune cell population profiling over time 
o Antigen-specific T cell responses 
o Antigen-specific memory B cell responses 
o Total IgG responses  
o B cell and T cell repertoire 
o Changes in gene expression profile modules  
o Plasma levels of soluble mediators  
 


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3.5 
Stratification, Randomization, and Blinding 
When employed in any population, randomization will be accomplished through a password-protected, web-based 
randomization system. The investigators, clinic personnel, and participants will not be blinded to randomized treatment 
assignments. Statistical and project staff at the Statistical and Clinical Coordinating Center (SACCC) and the DAIT Medical 
Monitor and Project Manager will be unblinded to individual treatment assignments as well. Laboratories performing 
assays for this protocol will be blinded to the identity and group assignment of biological materials to be studied. 
The same password-protected, web-based system will be used for allocation of participants to arms and associated tasks 
and tracking when randomization is not employed. 
3.5.1 Adult Population 
3.5.1.1 
Adult Stage 1 
Participants who sign the informed consent form and meet all eligibility criteria for Adult Stage 1 will be assigned to 
cohorts defined by IS medication (Cohort A: MMF/MPA; Cohort B: MTX; and Cohort C: BCDT) and by the initial COVID-19 
vaccine regimen received (Moderna COVID-19 Vaccine, Pfizer-BioNTech COVID-19 Vaccine, or Janssen COVID-19 
Vaccine).Participants in Cohort C will be allocated to continuing to take their prescribed IS medications throughout the 
trial. Participants in Cohorts A and B will be randomized in a balanced fashion (1:1), within the cohorts defined by IS 
medication and initial COVID-19 vaccine regimen, to one of the available IS medication treatment plans (continue 
cohort-defining IS vs. withhold cohort-defining IS). Randomization will be performed using a permuted block design 
stratified by disease type.  
A total of 60 participants with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL will be randomized or allocated to 
each arm. In each arm, the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results ≤50 U/mL will be 
capped at 40 participants, and the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results >50 U/mL and 
≤200 U/mL will be capped at 40 participants.  
3.5.1.2 
Adult Stage 2 
Participants who have signed the informed consent form and meet all eligibility criteria for Adult Stage 2 will be 
allocated to cohorts defined by IS medication (Cohort D: MMF/MPA; Cohort E: MTX; and Cohort F: BCDT) and by the 
previous COVID-19 vaccine regimen. See Section 3.1.1.2 Adult Stage 2  for treatment arm vaccine assignments.  
Participants in Cohort D will withhold their MMF/MPA, participants in Cohort E will withhold their MTX, and any 
participants in Cohort F (BCDT) who are also taking MMF/MPA or MTX will withhold these medications. No 
randomization will be employed.  
A total of 80 participants with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL will be allocated to each arm. In 
each arm, the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results ≤200 U/mL will be capped at 
40 participants;  the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results > 200 U/mL and ≤2500 U/mL 
will be capped at 40 participants. 
3.5.2 Pediatric Population 
3.5.2.1 
Pediatric Stage 1  
Participants and their legal guardian(s) who sign the consent and assent forms, as appropriate to age, and meet all 
eligibility criteria for Pediatric Stage 1 will be assigned to cohorts defined by IS medication (Cohort A: MMF/MPA; Cohort 
B: MTX; and Cohort C: BCDT) and by the initial COVID-19 vaccine regimen received. Participants in Cohort C will be 
allocated to continuing to take their prescribed IS medications throughout the trial. Participants in Cohorts A and B will 
be randomized in a balanced fashion (1:1), within the cohorts defined by IS medication and initial COVID-19 vaccine 
regimen, to one of the available IS medication treatment plans (continue IS vs. withhold IS). Randomization will be 
performed using a permuted block design stratified by disease type. 
A total of 80 participants with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL will be randomized or allocated to 
each arm. In each arm, the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results ≤200 U/mL will be 


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capped at 40 participants, and the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results >200 U/mL and 
≤2500 U/mL will be capped at 40 participants.  
3.5.2.1 
Pediatric Stage 2 
Participants who have signed the informed consent and assent forms, as appropriate to age, and meet all eligibility 
criteria for Pediatric Stage 2 will be allocated to cohorts defined by IS medication (Cohort D: MMF/MPA; Cohort E: MTX; 
and Cohort F: B cell depletion therapy) and by the previous COVID-19 vaccine regimen (Pfizer-BioNTech COVID-19 
Vaccine in ages 2 through 17 years or Moderna COVID-19 Vaccine in ages 12 through 17 years).  Participants in Cohort D 
will withhold their MMF/MPA, participants in Cohort E will withhold their MTX, and any participants in Cohort F (B cell 
depletion therapy) who are also taking MMF/MPA or MTX will withhold these medications. No randomization will be 
employed.  
A total of 80 participants with a Roche Elecsys® Anti-SARS-CoV-2 S result ≤2500 U/mL will be allocated to each arm. In 
each arm, the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results ≤200 U/mL will be capped at 40 
participants, and the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S results > 200 U/mL and ≤2500 U/mL 
will be capped at 40 participants.  
4. 
Selection of Participants and Clinical Sites 
4.1 
Rationale for Study Population 
Patients with autoimmune disease are at higher risk for SARS-CoV-2 infection and inadequate response to initial 
COVID-19 vaccine regimen, both of which may be due in part to IS medication use. The 5 autoimmune diseases in adults 
and 4 autoimmune diseases in children included in this clinical trial were chosen for several reasons: 
1. They represent a broad spectrum of autoimmune disease. Three diseases (MS, RA, and SLE) are among the more 
common autoimmune diseases in adults in the US, and 3 diseases (JIA, pediatric SLE, and JDM) are among the 
most common autoimmune disease in pediatric populations.  
2. The medications of interest (MMF/MPA, MTX, and BCDTs) are used commonly for treatment of these 
autoimmune diseases.  
3. They comprise a population with significant ethnic and racial diversity that was underrepresented in the original 
clinical trials that were used to determine EUA eligibility and that have been more severely afflicted by 
COVID-19. 
4. Each of these diseases is studied at one or more of the NIAID-funded ACE Network institutions. This is 
important, as access to existing patient cohorts will be critical to rapid implementation of this clinical trial.  
Due to disease-associated immune abnormalities and IS medication use, the proposed patient population is at increased 
risk for AEs compared to a non-autoimmune disease population. The inclusion/exclusion criteria are designed to limit 
these risks and ensure the safety of those participating in the study. Specifically, participants with active disease at 
Screening or who have initiated new IS therapy within 8 weeks of Screening for active disease or with active infection 
will be excluded. Only autoimmune disease patients with a negative or suboptimal serologic response to the initial 
COVID-19 vaccine regimen will be included in Adult Stage 1. A suboptimal response to primary vaccine is defined as an 
Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL at the Screening visit. In Pediatric Stage 1 and in Adult and Pediatric 
Stage 2, patients with a negative or suboptimal serologic response will be included along with patients with a low 
immune response, defined as an Elecsys® Anti-SARS-CoV-2 S result >200 U/mL and ≤2500 U/mL. Other antibody and 
cellular measures of response will be tested in the trial.  
In order to maximize participant response to Stage 2 vaccination, all participants will withhold MTX or MMF/MPA 
around vaccination. In addition, enrollment into Pediatric Stage 2 of participants who have previously received doses of 
the Moderna COVID-19 Vaccine and are to receive the Pfizer COVID-19 Vaccine is limited to individuals aged 12 through 
17.  


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The CDC recommends bivalent COVID-19 vaccines for moderately or severely immunocompromised individuals who are 
eligible to receive one under FDA EUA [55]. If a bivalent version of a COVID-19 vaccine is not available for a participant 
via the ACV01 study design but is available through the community, the participant will be directed to obtain the 
bivalent COVID-19 vaccine in the community.  
Due to the rapid nature of the evaluation of the COVID pandemic, the speed with which COVID vaccinations are coming 
into use, and ongoing data generated in the observational studies and in autoimmune disease cohorts, an adaptive 
clinical trial design will be used in this study. The initial IS medications, MMF/MPA, MTX, and BCDTs were originally 
selected as those that have a deleterious impact on vaccination response. However, as the trial evolves, and other 
autoimmune disease therapies emerge as negatively impacting COVID-19 vaccination effects then they may be added to 
the trial. Second, as data emerges, it may become evident through the ACV02 observational study, cohort studies, 
published literature, or real-world exposures that other autoimmune diseases treated with the therapies included in this 
trial are more severely impaired in their vaccination responses. If so, and if additional resources are available, then other 
autoimmune diseases, such as psoriasis, psoriatic arthritis, vasculitis, inflammatory bowel disease, or others may be 
added to the protocol through the adaptive design.  
4.2 
Inclusion and Exclusion Criteria 
Prior to evaluation of the entry criteria for a potential participant, the participant’s cohort placement and qualifying 
disease will be determined according to the description in Section 8.1.2.2 Determination of Participant Cohort and 
Identification of Qualifying Disease. 
4.2.1 Inclusion and Exclusion Criteria for Adult Participants 
4.2.1.1 
Inclusion and Exclusion Criteria for Adult Stage 1 
4.2.1.1.1 
Inclusion Criteria for Adult Stage 1 
Individuals who meet all of the following criteria are eligible for randomization/allocation as study participants in Adult 
Stage 1:  
1. Individuals 18 years of age or older that meet classification criteria for SLE, SSc, RA, MS, or pemphigus. 
2. Participants must meet the 2019 American College of Rheumatology/European League Against Rheumatism 
(ACR/EULAR) [2] or 2012 Systemic  Lupus International Collaborating Clinics (SLICC) classification criteria for SLE 
[3], the 2010 ACR/EULAR classification criteria for RA [4],  the 2013 EULAR/ACR classification criteria for SSc [5], 
the 2017 McDonald [6] criteria for MS, and the international consensus criteria for pemphigus [7]. 
a. If a participant has been diagnosed with more than one autoimmune disease, the participant will be 
assessed based on the disease that is selected for study entry.  
3. Willing and able to sign informed consent. 
4. Documented full COVID-19 vaccination (CDC card or documentation in medical records) that was completed at 
least 4 weeks prior and no more than 52 weeks prior to the Screening visit. 
5. Negative or suboptimal serologic response to initial COVID-19 vaccine regimen, defined as an Elecsys® Anti-
SARS-CoV-2 S result ≤200 U/mL, at Screening visit. 
a. Initial COVID-19 vaccine regimen is defined as either: 
i. 2 doses of the Pfizer-BioNTech COVID-19 Vaccine 
ii. 2 doses of the Moderna COVID-19 Vaccine 
6. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 1000 mg per day)/MPA (minimum of 720 mg per day), MTX (minimum of 7.5mg 
per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, or 
ofatumumab).  


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a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
randomization and be taking the same medications (regardless of dose) as at the time of the initial 
COVID-19 vaccine regimen. Note: Participants who withheld their IS medications around their initial 
vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, the participant must have received an anti-CD20 or an anti-CD19 BCDT in 
the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or MTX, in the 4 weeks prior to Screening, 
excluding the following:  
a. Hydroxycholoroquine (HCQ),  
b. Intraarticular steroids,   
c. The addition of prednisone at ≤10mg per day or prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or chronic 
obstructive pulmonary disease (COPD), are permitted. 
4.2.1.1.2 
Exclusion Criteria for Adult Stage 1 
Individuals who meet any of these criteria are not eligible for randomization/allocation as study participants in Adult 
Stage 1:  
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine regimen, to any component of any of the 
COVID-19 vaccines, or to polyethylene glycol (PEG).  
3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA or 
MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Screening period resulting in: 
a. An increase/addition of any IS medications, or  
b. A suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of a COVID-19 vaccine booster prior to Screening with the Moderna COVID-19 Vaccine, Pfizer-BioNTech 
COVID-19 Vaccine, or Janssen COVID-19 Vaccine. 
8.  Inflammatory myocarditis/pericarditis following initial COVID-19 vaccine regimen.  
9. Participants with active, ongoing chronic infections, including participants with evidence of: 
a. Human Immunodeficiency Virus (HIV).  
b. Hepatitis B as indicated by surface antigen.  
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody 
positive, they will be eligible to participate in the study if he/she is negative for viral load at Screening. 


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Note: Participants are permitted to be on chronic prophylactic antimicrobial therapy.  
10. Participants with common variable immunodeficiency disease, as well as any participants currently receiving 
immune globulin replacement therapy. 
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed against 
SARS-CoV-2 within 30 days of Screening. 
12. Participants who have received any live vaccines within 2 months of the anticipated study vaccine dose or who 
will have need of a live vaccine at any time during the study. 
13. Currently pregnant or breastfeeding.  
14. Participants who are planning a pregnancy during the course of the trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 
5 half-lives (whichever is longer) of Screening.  
18. Concurrent treatment with cyclophosphamide, cladribine, alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a solid organ transplant.  
20. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness. 
21. Taking both MMF/MPA and MTX. 
22. Receiving other investigational BCDT as part of a clinical trial within 18 months of Screening, unless drug 
assignment is known and the participant received an anti-CD20 or CD19 drug. 
23. Participants with active systemic infections who have received systemic antimicrobials within the 14 days prior 
to Screening. 
4.2.1.2 
Inclusion and Exclusion Criteria for Adult Stage 2 
4.2.1.2.1 
Inclusion and Exclusion Criteria for Adult Stage 2 Newly Recruited 
Participants 
4.2.1.2.1.1 
Inclusion Criteria for Adult Stage 2 Newly Recruited Participants 
Individuals who meet all of the following criteria are eligible for enrollment as participants in Adult Stage 2:  
1. Individuals 18 years of age or older that meet classification criteria [1-6] for SLE, SSc, RA, MS, or pemphigus. If a 
participant has been diagnosed with more than one autoimmune disease, the participant will be assessed based 
on the disease that is selected for study entry. 
2. Willing and able to sign informed consent. 
3. Documented full COVID-19 vaccination (CDC card or documentation in medical records). 
4. Received an additional COVID-19 vaccine dose (documented by CDC card or in medical records) that was 
completed at least 4 weeks prior and no more than 48 weeks prior to the Stage 2 Screening visit.  
5. Negative or suboptimal serologic response to a previous COVID-19 vaccine administration in one of the 
qualifying regimens, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 


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≤200 U/mL, or a low immune response, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL, 
within 4 weeks of the Stage 2 Baseline/Week 0 visit. 
6. The regimens of COVID-19 vaccination that qualify are as follows: 
a. 3 doses of the Pfizer-BioNTech COVID-19 Vaccine 
b. 3 doses of the Moderna COVID-19 Vaccine 
c. 2 doses of the Janssen COVID-19 Vaccine 
d. 4 or more doses of a single mRNA vaccine (Pfizer-BioNTech COVID-19 Vaccine OR Moderna COVID-19 
Vaccine) 
e. 3 or more doses of a mixture of mRNA vaccines (Pfizer-BioNTech COVID-19 Vaccine OR Moderna COVID-
19 Vaccine) 
7. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 1000 mg per day)/MPA (minimum of 720 mg per day), MTX (minimum of 7.5mg 
per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, or 
ofatumumab).  
a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
allocation and be taking the same medications (regardless of dose) as at the time of the initial COVID-19 
vaccine regimen. Note: Participants who withheld their IS medications around their initial vaccinations 
are eligible to participate.  
b. If enrolling in the BCDT cohort, the participant must have received an anti-CD20 or an anti-CD19 BCDT in 
the past 18 months.  
8. No changes in background IS medications, including MMF/MPA or MTX, in the 4 weeks prior to Stage 2 
Screening, excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at ≤10mg per day or prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or COPD, are 
permitted. 
4.2.1.2.1.2 
Exclusion Criteria for Adult Stage 2 Newly Recruited Participants 
Individuals who meet any of these criteria are not eligible for enrollment as participants in Adult Stage 2:  
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol. 
2. History of severe allergic reaction to the COVID-19 vaccine, or to any component of the COVID-19 vaccine, that is 
to be administered in Stage 2, including polysorbate for participants receiving the Sanofi-GSK COVID-19 Vaccine, 
or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA or 
MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a. An increase/addition of any IS medications, or  


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b. A suggestion of MS relapse per the investigator. 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Stage 2 Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 Screening. 
7. Receipt of a mixture of Janssen COVID-19 vaccines and mRNA COVID-19 vaccines  (in any order or combination) 
prior to Stage 2 Screening. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 vaccine doses.  
9. Participants with active, ongoing chronic infections including participants with evidence of: 
a. HIV. 
b. Hepatitis B as indicated by surface antigen.  
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody 
positive, they will be eligible to participate in the study if he/she is negative for viral load at Stage 2 
Screening.  
Note: Participants are permitted to be on chronic prophylactic antimicrobial therapy. 
10. Participants with common variable immunodeficiency disease, as well as any participants currently receiving 
immune globulin replacement therapy. 
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed against 
SARS-CoV-2 within 30 days of Stage 2 Screening. 
12. Participants who have received any live vaccines within 2 months of the anticipated study vaccine dose or who 
will have need of a live vaccine at any time during the study. 
13. Currently pregnant or breastfeeding.  
14. Female participants who are planning a pregnancy during the course of the trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 
5 half-lives (whichever is longer) of Stage 2 Screening.  
18. Concurrent treatment with cyclophosphamide, cladribine, alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a solid organ transplant. 
20. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness. 
21. Taking both MMF/MPA and MTX. 
22. Receiving other investigational BCDT as part of a clinical trial within 18 months of Stage 2 Screening, unless drug 
assignment is known and the participant received an anti-CD20 or CD19 drug. 
23. Participants with active systemic infections who have received systemic antimicrobials within the 14 days prior 
to Stage 2 Screening. 
 


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4.2.1.2.2 
Inclusion and Exclusion Criteria for Adult Stage 2 Rollover Participants 
Individuals who were previously enrolled in Adult Stage 1 or Adult Stage 2 will have met some inclusion and exclusion 
criteria at that time. Only a subset of the criteria for (re-)entering Adult Stage 2 will be assessed in rollover participants 
at the time of screening for Stage 2. The criteria below are numbered to match the criteria for newly recruited 
participants. The criteria that are not noted below do not need to be reassessed for rollover participants.  
4.2.1.2.2.1 
Inclusion Criteria for Adult Stage 2 Rollover Participants 
Individuals who meet all of the following criteria are eligible to (re-)enter Adult Stage 2:  
4. Received an additional COVID-19 vaccine dose that was completed at least 4 weeks prior and no more than 48 
weeks prior to the Stage 2 vaccination. 
5. Negative or suboptimal serologic response to a previous COVID-19 vaccine administration in one of the 
qualifying regimens, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL, 
within 4 weeks of the Stage 2 Baseline/Week 0 visit. 
The regimens of COVID-19 vaccination that qualify are as follows: 
a. 3 doses of the Pfizer-BioNTech COVID-19 Vaccine 
b. 3 doses of the Moderna COVID-19 Vaccine 
c. 2 doses of the Janssen COVID-19 Vaccine 
d. 4 doses of a combination of mRNA vaccines (i.e., Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 
Vaccine) 
6. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 1000 mg per day)/MPA (minimum of 720 mg per day), MTX (minimum of 
7.5 mg per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, 
ofatumumab).  
a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
allocation and be taking the same medications (regardless of dose) as at the time of the initial COVID-19 
vaccine regimen. Note: Participants who withheld their IS medications around their initial vaccinations 
are eligible to participate.  
b. If enrolling in the BCDT cohort, the participant must have received an anti-CD20 or an anti-CD19 BCDT in 
the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or MTX, in the 4 weeks prior to Stage 2 
Baseline/Week 0 visit, excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at ≤10mg per day or prednisone at any dose when given for ≤3 days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or COPD, are 
permitted. 
4.2.1.2.2.2 
Exclusion Criteria for Adult Stage 2 Rollover Participants 
Individuals who meet any of these criteria are not eligible to (re-)enter Adult Stage 2:  
2. History of severe allergic reaction to the COVID-19 vaccine, or to any component of the COVID-19 vaccine, that is 
to be administered in Stage 2, including polysorbate for participants receiving the Sanofi-GSK COVID-19 Vaccine, 
or to PEG.  


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3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA or 
MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a. An increase/addition of any IS medications, or  
b. A suggestion of MS relapse per the investigator. 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Stage 2 Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 Screening or Stage 2 Baseline/Week 0. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 vaccine doses.  
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed against 
SARS-CoV-2 within 30 days of Stage 2 Screening. 
13. Currently pregnant or breastfeeding.  
14. Female participants who are planning a pregnancy during the course of the trial.  
15. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
16. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
17. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 
5 half-lives (whichever is longer) of Stage 2 Screening.  
18. Concurrent treatment with cyclophosphamide, cladribine, alemtuzumab, or mitoxantrone. 
19. Participants currently on any type of dialysis, or who have received a solid organ transplant. 
20. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness. 
23. Participants with active systemic infections who have received systemic antimicrobials within the 14 days prior 
to Stage 2 Baseline/Week 0. 
4.2.2 Inclusion and Exclusion Criteria for Pediatric Participants 
4.2.2.1 
Inclusion and Exclusion Criteria for Pediatric Stage 1  
4.2.2.1.1 
Inclusion Criteria for Pediatric Stage 1 
Individuals who meet all of the following criteria are eligible for enrollment randomization/allocation as participants in 
Pediatric Stage 1: 
1. Individuals 2-17 years of age that meet classification criteria for SLE, JIA, POMS, or JDM. Note: Juvenile idiopathic 
arthritis includes the following conditions: polyarticular JIA (both RF + and -), oligoarticular persistent and 
oligoarticular extended JIA, psoriatic arthritis, and enthesitis related JIA. 


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a. Participants must meet the 2017 EULAR/ACR classification criteria for adult and juvenile idiopathic 
inflammatory myopathies and their major subgroups [8], the International League of Associations for 
Rheumatology (ILAR) classification for JIA [4], the 2017 McDonald [6] criteria for MS, or the Bohan and 
Peter criteria or the 2017 EULAR/ACR classification criteria for JDM.  
b. If a participant has been diagnosed with more than one autoimmune disease, the participant will be 
assessed based on the disease that is selected for study entry.  
2. Parents/guardians of all pediatric participants and participants ages 14 – 17 must be willing and able to sign 
informed consent. Participants ages 7-13 must be willing and able to sign assent. 
3. Documented EUA-authorized or FDA-approved COVID-19 vaccine doses (CDC card or documentation in medical 
records) that was completed at least 4 weeks prior and no more than 52 weeks prior to the Screening visit. 
4. Negative or suboptimal serologic response to initial EUA-authorized or FDA-approved COVID-19 vaccine doses, 
defined as an Elecsys® Anti-SARS-CoV-2 S result ≤200 U/mL, or a low immune response, defined as an Elecsys® 
Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL,  within 4 weeks of the Stage 1 Baseline/Week 0 visit. 
a. Initial COVID-19 vaccine regimen is defined as: 
i. Pfizer-BioNTech COVID-19 Vaccine (2 through 4 years of age): 3 age-appropriate doses.  
ii. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years of age): 2 age-appropriate doses. 
iii. Moderna COVID-19 Vaccine (2 through 17 years of age): 2 age-appropriate doses. 
5. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum of 5 mg 
per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, or 
ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
randomization and be taking the same medications (regardless of dose) as at the time of the initial 
COVID-19 vaccine regimen. Note: Participants who withheld their IS medications around their initial 
vaccinations are eligible to participate.  
b. If enrolling in the BCDT cohort, participant must have received an anti-CD20 or an anti-CD19 BCDT in the 
past 18 months.  
6. No changes in background IS medications, including MMF/MPA or MTX, in the 8 weeks prior to Screening, 
excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or prednisone at any dose when given for ≤3 
days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or COPD, are 
permitted. 
4.2.2.1.2 
Exclusion Criteria for Pediatric Stage 1 
Individuals who meet any of these criteria are not eligible for randomization/allocation as participants in Pediatric Stage 
1:  
1. Inability or unwillingness of a participant to give assent or consent; or of a parent/guardian to give written 
informed consent, or of either to comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine regimen, or any component of any of the 
COVID-19 vaccines, or to PEG.  


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3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA or 
MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Screening period resulting in: 
a.  an increase/addition of any IS medications, or  
b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of a COVID-19 vaccine booster prior to Screening. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 vaccine doses. 
9. Participants with active, ongoing chronic infections. 
Note: Participants are permitted to be on chronic prophylactic antimicrobial therapy. 
10. Participants with common variable immunodeficiency disease, as well as any participants currently receiving 
immune globulin replacement therapy. 
Note: Participants on IVIG therapeutically may enter the study provided they have sufficiently quiet disease that 
they can withhold their IVIG from 8 weeks prior to the Screening visit through 4 weeks after vaccination. 
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed against 
SARS-CoV-2 within 30 days of Screening. 
12. Participants who have received any live vaccines within 2 months of the anticipated study vaccine dose or who 
will have need of a live vaccine at any time during the study. 
13. Currently pregnant or breastfeeding (postmenarchal females must have a negative urine pregnancy test at 
Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 
5 half-lives (whichever is longer) of Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a solid organ transplant.  
19. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness must not be allowed to participant in this study. 
20. Taking both MMF/MPA and MTX. 


