Analysis of the Immune Response to COVID-19 Vaccination and Outcomes in Individuals With and Without Immune Deficiencies and Dysregulations
Conditions: Immunodeficiencies, Immune Dysregulations
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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Abbreviated Title: COVID vaccine immune response
Version Date: June 13, 2022
NCT#: 04852276
Abbreviated Title: COVID vaccine immune response
NIH Institutional Review Board (IRB) #: 000384 
Version Date: June 13, 2022
Title: Analysis of the immune response to COVID-19 vaccination and outcomes in individuals 
with and without immune deficiencies and dysregulations 
National Institutes of Health 
(NIH) Principal Investigator:
Emily E. Ricotta, PhD, MSc
Epidemiology Unit
Laboratory of Clinical Immunology and Microbiology (LCIM)
Division of Intramural Research 
National Institute of Allergy and Infectious Diseases (NIAID)
NIH 
5601 Fishers Lane, 7D18
Bethesda, MD 20852
Phone: 301-761-7784
Email: emily.ricotta@nih.gov

Abbreviated Title: COVID vaccine immune response
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Table of Contents
STATEMENT OF COMPLIANCE ................................................................................................5
1
PROTOCOL SUMMARY.......................................................................................................6
1.1
Synopsis.........................................................................................................................6
1.2
Schedule of Activities ...................................................................................................9
2
INTRODUCTION .................................................................................................................12
2.1
Study Rationale ...........................................................................................................12
2.2
Background .................................................................................................................12
2.3
Risk/Benefit Assessment.............................................................................................13
2.3.1
Known Potential Risks ................................................................................................13
2.3.2
Known Potential Benefits............................................................................................13
2.3.3
Assessment of Potential Risks and Benefits................................................................14
3
OBJECTIVES AND ENDPOINTS.......................................................................................14
4
STUDY DESIGN ..................................................................................................................15
4.1
Overall design..............................................................................................................15
5
STUDY POPULATION........................................................................................................18
5.1
Inclusion Criteria.........................................................................................................18
5.2
Exclusion Criteria........................................................................................................18
5.2.1
Exclusion of Special Populations................................................................................19
5.3
Inclusion of Vulnerable Participants ...........................................................................19
5.4
Inclusion of Pregnant Women, Fetuses, or Neonates..................................................19
5.5
Lifestyle Considerations..............................................................................................19
5.6
Screen Failures ............................................................................................................19
5.7
Strategies for Recruitment and Retention ...................................................................20
5.7.1
Costs ............................................................................................................................20
5.7.2
Compensation..............................................................................................................20
6
PARTICIPANT DISCONTINUATION/WITHDRAWAL ..................................................21
6.1
Participant discontinuation/withdrawal from the study...............................................21
6.2
Lost to follow-up.........................................................................................................21
7
STUDY ASSESSMENTS AND PROCEDURES.................................................................21
7.1
Screening procedures ..................................................................................................21
7.1.1
Screening activities performed prior to obtaining informed consent..........................21

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7.1.2
Screening activities performed after obtaining informed consent...............................22
7.2
Clinical Evaluations ....................................................................................................22
7.3
Biospecimen Evaluations ............................................................................................23
7.3.1
Samples for Genetic/Genomic Analysis......................................................................23
7.4
Plan for the Return of Results .....................................................................................23
8
STATISTICAL CONSIDERATIONS ..................................................................................23
8.1
Study Hypotheses........................................................................................................23
8.2
Patient Populations for Analysis .................................................................................24
8.3
Sample Size Justification.............................................................................................24
8.4
Statistical Analysis ......................................................................................................27
8.4.1
Analysis of the Primary Endpoint ...............................................................................27
8.4.2
Analysis of the Secondary Endpoints..........................................................................27
9
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................28
9.1
Informed Consent Process...........................................................................................28
9.1.1
Consent/Assent Procedures and Documentation.........................................................28
9.1.2
Considerations for Consent of NIH Staff....................................................................29
9.1.3
Consent for minors when they reach the age of majority............................................29
9.1.4
Consent of Subjects who are/become Decisionally Impaired.....................................30
9.2
Study Discontinuation and Closure.............................................................................30
9.3
Confidentiality and Privacy.........................................................................................30
9.4
Future Use of Stored Specimens and Data..................................................................31
9.5
Safety Oversight..........................................................................................................31
9.6
Clinical Monitoring .....................................................................................................31
9.7
Quality Assurance and Quality Control ......................................................................32
9.8
Data Handling and Record Keeping............................................................................32
9.8.1
Data Collection and Management Responsibilities.....................................................32
9.8.2
Study Records Retention.............................................................................................32
9.9
Unanticipated Problems ..............................................................................................33
9.9.1
Definition of Unanticipated Problems (UP)................................................................33
9.9.2
Unanticipated Problem Reporting...............................................................................33
9.10
Protocol Deviations and Non-Compliance..................................................................33
9.10.1
NIH Definition of Protocol Deviation.........................................................................33

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9.11
Reporting to the NIAID Clinical Director...................................................................33
9.12
Publication and Data Sharing Policy...........................................................................34
9.12.1
Human Data Sharing Plan ...........................................................................................34
9.12.2
Genomic Data Sharing Plan ........................................................................................34
9.13
Conflict of Interest Policy ...........................................................................................34
ABBREVIATIONS .......................................................................................................................34
REFERENCES ..............................................................................................................................37

Abbreviated Title: COVID vaccine immune response
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STATEMENT OF COMPLIANCE
The protocol will be carried out in accordance with International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
NIH-funded investigators and study site staff who are responsible for the conduct, management, 
or oversight of NIH-funded studies have completed Human Subjects Protection and ICH GCP 
Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. In 
addition, all changes to the consent form will be IRB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent 
using a previously approved consent form.

Abbreviated Title: COVID vaccine immune response
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1
PROTOCOL SUMMARY
1.1
Synopsis
Title:
Analysis of the immune response to COVID-19 vaccination and 
outcomes in individuals with and without immune deficiencies 
and dysregulations
Study Description:
This prospective cohort study will assess the pre- and post-
vaccination immune responses in individuals with select 
immunodeficiencies and immune dysregulations compared to 
healthy volunteers who receive a coronavirus disease 2019 
(COVID-19) vaccine, as well as any adverse events (AEs) 
experienced after vaccination. All required study visits for this 
protocol may be conducted remotely; in-person visits at the NIH 
are optional. Subjects who have not yet been vaccinated will 
undergo baseline blood sampling using finger stick 
microsampler kits and/or venous blood draw within 7 days prior 
to receiving the vaccine. Additional samples will be requested 
from participants approximately 14-21 days   after dose 1 and  
21-28 days after dose 2 (if applicable). Optional samples may be 
collected at 6, 12, and 24 months post-vaccination. If 
subsequent booster doses are received while a participant is still 
on study, blood samples will again be requested approximately 
28 days after each booster dose, through the 5th Covid-19 
vaccine dose received, and then participants may proceed with 
the optional 6-, 12-, and 24-month follow-up sample collection. 
Participants who are able to attend in-person visits at NIH will 
have optional on-site blood draws 1 and 3 days after doses 1 and 
2 (as applicable). Research evaluations will include baseline 
severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-
2) antibody titers to the spike (S), nucleocapsid (N), and 
receptor binding domain (RBD) proteins, to assess pre-
vaccination SARS-CoV-2 exposure and evaluate responses to 
vaccination. Additional immune markers of interest may include 
presence of autoantibodies, transcriptomic profiling, T-cell 
receptor (TCR) repertoire, among others. Participants who only 
submit finger stick home microsampler kits at the timepoints 
listed above will be evaluated for SARS-CoV-2 antibody titers 
and autoantibodies only. All subjects will be asked at baseline 
about prior COVID-19 diagnosis, symptoms, and severity, and 
will be asked additional questions at follow-up timepoints 
(including after additional booster doses) about vaccine AEs 
using standardized questionnaires.

