covid-19 booster vaccine in autoimmune disease non-responders

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)

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)

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.

Eligibility criteria:
general adult inclusion criteria: 1. willing and able to sign informed consent 2. 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 stage 1 screening visit, or if participating in stage 2, no more than 48 weeks prior to the stage 2 screening visit. general exclusion criteria 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: 1. an increase/addition of any is medications, or 2. a suggestion of ms relapse per the investigator. 6. recent or current sars-cov-2 infection defined as: 1. documented sars-cov-2 infection in the past 30 days (from the day the participant is diagnosed by positive test to screening). 2. positive result on a molecular covid-19 test at 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. adults with evidence of hiv, hepatitis b indicated by surface antigen, and hepatitis c indicated by anti-hepatitis c antibody positivity will be excluded. if an adult is negative for hepatitis c viral load at screening, he/she will be eligible to participate. 10. participants with common variable immunodeficiency disease, as well as any participants currently receiving immune globulin replacement therapy. note: pediatric 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 (for pediatric participants postmenarchal females must have a negative urine pregnancy test at screening). 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. adult participants taking cladribine, alemtuzumab, or mitoxantrone will also be excluded. 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. adult general criteria inclusion criteria: 1. individuals 18 years of age or older that meet classification criteria for systemic lupus erythematosus (sle), systemic sclerosis (ssc), rheumatoid arthritis (ra), multiple sclerosis (ms), or pemphigus 2. participants must meet the 2019 acr/eular or 2012 slicc classification criteria for sle, the 2010 acr/eular classification criteria for ra, the 2013 eular/acr classification criteria for ssc, the 2017 mcdonald criteria for ms, and the international consensus criteria for pemphigus. 1. 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 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). 1. 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. 2. 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: 1. hcq, 2. intraarticular steroids, 3. the addition of prednisone at ≤10mg per day or prednisone at any dose when given for ≤3 days, and 4. corticosteroid bursts for non-autoimmune disease-related conditions, such as asthma or copd, are permitted. adult general exclusion criterion 1. inability or unwillingness of a participant to give written informed consent or comply with study protocol. 14. adult female participants who are planning a pregnancy during the course of the trial. adult stage 1-specific inclusion criterion 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. 1. 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 adult stage 1-specific exclusion criterion 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. adult stage 2 (newly recruited)-specific inclusion criteria 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. 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: 1. 3 doses of the pfizer-biontech covid-19 vaccine 2. 3 doses of the moderna covid-19 vaccine 3. 2 doses of the janssen covid-19 vaccine 4. 4 or more doses of a single mrna vaccine (pfizer-biontech covid-19 vaccine or moderna covid-19 vaccine) 5. 3 or more doses of a mixture of mrna vaccines (pfizer-biontech covid-19 vaccine or moderna covid-19 vaccine) adult stage 2 (newly recruited)-specific exclusion criteria: 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. adult stage 2 (rollover)-specific 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 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: 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. 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) general pediatric inclusion criteria 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. 1. participants must meet the 2017 eular/acr classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups, the international league of associations for rheumatology (ilar) classification for jia, the 2017 mcdonald criteria for ms, or the bohan and peter criteria or the 2017 eular/acr classification criteria for jdm. 2. 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. 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). 1. 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. 2. 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 general pediatric exclusion criteria 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. pediatric stage 1-specific inclusion criteria: 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 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. pediatric stage 1-specific exclusion criteria: individuals who meet any of these criteria are not eligible for randomization/allocation as participants in the pediatric portion of the study: 7. receipt of a covid-19 vaccine booster prior to screening. pediatric stage 2 (newly recruited)-specific inclusion criteria 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. c. moderna covid-19 vaccine (12 through 17 years of age): 3 full, age-appropriate doses of the moderna covid-19 vaccine pediatric stage 2 (newly recruited)-specific exclusion criteria: 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. pediatric stage 2 (rollover)-specific inclusion criteria: 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: 1. pfizer-biontech covid-19 vaccine (2 through 5 years of age): 4 full, age-appropriate doses of the pfizer-biontech covid-19 vaccine 2. 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. 3. moderna covid-19 vaccine (12 through 17 years of age): 3 full, age-appropriate doses of the moderna covid-19 vaccine

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