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21. Other investigational BCDT as part of a clinical trial within 18 months of Screening, unless drug assignment is 
known and the participant received an anti-CD20 or CD19 drug. 
22. Participants with active systemic infections who have received systemic antimicrobials within the 14 days prior 
to Screening. 
4.2.2.2 
Inclusion and Exclusion Criteria for Pediatric Stage 2 
4.2.2.2.1 
Inclusion and Exclusion Criteria for Pediatric Stage 2 Newly Recruited 
Participants 
4.2.2.2.1.1 
Inclusion Criteria for Pediatric Stage 2 Newly Recruited 
Participants 
Individuals who meet all of the following criteria are eligible for enrollment as participants in Pediatric Stage 2:  
1. Individuals 2-17 years of age that meet classification criteria for SLE, JIA, POMS, or JDM. Note: Juvenile idiopathic 
arthritis includes the following conditions: polyarticular JIA (both RF + and -), oligoarticular persistent and 
oligoarticular extended JIA, psoriatic arthritis, and enthesitis related JIA. 
a. Participants must meet the 2017 EULAR/ACR classification criteria for adult and juvenile idiopathic 
inflammatory myopathies and their major subgroups [8], the International League of Associations for 
Rheumatology (ILAR) classification for JIA [4], the 2017 McDonald [6] criteria for MS, or the Bohan and 
Peter criteria or the 2017 EULAR/ACR classification criteria for JDM.  
b. If a participant has been diagnosed with more than one autoimmune disease, the participant will be 
assessed based on the disease that is selected for study entry.  
2. Parents/guardians of all pediatric participants and participants ages 14 – 17 must be willing and able to sign 
informed consent. Participants ages 7-13 must be willing and able to sign assent. 
3. Documented full COVID-19 vaccination (CDC card or documentation in medical records). 
4. Received an additional COVID-19 vaccine dose (documented by CDC card or in medical records) that was 
completed at least 4 weeks prior and no more than 48 weeks prior to the Stage 2 Screening visit. 
5. Negative or suboptimal serologic response to homologous doses of COVID-19 vaccine in one of the qualifying 
regimens, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of ≤200 U/mL, or a 
low immune response, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL, within 4 weeks of 
the Stage 2 Baseline/Week 0 visit. 
 
The regimens of COVID-19 vaccination that qualify are as follows: 
a. Pfizer-BioNTech COVID-19 Vaccine (2 through 5 years of age): 4 full, age-appropriate doses of the Pfizer-
BioNTech COVID-19 Vaccine 
b. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years old): 3 full, age-appropriate doses of the Pfizer-
BioNTech COVID-19 Vaccine 
Note: Participants who are 5 years old and previously received the Pfizer-BioNTech COVID-19 
Vaccine may have received either age-appropriate regimen. See Section 3.1.2.2, Pediatric Stage 2 
for additional details.  
c. Moderna COVID-19 Vaccine (12 through 17 years of age): 3 full, age-appropriate doses of the Moderna 
COVID-19 Vaccine  
6. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum of 5 mg 


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per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, or 
ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
allocation and be taking the same medications (regardless of dose) as at the time of the initial COVID-19 
vaccine regimen. Note: Participants who withheld their IS medications around their initial vaccinations 
are eligible to participate.  
b. If enrolling in the B cell depleting therapy cohort, participant must have received an anti-CD20 or an 
anti-CD19 B cell depleting therapy in the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or MTX, in the 4 weeks prior to Screening, 
excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or prednisone at any dose when given for ≤3 
days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or COPD, are 
permitted. 
4.2.2.2.1.2 
Exclusion Criteria for Pediatric Stage 2 Newly Recruited 
Participants 
Individuals who meet any of these criteria are not eligible for enrollment as participants in Pediatric Stage 2:  
1. Inability or unwillingness of a participant to give assent or consent; or of a parent/guardian to give written 
informed consent, or of either to comply with study protocol. 
2. History of severe allergic reaction to the initial COVID-19 vaccine regimen, or any component of any of the 
COVID-19 vaccine, that is to be administered in Stage 2, or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA or 
MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Screening period resulting in: 
a.  an increase/addition of any IS medications, or  
b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 
a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Screening).  
b. Positive result on a molecular COVID-19 test at Screening. 
7. Receipt of an additional heterologous COVID-19 vaccine dose prior to Stage 2 Screening, i.e., a participant 
cannot have received a mixture of mRNA vaccines. 
8.  Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 vaccine doses.  
9. Participants with active, ongoing chronic infections. 


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Note: Participants are permitted to be on chronic prophylactic antimicrobial therapy.  
10. Participants with common variable immunodeficiency disease, as well as any participants currently receiving 
immune globulin replacement therapy. 
Note: Participants on IVIG therapeutically may enter the study provided they have sufficiently quiet disease that 
they can withhold their IVIG from 8 weeks prior to the Screening visit through 4 weeks after vaccination.  
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed against 
SARS-CoV-2 within 30 days of Screening. 
12. Participants who have received any live vaccines within 2 months of the anticipated study vaccine dose or who 
will have need of a live vaccine at any time during the study. 
13. Currently pregnant or breastfeeding (postmenarchal females must have a negative urine pregnancy test at 
Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 
half-lives (whichever is longer) of Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a solid organ transplant.  
19. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness must not be allowed to participant in this study. 
20. Taking both MMF/MPA and MTX. 
21. Other investigational B cell depleting therapy as part of a clinical trial within 18 months of Screening, unless drug 
assignment is known and the participant received an anti-CD20 or CD19 drug. 
22. Participants with active systemic infections who have received systemic antimicrobials within the 14 days prior 
to Screening. 
4.2.2.2.2 
Inclusion and Exclusion Criteria for Pediatric Stage 2 Rollover 
Participants 
Individuals who were previously enrolled in Pediatric Stage 1 will have met some inclusion and exclusion criteria at that 
time. Only a subset of the criteria for entering Pediatric Stage 2 will be assessed in rollover participants at the time of 
screening for Stage 2. The criteria below are numbered to match the criteria for newly recruited participants. The 
criteria that are not noted below do not need to be reassessed for rollover participants.  
4.2.2.2.2.1 
Inclusion Criteria for Pediatric Stage 2 Rollover Participants 
Individuals who meet all of the following criteria are eligible to continue as participants in Pediatric Stage 2:  
4. Received an additional COVID-19 vaccine dose that was completed at least 4 weeks prior and no more than 48 
weeks prior to the Stage 2 vaccination. 
5. Negative or suboptimal serologic response to a previous COVID-19 vaccine administration in one of the 
qualifying regimens, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) negative result or positive result of 
≤200 U/mL, or a low immune response, defined as an Elecsys® Anti-SARS-CoV-2 S (RBD) result of ≤2500 U/mL, 
within 4 weeks of the Stage 2 Baseline/Week 0 visit. 
 
The regimens of COVID-19 vaccination that qualify are as follows: 


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a. Pfizer-BioNTech COVID-19 Vaccine (2 through 5 years of age): 4 full, age-appropriate doses of the Pfizer-
BioNTech COVID-19 Vaccine 
b. Pfizer-BioNTech COVID-19 Vaccine (5 through 17 years old): 3 full, age-appropriate doses of the Pfizer-
BioNTech COVID-19 Vaccine 
Note: Participants who are 5 years old and previously received the Pfizer-BioNTech COVID-19 
Vaccine may have received either age-appropriate regimen. See Section 3.1.2.2, Pediatric Stage 2 
for additional details.  
c. Moderna COVID-19 Vaccine (12 through 17 years of age): 3 full, age-appropriate doses of the Moderna 
COVID-19 Vaccine  
6. Must be currently taking one of the following IS medications with or without additional disease-related 
medications: MMF (minimum of 250 mg per day)/MPA (minimum of 360 mg per day), MTX (minimum of 5 mg 
per week), or B cell depleting agents within the past 18 months (such as rituximab, ocrelizumab, or 
ofatumumab). 
a. If taking MMF/MPA or MTX, the participant must have initiated therapy at least 8 weeks prior to 
allocation and be taking the same medications (regardless of dose) as at the time of the initial COVID-19 
vaccine regimen. Note: Participants who withheld their IS medications around their initial vaccinations 
are eligible to participate.  
b. If enrolling in the B cell depleting therapy cohort, participant must have received an anti-CD20 or an 
anti-CD19 B cell depleting therapy in the past 18 months.  
7. No changes in background IS medications, including MMF/MPA or MTX, in the 4 weeks prior to Stage 2 
Baseline/Week 0, excluding the following:  
a. HCQ,  
b. Intraarticular steroids,   
c. The addition of prednisone at <0.15mg/kg/dose per day or prednisone at any dose when given for ≤3 
days, and   
d. Corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or COPD, are 
permitted. 
4.2.2.2.2.2 
Exclusion Criteria for Pediatric Stage 2 Rollover Participants 
Individuals who meet any of these criteria are not eligible to enter Pediatric Stage 2:  
2. History of severe allergic reaction to the initial COVID-19 vaccine regimen, or any component of any of the 
COVID-19 vaccine, that is to be administered in Stage 2, or to PEG.  
3. New diagnosis of malignancy that will require chemotherapy or immunotherapy, or ongoing treatment for a 
malignancy with chemotherapy or immunotherapy. 
4. Active disease (per the Investigator’s decision) resulting in inability to hold the IS therapy in the MMF/MPA 
or MTX arms of the study.  
a. The potential impact of temporarily holding medication for participants with a recent mild disease flare 
within 4 weeks should be carefully considered.  
5. Active disease during the Stage 2 Screening period resulting in: 
a.  an increase/addition of any IS medications, or  
b. a suggestion of MS relapse per the investigator 
6. Recent or current SARS-CoV-2 infection defined as: 


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a. Documented SARS-CoV-2 infection in the past 30 days (from the day the participant is diagnosed by 
positive test to Stage 2 Screening).  
b. Positive result on a molecular COVID-19 test at Stage 2 Screening or Stage 2 Baseline/Week 0. 
8. Inflammatory myocarditis/pericarditis within 6 weeks of any COVID-19 vaccine doses.  
11. Participants who received licensed or investigational monoclonal antibodies or plasma products directed 
against SARS-CoV-2 within 30 days of Stage 2 Screening. 
13. Currently pregnant or breastfeeding (postmenarchal females must have a negative urine pregnancy test at 
Screening) 
14. Hemoglobin (Hgb) <8.0 g/dL (80 g/L) 
15. Past or current medical problems or findings from physical examination or laboratory testing that are not 
listed above, which, in the opinion of the investigator, may pose additional risks from participation in the 
study, may interfere with the participant’s ability to comply with study requirements or that may impact the 
quality or interpretation of the data obtained from the study. 
16. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 
5 half-lives (whichever is longer) of Stage 2 Screening.  
17. Concurrent treatment with cyclophosphamide. 
18. Participants currently on any type of dialysis, or who have received a solid organ transplant.  
19. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either 
a psychiatric or physical (e.g., infectious disease) illness must not be allowed to participant in this study. 
22. Participants with active systemic infections who have received systemic antimicrobials within the 14 days 
prior to Stage 2 Baseline/Week 0. 
5. 
Known and Potential Risks and Benefits to Participants 
5.1 
Risks of Investigational Products 
5.1.1 Risks of COVID vaccine based on the mRNA vaccines (Moderna COVID-19 Vaccine and Pfizer-
BioNTech COVID-19 Vaccine) 
Adverse reactions reported in a clinical trial following administration of the Moderna COVID-19 Vaccine include pain at 
the injection site, fatigue, headache, myalgia, arthralgia, chills, nausea/vomiting, axillary swelling/tenderness, erythema 
at the injection site, swelling at the injection site, fever, and rash [48]. Groin swelling/tenderness was observed in 
individuals aged 17 months – 5 years. In addition, irritability/crying, swelling/tenderness in the groin, and loss of 
appetite adverse reactions were reported in individuals aged 6 – 36 months [61]. Severe allergic reactions have been 
reported following the Moderna COVID-19 Vaccine during mass vaccination outside of clinical trials, most commonly in 
participants with allergic history and usually within the first 15-20 minutes of vaccination [48]. Other side effects 
reported during post-authorization use include urticaria, myocarditis, pericarditis, and fainting associated with injection 
of the vaccine. 
Adverse reactions following the Pfizer-BioNTech COVID-19 Vaccine that have been reported in clinical trials include 
injection site pain, fatigue, headache, muscle pain, chills, joint pain, injection site swelling, fever, injection site redness, 
lymphadenopathy, nausea, malaise, pain in extremity, rash, decreased appetite, diarrhea, vomiting, arm pain, fainting in 
association with injection of the vaccine, and dizziness [58]. Severe allergic reactions have been reported following the 
Pfizer-BioNTech COVID-19 Vaccine during mass vaccination outside of clinical trials, most commonly in participants with 
allergic history and usually within the first 15-20 minutes of vaccination [58]. 


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Myocarditis and pericarditis adverse reactions have been noted following administration of both mRNA vaccines 
(Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine). These adverse reactions have been reported 
mainly in male adolescents and young adults after receipt of the second dose of vaccine [62]. Short-term follow-up data 
suggests most individuals have had complete resolution with conservative management, although some have required 
intensive care support. Long-term data are not available.  
Symptoms of myocarditis or pericarditis include chest pain, shortness of breath, or feelings of having a fast-beating, 
fluttering, or pounding heart, with onset of symptoms most commonly reported within a few days following vaccination. 
Symptoms may differ in younger pediatric populations, particularly in the 6 month to <5 year age group, and may 
include respiratory distress, fainting, irritability, lethargy, unusual and persistent cool, pale skin, or nonspecific 
gastrointestinal symptoms (poor feeding, abdominal pain, and vomiting). If any of these symptoms occur following 
vaccination, study participants should seek immediate medical attention and notify study site staff. Participants 
reporting acute chest pain, shortness of breath, palpitations, or other signs or symptoms of myocarditis or pericarditis 
within 6 weeks after vaccination must be referred to a cardiologist for evaluation and management. 
Syncope may occur with the administration of vaccines, particularly in adolescents.  
Two SAEs of facial swelling in individuals with a history of injection of dermatological fillers were reported following 
administration of the Moderna vaccine and were deemed as likely related to vaccine administration. 
SPIKEVAX (COVID-19 Vaccine, mRNA) and Moderna COVID-19 Vaccine can be used interchangeably. Moderna COVID-19 
Vaccine, Bivalent is made in the same way as SPIKEVAX and Moderna COVID-19 Vaccine, but it also contains an Omicron 
component to help prevent COVID-19 caused by the Omicron variant of SARS-CoV-2. Safety data with Moderna COVID-
19 Vaccine are relevant to Moderna COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the 
same process.  
COMIRNATY (COVID-19 Vaccine, mRNA) and the Pfizer-BioNTech COVID-19 Vaccine, when prepared according to their 
respective instructions for use, can be used interchangeably. The Pfizer-BioNTech COVID-19 Vaccine, Bivalent is made in 
the same way as COMIRNATY and Pfizer-BioNTech COVID-19 Vaccine but it also contains an Omicron component to help 
prevent COVID-19 caused by the Omicron variant of SARS-CoV-2. Safety data with Pfizer-BioNTech COVID-19 Vaccine are 
relevant to Pfizer-BioNTech COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same 
process.  
5.1.1.1 
Allergic Reactions and Anaphylaxis 
Allergic reactions have been reported to occur after vaccination with both the Moderna COVID-19 Vaccine and Pfizer-
BioNTech COVID-19 Vaccine. Allergic reactions range from mild to severe and include life-threatening anaphylactic 
reactions, although no deaths have been reported with either vaccine [48, 58].  
If a participant has an allergic reaction, he/she may need oral, intramuscular, or intravenous medications and will be 
treated per institutional standard (see Section 7.4 Rescue Medications). Emergency medications, oxygen, and 
equipment will be available to treat any allergic reactions.  
5.1.2 Risks of COVID vaccine based on the Janssen COVID-19 Vaccine 
Adverse reactions following administration of the Janssen COVID-19 Vaccine include injection site pain, erythema and 
swelling. Systemic reactions include headache, fatigue, myalgia, nausea, chills, and fever. Most solicited adverse 
reactions are mild to moderate, occur within 1-2 days of vaccine administration and have a median duration of 1-2 days 
[63]. Severe allergic reactions, including 1 case of anaphylaxis, have been reported following the Janssen COVID-19 
Vaccine administered in clinical studies [59]. 
Data from clinical studies showed numerical imbalance with more events in the vaccine arm in the following events [59]: 
1. Thromboembolic events including deep vein thrombosis, pulmonary embolism, transverse sinus thrombosis 
2. Seizures 
3. Tinnitus 


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5.1.2.1 
Thrombosis with Thrombocytopenia after Janssen COVID-19 
Vaccination 
Reports to the Vaccine Adverse Events Reporting System (VAERS) have provided evidence for an increased risk of 
thrombosis with thrombocytopenia syndrome (TTS) with onset of symptoms occurring one to two weeks following 
administration of the Janssen COVID-19 vaccine. Cases of TTS have been reported in males and females over a wide 
range of ages. The highest reporting rate (approximately 1 case per 100,000 doses) is in females aged 30-49. Overall, 
approximately 15% of cases have been fatal. The clinical course of TTS shares features with heparin-induced 
thrombocytopenia [59]. 
The following case definition of TTS were used:   
1. A thrombosis in an unusual location for a thrombus and new onset thrombocytopenia (platelet count 
<150,000/uL) any time after vaccination. OR 
2. New onset thrombocytopenia, thrombosis in an extremity vein, or the pulmonary artery in the absence of 
thrombosis at an unusual location and a positive anti-PF-4 antibody or functional heparin-induced 
thrombocytopenia. 
Providers should maintain a high index of suspicion for symptoms consistent with TTS within several weeks of receipt of 
the Janssen COVID-19 Vaccine.  
Recipients of the Janssen COVID-19 vaccine should seek immediate medical attention if they develop shortness of 
breath, chest pain, leg swelling, persistent abdominal pain, neurological symptoms, or petechiae beyond the site of 
vaccination.  
5.1.2.2 
Booster Doses in Immunologically Competent Individuals 
Additional safety concerns have not been identified with homologous booster doses of any of the 3 SARS-CoV-2 vaccines 
discussed above. 
An independent Phase 1/2 open-label clinical trial (NCT04889209) was conducted in the US that evaluated heterologous 
dosing of individuals who had completed a primary series of one of the 3 vaccine discussed above and had no evidence 
of infection with SARS-CoV-2. Adverse events were assessed through 28 days following the booster dose, and the data 
revealed no safety concerns for any of the 3 vaccines given as a heterologous dose compared with adverse reactions 
following the primary series dosing or an homologous booster dose.  
5.1.2.3 
Guillain Barré Syndrome after Janssen COVID-19 Vaccination  
After approximately 12.5 million doses of the Janssen vaccine were administered, a review of data from VAERS identified 
100 occurrences of Guillain Barré Syndrome (GBS) following administration of the Janssen COVID-19 Vaccine[64]. Of the 
100 cases of GBS following Janssen vaccine administration, 95 were categorized as serious and resulted in 
hospitalization, and 1 death was reported[64]. These events suggest an increased risk of GBS during the 42 days 
following Janssen COVID-19 Vaccine administration[59].  
5.1.2.4 
Syncope 
Syncope may occur in association with administration of injectable vaccines. 
5.1.3 Risks of COVID vaccine based on the Sanofi-GSK COVID-19 Vaccine 
Expected risks of the Sanofi-GSK COVID-19 Vaccine and AS03 adjuvant, based on the Sanofi Pasteur CoV2 preS dTM-
AS03 adjuvanted vaccine Investigator’s Brochure (v11; 25MAR2022) and the AS03 Adjuvant System Investigational 
Brochure (Edition 2, Version 2; 10MAR2022), include solicited injection site and systemic events. Injection site reactions 
may include injection site pain, injection site erythema, injection site swelling, injection site pruritus, upper limb edema, 
and, possibly, the extensive swelling of the vaccinated limb extending beyond the closest joint. Systemic reactions may 
include fatigue, nausea, diarrhea, fever, headache, malaise, myalgia, arthralgia, and chills as separate events or a 
combination of events. 


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Potential (not observed in clinical trials) class effect for all vaccines include anaphylactic reactions, vaccine-associated 
enhanced disease, exacerbation of pre-existing or development of new immune-mediated disease, and vasovagal 
reactions or psychogenic reactions. 
5.2 
Risks of Other Protocol-specified Medications 
There are no other protocol-mandated medications. All other medications used by participants are prescribed for their 
underlying conditions and will be recorded on the appropriate electronic case report form (eCRF). Depending on 
assignment, participants may be instructed to hold their MTX or MMF/MPA during the period around their vaccination. 
5.3 
Risks of Study Procedures  
5.3.1 Risks Associated with Withdrawal of IS Medications 
Participants in Cohorts A and B may be randomized to withdraw their cohort-defining IS medications around the time of 
the additional homologous vaccine dose. Withdrawal of IS medications could lead to disease exacerbation and flare. 
Participants will be evaluated for increases in disease activity during the Baseline/Week 0 visit prior to administration of 
the additional homologous vaccine dose.  
5.3.2 Risks Associated with Blood Collection 
Risks associated with drawing blood include possible pain when the needle is inserted, as well as bleeding, bruising 
and/or infection at the puncture site. Some people may experience lightheadedness, nausea, or fainting. National 
Institutes of Health (NIH) guidelines for blood collection (amount and frequency) will be followed [65]. 
5.3.3 Risks Associated with Physical Exam 
There are no known risks associated with the physical exam. 
5.3.4 Risks Associated with Medical History or Participant Diary 
There is a possibility that participants may find questions about their medical history or questions asked on the 
participant diary to be too personal. Participants may refuse to answer any questions that make them feel 
uncomfortable. There is also a possibility that a participant’s answers may be read by others; however, participants’ 
records are carefully protected so this is very unlikely. See Section 17.3 Privacy and Confidentiality for more information.  
5.3.5 Risks Associated with Urine Collection 
There are no risks associated with urine sample collection.  
5.3.6 Risks Associated with Nasal Swab Collection 
Nasal swab collection may cause localized discomfort. The participant may experience moderate discomfort, and in rare 
instances, nosebleeds can occur as a result of nasopharyngeal, nasal swab and/or other mechanistic oronasal samples. 
The participant may also experience watery eyes and/or coughing, but only for the short duration of the swab. 
5.4 
Potential Benefits 
There is no guaranteed benefit to participants. Recent preliminary reports have suggested that individuals with 
autoimmune disease on IS medications may not develop a protective immune response to vaccination against SARS-
CoV-2. Information gained from this study may identify reasons for the lack of response, enhance understanding of the 
immunologic mechanism for protective response other than antibody titers and/or identify clinical methods of 
improving the vaccine response by inducing higher levels of antibodies or cell mediated immunity in individuals with 
suboptimal antibody responses to primary vaccination [19].  
 