Abbreviated Title: COVID vaccine immune response
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Primary Objective:
To characterize the immune response to COVID-19 vaccination 
among immunodeficient and immune dysregulated individuals 
compared to healthy volunteers.
Secondary Objectives:

To characterize the COVID-19 vaccine-associated AEs 
among immunodeficient and immune dysregulated 
individuals compared to healthy volunteers.
Exploratory Objectives:

Assess the relationship between prior SARS-CoV-2 infection 
and vaccine-induced immune response.

To characterize pre-vaccine COVID-19 disease prevalence 
and severity among immunodeficient and immune 
dysregulated individuals.

To assess induction, strength, and durability of T- and B-cell-
specific immune responses to SARS-CoV-2 (as measured by 
frequency and diversity of SARS-CoV-2 specific T and B 
cell clonotypes and titers of specific antibody responses), and 
their correlation to the underlying immune 
deficiency/dysregulation.

To characterize autoantibodies present in immunodeficient 
and immune dysregulated individuals before and after 
COVID-19 vaccination.

To assess the incidence of post-vaccination breakthrough 
SARS-CoV-2 infection and to determine the SARS-CoV-2 
virus genomic sequence in such cases.
Primary Endpoint:
Change in S and RBD immunoglobulin G (IgG) antibody titer 
from baseline to 14-21 days or 21-28 days (depending on 
vaccine manufacturer and platform) after vaccine dose 1, and 
21-28 days after dose 2 and any subsequent doses (depending 
on vaccine manufacturer and platform).
Secondary Endpoints:

Incidence of vaccine-associated AEs experienced by 
immunodeficient individuals compared to healthy volunteers.
Exploratory Endpoints:

Characterization of post-vaccine immune response and AEs 
in patients with antibody evidence of prior SARS-CoV-2 
infection

Pre- and post-vaccination incidence of COVID-19-associated 
symptoms experienced in individuals with immune 
deficiency/dysregulation who are positive for SARS-CoV-2 
by serology or diagnostic polymerase chain reaction (PCR).

Characterize how various forms of immune deficiency or 
dysregulation impact generation, strength, and durability of 
T- and B-cell responses. 

Abbreviated Title: COVID vaccine immune response
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
Incidence of autoantibodies pre- and post-COVID-19 
vaccination comparing individuals with immune 
deficiency/dysregulation to healthy volunteers.

Incidence and genetic sequence of post-vaccination SARS-
CoV-2 infection as reported by patient and confirmed by 
PCR and sequencing.
Sample Size:
N=500 (n=400 with immune deficiency/dysregulation, n=100 
healthy volunteers)
Accrual Ceiling:
N=600
Study Population:
We will enroll individuals 3 years of age and older who are 
receiving COVID-19 vaccination outside of this study. Affected 
study participants must have evidence of a primary or secondary 
immune deficiency or dysregulation as documented on another 
NIAID protocol or by an outside physician. Control participants 
will be healthy volunteers, and may include unaffected relatives 
of immunodeficient/dysregulated participants.
Description of 
Sites/Facilities Enrolling 
Participants:
This is a single-site study being conducted at the NIH Clinical 
Center (CC) via in-person and remote visits. Subjects may be 
recruited from existing NIH protocols. They may also be 
referred from community practitioners who see this population. 
Healthy volunteers may also be recruited through the NIH 
Clinical Research Volunteer Program, the Office of Patient 
Recruitment, MMG Patient Recruitment, ResearchMatch, or 
BuildClinical. Individuals may be enrolled in person or 
remotely.
Study Duration:
4 years
Participant Duration:
Up to 24 months from participant’s last vaccine dose. This may 
be extended for participants who receive additional booster 
doses and agree to additional extension visits, up to 2 years after 
the booster vaccination, through the 5th dose only.

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1.2
Schedule of Activities
Study Day (window)
Screening 
and 
Baseline*
Vaccine dose 1 
Follow-up
Vaccine dose 2
Follow-up‡
Optional Follow-
up†
Evaluation
-7 to 0
1 day after 
vaccination§
3 days after 
vaccination§
14-21 OR 21-
28 days after 
vaccination**
1 day after 
vaccination§
3 days after 
vaccination§
21-28 days 
after 
vaccination**
6, 12, and 24, 
months (±2 weeks) 
after last 
vaccination
Informed consent
X
Clinical Procedures and Evaluations
COVID-19 history and symptom 
questionnaire
X
Baseline medical history and 
screening questionnaire
X
Changes in medical history 
questionnaire
X
X
X
Electronic AE questionnaire^
X
X
Behavioral questionnaire
X
Clinical Laboratory Evaluations^^
Blood Volume (mL)
CBC with differential 
3 mL
4 mL
4 mL
3 mL
4 mL
4 mL
3 mL
TBNK lymphocyte phenotyping/
flow/cytek
[X]
[X]
[X]
[X]

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Research Laboratory 
Evaluations^^
Blood Volume (mL)
Mitra microsampler¶

SARS-CoV-2 antibody (S, 
RBD, N – IgG, IgM, IgA) 

Autoantibodies
0.8 mL
0.8 mL
0.8 mL
0.8 mL
Serum (red cap) ††

Neutralizing SARS-CoV-2 
antibodies
5 mL
5 mL
5 mL
5 mL
5 mL
5 mL
5 mL
5 mL
Plasma isolation (EDTA purple 
cap) ¶

DNA isolation (for high 
throughput sequencing 
of TCR/BCR repertoire 
and for genetic studies)
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
PAXgene tube††

Whole blood RNA
2.5 mL
2.5 mL
2.5 mL
2.5 mL
2.5 mL
2.5 mL
2.5 mL
2.5 mL
PBMC isolation 
(sodium heparin green top OR 
EDTA purple cap) ††

Lymphocyte/plasmablast

Functional T cells
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
10 mL
Saliva‡‡

SARS-CoV-2 PCR and 
sequencing
Bi-weekly through 6 months
Daily Blood Volume 
31.3 mL
31.5 mL
31.5 mL
31.3 mL
31.5 mL
31.5 mL
31.3 mL
31.3 mL
Cumulative Blood Volume
31.3 mL
62.8 mL
94.3 mL
125.6 mL
157.1 mL
188.6 mL
219.9 mL
251.2 mL (6 mos.)
282.5 mL (12 mos.)
313.8 mL (24 mos.)
[X] = will be performed with portion of sample collected for CBC with differential and does not require additional volume.