 


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6. 
Investigational Agents  
The investigational agents provided in the study include: the Moderna COVID-19 vaccines, the Pfizer-BioNTech vaccines, 
the Janssen COVID-19 vaccine, and the Sanofi-GSK CoV2 preS dTM-AS03 adjuvanted vaccine.  The vaccines no longer 
offered in the study are indicated in the sections below.  
Additional details regarding vaccine storage, dosage, preparation, and administration can be found in the ACV01 
Pharmacy Manual. Vaccine administration details will be recorded on the Vaccine Administration eCRF.  
6.1 
Investigational Agent #1: Moderna COVID-19 Vaccine 
The Moderna COVID-19 vaccines are being used in the study to provide additional booster doses to eligible study 
participants.  
The table below describes the Moderna COVID-19 Vaccine dosing used in ACV01 protocol v7.0: 
Table 10. Moderna COVID-19 Vaccine Dosing 
Age of Participant 
Stage 1 Dose 
Stage 2 Dose  
2 years through 5 years 
25 mcg  
(Bivalent) 
25 mcg  
(Bivalent) 
6 years through 11 years 
50 mcg  
(Bivalent) 
50 mcg  
(Bivalent) 
12 years through 17 years 
100 mcg  
(Bivalent) 
100 mcg  
(Bivalent) 
18 years and older 
N/A (Closed) 
100 mcg  
(Bivalent) 
 
 
 




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6.2 
Investigational Agent #2: Pfizer-BioNTech COVID-19 Vaccine 
The Pfizer-BioNTech COVID-19 vaccines are being used in the study to provide additional booster doses of vaccine to 
eligible participants.  
The table below describes the Pfizer-BioNTech COVID-19 Vaccine dosing provided in the ACV01 protocol v7.0: 
Table 12. Pfizer-BioNTech COVID-19 Vaccine Dosing 
Age of Participant 
Stage 1 Dose 
Stage 2 Dose (Alternative Dose) 
2 years through 4 years 
3 mcg 
 (Bivalent) 
N/A 
5 years through 11 years 
10 mcg  
(Bivalent) 
N/A 
12 years through 17 years 
30 mcg  
(Bivalent) 
30 mcg  
(Bivalent) 
18 years and older 
N/A (Closed) 
30 mcg  
(Bivalent) 
 
 
 


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The table below describes details on the Pfizer-BioNTech COVID-19 Vaccine products provided in ACV01 Protocol v7.0: 
Table 13. Pfizer-BioNTech COVID-19 Vaccine Products 
COVID-19 Vaccine 
Information & Vial cap 
color/Label Border 
Pfizer Maroon Cap/Maroon Label 
Border BIVALENT  Vaccine; Currently 
Provided in ACV01 
Pfizer Orange Cap/Orange Label 
Border BIVALENT Vaccine; Currently 
Provided in ACV01 
Pfizer Gray Cap/Gray Label Border 
BIVALENT Vaccine; Vaccine 
Currently Provided in ACV01 
EUA Approved Age 
6 months through 4 years  
5 years through 11 years 
12 years and older 
Age of ACV01 Study 
Participants 
2 years through 4 years (Stage 1 only) 
5 years through 11 years (Stage 1 only) 
12 years through 17 years  
18 years and older (Stage 2 only) 
 
Pharmaceutical 
Formulation  
➤ Each 0.2 mL dose of vaccine 
contains:  
    ✓ modRNA*: 3 mcg  
    ✓ Tromethamine: 0.006 mg  
    ✓ Tromethamine hydrochloride: 
0.04 mg    
    ✓ Sucrose: 3.2 mg  
    ✓ Total lipid content: 0.075 mg 
(0.04 mg 
((4hydroxybutyl)azanediyl)bis(hexane-
6,1-diyl)bis(2-hexyldecanoate), 0.005 
mg 2[(polyethylene glycol)-2000]N,N-
ditetradecylacetamide, 0.01 mg 1,2-
distearoyl-sn-glycero-3-
phosphocholine, and 0.02 mg 
cholesterol)     
    ✓ The diluent (sterile 0.9% Sodium 
Chloride Injection, USP) contributes 
1.52 mg sodium chloride per dose 
➤ Contains no preservative and the 
vial stoppers are not made with 
natural rubber latex 
 
*Each 0.2 mL dose of the Pfizer-
BioNTech COVID-19 Vaccine, Bivalent 
is formulated to contain 1.5 mcg of 
modRNA encoding the (S)-
glycoprotein of SARS-CoV-2 Wuhan-
Hu-1 strain (Original) and 1.5 mcg of 
modRNA encoding the S glycoprotein 
of SARS-CoV-2 Omicron variant 
lineages BA.4 and BA.5 (Omicron 
BA.4/BA.5). The S-proteins of the 
SARS-CoV-2 Omicron variant lineages 
BA.4 and BA.5 are identical.  
➤ Each 0.2 mL dose of vaccine 
contains:  
    ✓ modRNA*: 10 mcg  
    ✓ Tromethamine: 0.02 mg  
    ✓ Tromethamine hydrochloride: 0.13 
mg      
    ✓ Sucrose: 10.3 mg  
    ✓ Total lipid content: 0.25 mg (0.14 
mg 
((4hydroxybutyl)azanediyl)bis(hexane-
6,1-diyl)bis(2-hexyldecanoate), 0.02 mg 
2[(polyethylene glycol)-2000]N,N-
ditetradecylacetamide, 0.03 mg 1,2-
distearoyl-sn-glycero-3-
phosphocholine, and 0.06 mg 
cholesterol) 
    ✓ The diluent (sterile 0.9% Sodium 
Chloride Injection, USP) contributes 0.9 
mg sodium chloride per dose. 
➤ Contains no preservative and the 
vial stoppers are not made with natural 
rubber latex 
 
*Each 0.2 mL dose of the Pfizer-
BioNTech COVID-19 Vaccine, Bivalent is 
formulated to contain 5 mcg of a 
nucleoside-modified messenger RNA 
(modRNA) encoding the viral spike (S) 
glycoprotein of SARS-CoV-2 Wuhan-Hu-
1 strain (Original) and 5 mcg of 
modRNA encoding the S glycoprotein 
of SARS-CoV-2 Omicron variant 
lineages BA.4 and BA.5 (Omicron 
BA.4/BA.5). The S-proteins of the SARS-
CoV-2 Omicron variant lineages BA.4 
and BA.5 are identical. 
➤ Each 0.3 mL dose of vaccine 
contains:  
    ✓ modRNA*: 30 mcg  
    ✓ Tromethamine: 0.06 mg  
    ✓ Tromethamine hydrochloride: 
0.4 mg    
    ✓ Sucrose: 31 mg  
    ✓ Total lipid content: 0.76 mg 
(0.43 mg ((4-
hydroxybutyl)azanediyl)bis(hexane-
6,1diyl)bis(2-hexyldecanoate), 0.05 
mg 2[(polyethylene glycol)-2000]-
N,N-ditetradecylacetamide, 0.09 
mg 1,2distearoyl-sn-glycero-3-
phosphocholine, and 0.19 mg 
cholesterol) 
➤ Contains no preservative and 
the vial stoppers are not made with 
natural rubber latex 
 
*Each 0.3 mL dose of the Pfizer-
BioNTech COVID-19 Vaccine, 
Bivalent is formulated to contain 
15 mcg of a nucleoside-modified 
messenger RNA (modRNA) 
encoding the viral spike (S) 
glycoprotein of SARS-CoV-2 
Wuhan-Hu-1 strain (Original) and 
15 mcg of modRNA encoding the S 
glycoprotein of SARS-CoV-2 
Omicron variant lineages BA.4 and 
BA.5 (Omicron BA.4/BA.5). The S-
proteins of the SARS-CoV-2 
Omicron variant lineages BA.4 and 
BA.5 are identical. 
Dosage Form 
Suspension for IM injection 
Suspension for IM injection 
Suspension for IM injection 
Final Concentration  
15 mcg/mL (After Dilution) 
50 mcg/mL (After Dilution) 
100 mcg/mL  
Total Dose and 
Volume Per Vial 
40 mcg/ 2.6 mL (After Dilution) 
130 mcg/2.6 mL (After Dilution) 
225 mcg/ 2.25 mL 
No. of Doses Per Vial 
10 doses (After Dilution) 
10 doses (After Dilution) 
6 doses of 30 mcg  
Dilution Required? 
YES; 2.2 mL of 0.9% NS 
YES; 1.3 mL of 0.9% NS 
NO 
ACV01 mRNA Dose 
and Volume  
3 mcg/ 0.2 mL  
10 mcg/ 0.2 mL  
30 mcg/ 0.3 mL 
ACV01 Number of 
Doses Per Vial  
Multiple Dose Vial:  
10 doses of 3 mcg (After Dilution) 
Multiple Dose Vial:  
10 doses of 10mcg (After Dilution) 
Multiple Dose Vial: 
 6 doses of 30 mcg  






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6.4 
Investigational Agent #4: Sanofi-GSK COVID-19 Vaccine 
The Sanofi Pasteur Monovalent (B.1.351) CoV2 preS dTM-AS03 adjuvanted vaccine, referred to as the Sanofi-GSK COVID-
19 Vaccine in this protocol, is under investigational use to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 
years of age and older. Eligible study participants will receive one dose of vaccine. 
The table below describes details on the Sanofi-GSK CoV2 preS dTM-AS03 Adjuvanted Vaccine product provided in 
ACV01 Protocol v7.0: 
Table 15. Sanofi-GSK COVID-19 Vaccine Product 
AGE of ACV01 Study Participants 
Adult participants only (18 years and older) 
 
Sanofi GSK COVID-19 Vaccine 
Components 
Pharmaceutical Formulation  
 
(CoV2 preS dTM antigen and AS03 are 
mixed together to form the prepared 
vaccine) 
 
CoV2 preS dTM antigen is a sterile, clear, 
colorless solution (with possible presence 
of endogenous particles) of SARS-CoV-2 
prefusion S proteins for intramuscular 
injection. The CoV2 preS dTM antigen 
contains phosphate-buffered saline (PBS) 
buffer, residual amounts of baculovirus 
and Spodoptera frugiperda cell proteins 
(≤2 to 3 μg), baculovirus and cellular 
deoxyribonucleic acid (DNA, ≤10 ng). 
 
AS03 is an adjuvant system containing α-
tocopherol and squalene in an oil/water, 
whitish to yellowish, homogenous, milky 
liquid emulsion.   
AS03 also contains the following 
excipients: Sodium chloride, Sodium 
dihydrogen phosphate, Potassium 
dihydrogen phosphate, Potassium 
chloride, Water for injection 
Sanofi Pasteur and GSK monovalent 
(B.1.351) CoV2 preS dTM-AS03 COVID-
19 Prepared Vaccine 
➤ Each 0.5 mL dose contains the following:  
✓ preS-delta TM B.1.351, prefusion S delta TM B.1.351 COVID-19 antigen: 5 mcg 
    • Sodium phosphate monobasic monohydrate 
    • Sodium phosphate dibasic dodecahydrate 
    • Sodium chloride  
    • Polysorbate 20 
    • Water for injection 
✓ AS03 adjuvant (full dose) is an oil-in-water emulsion containing squalene: 10.69 mg 
    • DL-α- tocopherol: 11.86 mg 
    • Polysorbate 80: 4.86 mg 
Dosage Form 
Liquid emulsion for IM injection 
Concentration of Prepared Vaccine  
10 mcg/mL (After mixing antigen and AS03 adjuvant) 
Total Dose and Volume per Vial   
CoV2 preS dTM antigen: 3 mL and AS03: 3mL; Total of 6 mL after mixing  
No. of doses Per Vial  
10 doses (After Mixing) 
Dilution Required?  
NO, but need to mix antigen and AS03 adjuvant together 
ACV01 Dose and Volume  
5 mcg/ 0.5mL  
ACV01 Number of Doses Per Vial 
Multiple Dose Vial: 10 doses (After Mixing) 
 
 
6.5 
Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62), the investigator bears the responsibility to maintain 
adequate investigational product (IP) disposition records (receipt, storage, dispense, return, and destruction). DAIT/ 
NIAID requires the principal investigator(s) to delegate the IP disposition responsibility to a licensed/registered 
pharmacist at a registered investigational pharmacy at a clinical research site. Detailed information on investigational 
pharmacy requirements is provided in the DAIT Pharmacy Guidelines. All IP inventory and dispensing will be 
documented using a DAIT/ NIAID main accountability as well as participant-specific dispensing fillable PDF forms or 


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electronic logs that are 21 CFR 11 compliant and approved by DAIT/NIAID. The participant dispensing log(s) will be kept 
current and will contain the identification of each participant as well as the date and quantity of each IP prepared and 
dispensed. Detailed IP shipment records to each clinical site’s investigational pharmacy will be maintained by the DAIT/ 
NIAID’s Clinical Product Center (EMINENT Services Corporation). All records regarding IP disposition will be available for 
inspection. All remaining unused IP will be returned to the IND Sponsor (DAIT/ NIAID) or sponsor’s representative after 
study termination or destroyed with the prior approval from the sponsor in accordance with applicable federal and state 
laws as well as the study site procedures. 
6.6 
Assessment of Participant Compliance with Investigational Agent 
Participants in this study will receive the assigned vaccine under direct observation.  
6.7 
Toxicity Prevention and Management 
Participants will receive investigational agents in facilities where the investigative team is familiar and practiced in the 
treatment and care of participants with systemic autoimmune diseases and complications associated with those 
disorders and the associated treatments. Vaccinations will also only be given by personnel trained in recognizing and 
managing treatment of systemic allergic reactions and in areas equipped with the necessary medications and supplies to 
treat systemic allergic reactions. Participants who are experiencing a disease flare at Baseline/Week 0, or who meet any 
of the conditions listed in Section 8.1.3 Baseline (Week 0/Day 1) Visit will not proceed with vaccination. Refer to Section 
5.1.1.1 Allergic Reactions and Anaphylaxis and Section 7.4 Rescue Medications. 
7. 
Other Medications 
7.1 
Concomitant Medications 
7.1.1 Protocol-mandated Medications 
There are no protocol-mandated medications in this clinical trial. However, there is protocol-mandated temporary 
cessation as follows: 
• 
Adult and Pediatric Stage 1 participants: 
o There will be a protocol-mandated temporary cessation of cohort-defining IS in some participants in 
Cohort A (MMF/MPA) and Cohort B (MTX). 
• 
Adult and Pediatric Stage 2 participants: 
o There is a protocol-mandated temporary cessation of cohort-defining IS in all Cohort D (MMF/MPA) and 
Cohort E (MTX) participants. 
o Any participants in Cohort F (BCDT) who are also taking MMF/MPA or MTX will have a protocol-
mandated temporary cessation of their MMF/MPA or MTX dose.  
Adult and Pediatric Stage 1 in Cohort A: MMF/MPA and Cohort B: MTX that are randomized to hold these medications at 
the time of the additional homologous vaccine dose (per Section 3.1 Description of Study Design) and all Adult and 
Pediatric Stage 2 participants will be required to hold these medications as follows: 
• 
Participants taking MMF/MPA (any dose) will hold the doses for 3 days before and 10 days after their vaccine 
dose.  
o Participants taking additional IS medications (such as tumor necrosis factor [TNF] inhibitors, JAK 
inhibitors, abatacept, belimumab, etc.) will be required to continue them during the time of the 
additional vaccine dose. 
• 
Participants taking MTX (at any dose) will be required to hold their weekly dose for at least 7 days before their 
vaccine dose and for at least 7 days after administration of the vaccine. In total, the participant should not hold 
their MTX for more than 21 days.  


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o Participants taking additional IS medications (such as TNF inhibitors, JAK inhibitors, abatacept, 
belimumab, etc.) will be required to continue them during the time of their vaccine dose. 
Participants that are randomized to continue medications (per Section 3.1 Description of Study Design) are required to 
maintain a stable dose of medication during the same period (Cohort A: MMF/MPA from 3 days before to 10 days after 
the additional homologous vaccine dose; Cohort B: MTX from 7 days before to 7 days after the additional homologous 
vaccine dose) unless they experience a change in disease activity requiring medication changes.  
All participants in Cohort C: B-cell depleting therapy will continue to take their prescribed medications throughout the 
trial, unless they experience a change in disease activity requiring medication changes. It is preferred that these 
medications be stabilized before entry and continued wherever practical without variation of dose or regimen during 
the study. 
7.1.2 Other permitted concomitant medications 
Other than the prohibited medications listed in Section 7.3 Prohibited Medications, treatment with concomitant 
medications for treatment of SLE, RA, MS, pemphigus, and SSc in adult participants and JIA, JDM, pediatric SLE, and 
POMS in pediatric participants is permitted throughout study participation. Permitted concomitant medications include 
B cell modulating therapies such as epratuzumab (anti-CD22, modulates B cell signaling) or agents that target 
B-lymphocyte stimulator (BlyS; belimumab, atacicept), but these agents are not considered to be BCDT for defining 
assignment to Cohort C.  
Concomitant therapies taken for the long-term treatment of pre-existing conditions other than SLE, RA, MS, pemphigus, 
and SSc should be continued during the study, provided that they are in accordance with the exclusion criteria. Other 
permitted concomitant medications may not change between Randomization/Allocation and the Baseline/Week 0 visit. 
This includes the addition of new medications, or changes in dose and/or frequency of existing medications.  
7.2 
Prophylactic Medications 
Female participants of childbearing potential will be counseled to use an effective method of contraception (e.g., total 
abstinence, oral contraceptives, intrauterine devices, barrier method with spermicide, surgical sterilization or surgically 
sterilized partner, medroxyprogesterone acetate, levonorgestrel implant, etonogestrel/ethinyl estradiol vaginal ring, or 
hormonal implants) for the duration of study participation. 
7.3 
Prohibited Medications 
All participants are to have access to any care deemed medically necessary, but administering the following medications, 
for the purposes of this study, are prohibited and will be considered protocol deviations unless otherwise noted.  
• 
Any SARS-CoV-2 vaccine administered outside of the study is prohibited. 
• 
All other vaccines administered outside of the study are prohibited between Screening and Week 4 during Stage 
1 participation and between Screening and Week 4 during Stage 2 participation. 
• 
Other vaccines, including the flu vaccine, administered within 4 weeks prior to a study visit, starting with the 
Baseline visit.  
• 
Intravenous or subcutaneously administered immune globulin within 4 weeks prior to a study visit 
• 
Monoclonal antibodies for pre-exposure prophylaxis are prohibited between Screening and Week 4 during Stage 
1 participation and between Screening and Week 4 during Stage 2 participation.  
If a participant takes a prohibited medication during the study, it should be recorded as a protocol deviation in the eCRF. 
Participants who received a SARS-CoV-2 vaccine outside of the study will be withdrawn. All other participants will 
continue to be followed for safety. 
7.4 
Rescue Medications  
The following medications may be used to treat an allergic reaction:   
• 
Epinephrine 1 mg/mL; 0.3 – 0.5 mg intramuscularly 


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• 
β-adrenergic agonist inhaler or nebulizer (e.g., albuterol)  
• 
Antihistamines 
• 
Steroids  
• 
Intravenous fluids 
• 
Oxygen 
Guidelines for the treatment of systemic allergic reactions are detailed in the Manual of Procedures (MOP). Rescue 
medications should be recorded on the Concomitant Medications eCRF. 
8. 
Study Procedures 
8.1 
Adult Stage 1 Study Procedures 
8.1.1 Visit Windows 
Appendix 20.1, Table 17 presents the Schedule of Events for participants in Adult Stage 1. The visit windows are defined 
below: 
• 
Screening until Randomization/Allocation: up to 21 days from time of obtaining informed consent until the 
participant is determined to meet study entry criteria (allocation for Cohort C) or randomization (for Cohorts A 
and B). 
• 
Randomization: phone visit that must occur at least 7 days prior to administration of the additional homologous 
vaccine dose at the Baseline/Week 0 visit for Cohorts A and B.  
o See Section 8.1.2.4 Randomization/Allocation for more details on Randomization visit activities.  
• 
Baseline (Week 0/Day 1) 
o See Section 8.1.3 Baseline (Week 0/Day 1) Visit for more details on Baseline visit activities. 
• 
Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
• 
Week 4: (+/- 1 week)  
• 
Week 12: (+/- 2 weeks)  
• 
Week 24: (+/- 2 weeks)  
• 
Week 36: (+/- 2 weeks) 
• 
Week 48 (End of Study): (+/- 2 weeks) 
8.1.2 Screening and Randomization/Allocation 
8.1.2.1 
Pre-Screening  
An optional Pre-Screening visit may be conducted to confirm that a participant has had a negative or suboptimal 
response to initial COVID-19 vaccine regimen prior to Screening. This study will be explained in lay language to each 
potential participant. Each participant will sign an informed consent form before committing to study Pre-Screening 
procedures. Pre-Screening procedures at the study site will vary by method of recruitment as outlined below:  
Study site personnel are responsible for the following: 
1. Consent the participant for an ACV01 Pre-Screening Evaluation. 
2. Conduct the rapid result or other antibody testing.  
3. Invite the participant to an ACV01 Screening Visit if the result is negative or weakly positive per the site 
preferred antibody test method. 


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8.1.2.2 
Determination of Participant Cohort and Identification of Qualifying 
Disease 
Prior to screening a potential participant, the site needs to determine which IS Cohort the participant will be assigned to 
and identify the participant’s qualifying autoimmune disease.  
Cohorts: The ACV01 study will be accepting participants who are taking 3 types of IS medications: MMF or MPA, MTX, 
and BCDTs. The criteria for assignment to each cohort are listed below: 
• 
Cohort A: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA will be placed in this cohort.  
 
Participants may not also be taking MTX.  
 
Participants may not have taken anti-CD20 and anti-CD19 BCDT in the past 18 months.  
• 
Cohort B: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX will be placed in this cohort.  
 
Participants may not also be taking MMF/MPA.  
 
Participants may not have taken anti-CD20 and anti-CD19 BCDT in the past 18 months.  
• 
Cohort C: Receipt of anti-CD20 or anti-CD19 BCDT within the past 18 months (± other rheumatic disease 
medications) 
o Participants who have taken B cell depletion medications in the past 18 months will be placed in this 
cohort.  
 
Participants may also be taking MMF/MPA or MTX. 
Qualifying Autoimmune Diseases: The ACV01 Adult Stage 1 study will be accepting adult participants diagnosed with 
SLE, RA, MS, SSc, or pemphigus. In the event that a participant has more than one of these 5 diseases, disease activity 
assessments will be collected throughout the trial for only the disease associated with IS medication cohort assignment 
at entry into the trial.  
8.1.2.3 
Screening 
The research study will be explained in lay terms to each potential Stage 1 participant. The potential participant will sign 
an Institutional Review Board (IRB)-approved informed consent form before undergoing any study procedures. Once the 
informed consent has been signed, the participant will be assigned a unique participant number. At this time, study-
specific procedures may be performed.  
The purpose of the screening period, which begins at the time of signed consent, is to confirm eligibility to enter the 
study. All screening procedures, assessments, and laboratory measures to determine participant eligibility will be 
conducted within a 21-day screening window with shorter time periods expected for most participants.  
The assessment of eligibility may take a series of visits that occur on separate days. The Screening visit biomarkers 
should reflect, as much as possible, the biometrics of the participant prior to any study procedures.  
The following procedures, assessments, and laboratory measures will be conducted:  
1. Informed Consent 
2. Demographics 
3. Medical History 
4. Concomitant Medications (including contraceptives) 
5. Comprehensive Physical Exam 
6. Vital Signs  


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7. Confirmation of Disease Classification Criteria Assessment 
a. 2019 ACR/EULAR or 2012 SLICC classification criteria for SLE 
b. 2010 ACR/EULAR classification criteria for RA 
c. 2013 EULAR/ACR classification criteria for SSc 
d. 2017 McDonald diagnostic criteria for MS 
e. International consensus criteria for pemphigus 
8. Complete assessments of disease activity: H-SLEDAI and PGA for SLE; DAS28-CRP and PtGA for RA; patient self-
reported disease flare and Modified Rodnan Skin Score for SSc; physician-assessed relapse for MS; PDAI for 
pemphigus 
9. Review of initial COVID-19 vaccination record and antibody response 
10. Central laboratory assessments for all participants 
a. Infectious Disease Testing:  HIV, Hepatitis B surface antigen, Hepatitis C antibody with viral load if 
indicated  
b. Elecsys® Anti-SARS-CoV-2 S assay to assess response to initial COVID-19 vaccine regimen  
c. Complete blood count (CBC) with differential  
d. Comprehensive metabolic panel (CMP), estimated glomerular filtration rate (eGFR) 
11. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing:   
b. Urine pregnancy test (women of child-bearing potential only) 
12. Disease-specific laboratory assessments: 
a. RA participants only 
i. C-Reactive Protein (CRP) 
b. SLE participants only 
i. Anti-dsDNA, C3, C4 
ii. Random urine protein-creatinine ratio 
iii. Urinalysis (microscopic) 
c. B-cell depleting therapy participants only 
i. If on CD20 depleting agent, CD19+ B cells 
d. Pemphigus participants only 
i. Anti-desmoglein 1/3 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA) 
13. Inclusion/Exclusion criteria assessment 
Participants with abnormal laboratory values that prohibit entry may be re-tested once during the screening period, 
which may last up to 21 days. Participants who screen fail may be rescreened one time and must repeat all screening 
assessments. Any further rescreening activity requires approval by the medical monitor. 
During the Screening visit, the site will review vaccine eligibility criteria, per Section 8.1.3 Baseline Visit with the 
participant.  
 


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8.1.2.3.1 
Evaluation of Eligibility and Randomization/Allocation 
Cohorts A (MMF/MPA) or B (MTX): If the participant meets all eligibility criteria, then proceed as follows: 
• 
Schedule Baseline/Week 0 Visit (within 28 days of first Screening assessment). 
• 
Randomize the participant (within 21 days of screening and at least 7 days prior to the scheduled 
Baseline/Week 0 visit). 
Cohort C (BCDT):  If the participant meets all eligibility criteria, then proceed as follows: 
• 
Schedule Baseline/Week 0 Visit (within 28 days of first Screening assessment). 
8.1.2.4 
Randomization/Allocation 
Randomization is a phone visit that will occur up to 21 days after Screening and at least 7 days prior to the 
Baseline/Week 0 visit for participants in Cohorts A (MMF/MPA) and B (MTX). During Randomization, sites will call 
participants to confirm that concomitant medication and medical history data continue to meet eligibility criteria. After 
eligibility is confirmed, the site will randomize the participant to an IS medication treatment plan per Section 3.1 
Description of Study Design. If the participant is randomized to withhold cohort-defining IS medication treatment, the 
site will communicate the details of the medication hold to the participant per Section 7.1.1 Protocol-mandated 
Medications. The site will inform the participant that there should be no changes to his/her other existing medications 
between Randomization and the Baseline/Week 0 visit.  
For Stage 1, allocation is the confirmation that participants in Cohort C have met all study entry criteria and may proceed 
to the Baseline/Week 0 visit. The site will inform the participant that there should be no changes to his/her other 
existing medications between Allocation and the Baseline/Week 0 visit. 
8.1.3 Baseline (Week 0/Day 1) Visit 
Eligible participants who meet all inclusion criteria and none of the exclusion criteria will proceed with visits and 
assessments according to Section 20.1 Schedule of Events. Eligible participants will be assessed for disease activity and 
SARS-CoV-2 infection at the Baseline/Week 0 visit, prior to receipt of an additional homologous vaccine dose. Prior to 
administering the additional homologous vaccine dose at the Baseline visit, the site will confirm the participant meets 
vaccine eligibility per the criteria below: 
• 
No increase to the permitted concomitant medications in participants in Cohorts A and B between 
Randomization and Baseline/Week 0.  
• 
No B-cell depletion infusions or changes in permitted concomitant medications in participants in Cohort C 
between allocation and Baseline/Week 0.  
• 
No clinically active disease (including myocarditis or pericarditis) at Baseline/Week 0 resulting in an 
increase/addition of IS medications. For participants with MS, no suggestion of a MS relapse per the 
investigator. 
• 
No active myocarditis or pericarditis based on review of clinical symptoms. 
• 
No positive molecular COVID-19 test at Baseline/Week 0. 
• 
No increase in oral, intramuscular, or intravenous steroids within 14 days of Baseline/Week 0. 
If the vaccine cannot be administered at the Baseline/Week 0 visit, it must be administered during the following 
2-3 days. Vaccine eligibility will be confirmed prior to administration of the vaccine. Administration of the additional 
homologous vaccine dose must occur within 28 days of the Screening visit. 
If a participant is not eligible to receive the additional homologous vaccine dose at Baseline/Week 0, he/she will be 
terminated from the study. The participant may rescreen under a new participant ID after 30 days from the 
determination of vaccine ineligibility. Participants who were randomized to withhold cohort-defining IS medications 
before the Baseline visit and who are not eligible to receive an additional homologous vaccine dose at that visit, may 
restart their IS medications immediately. The participant will be replaced.  


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See Section 8.1.4 Study Procedures and Assessments for more information on individual clinical and research 
assessments.  
If the participant is randomized to the withhold cohort-defining IS medication treatment plan, the site will call the 
participant after the Baseline visit to provide instructions on resuming IS medication per Section 7.1.1 Protocol-
mandated Medications. 
8.1.4 Study Procedures and Assessments  
8.1.4.1 
General Assessments 
• 
Informed Consent Process 
• 
Demographics. Participants should provide demographic information. In particular, race and ethnicity should be 
self-identified. 
• 
Medical History. Medical history will be performed as part of screening activities and standard medical care. The 
medical history assessment will include current illnesses/conditions and past medical history. 
• 
Concomitant Medications (including contraceptives). A current list of prescription and over-the-counter 
medications, supplements, and treatments will be obtained. Assessment of eligibility should include a review of 
permitted and prohibited medications. The medication, dose, frequency, route, start date, stop date, and 
indication should be captured. 
• 
Comprehensive Physical Examination (Screening Only). Physical examinations are to include, at least, the 
following systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, 
cardiovascular, abdominal, neurological, & musculoskeletal/extremities. 
• 
Targeted physical examination: to be guided by participant complaints and prior abnormalities.  
• 
Neurological Exam:  for all MS participants and for participants with other diagnoses who have a neurological 
complaint after Screening.  
• 
Vital Signs. Height will only be collected at Screening. Weight, temperature, pulse, and blood pressure will be 
collected at each visit. Vital signs should be obtained with the participant in a seated position, and prior to taking 
samples for laboratory testing at applicable study visits. 
• 
Adverse Events 
• 
Vaccine Reaction Diary Overview, Training, & Distribution: Participants will be provided access to an electronic 
7-day diary to aid in recording solicited local and systemic reactions to the vaccine, as well as symptoms of a 
potential allergic reaction, unsolicited AEs, and concomitant medications, including start and stop dates. The 
diary will include instructions for participants on how to take an oral temperature and how to measure injection 
site reactions. A paper copy of the diary may be provided for participants who do not have a device to access the 
electronic diary or as a backup collection tool. A member of the study team will review the information in the 
diary with the participant, including how to use and access the electronic diary. As some solicited adverse events 
and grading scales are age-dependent and apply only to the pediatric population,  separate age-specific Pediatric 
Vaccine Reaction Diaries will be provided to pediatric participants.  
8.1.4.2 
Disease-Specific Assessments 
• 
SLE Disease Assessments 
o H-SLEDAI 
o Thanou modified SELENA-SLEDAI Flare Index 
• 
SSc Disease Assessments 
o Flare assessment for SSc (including patient reported flare assessment) 


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o Modified Rodnan Skin Score  
• 
MS Disease Assessments 
o Physician-assessed relapse for MS  
o Expanded Disability Status Scale (EDSS [at Baseline/Week 0]) 
 
If an MS relapse is suspected, the EDSS will be assessed at the following time points:  
• 
Time of suspected relapse 
• 
Time of relapse recovery (to occur 8-12 weeks after the suspected relapse EDSS 
assessment) 
• 
RA Disease Assessments 
o DAS28-CRP 
• 
Pemphigus Disease Assessments 
o PDAI 
o Flare assessment for pemphigus 
8.1.4.3 
Participant- and Clinician-reported Outcomes 
• 
Participant Reported Outcomes 
o PROMIS-29 
o PtGA 
o PGI-C 
• 
Clinician Reported Outcomes 
o PGA 
o CGI-C 
8.1.4.4 
Clinical Laboratory Assessments 
Blood and urine for the clinical laboratory assessments listed below will be collected per Section 20.1 Schedule of 
Events. The results will be evaluated for safety by the site investigator. Abnormal tests that meet grading and reporting 
criteria will be reported as adverse events (See Section 12.3 Grading and Attribution of Adverse Events). 
• 
Local Laboratory Assessments 
o Pregnancy Testing (Women of Childbearing Potential Only). Urine pregnancy test at Screening and 
Baseline/Week 0 visit. 
o Molecular COVID-19 Testing Baseline/Week 0/Day 1 molecular COVID-19 Testing can be collected and 
run and the results reported by a community-based laboratory (national chain pharmacy, Local MD 
office, State or Local Government run testing center, Urgent Care Center) not listed on the 1572. This 
test must be performed within the 48 hours prior to the Baseline/Week 0/Day 1 visit. For additional 
details, please see the ACV01 Manual of Procedures. 
• 
Central Laboratory Assessments 
o Hematology, including complete blood count (CBC) with differential. 
o Blood Chemistry including CMP, eGFR. 


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o Detection of antibodies against SARS-CoV-2 Spike protein (IgG) using the Roche Elecsys® Anti-SARS-
CoV-2 S electrochemiluminescence immunoassay intended for qualitative and semi-quantitative 
detection of antibodies to SARS‑CoV‑2 spike protein (RBD) in human serum. 
o Disease-specific laboratory assessments: 
 
RA participants only 
• 
C-Reactive Protein (CRP) 
 
SLE participants only 
• 
Anti-dsDNA, C3, C4 
• 
Random urine protein-creatinine ratio 
• 
Urinalysis: microscopic 
 
B-cell depleting therapy participants only 
• 
If on CD20 depleting agent, CD19+ B cells 
 
Pemphigus participants only 
• 
Anti-desmoglein 1/3 IgG autoantibodies by ELISA 
8.1.4.5 
Mechanistic Specimens  
• 
Serum 
o Antibody levels will be tested at each time point to test for IgG and immunoglobulin M (IgM) 
responses against SARS-CoV-2 spike, receptor binding domain, and nucleocapsid proteins. 
• 
Whole blood/peripheral blood mononuclear cell (PBMC)/plasma/DNA 
• 
RNA assays 
8.1.5 Unscheduled Visits  
If disease activity increases or other concerns arise between regularly scheduled visits, participants should be instructed 
to contact study personnel and may be asked to return to the study site for an “unscheduled” visit.  
8.1.6 Early Termination 
An Early Termination Visit should be requested for participants who withdraw from the study prior to study completion. 
Assessments to be conducted at an early termination visit can be found in Section 20.1 Schedules of Events. 
 
8.2 
Adult Stage 2 Study Procedures 
8.2.1 Visit Windows 
8.2.1.1 
Visit Windows for Adult Stage 2 Newly Recruited Participants 
Appendix 20.1, Table 18 presents the Schedule of Events for participants who are newly recruited to Adult Stage 2. The 
visit windows are defined below: 
• 
Screening and Allocation: 28 to 7 days prior to the S2 Baseline/Week 0 visit. 
• 
Baseline (Week 0/Day 1) 
o See Section 8.2.4 Baseline (Week 0/Day 1) Visit  for more details on Baseline/Week 0 visit activities. 
• 
Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
• 
Week 4: (+/- 1 week)  


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• 
Week 12: (+/- 2 weeks)  
• 
Week 24: (+/- 2 weeks)  
• 
Week 36: (+/- 2 weeks) 
• 
Week 48 (End of Study): (+/- 2 weeks) 
8.2.1.2 
Visit Windows for Adult Stage 2 Rollover Participants 
Participants can roll over into Stage 2 via two pathways: 
• 
Stage 1 participant rolls over to Stage 2 
o A Stage 1 participant who has a Roche Elecsys result ≤2500 U/mL at a post-Baseline visit may elect to roll 
over into Stage 2, starting the Stage 2 schedule of events for rollovers.  
• 
Stage 2 participant rolls over to a different Stage 2 treatment arm 
o A Stage 2 participant who received an alternative mRNA vaccine dose and has a Roche Elecsys result 
≤2500 U/mL at a post-Baseline visit may elect to re-enter Stage 2, restarting the Stage 2 schedule of 
events for rollovers.  
For participants rolling into Adult Stage 2, the visit windows are defined below. 
• 
Total Screening Period:  
o Up to 28 days from the Stage 1 or Stage 2 Visit at which negative, suboptimal or low immune response 
to the previous COVID-19 vaccine was obtained until the S2 Baseline/Week 0 visit. 
 
If the S2 Baseline/Week 0 visit cannot be conducted within 28 days of the qualifying Follow-up 
Visit noted above, the participant will return to the site for a full S2 Screening visit, as described 
in Section 8.2.2.3.2 Screening for Adult Stage 2 Rollover Participants. 
o S2 Screening Phone Visit: at least 7 days prior to administration of the alternative vaccine at S2 
Baseline/Week 0.  
 
See Section 8.2.2.3.2 Screening for Adult Stage 2 Rollover Participants for more details on the 
screening procedures for rollover participants. 
• 
S2 Baseline (S2 Week 0/Day 1) 
o See Section 8.2.4 Baseline (Week 0/Day 1) Visit for more details on the S2 Baseline/Week 0 visit 
activities. 
• 
S2 Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
• 
S2 Week 4: (+/- 1 week)  
• 
S2 Week 12: (+/- 2 weeks)  
• 
S2 Week 24: (+/- 2 weeks)  
• 
S2 Week 36: (+/- 2 weeks) 
• 
S2 Week 48 (End of Study): (+/- 2 weeks) 
8.2.2 Screening and Allocation 
8.2.2.1 
Pre-Screening  
8.2.2.1.1 
Pre-Screening for Adult Stage 2 Newly Recruited Participants 
An optional Pre-Screening visit may be conducted to confirm that a participant has had a negative,  suboptimal, or low 
immune response to initial COVID-19 vaccine regimen prior to Screening. This study will be explained in lay language to 
each potential participant. Each participant will sign an informed consent form before committing to study Pre-
Screening procedures. Pre-Screening procedures at the study site will vary by method of recruitment as outlined below:  


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Study site personnel are responsible for the following: 
1. Consent the participant for an ACV01 Pre-Screening Evaluation. 
2. Conduct the rapid result or other antibody testing.  
3. Invite the participant to an ACV01 Screening Visit if the result is negative or weakly positive per the site 
preferred antibody test method. 
8.2.2.1.2 
Pre-Screening for Adult Stage 2 Rollover Participants 
Elecsys® Anti-SARS-CoV-2 S assay results for study participants from visits at Week 4 through Week 48 will be reviewed 
when received by study sites. Participants with a negative,  suboptimal, or low immune response at any visit following 
receipt of the previous COVID-19 vaccine dose will have the data from their last study visit pre-screened to determine if 
they may qualify for Stage 2.  
If a participant pre-screens successfully for Stage 2, the study site will contact the participant to offer them the 
opportunity to be fully screened for Stage 2.  
8.2.2.2 
Determination of Participant Cohort and Identification of Qualifying 
Disease 
Prior to screening a potential newly recruited participant, the site needs to determine to which IS cohort the participant 
will be allocated and identify the participant’s qualifying autoimmune disease.  
Note that the qualifying disease for rollover participants will be the same as for their previous Stage. 
Cohorts: Stage 2 will be accepting participants who are taking 3 types of IS medications: MMF or MPA, MTX, and BCDTs. 
The criteria for allocation to each cohort are listed below: 
• 
Cohort D: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA will be placed in this cohort.  
 
Participants may not also be taking MTX.  
 
Participants may not have taken anti-CD20 and anti-CD19 BCDT in the past 18 months.  
• 
Cohort E: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX will be placed in this cohort.  
 
Participants may not also be taking MMF/MPA.  
 
Participants may not have taken anti-CD20 and anti-CD19 BCDT in the past 18 months.  
• 
Cohort F: Receipt of anti-CD20 or anti-CD19 BCDT within the past 18 months (± other rheumatic disease 
medications) 
o Participants who have taken B cell depletion medications in the past 18 months will be placed in this 
cohort.  
 
Participants may also be taking MMF/MPA or MTX. 
Qualifying Autoimmune Diseases: The ACV01 study will be accepting participants diagnosed with SLE, RA, MS, SSc, or 
pemphigus. In the event that a participant has more than one of these 5 diseases, disease activity assessments will be 
collected throughout the trial for only the disease associated with IS medication cohort assignment at entry into the 
trial.  


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8.2.2.3 
Screening 
8.2.2.3.1 
Screening for Adult Stage 2 Newly Recruited Participants 
The research study will be explained in lay terms to each potential Stage 2 newly recruited participant. The potential 
participant will sign an IRB-approved informed consent form before undergoing any study procedures. Once the 
informed consent has been signed, the participant will be assigned a unique participant number. At this time, study-
specific procedures may be performed.  
The purpose of the screening period, which begins at the time of signed consent, is to confirm eligibility to enter the 
study. All screening procedures, assessments, and laboratory measures to determine participant eligibility will be 
conducted within a 21-day screening window with shorter time periods expected for most participants.  
The assessment of eligibility may take a series of visits that occur on separate days. The Screening visit biomarkers 
should reflect, as much as possible, the biometrics of the participant prior to any study procedures.  
The following procedures, assessments, and laboratory measures will be conducted:  
1. Informed Consent 
2. Demographics 
3. Medical History 
4. Concomitant Medications (including contraceptives) 
5. Comprehensive Physical Exam 
6. Vital Signs  
7. Confirmation of Disease Classification Criteria Assessment 
a. 2019 ACR/EULAR or 2012 SLICC classification criteria for SLE 
b. 2010 ACR/EULAR classification criteria for RA 
c. 2013 EULAR/ACR classification criteria for SSc 
d. 2017 McDonald diagnostic criteria for MS 
e. International consensus criteria for pemphigus 
8. Complete assessments of disease activity: H-SLEDAI, and PGA for SLE; DAS28-CRP, Tender/Swollen Joint Count, 
and PtGA for RA; patient self-reported disease flare and Modified Rodnan Skin Score for SSc; physician-assessed 
relapse for MS; PDAI for pemphigus 
9. Review of COVID-19 vaccination record and antibody responses, infections and treatments. 
10. Central laboratory assessments for all participants 
a. Infectious Disease Testing:  HIV, Hepatitis B surface antigen, Hepatitis C antibody with viral load if 
indicated  
b. Elecsys® Anti-SARS-CoV-2 S assay to assess response to initial COVID-19 vaccine regimen  
c. CBC with differential  
d. CMP, eGFR 
11. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing  
b. Urine pregnancy test (women of child-bearing potential only) 
12. Disease-specific laboratory assessments: 


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a. RA participants only 
i. CRP 
b. SLE participants only 
i. Anti-dsDNA, C3, C4 
ii. Random urine protein-creatinine ratio 
iii. Urinalysis (microscopic) 
c. B-cell depleting therapy participants only 
i. If on CD20 depleting agent, CD19+ B cells 
d. Pemphigus participants only 
i. Anti-desmoglein 1/3 IgG autoantibodies by ELISA 
13. Inclusion/Exclusion criteria assessment 
Participants with abnormal laboratory values that prohibit entry may be re-tested once during the screening period, 
which may last up to 21 days. Participants who screen fail may be rescreened one time and must repeat all screening 
assessments. Any further rescreening activity requires approval by the medical monitor. 
During the Screening visit, the site will review vaccine eligibility criteria, per Section 8.2.4 Baseline (Week 0/Day 1) Visit 
with the participant.  
8.2.2.3.2 
Screening for Adult Stage 2 Rollover Participants 
The study site will contact potential Stage 2 rollover participants to offer them the opportunity to be fully screened for 
Stage 2. There are two options for the conduct of Screening for Adult Stage 2 for rollover participants:  
• 
The screening process for Stage 2 may be able to be completed with only a telephone visit if the necessary 
information is available from the last study visit from Stage 1, informed consent can be appropriately 
completed, etc.  
o Notes:  
 
Information that may be available from the last study visit from Stage 1 includes lab tests for 
eligibility and disease-specific laboratory tests noted below.  
 
The pregnancy test and molecular COVID-19 tests do not need to be completed during the 
Stage 2 Screening period if the Screening visit is conducted by phone. In such cases, these 
assessments will be conducted at the beginning of the Stage 2 Baseline visit before the vaccine is 
administered.  
• 
If the needed data are not available from the previous Stage 1 visit or 28 days will have passed when the 
S2 Baseline/Week 0 visit is reached, then the Stage 2 Screening visit must be conducted at the clinical site.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility 
for Stage 2.  
1. Confirm that participant agrees to proceed to Stage 2. 
a. If the participant has not yet signed an informed consent form that includes a description of Stage 2, the 
participant must provide signed informed consent for Stage 2 screening to proceed. 
2. Updated Medical History 
3. Updated Concomitant Medications (including contraceptives) 
4. Updated Physical Exam 


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a. Results of the Targeted Physical Exam and the Neurological Exam from the most recent Stage 1 visit may 
be used to fulfill this assessment in place of a new Comprehensive Physical Exam 
5. Vital Signs  
6. AE assessment following vaccination in Stage 1 
7. Complete assessments of disease activity: H-SLEDAI and PGA, for SLE; DAS28-CRP and PtGA for RA; patient self-
reported disease flare and Modified Rodnan Skin Score for SSc; physician-assessed relapse for MS; PDAI for 
pemphigus 
8. Central laboratory assessments for all participants 
a. Response to previous COVID-19 vaccine dose assessed by Elecsys® Anti-SARS-CoV-2 S assay 
b. CBC with differential  
c. CMP, eGFR 
9. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing (only if the Stage 2 Screening visit is conducted at the clinical site) 
b. Urine pregnancy test (only if Stage the 2 Screening visit is conducted at the clinical site for women of 
child-bearing potential only) 
10. Disease-specific laboratory assessments: 
a. RA participants only 
i. CRP 
b. SLE participants only 
ii. Anti-dsDNA, C3, C4 
iii. Random urine protein-creatinine ratio 
iv. Urinalysis (microscopic) 
c. B-cell depleting therapy participants only 
v. If on CD20 depleting agent, CD19+ B cells 
d. Pemphigus participants only 
vi. Anti-desmoglein 1/3 IgG autoantibodies by ELISA 
11. Inclusion/Exclusion criteria assessment 
8.2.3 Evaluation of Eligibility and Allocation 
If the participant meets all eligibility criteria for Stage 2, then proceed as follows during the Screening phone call: 
• 
Allocate the participant to the appropriate cohort based on IS medication 
• 
If the participant previously received 3 doses of an mRNA vaccine, determine which alternative COVID-19 
vaccine the participant will receive. 
• 
Schedule S2 Baseline/Week 0 visit (within 28 days of the Stage 2 Screening assessments and no sooner than 
7 days from the Screening visit). 
• 
Communicate to the participant the details of the medication hold to the participant per Section 7.1.1 Protocol-
mandated Medications. 
• 
Inform the participant that there should be no changes to his/her other existing medications between Screening 
and the S2 Baseline/Week 0 visit. 


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8.2.4 Baseline (Week 0/Day 1) Visit 
Eligible participants who meet all inclusion criteria and none of the exclusion criteria for Stage 2 will proceed with visits 
and assessments according to Section 20.1 Schedule of Events, Table 18 (newly recruited participant) or Table 19 
(rollover participant). Eligible participants will be assessed for disease activity and SARS-CoV-2 infection at the S2 
Baseline/Week\ 0 visit, prior to receipt of an alternative vaccine dose. Prior to administering the alternative vaccine dose 
at the Baseline visit, the site will confirm the participant meets vaccine eligibility per the criteria below: 
• 
No increase to the permitted concomitant medications in participants in Cohorts D and E between S2 Screening 
and S2 Baseline/Week 0.  
• 
No B-cell depletion infusions or changes in permitted concomitant medications in participants in Cohort F 
between allocation and S2 Baseline/Week 0.  
• 
No clinically active disease (including myocarditis or pericarditis) at S2 Baseline/Week 0 resulting in an 
increase/addition of IS medications. For participants with MS, no suggestion of a MS relapse per the 
investigator. 
• 
No active myocarditis or pericarditis based on review of clinical symptoms. 
• 
No positive molecular COVID-19 test at S2 Baseline/Week 0. 
• 
No increase in oral, intramuscular, or intravenous steroids within 14 days of S2 Baseline/Week 0. 
If the vaccine cannot be administered at the S2 Baseline Week 0 visit, it must be administered during the following 
2-3 days. Vaccine eligibility will be confirmed prior to administration of the vaccine. Administration of the alternative 
vaccine dose must occur within 28 days of the S2 Screening visit (newly recruited participant) or 28 days of when the 
data used for screening were obtained (rollover participant). 
If a newly recruited participant is not eligible to receive the alternative vaccine dose at S2 Baseline Week 0, he/she will 
be terminated from the study (see Section 11.2 Participant Stopping Rules and Withdrawal Criteria), and the participant 
will be replaced. If a rollover participant is not eligible to receive the alternative vaccine dose at S2 Baseline Week 0, 
he/she will continue on the previous Schedule of Events. 
The participant may rescreen after 30 days from determination of vaccine ineligibility. New recruit participants who fail 
to receive the vaccine must be rescreened under a new participant ID. Participants who are not eligible to receive an 
alternative vaccine dose at that visit may restart their IS medications immediately.  
See Section 8.1.4 Study Procedures and Assessments for more information on individual clinical and research 
assessments.  
Sites will call all Stage 2 participants who withheld an IS medication after the S2 Baseline visit to provide instructions on 
resuming IS medication per Section 7.1.1 Protocol-mandated Medications. 
8.2.5 Study Procedures and Assessments  
Study procedures and assessments are as described in Section 8.1.4 Study Procedures and Assessments  
 
8.2.6 Unscheduled Visits  
Unscheduled visits are described in Section 8.1.5 Unscheduled Visits. 
8.2.7 Early Termination 
Early termination is described in Section 8.1.6 Early Termination. 
 