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Abbreviations: AE, adverse event; BCR, B cell receptor; CBC, complete blood count; COVID-19, coronavirus disease 2019; DNA, deoxyribonucleic acid; EDTA, 
ethylenediaminetetraacetic acid; Ig, immunoglobulin; PBMC, peripheral blood mononuclear cell; N, nucleocapsid; RBD, receptor binding domain; RNA, ribonucleic 
acid; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TBNK, T, B, and natural killer (cells); TCR, T cell receptor; NP, nasopharyngeal; OP, 
oropharyngeal; PCR, polymerase chain reaction.
*Baseline sampling and questionnaire can happen on the day of vaccination as long as it is prior to receiving the dose. Participants may enroll after vaccination 
was already performed. If these individuals do not have current plans for an additional booster dose, previous timepoint samples will not be obtained and they 
will proceed with the next relevant sampling timepoint. In this situation, if stored blood samples from studies in which subjects are concurrently enrolled are 
available, they will be used. If stored samples are not available, these samples will be considered waived. If these individuals plan to receive an additional booster 
vaccination(s), they will be enrolled prior to the booster dose and follow the normal schedule, including a baseline draw prior to the booster.
**The exact timing of these visits will depend upon vaccine manufacturer and platform (as detailed in the Manual of Procedures) but will fall within the ranges 
indicated. For subjects who decline participation in the optional long-term follow-up visits, study completion will end after the dose 1 or 2 follow-up visit(s), 
depending on whether the subject received a 1-dose or 2-dose vaccine. Each time a participant receives an additional booster dose while they are still on study, a 
21-28–day visit will be performed, and optional long-term follow-up visits will be offered. Samples will be requested from participants as scheduled after each 
vaccination and booster (+/- 7 days) however samples received outside of the requested windows are acceptable and will be analyzed at the discretion of the PI.
‡ Not all vaccines require a second dose and therefore these follow-up timepoints will be not applicable for participants receiving those vaccines.
^AE questionnaire will be administered after any additional booster dose.
^^Due to the ongoing pandemic, venous blood draws may be conducted at the NIH or at off-site facilities (e.g., subjects’ private physicians, Quest laboratories). 
Subjects will be provided microsampler kits for at-home fingerstick sample collection. Venous blood draw will be waived for participants who are unable to obtain 
one at any given timepoint. Microsamples will not be collected at on-site visits, as the small volume needed can be taken from another tube.
††May not be drawn at every visit, per PI discretion based on the participant’s underlying immunodeficiency and study timepoint.
†If the subject opts in for the optional follow-up, then the final study visit will be the last visit that the participant chooses to have.
‡‡Participants will be sent optional saliva collection kits to return to the NIH bi-weekly for PCR and genetic sequencing of the virus. Participants whose samples 
are PCR positive will be asked to submit an additional COVID-19 symptom questionnaire and will be referred for care as needed. Each time a participant receives 
an additional booster dose while they are still on study, they may participate in optional bi-weekly saliva collections for an additional 6-month period.
§Optional additional visits for participants having specimens drawn at NIH only.
¶Only 1 sample type is required for off-site visits (either Mitra microsampler or plasma isolation). Plasma isolation is the preferred sample type.

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2
INTRODUCTION
2.1
Study Rationale
COVID-19 is caused by the novel SARS-CoV-2 and is associated with a hyper-inflammatory 
immune response which leads to severe and potentially life-threatening symptoms. Little is 
known about how and the extent to which COVID-19 presents in people with 
immunodeficiencies, but because of the known severity of the illness in the general population, 
vaccination against SARS-CoV-2 is critical. Understanding whether immunodeficient 
individuals produce an adequate immune response to the COVID-19 vaccine, as well as the 
number and type of AEs experienced in these people is necessary. 
2.2
Background 
The novel human coronavirus SARS-CoV-2 is transmitted primarily via respiratory particles and 
infects the respiratory tract via the receptor angiotensin-converting enzyme 2 (ACE2), which is 
highly expressed in the respiratory tract as well as on various epithelial tissues throughout the 
body.1 This receptor is also used by SARS-CoV, however SARS-CoV-2 has been found to bind 
to ACE2 with higher affinity than SARS-CoV, potentially increasing the infectivity seen with 
this virus.2 Since the beginning of the pandemic, and as of the writing of this protocol (a period 
of just over 1 year), SARS-CoV-2 has resulted in over 93 million confirmed infections globally, 
with over 2 million deaths.3 
The disease caused by this virus, COVID-19, has a wide range of clinical manifestations, from 
completely asymptomatic or mild disease, to severe illness requiring hospitalization, to long-
term sequelae (dubbed “long COVID”). Much of the pathology associated with COVID-19 is 
due to an aggressive immune response which can result in airway damage and acute respiratory 
distress syndrome (ARDS), among other pathologies.4 Unfortunately, there is currently little to 
no published data on the extent to which COVID-19 is experienced in individuals with immune 
deficiencies, especially those caused by inborn errors. It is important to know the incidence and 
clinical presentation of COVID-19 in these individuals to further our understanding of the role 
immune system activation plays in the development and progression of COVID-19. 
Additionally, with the recent emergency use authorizations (EUAs) granted by the US Food and 
Drug Administration (FDA) for two messenger RNA (mRNA)-based COVID-19 vaccines and 
subsequent approval of one of these, and with more vaccines in the pipeline, there is a need to 
understand the post-vaccine immune response in individuals after vaccination to ensure adequate 
induction and duration of protection. However, individuals with immunodeficiencies are 
typically excluded from vaccine trials measuring safety and immunogenicity, as was the case for 
the two COVID-19 vaccines currently authorized or approved. These groups of people must be 
evaluated to determine the efficacy and tolerability of vaccines, especially in light of concerning 
anaphylaxis episodes in a minority of people who were vaccinated against COVID-19.8
There is some literature regarding the immune response in individuals with inborn errors of 
immunity to vaccination, including inactivated or subcomponent vaccines like the influenza or 
Haemophilus influenzae type b vaccines, 5,6 and live-attenuated vaccines such as the measles-
mumps-rubella and varicella vaccines.7 Depending on the immunologic defect, vaccine 
immunogenicity can vary widely, leaving some immunodeficient individuals inadequately 
protected. For example, individuals with complement defects should produce B- and T-cells in 
levels relatively similar to that of healthy volunteers, while others, like those with Wiskott-