 


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8.3 
Pediatric Stage 1 Study Procedures 
8.3.1 Visit Windows 
Appendix 20.1, Table 20 presents the Schedule of Events for Stage 1 pediatric participants. The visit windows are defined 
below: 
• 
Screening until Randomization/Allocation: up to 21 days from time of obtaining informed consent until the 
participant is determined to meet study entry criteria (allocation for Cohort C) or randomization (for Cohorts A 
and B). 
• 
Randomization: phone visit that must occur at least 7 days prior to administration of the additional homologous 
vaccine dose at the Baseline/Week 0 visit for Cohorts A and B.  
o See Section 8.1.2.4 Randomization/Allocation for more details on Randomization visit activities.  
• 
Baseline (Week 0/Day 1) 
o See Section 8.1.3 Baseline (Week 0/Day 1) Visit for more details on Baseline visit activities. 
• 
Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
o Pediatric participants may consent to an optional mechanistic specimen collection at Week 1. If the 
participant has consented to this mechanistic specimen collection, the Vaccine Diary Review will occur 
on site per the assessments outlined in Section 20.1 Schedules of Events, Table 20. 
• 
Week 4: (+/- 1 week)  
• 
Week 12: (+/- 2 weeks)  
• 
Week 24: (+/- 2 weeks)  
• 
Week 36: (+/- 2 weeks) 
• 
Week 48 (End of Study): (+/- 2 weeks) 
8.3.2 Screening and Randomization/Allocation 
8.3.2.1 
Pre-Screening 
An optional Pre-Screening visit may be conducted to confirm that a participant has had a negative or suboptimal, or low 
immune response to initial COVID-19 vaccine regimen prior to Screening. This study will be explained in lay language to 
each potential participant and his or her parent. Each participant and their parent/guardian will sign informed consent 
and assent forms, as appropriate to age of the participant, before committing to study Pre-Screening procedures. Pre-
Screening procedures at the study site will vary by method of recruitment as outlined below:  
Study site personnel are responsible for the following: 
1. Consent the participant for an ACV01 Pre-Screening Evaluation. 
2. Conduct the rapid result or other antibody testing.  
3. Invite the participant to an ACV01 Screening Visit if the result is negative or weakly positive per the site 
preferred antibody test method. 
8.3.2.2 
Determination of Participant Cohort and Identification of Qualifying 
Disease 
Prior to screening a potential participant, the site needs to determine which IS Cohort the participant will be assigned to 
and identify the participant’s qualifying autoimmune disease.  
Cohorts: Determination of participant cohort is described in Section 8.1.2.2 Determination of Participant Cohort and 
Identification of Qualifying Disease. 
Qualifying Autoimmune Diseases: The ACV01 study will be accepting pediatric participants diagnosed with pediatric 
SLE, JIA, JDM, or POMS. In the event that a participant has more than one of these 4 diseases, disease activity 


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assessments will be collected throughout the trial for only the disease associated with IS medication cohort assignment 
at entry into the trial. 
8.3.2.3 
Screening 
The research study will be explained in lay terms to each potential pediatric participant and his or her parent/guardian. 
The potential participant and their parent/guardian will sign IRB-approved informed consent and assent forms, as 
appropriate to the age of the participant, before undergoing any study procedures. Once the informed consent/assent 
forms have been signed, the participant will be assigned a unique participant number. At this time, study-specific 
procedures may be performed.  
The purpose of the screening period, which begins at the time of signed consent, is to confirm eligibility to enter the 
study. All screening procedures, assessments, and laboratory measures to determine participant eligibility will be 
conducted within a 21-day screening window with shorter time periods expected for most participants.  
The assessment of eligibility may take a series of visits that occur on separate days. The Screening visit biomarkers 
should reflect, as much as possible, the biometrics of the participant prior to any study procedures.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility:  
1. Informed Consent/Assent 
2. Demographics 
3. Medical History 
4. Concomitant Medications (including contraceptives) 
5. Comprehensive Physical Exam 
6. Vital Signs  
7. Confirmation of Disease Classification Criteria Assessment 
a. 2017 EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and 
their major subgroups for pediatric SLE 
b. 2010 ILAR classification criteria for JIA 
c. 2017 McDonald diagnostic criteria for MS 
d. Bohan and Peter criteria or the 2017 EULAR/ACR classification criteria for JDM. 
8. Complete assessments of disease activity: SLEDAI-2K for pediatric SLE; Tender/Swollen Joint Count for JIA; 
Physician-assessed relapse for POMS; Flare Assessment for JDM (Disease Activity Score [DAS]) and CMAS for 
JDM 
9. Review of initial COVID-19 vaccination record and antibody responses, infections and treatments. 
10. Central laboratory assessments for all participants 
a. Elecsys® Anti-SARS-CoV-2 S assay to assess response to initial COVID-19 vaccine regimen  
b. CBC with differential  
c. CMP, eGFR 
11. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing  
b. Urine pregnancy test (postmenarchal females must have a negative urine pregnancy test at Screening) 
12. Disease-specific laboratory assessments: 
a. Pediatric SLE participants only 


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i. Anti-dsDNA, C3, C4 
ii. Random urine protein-creatinine ratio 
iii. Urinalysis (microscopic) 
iv. Erythrocyte sedimentation rate (ESR) – local assessment 
b. JIA participants only 
i. CRP 
c. B-cell depleting therapy participants only 
i. If on CD20 depleting agent, CD19+ B cells 
d. JDM participants only 
i. Disease-specific tests assessed as part of the CMP: 
1. Creatine kinase (CK) only 
2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
ii. Aldolase 
13. Inclusion/Exclusion criteria assessment 
Participants with abnormal laboratory values that prohibit entry may be re-tested once during the screening period, 
which may last up to 21 days. Participants who screen fail may be rescreened one time and must repeat all screening 
assessments. Any further rescreening activity requires approval by the medical monitor. 
During the Screening visit, the site will review vaccine eligibility criteria, per Section 8.1.3 Baseline Visit with the 
participant.  
8.3.2.3.1 
Evaluation of Eligibility and Randomization/Allocation 
Evaluation of eligibility and randomization/allocation are described in Section 8.1.2.3.1 Evaluation of Eligibility and 
Randomization/Allocation. 
8.3.2.4 
Randomization/Allocation 
Randomization/allocation are described in Section 8.1.2.4 Randomization/Allocation. 
8.3.3 Baseline (Week 0/Day 1) Visit 
The Baseline visit is described in Section 8.1.3 Baseline (Week 0/Day 1) Visit. 
8.3.4 Study Procedures and Assessments 
8.3.4.1 
General Assessments 
General assessments are described in Section 8.1.4.1 General Assessments. 
 
 
8.3.4.2 
Disease-Specific Assessments 
• 
Pediatric SLE Disease Assessments 
o SLEDAI-2K  
o ACR Provisional Criteria for Global Flare in Childhood-onset SLE (for SLEDAI) 
• 
JIA Disease Assessments 


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o Tender/Swollen Joint Count 
o PASI  
 
Assessed for JIA participants with psoriatic arthritis only.  
 
This assessment will be conducted at Baseline/Week 0 and any time a flare is suspected. 
• 
POMS Disease Assessments 
o Physician-assessed relapse for MS  
o EDSS (at Baseline/Week 0) 
 
If a POMS relapse is suspected, the EDSS will be assessed at the following time points:  
• 
Time of suspected relapse 
• 
Time of relapse recovery (to occur 8-12 weeks after the suspected relapse EDSS 
assessment) 
• 
JDM Disease Assessments 
o Flare Assessment for JDM (Disease Activity Score [DAS]) 
o CMAS for JDM 
 
The CMAS is required for JDM participants ages 6-17.  
 
The CMAS is optional for JDM participants who are 2-5 years old.  
8.3.4.3 
Participant- and Clinician-reported Outcomes 
• 
Participant-reported Outcomes 
o PedsQL  
o PtGA 
o PGI-C 
• 
Clinician-reported Outcomes 
o PGA 
o CGI-C 
8.3.4.4 
Clinical Laboratory Assessments 
Blood and urine for the clinical laboratory assessments listed below will be collected per Section 20.1 Schedule of 
Events. The results will be evaluated for safety by the site investigator. Abnormal tests that meet grading and reporting 
criteria will be reported as adverse events (See Section 12.3 Grading and Attribution of Adverse Events). 
• 
Local Laboratory Assessments 
o Pregnancy Testing   Urine pregnancy test at Screening and Baseline/Week 0 visit will be conducted only 
on postmenarchal females. 
o Molecular COVID-19 Testing Baseline/Week 0/Day 1 molecular COVID-19 Testing can be collected and 
run and the results reported by a community-based laboratory (national chain pharmacy, Local MD 
office, State or Local Government run testing center, Urgent Care Center) not listed on the 1572. This 
test must be performed within the 48 hours prior to the Baseline/Week 0/Day 1 visit. For additional 
details, please see the ACV01 Manual of Procedures. 
o ESR (pediatric SLE participants only) 


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• 
Central Laboratory Assessments 
o Hematology, including CBC with differential. 
o Blood Chemistry including CMP, eGFR. 
o Detection of antibodies against SARS-CoV-2 Spike protein (IgG) using the Roche Elecsys® Anti-SARS-
CoV-2 S electrochemiluminescence immunoassay intended for qualitative and semi-quantitative 
detection of antibodies to SARS‑CoV‑2 spike protein (RBD) in human serum. 
o Disease-specific laboratory assessments: 
 
Pediatric SLE participants only 
• 
Anti-dsDNA, C3, C4 
• 
Random urine protein-creatinine ratio 
• 
Urinalysis ( microscopic ) 
 
JIA participants only 
• 
CRP 
 
B-cell depleting therapy participants only 
• 
If on CD20 depleting agent, CD19+ B cells 
 
JDM participants only 
• 
CK only 
• 
ALT/AST 
• 
Aldolase 
8.3.4.5 
Mechanistic Assessments 
o Mechanistic assessments are described in Section 8.1.4.5 Mechanistic Specimens. 
8.3.5 Unscheduled Visits 
Unscheduled visits are described in Section 8.1.5 Unscheduled Visits. 
8.3.6 Early Termination 
Early termination is described in Section 8.1.6 Early Termination. 
8.4 
Pediatric Stage 2 Study Procedures 
8.4.1 Visit Windows 
8.4.1.1 
Visit Windows for Pediatric Stage 2 Newly Recruited Participants 
Appendix 20.1, Table 21 presents the Schedule of Events for participants who are newly recruited to Pediatric Stage 2. 
The visit windows are defined below: 
• 
Screening and Allocation: 28 to 7 days prior to the S2 Baseline/Week 0 visit. 
• 
Baseline (Week 0/Day 1) 
o See Section 8.4.4 Baseline (Week 0/Day 1) Visit  for more details on Baseline/Week 0 visit activities. 
• 
Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
o Pediatric participants may consent to an optional mechanistic specimen collection at Week 1. If the 
participants have consented to this mechanistic specimen collection, the Vaccine Diary Review will occur 
on site per the assessments outlined in Section 20.1 Schedules of Events, Table 21. 


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• 
Week 4: (+/- 1 week)  
• 
Week 12: (+/- 2 weeks)  
• 
Week 24: (+/- 2 weeks)  
• 
Week 36: (+/- 2 weeks) 
• 
Week 48 (End of Study): (+/- 2 weeks) 
8.4.1.2 
Visit Windows for Pediatric Stage 2 Rollover Participants 
For participants rolling from Pediatric Stage 1 into Pediatric Stage 2, the visit windows are defined below: 
• 
Total Screening Period:  
o Up to 28 days from the Stage 1 Study Follow-up Visit at which negative, suboptimal or low immune 
response to the previous COVID-19 vaccine was obtained until the S2 Baseline/Week 0 visit. 
 
If the S2 Baseline/Week 0 visit cannot be conducted within 28 days of the qualifying Stage 1 
Follow-up Visit noted above, the participant will return to the site for a full S2 Screening visit, as 
described in Section 8.4.2.3.2 Screening for Pediatric Stage 2 Rollover Participants. 
o S2 Screening Phone Visit: at least 7 days prior to administration of the alternative vaccine at S2 
Baseline/Week 0.  
 
See Section 8.4.2.3.2 Screening for Pediatric Stage 2 Rollover Participants for more details on 
the screening procedures for rollover participants 
• 
S2 Baseline (S2 Week 0/Day 1) 
o See Section 8.2.4 Baseline (Week 0/Day 1) Visit for more details on the S2 Baseline/Week 0 visit 
activities. 
• 
S2 Week 1: Vaccine Diary Review Phone Visit (Day 8 – Day 12) 
• 
S2 Week 4: (+/- 1 week)  
• 
S2 Week 12: (+/- 2 weeks)  
• 
S2 Week 24: (+/- 2 weeks)  
• 
S2 Week 36: (+/- 2 weeks) 
• 
S2 Week 48 (End of Study): (+/- 2 weeks) 
8.4.2 Screening and Allocation 
8.4.2.1 
Pre-Screening  
8.4.2.1.1 
Pre-Screening for Pediatric Stage 2 Newly Recruited Participants 
An optional Pre-Screening visit may be conducted to confirm that a participant has had a negative,  suboptimal, or low 
immune response to initial COVID-19 vaccine regimen prior to Screening. This study will be explained in lay language to 
each potential participant. Each participant will sign an informed consent form before committing to study Pre-
Screening procedures. Pre-Screening procedures at the study site will vary by method of recruitment as outlined below:  
Study site personnel are responsible for the following: 
1. Consent the participant for an ACV01 Pre-Screening Evaluation. 
2. Conduct the rapid result or other antibody testing.  
3. Invite the participant to an ACV01 Screening Visit if the result is negative or weakly positive per the site 
preferred antibody test method. 
8.4.2.1.2 
Pre-Screening for Pediatric Stage 2 Rollover Participants 


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Elecsys® Anti-SARS-CoV-2 S assay results for Stage 1 participants from visits at Week 4 through Week 48 will be reviewed 
when received by study sites. Participants with a negative,  suboptimal, or low immune response at any visit following 
receipt of the previous COVID-19 vaccine dose will have the data from their last Stage 1 study visit pre-screened to 
determine if they may qualify for Stage 2.  
If a participant pre-screens successfully for Stage 2, the study site will contact the participant to offer them the 
opportunity to be fully screened for Stage 2.  
8.4.2.2 
Determination of Participant Cohort and Identification of Qualifying 
Disease 
Prior to screening a potential newly recruited participant, the site needs to determine to which IS cohort the participant 
will be allocated and identify the participant’s qualifying autoimmune disease.  
Note that the qualifying disease for rollover participants will be the same as for Stage 1. 
Cohorts: Stage 2 will be accepting participants who are taking 3 types of IS medications: MMF or MPA, MTX, and B cell 
depletion therapies. The criteria for allocation to each cohort are listed below: 
• 
Cohort D: Receipt of MMF or MPA (± other rheumatic disease medications, including biologics) 
o Participants who are taking MMF or MPA will be placed in this cohort.  
 
Participants may not also be taking MTX.  
 
Participants may not have taken anti-CD20 and anti-CD19 B cell depleting therapy in the past 
18 months.  
• 
Cohort E: Receipt of MTX (± other rheumatic disease medications, including biologics) 
o Participants who are taking MTX will be placed in this cohort.  
 
Participants may not also be taking MMF/MPA.  
 
Participants may not have taken anti-CD20 and anti-CD19 B cell depleting therapy in the past 
18 months.  
• 
Cohort F: Receipt of anti-CD20 or anti-CD19 B cell depletion therapy within the past 18 months (± other 
rheumatic disease medications) 
o Participants who have taken B cell depletion medications in the past 18 months will be placed in this 
cohort.  
 
Participants may also be taking MMF/MPA or MTX. 
Qualifying Autoimmune Diseases: The ACV01 study will be accepting participants diagnosed with SLE, JIA, JDM, or 
POMS. In the event that a participant has more than one of these 4 diseases, disease activity assessments will be 
collected throughout the trial for only the disease associated with IS medication cohort assignment at entry into the 
trial.  
8.4.2.3 
Screening 
8.4.2.3.1 
Screening for Pediatric Stage 2 Newly Recruited Participants 
The research study will be explained in lay terms to each potential pediatric participant and his or her parent/guardian. 
The potential participant and their parent/guardian will sign IRB-approved informed consent and assent forms, as 
appropriate to the age of the participant, before undergoing any study procedures. Once the informed consent/assent 
forms have been signed, the participant will be assigned a unique participant number. At this time, study-specific 
procedures may be performed.  


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The purpose of the screening period, which begins at the time of signed consent, is to confirm eligibility to enter the 
study. All screening procedures, assessments, and laboratory measures to determine participant eligibility will be 
conducted within a 21-day screening window with shorter time periods expected for most participants.  
The assessment of eligibility may take a series of visits that occur on separate days. The Screening visit biomarkers 
should reflect, as much as possible, the biometrics of the participant prior to any study procedures.  
The following procedures, assessments, and laboratory measures will be conducted:  
1. Informed Consent/Assent 
2. Demographics 
3. Medical History 
4. Concomitant Medications (including contraceptives) 
5. Comprehensive Physical Exam 
6. Vital Signs  
7. Confirmation of Disease Classification Criteria Assessment 
a. 2017 EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and 
their major subgroups for pediatric SLE 
b. 2010 ILAR classification criteria for JIA 
c. 2017 McDonald diagnostic criteria for MS 
d. Bohan and Peter criteria or the 2017 EULAR/ACR classification criteria for JDM. 
8. Complete assessments of disease activity: SLEDAI-2K for pediatric SLE; Tender/Swollen Joint Count for JIA; 
Physician-assessed relapse for POMS; Flare Assessment for JDM and CMAS for JDM 
9. Review of COVID-19 vaccination record and antibody responses, infections and treatments. 
10. Central laboratory assessments for all participants 
a. Elecsys® Anti-SARS-CoV-2 S assay to assess response to initial COVID-19 vaccine regimen  
b. CBC with differential  
c. CMP, eGFR 
11. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing  
b. Urine pregnancy test (postmenarchal females must have a negative urine pregnancy test at Screening) 
12. Disease-specific laboratory assessments: 
a. Pediatric SLE participants only 
i. Anti-dsDNA, C3, C4 
ii. Random urine protein-creatinine ratio 
iii. Urinalysis (microscopic) 
iv. Erythrocyte sedimentation rate (ESR) – local assessment 
b. JIA participants only 
i. CRP 
c. B-cell depleting therapy participants only 


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i. If on CD20 depleting agent, CD19+ B cells 
d. JDM participants only 
i. Disease-specific tests assessed as part of the CMP: 
1. Creatine kinase (CK) only 
2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
ii. Aldolase 
13. Inclusion/Exclusion criteria assessment 
Participants with abnormal laboratory values that prohibit entry may be re-tested once during the screening period, 
which may last up to 21 days. Participants who screen fail may be rescreened one time and must repeat all screening 
assessments. Any further rescreening activity requires approval by the medical monitor. 
During the Screening visit, the site will review vaccine eligibility criteria, per Section 8.4.4 Baseline (Week 0/Day 1) Visit 
with the participant.  
8.4.2.3.2 
Screening for Pediatric Stage 2 Rollover Participants 
The study site will contact potential Stage 2 rollover participants to offer them the opportunity to be fully screened for 
Stage 2. There are two options for the conduct of the full Screening for Pediatric Stage 2 for rollover participants:  
• 
The screening process for Stage 2 may be able to be completed with only a telephone visit if the necessary 
information is available from the last study visit from Stage 1, informed consent can be appropriately 
completed, etc.  
o Notes:  
 
Information that may be available from the last study visit from Stage 1 includes lab tests for 
eligibility and disease-specific laboratory tests noted below.  
 
The pregnancy test and molecular COVID-19 tests do not need to be completed during the 
Stage 2 Screening period if the Screening visit is conducted by phone. In such cases, these 
assessments will be conducted at the beginning of the Stage 2 Baseline visit before the vaccine is 
administered.  
• 
If the needed data are not available from the previous Stage 1 visit or 28 days will have passed when the 
S2 Baseline/Week 0 visit is reached, then the Stage 2 Screening visit must be conducted at the clinical site.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility 
for Stage 2.  
1. Confirm that participant agrees to proceed to Stage 2. 
a. If the participant has not yet signed an informed consent/assent form that includes a description of 
Stage 2, the participant must provide signed informed consent for Stage 2 screening to proceed. 
2. Updated Medical History 
3. Updated Concomitant Medications (including contraceptives) 
4. Updated Physical Exam 
a. Results of the Targeted Physical Exam and the Neurological Exam from the most recent Stage 1 visit may 
be used to fulfill this assessment in place of a new Comprehensive Physical Exam 
5. Vital Signs  
6. AE assessment following vaccination in Stage 1 


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7. Complete assessments of disease activity: SLEDAI-2K for pediatric SLE; Tender/Swollen Joint Count for JIA; 
Physician-assessed relapse for POMS; Flare Assessment for JDM and CMAS for JDM 
8. Response to previous COVID-19 vaccine dose assessed by Elecsys® Anti-SARS-CoV-2 S assay 
9. Central laboratory assessments for all participants 
a. Elecsys® Anti-SARS-CoV-2 S assay to assess response to previous COVID-19 vaccine dose  
b. CBC with differential  
c. CMP, eGFR 
10. Local laboratory assessments for all participants 
a. Molecular COVID-19 Testing (if Stage 2 Screening visit is conducted at the clinical site only) 
b. Urine pregnancy test (if Stage 2 Screening visit is conducted at the clinical site for women of child-
bearing potential only) 
11. Disease-specific laboratory assessments: 
a. Pediatric SLE participants only 
i. Anti-dsDNA, C3, C4 
ii. Random urine protein-creatinine ratio 
iii. Urinalysis (microscopic) 
iv. Erythrocyte sedimentation rate (ESR) – local assessment 
b. JIA participants only 
i. CRP 
c. B-cell depleting therapy participants only 
i. If on CD20 depleting agent, CD19+ B cells 
d. JDM participants only 
i. Disease-specific tests assessed as part of the CMP: 
1. Creatine kinase (CK) only 
2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
ii. Aldolase 
12. Inclusion/Exclusion criteria assessment 
8.4.3 Evaluation of Eligibility and Allocation 
If the participant meets all eligibility criteria for Stage 2, then proceed as follows during the Screening phone call: 
• 
Allocate the participant to the appropriate cohort based on IS medication 
• 
Schedule S2 Baseline/Week 0 visit (within 28 days of the Stage 2 Screening assessments and no sooner than 7 
days from the Screening visit). 
• 
Communicate to the participant the details of the medication hold to the participant per Section 7.1.1 Protocol-
mandated Medications. 
• 
Inform the participant that there should be no changes to his/her other existing medications between Screening 
and the S2 Baseline/Week 0 visit. 
8.4.4 Baseline (Week 0/Day 1) Visit 


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Eligible participants who meet all inclusion criteria and none of the exclusion criteria for Stage 2 will proceed with visits 
and assessments according to Section 20.1 Schedule of Events, Table 21 (newly recruited participant) or Table 22 
(rollover participant). Eligible participants will be assessed for disease activity and SARS-CoV-2 infection at the S2 
Baseline/Week 0 visit, prior to receipt of an alternative vaccine dose. Prior to administering the alternative vaccine dose 
at the Baseline visit, the site will confirm the participant meets vaccine eligibility per the criteria below: 
• 
No increase to the permitted concomitant medications in participants in Cohorts D and E between S2 Screening 
and S2 Baseline/Week 0.  
• 
No B-cell depletion infusions or changes in permitted concomitant medications in participants in Cohort E 
between allocation and S2 Baseline/Week 0.  
• 
No clinically active disease (including myocarditis or pericarditis) at S2 Baseline/Week 0 resulting in an 
increase/addition of IS medications. For participants with MS, no suggestion of a MS relapse per the 
investigator. 
• 
No active myocarditis or pericarditis based on review of clinical symptoms. 
• 
No positive molecular COVID-19 test at S2 Baseline/Week 0. 
• 
No increase in oral, intramuscular, or intravenous steroids within 14 days of S2 Baseline/Week 0. 
If the vaccine cannot be administered at the S2 Baseline Week 0 visit, it must be administered during the following 2-3 
days. Vaccine eligibility will be confirmed prior to administration of the vaccine. Administration of the alternative 
vaccine dose must occur within 28 days of the S2 Screening visit (newly recruited participant) or 28 days of when the 
data used for screening were obtained (rollover participant). 
If a newly recruited participant is not eligible to receive the alternative vaccine dose at S2 Baseline Week 0, he/she will 
be terminated from the study (see Section 11.2 Participant Stopping Rules and Withdrawal Criteria), and the participant 
will be replaced. If a rollover participant is not eligible to receive the alternative vaccine dose at S2 Baseline Week 0, 
he/she will continue on the previous Schedule of Events. 
The participant may rescreen after 30 days from determination of vaccine ineligibility. New recruit participants who fail 
to receive the vaccine must be rescreened under a new participant ID. Participants who are not eligible to receive an 
alternative vaccine dose at that visit may restart their IS medications immediately.  
See Section 8.3.4 Study Procedures and Assessments for more information on individual clinical and research 
assessments.  
Sites will call all Stage 2 participants who withheld an IS medication after the S2 Baseline visit to provide instructions on 
resuming IS medication per Section 7.1.1 Protocol-mandated Medications. 
8.4.5 Study Procedures and Assessments  
Study procedures and assessments are as described in Section 8.3.4 Study Procedures and Assessments  
8.4.6 Unscheduled Visits  
Unscheduled visits are described in Section 8.1.5 Unscheduled Visits. 
8.4.7 Early Termination 
Early termination is described in Section 8.1.6 Early Termination. 
9. 
Mechanistic Assays 
Planned and potential mechanistic assays for this study are noted below. Blood drawn from participants for mechanistic 
and clinical blood draws may not exceed NIH blood draw limits (550mL over 8 weeks). 
Antibody assays: Antibody levels will be tested at each time point to test for IgG and IgM responses against SARS-CoV-2 
spike, receptor binding domain, and nucleocapsid proteins using standardized ELISAs or comparable assays from the 