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Aldrich Syndrome, produce antibodies but a weak or absent T-cell response, and those with 
common variable immunodeficiency are only capable of producing T-cells without antibody. 
Because of this complexity, it is necessary to obtain a comprehensive understanding of the 
immunologic response to vaccines to better understand both the level of cellular and humoral 
protection against COVID-19 and also their estimated contribution to herd immunity. 
Unfortunately, individuals with immunodeficiencies are typically excluded from vaccine trials 
measuring immunogenicity and safety, as was the case for the COVID-19 vaccines currently 
authorized or approved for use in the United States. This creates a need to study AEs in 
immunodeficient people to determine the safety and tolerability of the COVID-19 vaccines, 
especially in light of concerning anaphylaxis episodes in a minority of people who were 
vaccinated against COVID-19,8 even though AEs in this group, specifically in individuals with 
impaired T-cell responses, are usually limited to live vaccines.
The aims of this study are to characterize the immune response to COVID-19 vaccination, the 
number and type of vaccine-associated AEs, and pre- and post-vaccine COVID-19 disease 
prevalence and severity in individuals with different types of immune defects. Potential diseases 
of interest that are followed at NIAID include those with neutrophil dysfunction such as chronic 
granulomatous disease and leukocyte adhesion deficiency; combined immune deficiencies such 
as DOCK8 (dedicator of cytokinesis 8) deficiency, leaky severe combined immunodeficiencies 
(SCIDs; e.g. RAG (recombination-activating gene) deficiency), X-linked immunodeficiency 
with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease (T-cell 
deficiency), STAT3 (signal transducer and activator of transcription 3) deficiency (Hyper IgE 
syndrome), defects of the PI3K (phosphoinositide 3-kinase) pathway; predominantly B 
lymphocyte defects such as X-linked agammaglobulinemia and common variable immune 
deficiency (CVID); defects of the Interleukin 12 (IL-12)/Interferon gamma (IFNg)/STAT1 
pathway; GATA2 deficiency; and those with immune activation such as neonatal-onset 
multisystem inflammatory disease (increased inflammasome activity) and autoimmune 
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).  
2.3
Risk/Benefit Assessment
2.3.1
Known Potential Risks
Blood collection: The risks of venous blood draws include pain, bruising, bleeding, fainting, 
and, rarely, infection. The risk of finger sticks include minor, transient pain.
Saliva collection: There are no risks associated with collection of saliva by expectoration.
Questionnaire completion: There is a minimal risk of loss of confidentiality of information 
collected in the questionnaires.
2.3.2
Known Potential Benefits
Participants will not receive direct benefit by participating in this study. The information learned 
in this study may improve the investigators’ understanding of the immune response and AE 
profile in individuals with immune deficiencies to COVID-19 vaccination, as well as the severity 
of COVID-19 in these individuals, which may have implications for individual care and further 
prevention of COVID-19. Such information may also be useful in designing more effective 
vaccines to prevent the spread of SARS-CoV-2, which may benefit others in the future.

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2.3.3
Assessment of Potential Risks and Benefits
COVID-19 is a global pandemic with few approved treatments and a wide range of disease 
presentations and outcomes. Better characterization of disease presentation and immune response 
in individuals with immune dysfunction, which is the objective of this study, may contribute to 
the knowledge of how the immune system responds to COVID-19 vaccination and how it 
contributes to COVID-19 disease development. While study participants will be exposed to some 
risk from blood draws, those risks are outweighed by the benefits to generalizable knowledge. 
3
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Justification for endpoints
Primary
To characterize the immune 
response to COVID-19 
vaccination among 
immunodeficient and immune 
dysregulated individuals 
compared to healthy 
volunteers.
Change in S and RBD IgG 
antibody titer from baseline to 
14-21 days or 21-28 days 
(depending on vaccine 
manufacturer and platform) 
after dose 1, and 21-28 days 
after dose 2 and any 
subsequent doses (depending 
on vaccine manufacturer and 
platform).
It is of interest to understand 
the changes in anti-SARS-
CoV-2 antibody levels 
induced by vaccination in 
individuals with immune 
deficiency/dysregulation.
Secondary
To characterize the COVID-19 
vaccine-associated AEs among 
immunodeficient and immune 
dysregulated individuals 
compared to healthy 
volunteers.
Incidence of vaccine-
associated AEs experienced 
by immunodeficient and 
immune dysregulated 
individuals compared to 
healthy volunteers.
It is of interest to understand 
the safety (by knowing the 
incidence of AEs) of 
COVID-19 vaccines in 
individuals with immune 
deficiency/dysregulation.
Exploratory
Assess the relationship 
between prior SARS-CoV-2 
infection and vaccine-induced 
immune response.
Characterization of post-
vaccine immune response and 
AEs in patients with antibody 
evidence of prior SARS-CoV-
2 infection compared to those 
without evidence of prior 
infection.
Because so many people 
have had SARS-CoV-2 
infections prior to 
vaccination, it is of interest 
to understand whether this 
affects the immune response 
to vaccination.

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To characterize pre-vaccine 
COVID-19 disease prevalence 
and severity among 
immunodeficient and immune 
dysregulated individuals.
Incidence of COVID-19-and 
associated symptoms 
experienced in individuals 
with immune 
deficiency/dysregulation who 
are positive for SARS-CoV-2 
by serology or diagnostic 
PCR.
It is of interest to understand 
the incidence and clinical 
presentation of COVID-19 
in individuals with immune 
deficiency/dysregulation, 
especially as COVID-19 is 
an inflammatory-mediated 
disease.
To assess induction, strength, 
and durability of T- and B-cell-
specific immune responses to 
SARS-CoV-2 (as measured by 
frequency and diversity of 
SARS-CoV-2 specific T and B 
cell clonotypes and titers of 
specific antibody responses), 
and their correlation to the 
underlying immune 
deficiency/dysregulation.
Characterization how various 
forms of immunodeficiency 
impact generation, strength, 
and durability of T- and B-
cell responses.
It is of interest to have a 
detailed understanding of 
the immune response to 
COVID-19 vaccination in 
individuals with immune 
deficiency/dysregulation.
To characterize autoantibodies 
present in immunodeficient 
and immune dysregulated 
individuals before and after 
COVID-19 vaccination.
Incidence of autoantibodies 
pre- and post-COVID-19 
vaccination comparing 
individuals with immune 
deficiency/dysregulation to 
healthy volunteers.
Autoantibodies are effectors 
of immune response and can 
influence the efficacy of 
vaccination.
To assess the incidence and 
genetic sequence of post-
vaccination SARS-CoV-2 
infection.
Incidence and genetic 
sequence of post-vaccination 
SARS-CoV-2 infection as 
reported by patient and 
confirmed by PCR and 
sequencing.
With the rise in genetic 
variants of SARS-CoV-2, it 
is important to understand 
how many vaccinated 
individuals are still 
susceptible to infection.
4
STUDY DESIGN
4.1
Overall design
This is a prospective, exploratory, cohort study to evaluate the baseline and post-vaccination 
immune responses in individuals with select immune deficiencies compared to healthy 
volunteers who receive a COVID-19 vaccine, as well as any AEs experienced after vaccinations. 
Due to the ongoing pandemic and limited availability of vaccines at the time of preparation of 
this protocol, participants will receive vaccine externally (i.e., via private physicians or 
community resources, and not as study interventions). Study visits may be conducted in person 
or remotely. If participants cannot attend in-person visits at the NIH CC, they can choose to have 
blood drawn at a primary care provider, academic hospital laboratory, or Quest Diagnostics, as 

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necessary, and will be sent sampling kits containing all tubes and instructions for the drawing 
facility. All participants will also be provided with microsampler kits and mailing supplies to 
collect and send in fingerstick samples if they are unable to obtain venous blood samples at an 
off-site facility. Participants will be asked to provide samples at baseline (collected within 7 days 
prior to receiving the vaccine), 14-28 days (depending on vaccine manufacturer and platform) 
after dose 1 and 21-28 days after dose 2 (if applicable). Samples will be requested from 
participants as scheduled after each vaccination (+/- 7 days) however samples received outside of 
the requested windows are acceptable and will be analyzed at the discretion of the PI.
Participants may enroll after vaccination was already performed. If these individuals do not have 
current plans for an additional booster dose, previous timepoint samples will not be obtained and 
they will proceed with the next relevant sampling timepoint. In this situation, if stored blood 
samples from studies in which subjects are concurrently enrolled are available, they will be used, 
otherwise they will be waived. If these individuals plan to receive an additional booster 
vaccination(s), they will be enrolled prior to the booster dose and follow the normal schedule, 
including a baseline draw prior to the booster.
Participants who are able to come to the NIH will have the additional option to provide blood 
samples at days 1 and 3 after each vaccination in order to capture immediate vaccine-induced 
perturbations of immune responses. Samples will be used to study short-term immunological 
effects of immunization and boosting. If additional booster doses are received, participants will 
be asked to submit optional blood samples 21-28 days after the booster vaccination(s), through 
the 5th dose of a COVID-19 vaccine.  Samples received outside of that window samples received 
outside of the requested windows are acceptable and will be analyzed at the discretion of the PI.  
Additional optional blood samples may be provided at approximately 6, 12, and 24 months after 
the final vaccination to assess long-term immunological persistence of vaccine-derived 
antibodies and T-cell responses. Research evaluations on these samples will include baseline and 
post-vaccine autoantibody levels as well as SARS-CoV-2 antibody titers to the S, N, and RBD 
proteins. Serology has been validated across fresh serum and dried blood samples collected using 
microsamplers (see Figure below)8. Venous blood draw may be waived if a participant is unable 
to obtain it at any given timepoint.

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Figure 1. Quantification of antibody concentration utilizing 4PL sigmoidal model of recombinant 
antibody spiked into seronegative blood. A) Anti-RBD recombinant human antibody (IgG and IgM) was 
added to whole blood from two seronegative donors, then absorbed to microsamplers and remaining blood was 
spun down to isolate serum and analyzed on full spike ectodomain trimer (spike) or receptor-binding domain 
(RBD) ELISA. Data are mean ± SEM, n = 3, red = microsampler eluate, gray = matched serum. B) Direct 
comparison of absorbance of range of recombinant antibody concentration in serum (y axis) versus 
microsampler (x axis) blood samples. C) Sigmoidal four-parameter logistic (4PL) curve fitting to recombinant 
antibody dilution series, 95% confidence intervals shown shaded around fit curve, n = 12 replicates per data 
point, red = Spike IgG, orange = RBD IgG, blue = Spike IgM, purple = RBD IgM. D) Quantification of IgG 
levels in a sample high-incidence population. E) Upper limit of quantification at 1:400 dilution of serum into 
ELISA (1:10 dilution of microsampler eluate), n =68. From ref 8
Additional research evaluations include analysis of the nature, diversity, and frequency of SARS-
CoV-2 specific T- and B-cell receptor clonotypes. These evaluations will be used to assess pre-
vaccination SARS-CoV-2 exposure and expected response to vaccination. Additional research 
evaluations may include virus neutralization assays to assess antibody functional response, flow 
cytometry, and transcriptome and genetic analyses. Comparisons of the immune response will be 
made among immunodeficiency/dysregulation subtypes and against healthy controls. This will 
allow characterization of the differences in post-vaccination immune responses and AE 
presentation.

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Subjects will be asked at baseline about prior COVID-19 diagnosis, symptoms, and severity 
using standardized questionnaires. This will allow us to characterize the different manifestations 
of COVID-19, potentially including a lack of hyper-inflammatory symptoms associated with 
severe disease due to dysregulation of the immune response that will be present in many of the 
study participants. To conduct active screening for post-vaccination COVID-19 infections, 
participants will be sent optional saliva collection kits to return to the NIH bi-weekly for 6 
months, for PCR and genetic sequencing of the virus. Participants whose samples are PCR 
positive will be asked to submit an additional COVID-19 symptom questionnaire and will be 
referred for care as needed. Each time a participant receives an additional booster dose while 
they are still on study (through the 5th COVID-19 vaccine a person receives), they may 
participate in optional bi-weekly saliva collections for an additional 6-month period. Since this is 
optional, saliva samples received outside of the requested windows are acceptable and will be 
analyzed at the discretion of the PI.   At follow-up timepoints, participants will be asked about all 
possible vaccine-related AEs, which will be particularly important given recent information 
about possible vaccine-induced anaphylaxis. 
5
STUDY POPULATION
5.1
Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet the following criteria:
1. Aged 3 years and older.
2. Must be eligible to receive (based on official FDA authorization or approval) and scheduled 
to receive or have already received a COVID-19 vaccine outside of this study.
3. Must meet the definition of affected participant or control participant:
a.
Affected participants must have evidence of a primary or secondary immune 
deficiency or dysregulation under another NIAID protocol or as documented by an 
outside physician.
b. Control participants are healthy volunteers that do not have evidence of a primary or 
secondary immune deficiency or dysregulation and may include unaffected relatives of 
affected participants.
4. Ability to provide informed consent.
5. Willing to have blood samples stored for future research.
6. Able to proficiently speak, read, and write English.
5.2
Exclusion Criteria
Individuals meeting any of the following criteria will be excluded from study participation:
1. Receipt of any other vaccine within 14 days prior to screening.
2. Planned non-COVID-19 vaccination within 28 days after COVID-19 vaccination(s).
3. Any condition that, in the opinion of the investigator, contraindicates participation in this 
study (e.g. specific autoinflammatory diseases, interferonopathies). 
4. Self-reported history of HIV.

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5.2.1
Exclusion of Special Populations 
Children: Children <3 years old will be excluded from enrollment in this study because this 
population is not typically seen at NIAID.
Non-English speakers: Because this study will use questionnaires that are not validated in 
languages other than English, individuals who are not fluent in English will be excluded from 
enrollment.
5.3
Inclusion of Vulnerable Participants
Children: As the immune deficiencies and dysregulations being studied under this protocol 
affect all age ranges, information gathered from all eligible children (both affected and control 
participants) will be important for providing a full understanding of any potential differential 
effects across age ranges. Children will only be enrolled if there is FDA authorization or 
approval for use of a COVID-19 vaccine in that age group.
Adult subjects who lack capacity to consent to research participation: Individuals who are 
unable to provide initial informed consent are excluded from the study. If participants lose the 
ability to provide ongoing consent subsequent to giving initial consent, they will be withdrawn 
from the study. 
NIH staff or family members of study team members: NIH staff and family members of study 
team members may be enrolled in this study if they meet the study entry criteria. Neither 
participation nor refusal to participate in the research will have an effect, either beneficial or 
adverse, on an individual’s employment or position at NIH.
Every effort will be made to protect subject information, but such information may be available 
in medical records and may be available to authorized users outside of the study team in both an 
identifiable and unidentifiable manner.
The NIH investigator will provide and request that the NIH staff member review the Frequently 
Asked Questions (FAQs) for Staff Who are Considering Participation in NIH Research and the 
Leave Policy for NIH Employees Participating in NIH Medical Research Studies (NIH Policy 
Manual 2300-630-3). Please see section 9.1.2 for consent of staff members.
5.4
Inclusion of Pregnant Women, Fetuses, or Neonates
As accumulating data indicate that the vaccines are safe and effective in pregnant people, this 
protocol will allow the enrollment of this population to allow evaluation of the immune response 
to COVID-19 vaccines in pregnant people with immune disorders, which may differ from the 
response in non-pregnant people.
5.5
Lifestyle Considerations
Not applicable.
5.6
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. Individuals who do not meet the criteria for participation 
in this study (screen failure) may be rescreened if they turn 12 before the study enrollment closes 
and have not yet received a COVID-19 vaccination, if the participant’s time since non-COVID-