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NIAID-VRC, Seronet, or one of the ACE Centers. Additional assays testing for antibody responses against variants or 
providing epitope specificity, such as through on the University of Texas Southwestern or Stanford arrays [66], may be 
tested if resources are available. Assays to test for anti-cytokine, autoantibody, anti-adenoviral, and anti-RNA responses 
may also be tested by the aforementioned combination arrays, ELISAs or a combination of these. Finally, novel assays 
for antibodies may also be included, as possible. For example, the Ring laboratory (Yale) is using a novel Rapid 
Extracellular Antigen Profiling (REAP) assay to assess 2,770 extracellular and secreted proteins which have been 
informative in post-COVID infection [67]. Serum will be used for these assays.  
Neutralizing assays: Assays will also be performed to see whether neutralizing antibodies are produced in autoimmune 
disease participants after additional vaccine administrations. Using the microneutralization assays by plaque reduction 
in use at the NIAID-VRC, Seronet or at an ACE Center, presence/absence and titer of neutralization will be recorded for 
each sample. Alternatively, pseudoneutralization assays, where the spike antigen is transfected into a lentiviral vector-
based assay could be used as a surrogate. Another option would be the competition ELISA-based surrogate virus 
neutralization assay (sVNT) for rapid screening of all samples; however, this assay is not as useful for lower 
concentration neutralization and may not be ideal for autoimmune disease patient samples. Assays will follow the 
published literature [68]. Serum will be used for these assays.  
Antigen-specific T cell responses and T cell repertoires: Autoimmune disease patients, especially those on BCDTs, may 
have undetectable SARS-CoV-2 antibodies but still mount effective T cell responses against the virus. Using T cell assays 
in place in the Bar-Or, Pillai, or NIAID labs, briefly PBMCs from each individual sample will be stimulated with SARS-CoV-2 
spike protein, other SARS-CoV-2 antigens, positive (PMA) and negative controls, followed by readouts such as IFN 
gamma ELISPOT [69] or by CD4+ interferon gamma and/or Interleukin-2 (IL-2) and/or Tumor Necrosis Factor alpha (TNF-
α) and/or CD40 Ligand (CD40L) secretion/expression by intracellular staining [70]. Please see the ACV01 Lab Manual for 
more information. T cell epitope mapping and TCR utilization assays may be performed in future use assays. Frozen 
PBMCs will be used for these assays.  
Antigen-specific memory B cell responses and B cell repertoires: In addition to antibodies and T cell mediated 
immunity, memory B cell responses will also be assessed. Peripheral blood mononuclear cells (PBMCs) will be stimulated 
with SARS-CoV-2 spike or receptor binding domain and cells assessed for antibody production by ELISPOT. Alternatively, 
after discussion with the ACE Network investigators, whole blood stimulations with spike antigens may be performed 
with each blood draw with stabilization to allow the evaluation of B cell and T cell responses post-vaccination as has 
been performed for COVID-19 infection [71]. From an immunological standpoint, and in addition to overall profiling, 
detailed studies of antigen-specific B cell responses will be studied in order to understand:  a) the cellular compartments 
in which SARS-CoV-2-specific B cell memory resides; b) its quality, magnitude and distribution within the population; 
c) its provenance (whether from early or late cellular precursors); and d) its concordance or conversely, uncoupling from 
serological responses. This approach would enable the group to differentiate between different types of long-term 
memory responses, including long-term serological memory (dependent on the generation of long-lived plasma cells 
(LLPC); and cellular memory (B cell memory with or without serological memory). Additional B cell repertoire sequencing 
may be performed in a subset of patients as well. Frozen PBMCs, or whole blood, will be used for these assays. Dr. 
Patrick Wilson has developed all the assays for SARS-CoV-2-specific B cell characterization and could be involved in 
performing these studies with ACV01 samples. 
Immunophenotyping and Immune cell population profiling over time: In addition to the above assessments of antigen-
specific B and T cell responses, additional immunophenotyping of samples will be performed, at least on a subset of 
individuals and time points, to determine cell populations that correlate with adequate vaccination responses after 
additional study vaccine dose administration, either with an mRNA vaccine, a vector-based COVID-19 vaccine, or a 
protein-based COVID-19 vaccine compared to inadequate responders. Deep immunophenotyping will be performed 
using the standard panels of the NIAID HIPCs by CyTOF or high dimensional flow cytometry as performed by one of the 
ACE Centers [72, 73]. Stabilized whole blood or PBMCs will be used for these assays. Please see the Lab Manual for 
additional details. 
Gene expression profiling, soluble mediators, autoantibody assessments, and individual hypothesis testing:  Several 
ACE Centers have specific hypotheses that they would like to test with this unique participant collection to determine 
whether specific immune cell types or pathways associate with neutralizing SARS-CoV-2 responses after vaccination. A 


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few examples are listed here and others will use the stored biospecimens outlined below. Through work in SLE with 
influenza and varicella (Zostavax) vaccination, ACE investigators have found that individuals with poor vaccine responses 
have a higher baseline IFN response [74, 75]. Other work has shown that individuals with increased numbers of CD86 
positive naïve B cells, or activated CD11b+ monocytes (or both) are at higher risk of disease flare within the next 
4-6 weeks [76]. Increased numbers of CD319+ T cells are found in systemic sclerosis patients compared to controls [77], 
and can be assessed across autoimmune diseases in this cohort and tested for association with impaired vaccine 
responses. RNA will be isolated from PAXgene tubes and transcript profiles determined by RNAseq. Module expression 
will be determined as per the Pascual group and modules assessed for association with impaired vaccination responses 
[78]. Soluble mediator levels of cytokines, chemokines, and soluble receptors will be tested in plasma as outlined by the 
James group [79]. Immunophenotyping data will be used from above to test other hypotheses [78]. Autoantibody 
profiling, related to the individual autoimmune diseases and with a broader coverage such as an autoantigen array, will 
be done at each visit to determine effects of an additional study vaccine dose on autoantibody production. Specific 
questions about changes in autoantibody concentration, isotypes, avidity, new specificities, and epitope expansion could 
be addressed, as funding allows.  
scRNAseq, CITE-seq, scATAC-seq (TEA-Seq): Finally, in another subset analysis, smaller groups of participants on similar 
background meds who do and do not respond to an additional study vaccine dose will be tested by single cell 
technologies to generate additional hypotheses regarding the cell types, cell subsets, and immune cell pathways 
associated with impaired vaccination responses within and across autoimmune diseases. These assays will use frozen 
PBMCs (or stabilized whole blood) and will use the approaches in standard use within one of the ACE Network Centers. 
Together, the data assembled through these mechanistic studies will inform the community about the mechanisms of 
vaccine response, and non-response, in autoimmune disease patients, as well as potentially in others taking similar 
medications. Information may also be uncovered regarding autoimmune disease pathogenesis, predictors of vaccine 
response, and autoimmune disease flare. 
Background IS Medication Testing: A critical part of this study is to discover if withholding cohort-defining IS 
medications influences response to the additional vaccine dose. In order to determine if there is a correlation between 
IS medication level in the blood and vaccine response, a whole blood specimen will be collected at the Baseline/Week 0 
visit for all participants in Cohorts A (MMF/MPA) and B (MTX). If the primary endpoint analysis yields no quantifiable 
difference between treatment arms withholding IS medication and those continuing their medication in Cohort A 
(MMF/MPA) and Cohort B (MTX), the Baseline whole blood and serum specimens will be tested to gain additional insight 
into a relationship between medication blood levels and vaccine response.  
Optional Site-specific Sub-studies: The mechanistic assays noted above represent a small portion of the research that 
can be completed on autoimmune patients receiving an additional COVID-19 vaccine dose. This study presents a unique 
opportunity to collect data during a critical time in our vaccine response timeline. Individual site investigators may 
choose to collect additional optional specimens from Baseline/Week 0 to Week 4 to complete mechanistic analysis of 
their own. All optional mechanistic specimen sub-studies will be detailed in site-specific informed consent forms.  
Optional Week 1 Pediatric Specimen Collection: Pediatric participants may choose to participate in an optional 
specimen collection during the Week 1 Vaccine Diary Review visit (window: Day 7-14). Procedures for this visit are 
outlined in Section 20.1 Schedules of Events. 
10. 
Biospecimen Storage 
The ACE Network investigators will also discuss and prioritize other assays to be performed on the longitudinal samples 
from this autoimmune disease COVID vaccination trial. To facilitate these future studies, the following biospecimens will 
be collected at participating sites, processed and stored at the Oklahoma Medical Research Foundation (OMRF) College 
of American Pathologists (CAP)-certified Biorepository. These biospecimens include: serum, plasma, peripheral blood 
mononuclear cells, RNA isolated from PAX gene tubes, and DNA isolated from buffy coats. Individuals will be asked to 
provide consent for genetic studies and to have data, including genetic and gene expression, stored in an NIH-approved 
public database. Individuals will be able to opt out of genetic testing based upon their preference. Samples will be used 
within the ACE Network or by outside investigators with compelling questions who collaborate with one of the ACE 


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Network investigators. Samples will be stored for up to 4 years after the completion of the trial (or for longer in an ACE 
Network Biorepository or other biorepository approved by NIAID DAIT and the ACE Network. If the NIAID ACE Network 
were to disband, then NIAID DAIT will work with the housing institution for the final dispensation of the samples.  
11. 
Criteria for Participant and Study Completion and Premature Study Termination 
11.1 
Participant Completion 
Participation will be considered to be complete when the Week 48 visit of the participant’s last stage of participation is 
complete. 
11.2 
Participant Stopping Rules and Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant and/or legal guardian elects to withdraw consent from all future study activities, including 
follow-up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish 
contact with the participant have failed).  
3. The participant dies.  
4. The Investigator no longer believes participation is in the best interest of the participant. 
5. The participant does not receive the additional vaccine dose at Baseline/Week 0 or S2 Baseline/Week 0 (new 
recruits only) for any reason, including the criteria listed in Section 8.1.3 Baseline (Week 0/Day 1) Visit or at 
Section 8.2.4 Baseline (Week 0/Day 1) Visit, respectively. 
6. The participant receives a SARS-CoV-2 vaccine outside of the study. 
11.3 
Participant Replacement 
Participants who withdraw or are withdrawn will not be replaced if they have received a vaccine dose at a given stage of 
the study. If a Stage 1 or newly recruited Stage 2 participant is randomized or allocated to a study arm but does not 
receive the vaccine, the participant will be withdrawn and will not be counted toward the total accrual objective. If a 
Stage 2 rollover patient is allocated to a study arm but does not receive the vaccine, the participant will continue on 
their previous Schedule of Events  and will not be counted toward the Stage 2 accrual objective. Additional participants 
will be consented and randomized/allocated to achieve the accrual objective(s).  
11.4 
Follow-up after Early Study Withdrawal 
Participants who prematurely withdraw (without withdrawing consent) or who are withdrawn may be asked to 
complete a final phone visit to assess any AEs and concomitant medications as applicable depending on when they are 
withdrawn relative to the visit schedule. Participants who are withdrawn from the study prior to receipt of study 
treatment will not be followed after their last completed study visit. Monitoring of a pregnant participant will continue 
until the conclusion of the pregnancy.  
11.5 
Study Stopping Guidance 
If any of the events listed, other than myocarditis/pericarditis, in Section 12.8.2.2 Ad hoc DSMB Reviews occur, the Data 
Safety Monitoring Board (DSMB) chair will be notified, and a review of safety data will be performed to determine if 
consent of potential participants, randomization/allocation, and/or administration of investigational study medication 
should be halted. If 2 weeks has elapsed and the DSMB has not met, then no new participants will be consented, 
allocated, or randomized until after the DSMB completes review of the safety data.  
For any NCI-CTCAE Grade 2 or higher myocarditis or pericarditis that occurs within 6 weeks of vaccine administration, 
the DSMB chair be notified of the event within 3 business days from when the AESI was reported to DAIT/NIAID (see 
Section 12.5.2). The DSMB chair will adjudicate whether an expedited, ad hoc safety review by the full DSMB is required. 


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12. 
Safety Monitoring and Reporting 
12.1 
Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. Adverse events that are classified as serious 
according to the definition of health authorities must be reported promptly (per Section 12.5 Reporting Adverse Events 
and Serious Adverse Events to Sponsor (DAIT/NIAID) to the Sponsor (DAIT/NIAID). Appropriate notifications will also be 
made to site principal investigators, Institutional Review Boards (IRBs), and the FDA.  
Information in this section complies with International Conference on Harmonisation (ICH) Guideline E2A: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, ICH Guideline E6(R2) Good Clinical Practice: 
Integrated Addendum to ICH E6(R2), and 21CFR Parts 312 and 320, and applies the standards set forth in the National 
Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm#ctc 50). 
12.2 
Definitions 
12.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the use of an intervention in humans, whether or not 
considered intervention related (see 21 CFR 312.32(a)).  
An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug and does not imply any judgment about causality. An AE can arise with any 
use of the drug (e.g., off-label use or in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
12.2.1.1 
Suspected Adverse Reaction (SAR)  
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the investigational drug [or 
investigational study therapy regimen] caused the AE. For the purposes of safety reporting, ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the AE. An SAR implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a drug (21 CFR 312.32(a)). 
12.2.1.2 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction  
An AE or SAR is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application, as amended. 
12.2.1.3 
Solicited Adverse Events (Reactogenicity) 
Solicited AEs are predefined local and systemic events for which the participants will be specifically questioned, and 
which will be noted by these participants. In this study, queried symptoms will include: 
• 
Injection site reaction such as pain, erythema, induration/edema as well as development of papules, and 
ulceration.  
• 
Axillary lymphadenopathy.  
• 
Solicited systemic reactions including fever (assessed as daily oral temperature), chills, myalgia, arthralgia, 
fatigue*, headache*, nausea*, vomiting, hives, and diarrhea.  
*Participants that are 2-3 years old will have sleepiness, irritability/crying, and loss of appetite assessed 
rather than fatigue, headache, and nausea.  
• 
Increased shortness of breath, chest pain**, swelling/pain in arm or leg**. 
**These symptoms will be assessed in participants age 5 years and above. 


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• 
Increase in symptoms of the participant’s underlying autoimmune disease. 
12.2.2 Unsolicited Adverse Event 
For the purpose of this protocol, an AE is considered “unsolicited” when it is collected through an open-ended question 
and it is not specified as a solicited AE.  
12.2.3 New-onset Chronic Medical Condition (NOCMC) 
A NOCMC is defined as any new International Statistical Classification of Diseases and Related Health Problems (ICD) 
diagnosis that is applied to the study participant during the course of the study, after receipt of the vaccine, that is 
expected to continue for at least 3 months and requires continued health care intervention.  
12.2.4 Medically Attended Adverse Event 
Medically attended adverse event (MAAE) is defined as a hospitalization, emergency room visit, or an otherwise 
unscheduled visit to or from medical personnel for any reason that is considered possibly related or related to study 
vaccine. 
12.2.5 Adverse Events of Special Interest 
Adverse events of special interest (AESIs) include the following: 
• 
Myocarditis (probable and confirmed cases)  
• 
Pericarditis  
See Appendix 20.8 for cases definitions of probable and confirmed myocarditis and pericarditis according to the 
Centers for Disease Control and Prevention (CDC) criteria  
In addition, the following AESI will collected  in the arms in which the Sanofi-GSK COVID-19 Vaccine is administered.  
• 
New onset of potential immune-mediated diseases (pIMDs). 
 
See Appendix 20.7. Disease flares of the underlying autoimmune disease, including new manifestation of the 
disease will not be captured as an AESIs. Disease flares should be reported following Section 12.4.2 Increase in 
Autoimmune Disease Activity. 
pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic 
disorders of interest which may or may not have an autoimmune etiology. AEs that need to be recorded and 
reported as pIMDs, including those listed in Appendix20.7. 
However, the Investigator will exercise their medical and scientific judgment in deciding whether other diseases 
have an autoimmune origin (that is pathophysiology involving systemic or organ-specific pathogenic 
autoantibodies) and should also be recorded as a pIMD. When there is enough evidence to make any of the 
diagnoses mentioned in Appendix 20.7 the AE must be reported as a pIMD. Symptoms, signs or conditions which 
might (or might not) represent the above diagnoses, should be recorded and reported as AEs but not as pIMDs 
until the final or definitive diagnosis has been determined, and alternative diagnoses have been eliminated or 
shown to be less likely. 
12.2.6 Serious Adverse Event (SAE) 
An AE or SAR is considered “serious” if, in the view of either the investigator or Sponsor (DAIT/NIAID), it results in any of 
the following outcomes (21 CFR 312.32(a)): 
1. Death. 


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2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the investigator or 
Sponsor [add DAIT/NIAID or other Sponsor, if applicable], its occurrence places the participant at immediate risk 
of death. It does not include an AE or SAR that, had it occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol-mandated procedures are not to 
be reported as an SAE unless hospitalization is prolonged due to complications. 
12.3 
Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
12.3.1.1 
Grading of Solicited Adverse Events 
Participants will grade solicited AEs using a 0-3 participant symptom rating scale as outlined in the Vaccine Reaction 
Diary instructions (Appendix 20.3 Adult Vaccine Reaction Diary).  
Participant Symptom Rating Scale 
• 
0 = No symptoms 
• 
1 = Mild: Present, but did not require over-the-counter or prescription medications; did not interfere with daily 
activities 
• 
2 = Moderate: Required over-the-counter or prescription medications; caused some interference with daily 
activities 
• 
3 = Severe: Required over-the-counter or prescription medications; significant, incapacitating discomfort 
preventing daily activities 
12.3.1.1.1 
Grading of Pediatric Gastrointestinal Solicited Adverse Events 
Pediatric participants will grade nausea, vomiting, and diarrhea solicited adverse events using a 0-3 symptom-specific 
rating scale as noted below and in the Vaccine Reaction Diary for Pediatric Participants (Appendices20.4, 20.5, 20.6): 
Nausea/Vomiting 
• 
0 = No symptoms 
• 
1 = Mild: 1 to 2 times in 24 hours 
• 
2 = Moderate: > 2 times in 24 hours 
• 
3 = Severe: Prevents daily activity 
Diarrhea 
• 
0 = No symptoms 
• 
1 = Mild: 2 to 3 loose stools in 24 hours 
• 
2 = Moderate: 4 to 5 loose stools in 24 hours 
• 
3 = Severe: 6 or more loose stools in 24 hours 


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12.3.1.2 
Grading of Allergic Reactions 
The investigator will grade severity of systemic allergic reactions on a scale of 1 to 5 according to criteria set forth in the 
Consortium of Food Allergy Research (CoFAR) Grading Scale modified for use in adults only (See Appendix 20.2 CoFAR 
Grading Scale for Systemic Allergic Reactions Version 3.0). 
12.3.1.3 
Grading of Liver Function Abnormalities 
Liver function abnormalities will be graded using alternative criteria, which are based on the NCI-CTCAE version 4.0, and 
are defined relative to the upper limit of normal (ULN) as follows: 
• 
Aspartate aminotransferase [AST] increased 
o Grade 1: >ULN – 3.0x ULN 
o Grade 2: >3.0x ULN - 5.0x ULN 
o Grade 3: >5.0x ULN - 20.0x ULN  
o Grade 4: >20.0x ULN 
• 
Alanine aminotransferase [ALT] increased 
o Grade 1: >ULN – 3.0x ULN 
o Grade 2: >3.0x ULN - 5.0x ULN 
o Grade 3: >5.0x ULN - 20.0x ULN  
o Grade 4: >20.0x ULN 
• 
Alkaline phosphatase [ALP] increased 
o Grade 1: >ULN – 2.5x ULN 
o Grade 2: >2.5x ULN - 5.0x ULN 
o Grade 3: >5.0x ULN - 20.0x ULN  
o Grade 4: >20.0x ULN 
• 
Blood bilirubin increased  
o Grade 1: >ULN – 1.5x ULN 
o Grade 2: >1.5x ULN - 3.0x ULN 
o Grade 3: >3.0x ULN - 10.0x ULN  
o Grade 4: >10.0x ULN  
12.3.1.4 
Grading of All Other Events 
The study site will grade the severity of all other AEs experienced by the study participants according to the criteria set 
forth in the NCI-CTCAE version 5.0 as deemed appropriate for the 5 adult autoimmune diseases and 4 pediatric 
autoimmune diseases, and use of background IS medications of interest in this trial. This document (referred to herein 
as the NCI-CTCAE manual) provides a common language to describe levels of severity, to analyze and interpret data, and 
to articulate the clinical significance of all AEs.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: 
Grade 1 = mild adverse event 
Grade 2 = moderate adverse event 
Grade 3 = severe or disabling adverse event  


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Grade 4 = life-threatening or urgent intervention 
Grade 5 = death 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a radiograph, 
an ultrasound, an electrocardiogram, etc.), a treatment-emergent AE is defined as an increase in grade from Baseline or 
from the last post-Baseline value, that does not meet grading criteria. Changes in grade from Screening to Baseline will 
also be recorded as AEs if related to a study-mandated procedure, treatment, or change in treatment (but are not 
treatment-emergent). If a specific event or result from a given clinical or laboratory evaluation is not included in the 
NCI-CTCAE manual, then an abnormal result would be considered an AE if changes in therapy or monitoring are 
implemented as a result of the event/result. 
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
12.3.2 Attribution Definitions 
Solicited AEs will be attributed as being related to the study-provided vaccine. The relationship, or attribution, of all 
other AEs to the study-provided vaccine or study procedure(s) will initially be determined by the site investigator and 
recorded on the appropriate AE eCRF. Final determination of attribution for safety reporting will be determined by the 
DAIT/NIAID Medical Monitor. The relationship of an AE to vaccine, study therapy regimen, or study procedures will be 
determined using the descriptors and definitions provided in Table 16, Attribution of Adverse Events.  
Table 16. Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational product 
and/or other concurrent mandated study therapy or 
study procedure) 
UNRELATED CATEGORY 
1 
Not 
Related 
The adverse event is clearly not related:  there is 
insufficient evidence to suggest a causal relationship. 
 RELATED CATEGORIES 
2 
Possibly 
Related 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal 
relationship. 
3 
Related 
The adverse event is clearly related. 
 
12.4 
Collection and Recording of Adverse Events 
12.4.1 Collection Period For All Cohorts 
For this study, the timelines below apply after each study-administered vaccine: 
• 
Solicited AEs (all grades) will be collected from Day 1 (vaccine administration) through 7 days post study 
vaccination.  
• 
Unsolicited AEs will be collected as follows:  
o Any unsolicited AEs that are Grade 3 or higher will be collected from randomization/allocation through 
vaccination administration. 
o All unsolicited AEs (all grades) will be collected from Day 1 through Day 28. 


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o Any flares of a secondary autoimmune disease will be reported as an unsolicited AE (all grades) and will 
be collected from Day 1 through the end of the participant’s study participation.  
• 
AESIs will be collected as follows: 
o Pericarditis/myocarditis events will be collected in all treatment arms. NCI-CTCAE Grade 2 or higher 
myocarditis and pericarditis events from Day 1 through the end of the participant’s study participation. 
o New onset of pIMDs will only be collected in arms where the Sanofi-GSK COVID-19 Vaccine is 
administered. All grades will be collected from Day 1 through the end of the participant’s study 
participation.  
• 
SAEs, MAAEs, and NOCMCs will be collected from Day 1 through the end of the participant’s study participation, 
regardless of NCI-CTCAE grade. 
• 
COVID-19 diagnoses (all grades) confirmed by molecular COVID-19 testing will be collected from Day 1 through 
the end of the participant’s study participation.  
12.4.2 Increase in Autoimmune Disease Activity 
Any increase in autoimmune disease activity (flare/relapse) for the participant’s qualifying autoimmune disease will not 
be reported as an AE. These events will be collected and reported on the disease-specific assessment eCRFs. 
(Section 8.1.4.2 Disease-Specific Assessments). 
12.4.3 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the participant. 
• 
Interviewing the participant [e.g., using a checklist, structured questioning, diary, etc.]. 
• 
Receiving an unsolicited complaint from the participant. 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an AE, as 
defined in Section 12.3 Grading and Attribution of Adverse Events. 
12.4.4 Recording Adverse Events 
AEs will be recorded on the clinic’s progress notes or other source documents in the participant’s chart. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation. For AEs where an abnormal value or result of a clinical or laboratory evaluation is observed (see 
Section 12.3.1 Grading Criteria), resolution is defined as the first value post abnormality that is in the normal range 
(Grade 0). 
12.5 
Reporting Adverse Events and Serious Adverse Events to Sponsor (DAIT/NIAID) 
12.5.1 Reporting Adverse Events 
This section describes the responsibilities of site investigators to report AEs to the Sponsor (DAIT/NIAID) via the 
DAIT-SACCC.  
Sites are responsible for ensuring the participant completion of the 7-day Vaccine Reaction Diary and assisting 
participants with entry of all Vaccine Reaction Diary data into the electronic e-Diary in the MyOwnMed portal, if 
required.  
Investigators are responsible for reporting solicited AEs in electronic data capture (EDC) in the following special cases:  
• 
If a solicited AE is also an SAE or MAAE, it must be entered in EDC to capture additional information about the 
event.  