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19 vaccination has passed 14 days and they remain unvaccinated for COVID-19, or their medical 
status changes such that the PI feels exclusion is no longer necessary.
5.7
Strategies for Recruitment and Retention
Immunodeficient individuals will be recruited from NIAID protocols that evaluate primary or 
secondary immune deficiencies. Potential subjects will be identified by discussion between the 
study teams and review of medical and research records if necessary. They may also be referred 
from community practitioners who see this population.
Healthy adult volunteers will be recruited through the NIH Clinical Research Volunteer 
Program, the Office of Patient Recruitment, MMG Patient Recruitment, ResearchMatch, or 
BuildClinical. Volunteers will also be recruited from existing NIH protocols, including but not 
limited to protocol 18-I-0101 (“Sample Collection From Healthy Volunteers For Assay 
Optimization”), 93-I-0119 (“Detection and Characterization of Host Defense Defects”), 18-I-
0041 (“Investigating the Mechanistic Biology of Primary Immunodeficiency Disorders”), 11-I-
0187 (“Natural History of Individuals with Immune System Problems that Lead to Fungal 
Infections”), and 17-I-0122 (“NIAID Centralized Sequencing Protocol”). Healthy relatives of 
immunodeficient participants can be recruited for participation as controls if they meet 
enrollment criteria.
An IRB-approved recruitment email will be distributed to potential participants, and flyers with 
study team contact information will be posted throughout the CC and provided to community 
practitioners to share with potentially eligible patients. We may also conduct outreach activities 
with local groups involving patients with immune deficiencies (eg, support groups and patient 
advocacy groups). Interested individuals may also contact the study team directly via email.
A pre-screening phone call will be conducted with individuals who express interest, for an initial 
discussion of eligibility (including any past SARS-CoV-2 testing) and scheduling prior to the 
screening visit.
5.7.1
Costs
There will be no costs to participants for procedures performed at the NIH CC. Similarly, 
participants will not incur costs for blood drawn at Quest laboratories, as Quest will be paid 
directly through a contract set up for this purpose. Participants may incur costs of blood draws 
performed at off-site facilities other than Quest laboratories; in this case, they will be reimbursed 
up to $85 for each blood draw. 
5.7.2
Compensation
Compensation will be dependent on the sample collections and study visits that a subject 
participates in. Participants will be compensated maximum amounts as follows:
-
$10/off-site microsampler or $20/off-site venous blood x up to 6 timepoints
-
$50/on-site venous blood x up to 10 timepoints
-
$10/on time x up to 2 timepoints (for on-time completion of follow-up at 14-21 or 21-28 
days after each vaccination)
-
$10 bonus (for completing all sample collections)
-
$5/saliva x 13 timepoints

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Participants may receive a total maximum compensation of $595 for participating in all possible 
on-site sample collections and visits. If participants participate in additional visits following 
booster vaccination(s), they will be compensated for each additional visit/sample collection 
according to the amounts listed above. 
6
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
6.1
Participant discontinuation/withdrawal from the study
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons:

Refusal to submit blood samples for testing

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Screen failure
The reason for participant discontinuation or withdrawal from the study will be recorded.
6.2
Lost to follow-up
A participant will be considered lost to follow-up if they fail to provide required post-vaccine 
blood samples and are unable to be contacted by the study site staff. 
The following actions will be taken if a participant fails to return required study samples:

A study staff member will attempt to contact the participant and reschedule the missed 
sample within the allowable window if possible, counsel the participant on the 
importance of maintaining the assigned sample schedule and ascertain if the participant 
wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make a 
reasonable effort to regain contact with the participant (where possible, 3 telephone 
calls). These contact attempts should be documented in the participant’s medical record 
or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
All samples and data received prior to a subject dropping out or being lost to follow-up will be 
analyzed unless the participant explicitly requests their data not be included.
7
STUDY ASSESSMENTS AND PROCEDURES
The following study assessments and procedures will be performed according to the schedule 
provided in section 1.2.
7.1
Screening procedures
7.1.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in-person, or telephone communications with prospective subjects. 

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
Review of the NIH CC patient medical records (if applicable).
7.1.2
Screening activities performed after obtaining informed consent
After the subject signs the consent form, eligibility will be confirmed and the baseline study 
procedures will continue.
7.2
Clinical Evaluations
Medical and medication history: Subjects enrolled on a protocol at NIAID will have their 
clinical history extracted from the NIH Clinical Research Information System (CRIS) for 
complete review of medical and medication history, including review of vaccination history and 
SARS-CoV-2 testing and symptom history. The questionnaire (described below) will also elicit 
information about relevant medical history, including history of SARS-CoV-2 infection. Subjects 
not enrolled on another NIAID protocol will undergo standard medical and medication history 
review by questioning.
Venous blood draw: Blood will be collected by venipuncture for laboratory testing (section 1.2) 
and storage. If participants cannot be brought to the NIH CC due to the ongoing COVID-19 
pandemic, individuals can choose to have blood drawn at a primary care provider, academic 
hospital laboratory, Quest Diagnostics, or through collaboration with the Immune Deficiency 
Foundation, as necessary. Samples collected at clinics or at Quest may be labeled with a coded 
identifier, gender, and date of birth, as required by the local facility. The amount of blood drawn 
for research purposes in pediatric subjects will not exceed 5 mL/kg in a single day or 9.5 mL/kg 
over any eight-week period, in accordance with the CC Medical Administrative Series Policy 
M95-9 Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical Center. The 
amount of blood drawn from pregnant participants will not exceed 50 mL over any eight-week 
period.
Fingerstick blood collection: All participants will be provided with a microsampler kit and 
mailing supplies to collect an at-home blood sample by fingerstick and send it to the CC. The 
sample will be used for laboratory testing (section 1.2) and storage.
Saliva collection: All participants will be provided with saliva collection kits and mailing 
supplies to collect post-vaccination saliva samples to return to the CC. 
Electronic questionnaires: Five separate Research Electronic Data Capture system (REDCap) 
questionnaires will be completed electronically in REDCap by subjects and/or their 
parents/guardians throughout the study. A link to the questionnaires will be sent to the personal 
email address on file. The baseline questionnaire will capture medical history, and any COVID-
19 symptoms, severity, and treatment the participant may have experienced. The follow-up 
questionnaires will assess changes in health history or medications and AEs following study 
vaccination. An optional survey will ask participants about their beliefs and behaviors around 
COVID-19 vaccinations, and whether they have changed since before the primary vaccine series 
and/or booster doses. The questionnaires and their timing are listed below:
1. Baseline medical history and screening questionnaire (Baseline)
2. COVID-19 baseline/post-vaccine infection symptom questionnaire (Baseline and 
following COVID-19 infection)
3. Changes in medical history questionnaire (Following sample collection)
4. Post-vaccine adverse events questionnaire (Following vaccination)

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5. COVID-19 Attitudes and Behaviors Survey (Following primary series and/or booster)
AE assessment: Only AEs related to study procedures (blood draw, fingerstick, and saliva 
collection) will be followed. COVID-19 vaccines are not administered as study procedures under 
this protocol; therefore, while we are interested in collecting AEs related to vaccination in our 
study population, these are not considered study-related events and will not be followed as such. 
Subjects will be assessed for AEs at each study visit. Information on AEs related to the study 
procedures that develop within 2 days after the procedure will be collected by participant report 
and followed through resolution or until the site investigator judges that the event has stabilized 
and no additional follow-up is required.
7.3
Biospecimen Evaluations
Pre- and post-vaccination whole blood samples will be processed to isolate serum, peripheral 
blood mononuclear cells (PBMCs), RNA, and DNA. Specimens will be processed at the 
Neutrophil Monitoring Laboratory (NML), LCIM, and the Laboratory of Virology at the Rocky 
Mountain Laboratories at NIAID, the Department of Laboratory Medicine (DLM) at NIH, and 
the Section on Immunoengineering (IE) at the National Institute of Biomedical Imaging and 
Bioengineering (NIBIB). The saliva testing for SARS-CoV-2 using PCR will be performed in 
the DLM under an EUA.
Sample types, volumes, and laboratory evaluations are provided in section 1.2. For pediatric 
subjects, blood volume limitations may preclude execution of all the tests required. In such 
cases, the PI will prioritize which tests will be performed.
7.3.1
Samples for Genetic/Genomic Analysis
Targeted genetic analyses may include high throughput sequencing of T- and B-cell receptor 
repertoires, human leukocyte antigen (HLA) typing, and single nucleotide polymorphism (SNP) 
chips. This study will not involve genetic tests intended to discover disease-determining genes, 
but will only involve amplification of rearranged TCR immunoglobulin heavy chain (IGHC) 
gene segments. It is possible that the investigators might refer interested participants and their 
families to the Centralized Sequencing Initiative protocol (17-I-0122). If a participant chooses to 
co-enroll on this protocol and 17-I-0122, we will have access to the identified findings from 
whole genome/exome sequencing via the Genomic Research Information System platform for 
use in this study to confirm a known genetic mutation or update information about a participant’s 
immune status if an unknown but clinically significant mutation is discovered. The informed 
consent document will address the sharing of data between studies, and no additional samples 
outside of those required of each protocol will be obtained.
If a saliva sample is found to be positive for SARS-CoV-2, the virus will be isolated from the 
sample for genomic profiling. The viral genetic sequences will be deposited into GenBank, along 
with donor participant information that includes age category, sex, and whether the donor is 
immune compromised. No human genetic information will be shared in this process, as the goal 
is sequencing of the virus and any human data will be filtered out.
7.4
 Plan for the Return of Results
Analyses under this protocol may identify results or incidental findings that are relevant to the
health or medical care of subjects (either affected participants or healthy controls). Results of 
clinical laboratory assessments performed on this study (ie, CBC w/differential) will be returned 

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to participants, as will results of the SARS-CoV-2 PCR tests. All other laboratory assays, 
including the SARS-CoV-2 antibody tests, are for research only, and a result would only be 
returned if confirmatory testing in a laboratory certified by the Clinical Laboratory Improvement 
Amendments (CLIA) is available. If needed, the study team will contact the subject and request a 
sample for confirmatory testing or recommend other laboratories where they can go for testing. 
After confirmation, the principal investigator or designee will contact the subject to inform them 
of the finding and counsel them on the result. The study team may also provide consultation with 
a subject’s healthcare provider based on the result.
8
STATISTICAL CONSIDERATIONS
8.1
Study Hypotheses
This is an exploratory study to characterize the immune response and vaccine-associated AEs in 
individuals with a variety of immune disorders who receive COVID-19 vaccination, in addition 
to describing disease prevalence and severity among subjects previously infected with SARS-
CoV-2 and whether this affects vaccine immune response. We therefore hope to generate and 
test a number of hypotheses, including but not limited to:
1. Assessing whether and which of the immune correlates measured for the primary, 
secondary and exploratory endpoints change significantly after vaccination from baseline, 
comparing the response among various immune deficiency/dysregulation conditions and 
healthy volunteers (longitudinal change in immune response).
2. Assessing whether and which of the immune correlates measured for the primary, 
secondary, and exploratory end-points are significantly different among various immune 
disorder subgroups and healthy volunteers (cross-sectional immune response).
3. Assessing whether the dose 1 antibody response is correlated with the dose 2 antibody 
response among various immune disorder subgroups and healthy volunteers.
4. Assessing the incidence of vaccine-associated AEs among various immune disorder 
subgroups and healthy volunteers.
5. Assessing the prevalence and severity of COVID-19 symptoms among various immune 
disorder subgroups and healthy volunteers.
8.2
Patient Populations for Analysis
The numbers provided for each group are an estimated number to be enrolled for each immune 
deficiency/dysregulation sub-group: 
1. Combined immunodeficiencies (n=50)  
2. Predominantly antibody deficiencies (n=40) 
3. Disorders of immune regulation (n=40-60) 
4. Congenital defects of phagocyte number or function (n=40-60)
5. Defects of intrinsic and innate immunity (n=25-30) 
6. Autoinflammatory disorders (n=20) 
7. Complement deficiencies (n=5-10)
8. Bone marrow failure syndrome (n=5-10) 

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9.
Subjects with inborn errors of immunity who have received hematopoietic stem cell 
transplantation or gene therapy (n=20-30) 
10. Subjects with secondary immunodeficiencies, to include those who have received 
hematopoietic stem cell transplantation or gene therapy (n=30-50) 
11. Healthy volunteers (n=120 [2:1 healthy to largest immunodeficiency group])
Healthy volunteers will be enrolled to be representative of binned-age groups and sex 
distribution of the immune deficient study population. Age bins will be (3-5], (5-12], (12-16], 
(16-25], (25-45], (45-65], and 65+.  
8.3
Sample Size Justification
The sample sizes proposed in this protocol were set based on the primary objectives of this 
study, which are to characterize the immune response to COVID-19 vaccination as measured by 
enzyme-linked immunosorbent assay (ELISA) anti-S-2P and anti-RBD IgG titers at 
approximately 3-4 weeks following each vaccination and in long-term follow-up. The following 
sample size determination is based on results of the phase 1 dose escalation study of the Moderna 
mRNA vaccine.9 Fifteen participants received a dose of 100 ug of vaccine, and the means and 
standard errors of the log10 antibody titers at the nearest timepoints to the times at which we 
propose to collect samples are summarized in the table below.  
Target
Study day
Mean log10-titer (Standard error)
S-2P
29
5.04 (0.28)
56
5.89 (0.19)
RBD
29
4.97 (0.38)
56
5.57 (0.27)
We assume that healthy volunteers in the upcoming trial have similar immune responses to those 
reported in the Moderna Phase I trial, and that immune deficiency/dysregulation shifts the log10-
titer distribution among individuals with immune deficiency/dysregulation but does not change 
the standard deviation of the responses. We also suppose that healthy volunteers and immune 
deficient/dysregulated individuals have similar baseline distributions, which is reasonable as 
both groups are naïve at baseline. As we were unable to obtain specific estimates of antibody 
responses to the Pfizer vaccine that could be used to estimate the sample size for this study, we 
are left to assume that responses to the Pfizer vaccine are similar to the Moderna vaccine.  
Using the estimates from the Moderna study, we calculate, and plot below, the smallest 
differences in mean log-titers that we would be able to detect using a two-sided two-sample t-test 
with either 80% or 90% power while controlling the type I error rate at α=0.05 as a function of 
sample size. We also display the widths of 95% confidence intervals for a difference in mean 
log-titers. As an example, a sample size of 20 immune deficient/dysregulated individuals and 20 