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• 
If a solicited AE, previously reported in MyOwnMed, is found to be ongoing at Day 7 (post vaccination), the 
solicited AE must be entered in EDC so it can be followed to resolution, with or without sequelae.  
• 
Unsolicited AEs (unrelated to reactogenicity) that are entered into the Vaccine Reaction Diary and are also 
identified during the Week 1 visit are to be reported in EDC and graded according to the criteria defined in 
Section 12.3.1 Grading Criteria.  
All grade ≥1 diagnoses of COVID-19 disease confirmed by molecular COVID-19 testing (or alternative test per 
institutional standards) will be reported to the Sponsor as AEs. 
All MAAE, NOCMC, AESIs, and SAEs (listed in Section 12.4 Collection and Recording of Adverse Events) will be reported 
until the end of the study. Unless otherwise noted below in Section 12.5.2 Reporting Serious Adverse Events, SAEs and 
AESIs will be reported within 24 hours. Unsolicited AEs, MAAEs, and NOCMCs must be recorded on the appropriate eCRF 
within 5 days of discovery of the event. Whenever possible, a diagnosis should be provided rather than compilation of 
signs/symptoms, with grade of the event dictated by highest grade of the sign/symptom component. 
12.5.2 Reporting Serious Adverse Events 
This section describes the responsibilities of the site investigator to report SAEs and AESIs to the sponsor via the eCRF. 
Timely reporting of AEs is required by 21 CFR and ICH E6 R2 guidelines.  
Site investigators will report all SAEs (see Section12.2.6 Serious Adverse Event (SAE)) and AESIs (see Section 12.2.5 
Adverse Events of Special Interest), regardless of relationship or expectedness within 24 hours of discovering the event. 
For SAEs and AESIs, all requested information on the AE/SAE eCRF will be provided. However, unavailable details of the 
event will not delay submission of the known information. As additional details become available, the AE/SAE eCRF will 
be updated and submitted. 
When a site investigator identifies an SAE or AESI specified above, he or she must notify DAIT/NIAID via the DAIT-SACCC 
within 24 hours. Site investigators are to report these events on the SAE eCRF in EDC. Should EDC become unavailable/ 
inaccessible, the site investigator should notify DAIT/NIAID via the DAIT-SACCC email at 
Rho_productsafety@rhoworld.com. This email can serve as the initial notification; however, within the next business 
day, the SAE eCRF must be completed. 
All requested information on the SAE eCRF should be provided. Unavailable details of the event at time of initial report 
should not delay submission of known information. The initial report should include at a minimum: AE term, relationship 
to vaccine, and reason why event is serious (per definitions). Supplementary CRF pages including medical history, 
concomitant medications, demographics, study drug administration, and death must be provided. As additional details 
become available, the SAE eCRF should be updated and submitted. Each SAE or AESI must be signed by the investigator 
in the EDC system at the time of initial submission and upon SAE or AESI closure. If an SAE or AESI is determined to 
require an expedited report to a Health Authority, then the SAE or AESI will be signed by the investigator on a more 
frequent basis. With each iteration of the form, the investigator (or designated sub-investigator) must sign the form 
electronically. 
For additional information regarding SAE reporting, contact Rho Product Safety (DAIT-SACCC):  
  
 
 
  
  
 
 
 


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12.5.3 Reporting to Health Authority 
After an AE requiring 24 hour reporting (per Section 12.5.2 Reporting Serious Adverse Events) is submitted by the site 
investigator and assessed by DAIT/NIAID, there are 2 options for DAIT/NIAID to report the AE to the appropriate health 
authorities (Annual Reporting and Expedited Reporting). 
12.5.3.1 
Annual Reporting 
Per 21 CFR 312.33, DAIT/NIAID will include in the Investigational New Drug Application (IND) Annual Report to FDA all 
AEs classified as: 
• 
Serious, expected, SARs (see Section 12.2.1.1 Suspected Adverse Reaction (SAR) and Section 12.5.2 Reporting 
Serious Adverse Events). 
• 
Serious and not a SAR (see Section 12.2.1.3 Solicited Adverse Events (Reactogenicity)). 
• 
Pregnancies. 
Note that all AEs (not just those requiring 24-hour reporting) will be reported in the IND Annual Report. 
12.5.3.2 
Expedited Safety Reporting  
This option, with 2 possible categories, applies if the AE is classified as one of the following: 
Category 1:  Serious and unexpected suspected adverse reaction [SUSAR] (see Section 12.2.1.1 Suspected Adverse 
Reaction (SAR) and Section 12.2.1.2 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction and 21 CFR 
312.32(c)(1)i).  
The sponsor shall report any SAR that is both serious and unexpected. The sponsor shall report an AE as a SAR only if 
there is evidence to suggest a causal relationship between the study drug and the AE, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., 
angioedema, hepatic injury, or Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug exposure but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the 
underlying disease or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more frequently in the 
drug treatment group than in a concurrent or historical control group. 
Category 2: Any findings from studies that suggest a significant human risk  
The sponsor shall report any findings from other epidemiological studies, analyses of AEs within the current study or 
pooled analysis across clinical studies or animal or in vitro testing (e.g., mutagenicity, teratogenicity, carcinogenicity) 
that suggest a significant risk in humans exposed to the drug that would result in a safety-related change in the protocol, 
informed consent, and investigator brochure or package insert or other aspects of the overall conduct of the study.  
DAIT/NIAID shall notify the FDA and all participating investigators of expedited Safety Reports within 15 calendar days; 
unexpected fatal or immediately life-threatening suspected adverse reaction(s) shall be reported as soon as possible or 
within 7 calendar days.  
12.5.4 Mandatory reporting to Vaccine Adverse Event Reporting System 
Per the FDA EUA for the Pfizer-BioNTech COVID-19 Vaccine, FDA EUA for the Moderna COVID-19 Vaccine, the FDA EUA 
for the Janssen COVID-19 Vaccine, the site investigator or designee is responsible for mandatory reporting of the 
following to the Vaccine Adverse Event Reporting System (VAERS) [48, 58, 59]: 
• 
Vaccine administration errors, whether or not associated with an AE, 
• 
SAEs (irrespective of attribution to vaccination), 


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• 
Cases of Multisystem Inflammatory Syndrome in adults and children, and  
• 
Cases of COVID-19 that result in hospitalization or death. 
Vaccination providers may report to VAERS other AEs that are not required to be reported. 
The site investigator, or designee, is also responsible for recording vaccination information in the state/local 
jurisdiction’s Immunization Surveillance System or other designated system.  
12.5.5 Reporting of Adverse Events to Institutional Review Boards (IRBs)/Institutional Ethics 
Committees (IECs) 
All investigators shall report AEs and SAEs, including expedited reports, in a timely fashion to their respective local IRBs 
and single IRB in accordance with applicable regulations and guidelines. All safety reports to the FDA shall be distributed 
by the Sponsor (DAIT/NIAID) or designee to the single IRB and all participating institutions for local IRB submission if 
required. 
12.6 
 Pregnancy Reporting 
The investigator shall be informed immediately of any pregnancy in a study participant. The investigator shall counsel 
the participant and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring 
of the pregnant participant shall continue until the conclusion of the pregnancy.  
The investigator shall report to the SACCC all participant pregnancies within 1 business day of becoming aware of the 
event using the Pregnancy eCRF. The SACCC will report all pregnancies to DAIT/NIAID. All pregnancies identified during 
the study shall be followed to conclusion, and the outcome of each must be reported. The Pregnancy eCRF shall be 
updated and submitted to the SACCC when details about the outcome are available.  
Information requested about the delivery shall include: 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours after 
birth, if available 
• 
Any abnormalities. 
Should pregnancy complications result in an event meeting the SAE definition outlined in Section 12.2.6, such as 
congenital abnormality, birth defect, miscarriage, or medically indicated abortion, an SAE must be submitted to the 
SACCC using the SAE reporting procedures described above.  
12.7 
Reporting of Other Safety Information 
An investigator shall promptly notify their local and central IRB, in accordance with applicable regulations and 
guidelines, as well as the SACCC and DAIT/NIAID via email when an “unanticipated problem involving risks to 
participants or others” is identified, which is not otherwise reportable as an AE. 
12.8 
Review of Safety Information 
12.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the DAIT-SACCC compiling new and accumulating 
information on AEs, AESIs, SAEs, MAAEs, NOCMCs, and pregnancies recorded by the study site(s) on appropriate eCRFs. 
In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE and pregnancy reports 
received from the DAIT-SACCC. 
 


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12.8.2 DSMB Review  
12.8.2.1 
Planned DSMB Reviews  
The progress of the study will be monitored by the NIAID DSMB. The NIAID Autoimmune DSMB is chartered to review 
safety data and to make recommendations to NIAID regarding continuation, termination, or modification of the study. 
The DSMB will review the safety data within 6 months after the first participant is treated, and an initial review should 
occur no later than after this first arm has closed to enrollment and all participants completed 4 weeks of follow up. 
Following the initial review, the DSMB will review the safety data approximately every 6 months during planned DSMB 
Data Review Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported AEs, SAEs, 
MAAEs, NOCMCs, AESIs, and increases in autoimmune disease activity (flares/relapses). 
The DSMB chair will be informed of any IND Safety Reports in a timely manner in order to make a recommendation for 
an ad hoc full board review and /or protocol suspension. In addition, safety data will be reviewed by the DSMB when an 
event occurs that is of sufficient concern to the NIAID medical monitor or protocol co-chairs to warrant review, or when 
an event occurs that could contribute to a stopping rule.  
12.8.2.2 
Ad hoc DSMB Reviews  
12.8.2.2.1 
Ad Hoc DSMB Reviews for Adult Participants 
 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon for ad hoc 
reviews. The DSMB will  review any event that potentially impacts safety at the request of the protocol chair or 
DAIT/NIAID. Any of the following events will trigger an ad hoc DSMB Safety Review: 
• 
Death related to vaccine 
• 
Life-threatening AE (Grade 4) related to vaccine 
• 
Permanent or severe disability related to vaccine 
• 
Occurrence of a Grade 3 or higher, vaccine-related SAE of the same type in 3 or more of the study participants 
who have received a study treatment. Note: Only SAEs occurring within 24 weeks of a Day 1 visit will be counted.  
• 
Occurrence of a Grade 2 or higher myocarditis or pericarditis within 6 weeks of vaccine administration. Note: the 
DSMB chair will be notified within 3 business from when the AESI is reported to DAIT/NIAID. 
• 
Occurrence of severe flare or relapse after an additional homologous COVID-19 vaccine dose given at Stage 1, 
defined as within 12 weeks of the Stage 1 Baseline/Week 0 visit (vaccination), in 3 of the first 10 participants or 
30% thereafter, defined as follows. 
• 
Occurrence of severe flare or relapse after a subsequent alternative COVID-19 vaccine dose given at Stage 2, 
defined as within 12 weeks of the Stage 2 Baseline/Week 0 visit (vaccination), in 3 of the first 10 participants or 
30% thereafter. 
Severe flare or relapse is defined as follows: 
o RA: DAS28-CRP score >5.1. 
o SLE: Severe score on the SELENA-SLEDAI flare index. 
o SSc: Onset of new or significant worsening of internal organ involvement requiring hospitalization or 
change in treatment or worsening of skin thickening on the modified Rodnan skin score of >4 units 
[absolute change from screening visit].  
o MS: Clinical relapse meeting either the criteria specified in (a) with investigator determination of relapse 
or the criteria in (a) and (b) below:  


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a. Occurrence of new, recurrent or worsening neurological symptoms attributable to MS, that 
meet all of the following criteria: 
i. Appeared or evolved subacutely (over <3 months). 
ii. Persisting for >24 hours. 
iii. Cannot be attributed to confounding factors (e.g., fever, infection, injury, poor sleep, 
adverse reaction to medication). 
iv. Occur ≥ 30 days after the onset of a prior confirmed relapse. 
b. New, recurrent or worsening neurological symptoms accompanied by corresponding objective 
worsening on neurologic examination with an increase of any one of the following in MS 
participants compared to the immediate prior assessment: 
i. ≥ 0.5 step(s) on the Expanded Disability Status Scale (EDSS), or 
ii. ≥ 2 points on one Functional Systems Score (FSS), or  
iii. ≥ 1 point on two or more FSS. 
Episodic spasms, sexual dysfunction, fatigue, mood change, or bladder or bowel urgency or incontinence 
will not suffice to establish a relapse. Sexual dysfunction and fatigue will not contribute to the EDSS or 
FSS for assessing MS relapse. 
o Pemphigus: 3 or more new lesions a month that do not heal spontaneously within 1 week or by the 
extension of established lesions in a participant who has achieved disease control. 
After review of the safety data, the DSMB will make recommendations regarding study conduct, including modifications 
and/or continuation. The DSMB will recommend and DAIT/NIAID, as Sponsor, will determine whether protocol changes 
should be implemented and/or whether and when consenting, allocation, randomization, and vaccinations can resume.  
12.8.2.2.2 
Ad Hoc DSMB Reviews for Pediatric Participants 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon for ad hoc 
reviews. The DSMB will  review any event that potentially impacts safety at the request of the protocol chair or 
DAIT/NIAID. Any of the following events will trigger an ad hoc DSMB Safety Review: 
• 
Death related to vaccine 
• 
Life-threatening AE (Grade 4) related to vaccine 
• 
Permanent or severe disability related to vaccine 
• 
Occurrence of a Grade 3 or higher, vaccine-related SAE of the same type in 3 or more of the study participants 
who have received a study treatment. Note: Only SAEs occurring between Day 1 and the Week 24 study visit will 
be counted.  
• 
Occurrence of a Grade 2 or higher  myocarditis or pericarditis within 6 weeks of vaccine administration. Note: 
the DSMB chair will be notified within 3 business days from when the AESI is reported to DAIT/NIAID. 
• 
Occurrence of severe flare or relapse after an additional homologous COVID-19 vaccine dose given at Stage 1, 
defined as within 12 weeks of the Stage Baseline/Week 0 visit (vaccination), in 3 of the first 10 participants or 
30% thereafter, defined as follows. 
• 
Occurrence of severe flare or relapse after a subsequent alternative COVID-19 vaccine dose given at Stage 2, 
defined as within 12 weeks of the Stage 2 Baseline/Week 0 visit (vaccination), in 3 of the first 10 participants or 
30% thereafter. 
Severe flare or relapse is defined as follows: 
o JIA:  


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a. JADAS10 >17 (polyarthritis, enthesitis-related JIA, and psoriatic arthritis), JADAS10 >13 (for 
oligoarthritis) 
b. PASI ≥12 (for psoriatic arthritis)     
o Pediatric SLE: ≥ 6.4 on the SLEDAI-based ACR provisional criteria for global flares in childhood-onset SLE 
o JDM: Decline in CMAS to <30 or JDM DAS>5 
o POMS: Clinical relapse meeting either the criteria specified in (a) with investigator determination of 
relapse or the criteria in (a) and (b) below:  
a. Occurrence of new, recurrent or worsening neurological symptoms attributable to MS, that 
meet all of the following criteria: 
v. Appeared or evolved subacutely (over <3 months) 
vi. Persisting for >24 hours. 
vii. Cannot be attributed to confounding factors (e.g., fever, infection, injury, poor sleep, 
adverse reaction to medication) 
viii. Occur ≥ 30 days after the onset of a prior confirmed relapse. 
b. New, recurrent or worsening neurological symptoms accompanied by corresponding objective 
worsening on neurologic examination with an increase of any one of the following compared to 
the immediate prior assessment: 
i. ≥ 0.5 step(s) on the EDSS scale, or 
ii. ≥ 2 points on one Functional Systems Score (FSS), or  
iii. ≥ 1 point on two or more FSS. 
Episodic spasms, sexual dysfunction, fatigue, mood change, or bladder or bowel urgency or incontinence 
will not suffice to establish a relapse. Sexual dysfunction and fatigue will not contribute to the EDSS or 
FSS for assessing MS relapse. 
After review of the safety data, the DSMB will make recommendations regarding study conduct, including modifications 
and/or continuation. The DSMB will recommend and DAIT/NIAID, as Sponsor, will determine whether protocol changes 
should be implemented and/or whether and when consenting, allocation, randomization, and vaccinations can resume.  
12.8.2.2.3 
Temporary Suspension of Randomization/Allocation and Vaccinations 
Section 11.5 Study Stopping Guidance outlines the procedure for DSMB ad hoc review due to the events listed in 
Section 12.8.2.2 Ad hoc DSMB Reviews. If during the ad hoc review, the DSMB determines that a temporary halt in 
randomization/allocation is required, participants who received vaccination prior to the temporary halt will continue in 
the study as planned. During the halt in randomization/allocation, recruitment, screening and consenting may continue, 
but no additional study vaccine doses will be administered.  
13. 
Statistical Considerations and Analytical Plan 
13.1 
Overview  
This is a randomized, multi-site, adaptive, open-label clinical trial comparing the immune response of different 
additional doses of COVID-19 vaccine in participants with autoimmune disease requiring IS medications. All study 
participants will have negative serologic or suboptimal responses to an initial COVID-19 vaccine regimen (Adult and 
Pediatric Stage 1) or a negative, suboptimal, or low immune response to initial COVID-19 vaccine regimen plus additional 
COVID-19 vaccinations (Adult and Pediatric Stage 2). We will focus on 5 autoimmune diseases in adult participants (SLE, 
RA, MS, SSc, and pemphigus) and 4 autoimmune diseases in pediatric participants (JIA, pediatric SLE, JDM, and POMS). 


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The primary objective is to determine the proportions of adult and pediatric participants who have a protective antibody 
response at Week 4 assessed by the NIAID-VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay. 
Response will be assessed within subgroups defined by the magnitude of immune response to prior vaccines, age, 
categories of IS medications, type of vaccine, and whether IS medications are continued or withheld around 
administration of the additional homologous vaccine dose. 
13.2 
Endpoints 
Primary, secondary, and exploratory endpoints are listed in Sections 3.2 Primary Endpoint, 3.3 Secondary Endpoints, and 
3.4 Exploratory Endpoints, respectively. 
13.3 
Measures to Minimize Bias  
Participants will be assigned to cohorts defined by IS medication (Cohort A and D: MMF/MPA; Cohort B and E: MTX; and 
Cohort C and F: BCDT) and by the initial COVID-19 vaccine regimen received (Moderna COVID-19 Vaccine, Pfizer-
BioNTech COVID-19 Vaccine, or Janssen COVID-19 Vaccine). In Adult Stage 1 and the pediatric portion of the study, 
participants in Cohort C will be allocated to continue taking their prescribed IS medications throughout the trial. 
Participants in Cohort A and B will be randomized in a balanced fashion (1:1), within the cohorts defined by IS 
medication and initial COVID-19 vaccine regimen, to one of the available IS medication treatment plans (continue IS vs. 
withhold IS). Randomization will be performed using a permuted block design stratified by disease type. 
13.4 
Analysis Plan 
13.4.1 Analysis Populations 
The following populations will be defined separately for Stage 1 and Stage 2. 
Vaccinated population: will be defined as all participants who are randomized or allocated and receive study vaccine in 
the study. For all endpoints, participants will be evaluated by the actual vaccine received. In Cohorts A and B, 
participants will be analyzed in subgroups defined by randomized assignment to continue or withhold IS medications in 
the primary analysis.  
Per protocol populations: will be defined as the subgroup of participants in the vaccinated population who adhere to 
the treatment plan for IS medications defined in Section 7.1.1 Protocol-mandated Medications and have no major 
protocol deviations or ineligible entry criteria that would impact the vaccine response assessment at Week 4. 
Safety population: will be defined as all participants who initiate the treatment plan for IS medications or receive an 
additional dose of vaccine.  
13.4.2 Primary Analysis of Primary Endpoint   
The primary endpoint of a protective antibody response will be the proportion of participants who reach the laboratory-
defined threshold for the NIAID-VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay. Participants with 
missing Week 4 anti-COVID-19 antibody response data with a documented COVID infection will be considered as not 
having a protective antibody response. All other participants missing Week 4 anti-COVID-19 antibody response data will 
be considered to be missing-completely-at-random (MCAR). Intercurrent events which result in Week 4 anti-COVID-19 
antibody response data being unevaluable for immune response, including receipt of monoclonal antibodies or plasma 
products directed against SARS-CoV-2 and any SARS-CoV-2 vaccine outside of the study, will also result in data be 
considered to be missing-completely-at-random (MCAR).  
The primary analysis will be evaluated independently within each arm (defined by age, cohort, vaccine, and IS treatment 
plan) and within subgroups with either a negative or suboptimal response to prior vaccines (defined as Roche Elecsys® 
Anti-SARS-CoV-2 S result ≤200 U/mL) or with a low immune response (defined as Roche Elecsys® Anti-SARS-CoV-2 S 
result >200 U/mL and  ≤2500 U/mL). The primary analysis will be performed in the vaccinated population. The 
proportion of participants meeting a protective antibody response criteria will be reported in each arm and subgroup 
with 90% Clopper-Pearson confidence intervals and analyzed using a one-sided exact test with alpha = 0.05 against the 
null hypothesis that the probability of achieving a protective immune response is ≤0.25. P-values will not be adjusted for 


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multiple comparisons. The primary analysis will also be conducted in the subgroup of participants with a Roche Elecsys® 
Anti-SARS-CoV-2 S result ≤50 U/mL at the Screening visit. Each analysis will occur after the evaluable participants 
assigned to that arm have completed the Week 4 study visit or are withdrawn from the study. 
13.4.3 Supportive Analyses of the Primary Endpoint  
Supportive analyses will also use a multivariable regression model on the entire vaccinated population in order to 
estimate the rates of vaccine response within and across arms (age group, cohort, vaccine, and IS treatment plan group) 
using the logistic link function, and including baseline covariates for disease type (SLE, RA, MS, SSc, and pemphigus in 
adults and JIA, pediatric SLE, JDM, and POMS in pediatrics) and immune response to the initial COVID-19 vaccine 
regimen (anti-COVID-19 antibody negative or positive). Descriptive statistics will be used to summarize antibody 
response to the additional homologous vaccine dose on a continuous scale. Estimates of the average antibody response 
and variance within and across cohorts will be obtained from a multivariate general linear regression model. Based on 
published data on the assays, it is anticipated that log-transformation of assay values will allow for Gaussian 
assumptions to hold, but alternative Box-Cox transformations of the data may be explored to stabilize the variance.  
The primary and supportive analyses will also be replicated on the Per-protocol population and using alternative 
strategies for missing data. 
13.4.4 Analyses of Secondary and Other Endpoint(s) 
For Stage 1, the multivariable logistic and linear regression models defined in Section 13.4.3 Supportive Analyses of the 
Primary Endpoint above will be used to compare response to additional homologous doses of COVID-19 vaccine for a 
variety of subgroups. Appropriate contrasts will be defined to compare vaccine response for the following: 
• 
Continuing versus withholding IS medications will be compared within cohort (cohorts A and B only) and within 
and across type of vaccine. 
• 
The types of additional vaccine dose administered will be compared within cohorts and across cohorts, and 
within and across IS treatment plan groups. 
• 
Type of IS medications will be compared within and across each type of vaccine. 
• 
Age groups and type of disease will be compared within and across each type of vaccine. 
• 
Corticosteroid dose at baseline will be added as a covariate to the model to assess impact on vaccine response. 
• 
Immune response to the initial COVID-19 vaccine regimen will be assessed within and across each type of 
vaccine.  
• 
Additional covariates for disease activity, co-morbid illness, age, and sex may be added to assess whether the 
clinical parameters are associated with response to additional vaccine dose. 
Data for the Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine may be combined in the comparisons 
above to assess the effect of mRNA vaccines together.  
The incidence of seroconversion following additional vaccine doses of COVID-19 vaccine will be evaluated in the 
subgroups of participants that are anti-COVID-19 antibody negative at baseline using separately, (a) NIAID-VRC MSD 3 
plex (Wu-1 full-length spike, RBD, and N proteins) assay  with thresholds <1204.7, 517.9, and 9779.6 AU/mL, 
respectively, and (b) the Roche Elecsys® Anti-SARS-CoV-2 S electrochemiluminescence immunoassay with a threshold 
<0.80 U/mL. The proportions who seroconvert within and across arms will be summarized using 95% Clopper-Pearson 
confidence intervals, and comparisons will use a two-sample Binomial exact test with nominal two-sided alpha = 0.05. 
For the subgroups of participants that are anti-COVID-19 antibody positive at baseline using separately, (a) the NIAID-
VRC MSD 3 plex (Wu-1 full-length spike, RBD, and N proteins) assay, and (b)  the Roche Elecsys® Anti-SARS-CoV-2 S  
electrochemiluminescence immunoassay with a threshold ≥0.80 U/mL. Fold improvement for each assay will be defined 
as: 
Fold improvement = anti-COVID-19 Antibody Response Week 4
anti-COVID-19 Antibody Response Baseline
  


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Longitudinal changes in the anti-COVID-19 antibodies will be summarized over time by study visit using descriptive 
statistics. Details on handling missing data and intercurrent events, which result in anti-COVID-19 antibody response 
data being unevaluable for immune response, will be outlined in the statistical analysis plan. 
Longitudinal changes in neutralization and pseudoneutralization assays will be summarized by study visit using 
descriptive statistics. For secondary continuous efficacy endpoints, descriptive statistics will be used to summarize the 
distribution of scores in each arm; for adult participants, this will include the H-SLEDAI (SLE participants), 
Tender/Swollen Joint Count (RA participants), PDAI (pemphigus participants), modified Rodnan Skin Score (SSc 
participants), CGI-C, PtGA, PGI-C, PGA, and PROMIS 29, and for pediatric participants, this will include the SLEDAI-2K 
(SLE), Tender/Swollen Joint Count (JIA participants), MMT-8 and CMAS (JDM participants), CGI-C, PtGA, PGI-C, PGA, and 
PedsQL. The proportion of participants who meet definition for disease-specific flares, including the Thanou modified 
SELENA-SLEDAI Flare Index (SLE participants), patient-reported flare assessment (SSc participants), and physician-
assessed relapse (MS participants), will be summarized. The disease-specific flare endpoints will include Thanou 
modified SELENA-SLEDAI Flare Index (SLE participants), DAS28-CRP (RA participants), patient-reported flare assessment 
(SSc participants), flare assessment (pemphigus participants) and physician-assessed relapse (MS participants) in adults 
and the ACR Provisional Criteria for Global Flare in Childhood-onset SLE (for SLEDAI; pediatric SLE participants), 
physician-assessed relapse (POMS participants), and flare assessment (JDM participants).  
Descriptive statistics will be used to summarize the proportions of participants in the safety arm who experience safety 
endpoints. 
For Stage 2, analysis plans for primary and secondary endpoints will be repeated to evaluate the immune response to a 
subsequent alternative COVID-19 vaccine dose and to determine whether immunologic variables are associated with 
increased disease activity. 
13.4.5 Descriptive Analyses  
Summary descriptive statistics for baseline and demographic characteristics, disposition, and medication use will be 
provided for the safety and vaccinated populations. These data will be presented in the following manner:  
• 
Continuous data (e.g., age, weight, and height) will be summarized by mean, standard deviation, median, and 
range.  
• 
Categorical data (e.g., sex and race) will be presented as counts and percentages.  
All medications taken by or administered to study participants beginning 30 days before the Screening Visit and 
continuing throughout the study will be collected. All medications used will be coded according to the World Health 
Organization (WHO) drug dictionary. The number and percentage of participants receiving prior and concomitant 
medications/therapies will be presented overall and by medication class.  
13.5 
Interim Analysis  
13.5.1 Interim Analysis of Efficacy Data 
No interim analysis of efficacy data is planned for the study. 
13.5.2 Interim Analysis of Safety Data 
No interim analysis of safety data is planned for the study. Routine reviews by the NIAID DSMB will be conducted as 
planned in Section 12.8.2 DSMB Review. 
13.5.3 Futility Analysis 
No early stopping for futility is planned for this study. 
13.6 
Statistical Hypotheses  
The set of null hypotheses are that the true probability of a protective antibody response, π, is ≤0.25 in a given 
subpopulation, representing an inadequate improvement in anti-COVID-19 Antibody Response after administration of 


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an additional vaccine dose to warrant further investigation in that subpopulation. This will be tested within each arm 
indexed by cohort and age group (i), additional vaccine dose (j), and IS treatment plan (k)  
𝐻𝐻0,(𝑖𝑖,𝑗𝑗,𝑘𝑘): 𝜋𝜋(𝑖𝑖,𝑗𝑗,𝑘𝑘) ≤0.25  
The set of alternative hypotheses are that the true vaccine response rate, π, is >0.25 and may warrant further 
investigation in that subpopulation  
𝐻𝐻1,(𝑖𝑖,𝑗𝑗,𝑘𝑘): 𝜋𝜋(𝑖𝑖,𝑗𝑗,𝑘𝑘) > 0.25  
13.7 
Sample Size Considerations  
Early reports show that a significant number of individuals taking IS medications respond poorly or not at all to COVID-19 
vaccination. Ruddy et al. reported 26% of chronic inflammatory rheumatic disease patients had undetectable SARS-CoV-
2 antibody response after their first mRNA vaccine dose, but many seroconverted with the second dose such that only 
6% had persistent undetectable SARS-CoV-2 RBD antibodies [16]. However, those taking MMF or rituximab were at 
much higher risk of not mounting a detectable antibody response (89% and 67%, respectively)[17]. Another report has 
demonstrated diminished overall serologic response in adults with chronic inflammatory diseases, particularly in those 
treated with B-cell depletion or antimetabolites including MTX, with a 50-fold and 3-fold reduction in post-vaccine 
antibody titers relative to immunocompetent controls[80].  
Based on the emerging evidence in individuals taking IS medications, an ineffective rate of achieving a protective 
immune response after the additional vaccine dose was defined to be less than or equal to 0.25 (null hypothesis). The 
study is powered to reject the null hypothesis in each arm when the true response rate is 0.5 or greater as preliminary 
evidence the additional vaccine dose is effective in specific study population.  
The proportion of participants in each arm (cohort, additional vaccine dose, and IS treatment plan group) to receive an 
additional vaccine dose and achieve a protective antibody response at Week 4 will be evaluated using a one-sided exact 
test with alpha = 0.05 to test against a null hypothesis that the true response rate is ≤0.25. A sample size of 33 evaluable 
participants achieves at least 90% power to reject null hypothesis when the true response rate is 0.5 or greater. 
Secondary analyses will compare the rate of achieving a protective immune response across arms using the 
multivariable logistic regression model. For comparisons of single arms, 33 evaluable participants per arm will provide 
80% power to detect an odds ratio of 4.2 when the null hypothesis is true in one arm (improvement from 0.25 to 0.584). 
For comparisons that combine arms, pooling 3 arms (e.g., type of additional vaccine dose) will provide 80% power to 
detect an odds ratio of 2.3 (improvement to 0.394). 
In order to account for up to 20% dropout within a given arm of participants missing Week 4 anti-COVID-19 antibody 
response data without a documented COVID infection, 40 participants within each subgroup defined by the Roche 
Elecsys® Anti-SARS-CoV-2 S assay. In each arm, the number of participants with Roche Elecsys® Anti-SARS-CoV-2 S 
results ≤200 U/mL will be capped at 40 participants, and the number of participants with Roche Elecsys® Anti-SARS-CoV-
2 S results >200 U/mL and ≤2500 U/mL will be capped at 40 participants. 
An adaptive design will be employed such that cohorts may be added or modified in light of emerging evidence on 
autoimmune disease vaccination or of the development and authorization of COVID-19 vaccines.  
14. 
Identification and Access to Source Data 
14.1 
Source Data 
Source documents and source data are considered to be the original documentation where participant information, visit 
consultations, examinations, and other information are recorded. Documentation of source data is necessary for the 
reconstruction, evaluation and validation of clinical findings, observations and other activities during a clinical trial.  
The investigator should retain all documentation relating to the study (including but not limited to informed consent 
forms, source documentation, study vaccine records, eCRFs, and essential documents) for a period of at least 2 years 


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after the last marketing application approval or, if no application will be filed or if the application is not approved, 
2 years following the discontinuation of the investigation.  
If this requirement differs from any local regulations, the local regulations will take precedence unless the local 
retention policy is less than 2 years. 
At study closure, the investigator must inform DAIT/NIAID, or the SACCC as designee, of the long-term storage location 
of the study’s records and must inform DAIT/NIAID if that location changes subsequently. 
No study records should be destroyed without prior authorization from DAIT/NIAID. 
14.2 
Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID and authorized representatives 
of DAIT/NIAID, as well as to relevant health authorities. Authorized representatives as noted above are bound to 
maintain the strict confidentiality of medical and research information that may be linked to identified individuals. 
15. 
Quality Assurance and Quality Control 
The principal investigator (PI) is required to keep accurate records to ensure that the conduct of the study is fully 
documented. The PI is required to ensure that all eCRFs are completed for every participant entered in the trial. The 
period of record retention should be consistent with the record retention policies of the sponsoring agency or applicable 
regulatory agencies. However, in certain instances, documents should be retained for a longer period if required by the 
applicable regulatory agency or by the NIH. 
Data will be obtained from a variety of sources including, but not limited to laboratory notebooks, automated 
instrument output files, and clinical participant charts. Data from these source materials will be transmitted to the 
SACCC via one of two mechanisms. Data collected electronically at central laboratories will be transferred electronically 
directly from the laboratory to the SACCC using standard secure data transfer procedures. Data collected at the clinical 
sites will be transmitted to the SACCC using an internet-based remote data entry system. Clinical site personnel use an 
internet browser to key data into eCRFs; each eCRF page is submitted to the clinical database electronically as the page 
is completed. Univariate data validation tests are performed as the data are keyed. The clinical database is backed up 
nightly; backup tapes are saved in a secure, off-site location. At any time, authorized site personnel may log in to the 
remote data entry system, review and correct previously entered data, or key additional data. The data will be further 
validated per the study data validation plan via a series of computerized and manual edit checks, and all relevant data 
queries will be raised and resolved on an ongoing basis. Complete, clean data will be frozen to prevent further 
inadvertent modifications. All discrepancies will be reviewed and any resulting queries will be resolved with the 
investigators and amended in the database. All elements of data entry (i.e., time, date, verbatim text, and the person 
performing the data entry) will be recorded in an electronic audit trail to allow all data changes in the database to be 
monitored and maintained in accordance with federal regulations.  
The SACCC is responsible for regular inspection of the conduct of the trial, for verifying adherence to the protocol, and 
for confirming the completeness, consistency, and accuracy of all documented data.  
The SACCC will periodically visit the participating clinical sites and audit the source documents in order to validate the 
data in the SACCC central database. If on-site visits are not permitted at a site due to COVID-19 restrictions, source 
document review and other visit activities will be conducted remotely. Data will be provided using the participant’s 
identification number, the SACCC will not collect personally identifying information such as the participant’s name or 
social security number. Participants will provide demographic information such as race, ethnicity, and birth date. 
Data collected by the SACCC will be held in the strictest confidence, and are protected from access that could reveal 
personally identifying information about any participant in the trial. 
 
 


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16. 
Protocol Deviations 
16.1 
Protocol Deviation Definitions 
Protocol Deviation – Any change, divergence, or departure from the study design or procedures constitutes a protocol 
deviation. Protocol deviations occur for a variety of reasons, such as an investigator’s intentional or unintentional 
departure from the protocol, the participant’s lack of adherence to the protocol, or external/environmental factors (e.g., 
severe weather or holidays) that change the performance of a protocol. Some protocol deviations are anticipated 
and/or intentional; others are not. Some protocol deviations are known or identified before they occur; others are only 
discovered to have occurred after the fact. The investigators and site staff will conduct the study in accordance to the 
protocol; no deviations from the protocol are permitted or approved beforehand by the study Sponsor. 
Major Protocol Deviation (Protocol Violation) – A Protocol Violation is a deviation from the IRB-approved protocol that 
may affect the participant's rights, safety, or well-being and/or the completeness, accuracy and reliability of the study 
data. In addition, protocol deviations include willful or knowing breaches of HSP regulations, or policies, any action that 
is inconsistent with the NIH Human Research Protection Program’s research, medical, and ethical principles, and a 
serious or continuing noncompliance with federal, state, local or institutional human subject protection regulations, 
policies, or procedures. 
Non-Major Protocol Deviation – A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the participant's rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
16.2 
Reporting and Managing Protocol Deviations 
The study site PI has the responsibility to identify, document and report protocol deviations as directed by the study 
Sponsor. However, protocol deviations may also be identified during site monitoring visits or during other forms of study 
conduct review.  
When a deviation occurs, corrective actions may be necessary depending on the nature of the deviation. Risk 
assessment must occur by the PI and study Sponsor. The PI should ensure a procedure for the timely correction and 
documentation of problems identified by study personnel, outside monitors or auditors, or other parties involved in the 
conduct of a study. The depth of Corrective Action/Preventive Action (CAPA) required should match the risk and impact 
on safety of participants and/or the quality of the data. 
Upon determination that a protocol deviation has occurred, the PI/designated study staff will report the deviation 
according to the processes outlined for the study. A major deviation is to be reported within 3 business days and 
reported by the PI to the IRB per IRB reporting requirements. The study Sponsor will determine reportability of the 
deviation to the DSMB and FDA as applicable.  
17. 
Ethical Considerations and Compliance with Good Clinical Practice 
17.1 
Statement of Compliance 
This clinical study will be conducted using GCP, as delineated in FDA Guidance for Industry: E6R2 Good Clinical Practice: 
Integrated Addendum to ICH E6(R1), and according to the criteria specified in this study protocol. Before study initiation, 
the protocol and the informed consent documents will be reviewed and approved by an Institutional Review Board. Any 
amendments to the protocol or to the consent materials will also be approved by the IRB before they are implemented. 
17.2 
Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision. The PI or designee listed on the FDA 1572 will review the consent 
and/or assent and answer questions. The prospective participant and if applicable, the participant’s guardian will be told 
that being in the trial is voluntary and that he or she may withdraw from the study at any time, for any reason. All 
participants (and/or their legal guardian) will read, sign, and date a consent and/or assent form before undergoing any 


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study procedures. Consent/assent materials will be presented in participants’ primary language. A copy of the signed 
consent form will be given to the participant. The consent/assent process will be documented in the research or medical 
records. 
A separate assent form will be utilized to obtain assent from children 7-13 years of age, and participants 14 years of age 
and older will sign on the assent line on the main consent form. Consent will be obtained from participants who reach 
legal age of consent per state laws during participation in the trial. 
The consent process will be ongoing. The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study.  
17.3 
Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study. Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information. Site personnel will not transmit documents containing personal health identifiers to the study sponsor or 
their representatives. 
The study protocol, documentation, data and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
The study Monitor or other authorized representatives of the sponsor may inspect all documents and records required 
to be maintained by the Investigator, including but not limited to, medical records (office, clinic or hospital) and 
pharmacy records for the participants in this study. The clinical study sites will permit access to such records. 
18. 
Publication Policy 
The ACE Publication Policy will apply to publication of study results. Authorized study personnel may find details 
regarding the policy on the ACE study portal. Site investigators are encouraged to communicate and publish study 
results with prior notification of and review by DAIT/NIAID. 
 
 


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Munroe, M.E., et al., Pathways of impending disease flare in African-American systemic lupus erythematosus 
patients. J Autoimmun, 2017. 78: p. 70-78. 
80. 
Deepak, P., et al., Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA 
Vaccines to SARS-CoV-2. medRxiv, 2021. 
 
 
 


















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IParticipants in Cohort E (MTX) and participants in Cohort F (BCDT) who are also taking MTX will withhold their IS medication for at least 7 days prior to and at least 7 days after receipt of the alterative vaccine dose at Stage 2 
Baseline Week 0 (not to exceed 21 days withholding of MTX). If necessary, the site will call the participant between Stage 2 Screening and Stage 2 Baseline Week 0 to remind the participant to withhold his/her MTX. The site will 
call the participant after Stage 2 Baseline Week 0 to remind the participant to restart his/her MTX.  
JParticipants in Cohort D (MMF/MPA) and participants in Cohort F (BCDT) who are also taking MMF/MPA will withhold their IS medication for 3 days prior to and 10 days after receipt of the alternative vaccine dose at Stage 2 
Baseline Week 0. If necessary, the site will call the participant between Stage 2 Screening and Stage 2 Baseline Week 0 to remind the participant to withhold his/her MMF/MPA. The site will call the participant after S2 Baseline 
Week 0 to remind the participant to restart his/her MMF/MPA.  
KThe vaccine diary will be completed for 7 days after the alternative vaccine dose.  
L The H-SLEDAI and PGA will be collected at Stage 2 Screening for all SLE participants to assess disease activity. The Tender/Swollen Joint Count and PtGA at Stage 2 Screening will be collected for all RA participants to assess 
disease activity using DAS28-CRP. 
MThe EDSS will be collected whenever a MS relapse is suspected, and if applicable, at the time of relapse recovery (to occur 8-12 weeks after the suspected relapse EDSS assessment). 
N For women of childbearing potential. Stat urine HCG prior to vaccination may be performed locally with point of care testing. 
OIf the S2 Screening visit occurs onsite, the molecular COVID-19 test and urine pregnancy test will be conducted. If Stage 1 or Stage 2  visit data is being used to assess Stage 2 eligibility and screening, the molecular COVID-19 test 
and urine pregnancy tests will be conducted at the S2 Baseline visit only.  
PIf a participant is on a CD20 depleting agent, CD19+ B cells will be collected.  
QAntibody levels will be tested at each time point to test for IgG and IgM responses against SARS-CoV-2 spike, receptor binding domain, and nucleocapsid proteins. 
RAll Stage 2 Baseline Week 0 assessments (including confirmation of alternative vaccine dose eligibility) must be completed prior to administration of the alternative vaccine dose. If the alternative vaccine dose cannot be 
administered at Stage 2 Baseline Week 0, the alternative vaccine dose eligibility confirmation and administration of the alternative vaccine dose may occur 2-3 days after the Stage 2 Baseline Week 0 visit. Administration of the 
alternative vaccine dose must occur within 28 days of when the data used for screening were obtained. 
SModerna COVID-19 vaccine or Pfizer-BioNTech COVID-19 vaccine. 
TFor unscheduled visits conducted for disease activity increases, all disease-specific assessments and corresponding clinical laboratories are to be performed. For unscheduled visits conducted for a reason other than a disease 
activity increases, participants should be evaluated per clinical judgement of the investigator.  
 
 




















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20.2 
CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Reaction involving one of 
the following organ 
systems in which the 
symptoms are mild: 
 
Cutaneous Generalized 
pruritus, generalized 
urticaria, flushing, 
angioedema 
 
Upper respiratory 
Rhinitis, cough unrelated 
to laryngeal edema or 
bronchospasm 
 
Conjunctival 
Injection/redness, 
itching, tearing 
 
GI  
Nausea, abdominal pain 
(no change in activity 
level), single episode of 
vomiting and/or single 
episode of diarrhea 
Reaction involving two 
or more of the following 
organ systems in which 
the symptoms are mild: 
 
Cutaneous 
Generalized pruritus, 
generalized urticaria, 
flushing, angioedema 
 
Upper respiratory 
Rhinitis, cough unrelated 
to laryngeal edema or 
bronchospasm 
 
Conjunctival 
Injection/redness, 
itching, tearing 
 
GI 
Nausea, abdominal pain 
(no change in activity 
level), single episode of 
vomiting, and/or single 
episode of diarrhea 
 
OR 
 
Reaction involving at 
least one of the 
following organ systems 
in which the symptoms 
are moderate: 
Reaction involving one or 
more of the following 
organ systems: 
 
Lower respiratory 
Throat tightness, 
wheezing, chest 
tightness, dyspnea, cough 
that respond to short-
acting bronchodilator 
treatment (including IM 
epinephrine) with or 
without supplemental 
oxygen 
GI 
Severe abdominal pain, 
more than two episodes 
of vomiting and/or 
diarrhea 
 
 
Life-threatening reaction 
involving one or more of 
the following organ 
systems with or without 
other symptoms listed in 
Grades 1 to 3: 
Lower respiratory 
Throat tightness with 
stridor, wheezing, chest 
tightness, dyspnea, or 
cough associated with a 
requirement for 
supplemental oxygen 
and refractoriness to 
short-acting 
bronchodilator 
treatment (including IM 
epinephrine)1 
 
OR 
 
Respiratory compromise 
requiring mechanical 
support 
Cardiovascular 
Reduced BP with 
associated symptoms of 
end-organ dysfunction 
(e.g., hypotonia 
[collapse], syncope) 
defined as: 
• Children:  low systolic 
BP (age specific2) or 
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1. Examples of refractoriness could include continuous albuterol nebulizer or epinephrine IV infusion or more than three IM epinephrine injections. 
2. Low systolic BP for children is defined as: less than 70 mmHg from 1 month to 1 year of age, less than (70 mmHg + [2 x age]) from 1 to 10 years of age, 
and less than 90 mmHg from 11 to 17 years of age. 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
Cutaneous 
Generalized pruritus, 
generalized urticaria, 
flushing, angioedema 
 
Upper respiratory 
Rhinitis, cough unrelated 
to laryngeal edema or 
bronchospasm 
 
Conjunctival 
Injection/redness, 
itching, tearing 
 
GI 
Nausea, abdominal pain 
(with change in activity 
level), two episodes of 
vomiting and/or diarrhea 
>30% decrease in 
systolic BP 
• Adults: systolic BP of 
less than 90 mmHg or 
>30% decrease from 
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20.3 
Adult Vaccine Reaction Diary 
 
 


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20.4 
Pediatric Vaccine Reaction Diary (2 year old) 
 
 


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20.5 
Pediatric Vaccine Reaction Diary (3 – 4 year old) 
 
 
 


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20.6 
Pediatric Vaccine Reaction Diary (5 – 17 year old) 
 
 


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• Alopecia areata 
• Autoimmune / Immune mediated 
blistering dermatoses, including: 
o Bullous Dermatitis 
o Bullous Pemphigoid 
o Dermatitis herpetiformis 
o Epidermolysis bullosa acquisita (EBA) 
o Linear IgA-mediated bullous 
dermatosis (LABD), also known as 
Linear IgA disease 
o Pemphigus 
• Erythema multiforme 
• Erythema nodosum 
• Lichen planus, including: 
o Liquen planopilaris 
• Localized Scleroderma (Morphoea) 
o Eosinophilic fasciitis (also called 
Shulman syndrome) 
• Psoriasis 
• Pyoderma gangrenosum 
• Reactive granulomatous dermatitis, 
including : 
o Interstitial granulomatous dermatitis 
o Palisaded neutrophilic granulomatous 
dermatitis 
• Stevens-Johnson Syndrome (SJS), 
including: 
o Toxic Epidermal Necrolysis (TEN) 
o SJS-TEN overlap 
• Sweet’s syndrome, including: 
o Acute febrile neutrophilic dermatosis 
• Vitiligo 
• Large vessels vasculitis*, including: 
o Arteritic anterior ischemic optic 
neuropathy (AAION or arteritic AION) 
o Giant cell arteritis (also called 
temporal arteritis) 
o Takayasu's arteritis 
• Medium sized and/or small vessels 
vasculitis*, including: 
o Anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified) 
o Behcet's syndrome 
o Buerger’s disease 
(thromboangiitis obliterans) 
o Churg–Strauss syndrome (allergic 
granulomatous angiitis) 
o Erythema induratum (also known as 
nodular vasculitis) 
o Henoch-Schonlein purpura (also 
known as IgA vasculitis) 
o Microscopic polyangiitis 
o Necrotizing vasculitis 
o Polyarteritis nodosa 
o Single organ cutaneous vasculitis, 
including leukocytoclastic vasculitis, 
hypersensitivity vasculitis and acute 
hemorrhagic edema of infancy (AHEI) 
o Wegener's granulomatosis 
 
 
 
• Anti-synthetase syndrome 
• Capillary leak syndrome 
o Frequently used related terms 
include : “systemic capillary 
leak syndrome (SCLS)” or 
“Clarkson's Syndrome” 
• Goodpasture syndrome 
o Frequently used related terms 
include: “pulmonary renal syndrome” 
and “anti-Glomerular Basement 
Membrane disease (anti-GBM 
disease)” 
• Immune-mediated enhancement of disease, 
including: 
o Vaccine associated enhanced 
disease (VAED and VAERD). 
o Frequently used related terms 
include “vaccine-mediated enhanced 
disease (VMED)”, “enhanced 
respiratory disease (ERD)”, “vaccine-
induced enhancement of infection”, 
“disease enhancement”, 
“immune enhancement”, and 
“antibody-dependent enhancement 
(ADE) 
• Immunoglobulin G4 related disease 
• Langerhans' cell histiocytosis 
• Multisystem inflammatory syndromes, 
including: 
o Kawasaki’s disease 
o Multisystem inflammatory syndrome 
in adults (MIS-A) 
o Multisystem inflammatory syndrome 
in children (MIS-C) 
• Overlap syndrome 
• Raynaud’s phenomenon 
• Sarcoidosis, including: 
o Loefgren syndrome 
• Susac's syndrome 
*Adverse events of special interest (AESI) considered potentially applicable to COVID-19 vaccines as defined by the Safety Platform for 
Emergency Vaccines (SPEAC), based on known association with vaccination in general (see https://brightoncollaboration.us/wp-
content/uploads/2021/01/SO2_D2.1.2_V1.2_COVID-19_AESI-update-23Dec2020-review_final.pdf). SPEAC list extended with additional 
potential immune-mediated diseases. 
 
 
 


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20.8 
Case definitions of probable and confirmed myocarditis, pericarditis, and myopericarditis 
 
Condition 
Definition 
Acute 
myocarditis 
Probable case 
Confirmed case 
Presence of ≥1 new or worsening of the 
following clinical symptoms:* 
Presence of ≥1 new or worsening of the following 
clinical symptoms:* 
     • chest pain, pressure, or discomfort 
     • chest pain, pressure, or discomfort 
     • dyspnea, shortness of breath, or pain with 
breathing 
     • dyspnea, shortness of breath, or pain with 
breathing 
     • palpitations 
     • palpitations 
     • syncope 
     • syncope 
OR, infants and children aged <12 years might 
instead have ≥2 of the following symptoms: 
OR, infants and children aged <12 years might instead 
have ≥2 of the following symptoms: 
     • irritability 
     • irritability 
     • vomiting 
     • vomiting 
     • poor feeding 
     • poor feeding 
     • tachypnea 
     • tachypnea 
     • lethargy 
     • lethargy 
AND 
AND 
≥1 new finding of 
≥1 new finding of 
     • troponin level above upper limit of normal 
(any type of troponin) 
     • Histopathologic confirmation of myocarditis† 
     • abnormal electrocardiogram (ECG or EKG) 
or rhythm monitoring findings consistent with 
myocarditis§ 
     • abnormal cardiac function or wall motion 
abnormalities on echocardiogram 
     • cMRI findings consistent with myocarditis¶ in the 
presence of troponin level above upper limit of normal 
(any type of troponin) 
     • cMRI findings consistent with myocarditis¶ 
AND 
AND 
     • No other identifiable cause of the 
symptoms and findings 
     • No other identifiable cause of the symptoms and 
findings 
Acute 
pericarditis** 
Presence of ≥2 new or worsening of the following clinical features: 
     • acute chest pain†† 
     • pericardial rub on exam 


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Condition 
Definition 
     • new ST-elevation or PR-depression on EKG 
     • new or worsening pericardial effusion on echocardiogram or MRI 
Myopericarditis This term may be used for patients who meet criteria for both myocarditis and pericarditis. 
Abbreviations: AV = atrioventricular; cMRI = cardiac magnetic resonance imaging; ECG or EKG = electrocardiogram. 
* Persons who lack the listed symptoms but who meet other criteria may be classified as subclinical myocarditis (probable or 
confirmed). 
† Using the Dallas criteria (Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis. A histopathologic definition and classification. 
Am J Cardiovasc Pathol 1987; 1:3–14). Autopsy cases may be classified as confirmed clinical myocarditis on the basis of meeting 
histopathologic criteria if no other identifiable cause. 
§ To meet the ECG or rhythm monitoring criterion, a probable case must include at least one of 1) ST-segment or T-wave 
abnormalities; 2) Paroxysmal or sustained atrial, supraventricular, or ventricular arrhythmias; or 3) AV nodal conduction delays or 
intraventricular conduction defects. 
¶ Using either the original or the revised Lake Louise 
criteria. https://www.sciencedirect.com/science/article/pii/S0735109718388430?via%3Dihubexternal icon 
** https://academic.oup.com/eurheartj/article/36/42/2921/2293375external icon 
†† Typically described as pain made worse by lying down, deep inspiration, or cough, and relieved by sitting up or leaning forward, 
although other types of chest pain might occur.