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healthy volunteers should be sufficient to detect a true difference in mean anti-RBD log-titer of 
0.4 at day 29 with 90% power, or a true difference of 0.35 with 80% power, while controlling the 
type I error rate at α=0.05. We would also expect the width of a 95% confidence interval for the 
difference in mean log- titers to be approximately 0.35 units. It is also useful to consider the 
minimum detectable standardized effect size, also shown below, as antibody responses to other 
vaccines may differ from responses to the Moderna vaccine. Continuing with our example, a 
sample size of 20 participants per arm would be sufficient to detect a 1.05 standard deviation 
difference with 90% power using a two-sided two-sample t-test while controlling the type I error 
rate at α=0.05. 
 
Figure 2. Sample size estimates for primary endpoint. A) Lines represent number of participations required 
in each group and the smallest detectable differences in mean log-titers using a two-sided two-sample t-test 
with either 80% or 90% power while controlling the type I error rate at α=0.05. B) Widths of 95% confidence 
intervals for a difference in mean log-titers. C) Number of participants required in each group to detect 
differences in standardized antibody effect size using a two-sided two-sample t-test with either 80% or 90% 
power while controlling the type I error rate at α=0.05.
While it is hard to generalize antibody responses across the many immune conditions in this 
study given the phenotypic heterogeneity between and within diseases, patients in the following 
groups would generally be expected to have poor antibody responses to vaccination: 

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
Defects of cellular and humoral immunity (n=20) (e.g. RAG, DOCK8, adenosine 
deaminase [ADA], nuclear factor-kappa B essential modulator [NEMO])

Predominantly antibody deficiencies (n=40) (e.g. X-linked agammaglobulinemia [XLA], 
CVID, activated PI3K delta syndrome 1/2 [APDS1/2], Ras-related C3 botulinum toxin 
substrate 2 [RAC2], caspase recruitment domain-containing protein 11 [CARD11], gain-
of-function [GOF])
Hence, we expect to have adequate power to resolve differences in mean antibody responses 
between patients in these immune deficiency groups and healthy controls. Vaccine responses 
from other disease groups can be variable,10–12 but most would be expected to respond to 
vaccination. We would like to be able to detect at least a one standard deviation difference in 
mean log-titer for those immune deficient/dysregulated groups where we do not have prior 
information to inform our expectations about the magnitude of the difference vis-a-vis healthy 
controls. Therefore, the proposed sample sizes should suffice. 
8.4
Statistical Analysis
Multiple sets of analyses will be done to characterize the immune response in each of the groups 
of participants with immune deficiency/dysregulation:
1. Within-group: Estimate the vaccine response at each timepoint relative to baseline within 
an immune deficiency/dysregulation group.
2. Longitudinal between-groups: Compare the vaccine response profiles of different groups 
at sampling times.
3. Adjusted analyses controlling for SARS-CoV-2 infection.
For symptoms: focus will be on estimation of the proportion of symptoms that are present or 
absent in these individuals. Variables will be presented by frequency distribution (e.g. frequency 
counts, percentages, and 95% confidence intervals). In addition, this study will be used as the 
basis for hypothesis generation to explore disease manifestations in individuals with different 
types of immune deficiency/dysregulation if the number of enrolled individuals allow.
8.4.1
Analysis of the Primary Endpoint
Log transformed antibody measurements will be modeled within a mixed model repeated 
measures (MMRM) framework, which is a longitudinal mixed model with fixed effects for 
(categorical) timepoint, immune deficiency/dysregulation, and the interactions of timepoint with 
immune deficiency/dysregulation and timepoint with baseline measurement, along with possible 
adjustment other covariates, such as age and sex. In this framework, we also include correlated 
subject-level random effects for each timepoint to account for clustered data. This also allows us 
to estimate the correlation between antibody responses to the first and second doses of vaccine. 
MMRM models are an appropriate tool for assessing response profiles in longitudinal studies 
where missing data is expected and it is appropriate to assume that data are missing at random 
conditional on observable covariates.13,14 The previous sample size justifications based on two-
sample t-tests are likely to be slightly conservative as we expect the MMRM framework to make 
more efficient use of the data. Models will either be fit using the `nlme` package in R, or, if a 
Bayesian formulation is deemed to be preferable for the purpose of incorporating prior 
information, can be fit using the ‘brms’ and `rstanarm` packages. 

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8.4.2
Analysis of the Secondary Endpoints
We will calculate descriptive summaries, stratified by immune deficiency/dysregulation group, 
for incidence of vaccine-associated AEs listed in the Post-Vaccine Adverse Events questionnaire. 
Incidence of AEs among immune deficient/dysregulated patients will be compared with 
incidence among healthy volunteers using regression analyses, possibly adjusting for covariates, 
such as age and sex, as deemed appropriate. 
9
REGULATORY AND OPERATIONAL CONSIDERATIONS
9.1
Informed Consent Process
9.1.1
Consent/Assent Procedures and Documentation
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research subject. It is an ongoing conversation between 
the human research participant and the researchers that begins before consent is given and 
continues until the end of the participant’s involvement in the research. Discussions about the 
research will provide essential information about the study and include purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Coercion and undue influence will be 
minimized by informing participants that their decision to join the study will not affect any 
medical care they are currently receiving, or their eligibility to participate in other research 
studies at the NIH. Participants will be given the opportunity to ask questions and have them 
answered.
Informed consent will be obtained via telephone or video conference for participants unable to 
come to the NIH CC in person or will be obtained in person at the NIH by a study team member 
authorized to obtain consent. Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (eg, clinic consult room). When consent is conducted remotely, the participant will 
be informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. The participants will sign the informed consent document prior to 
undergoing any research procedures. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The researcher will document the signing of the consent form in the 
participant’s study record. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
Assent Process: Minor participants will be included in all discussions about the study, and age-
appropriate language will be used to describe the procedures and tests involved in this study, 
along with the risks, discomforts and benefits of participation. Minor participants aged 16 or 17 
years will provide assent by signing the informed consent document. Those aged 7 to 15 years 
will provide assent by signing the assent document. Children under the age of 7 will not be 
required to provide assent as they typically do not have the ability to fully understand the nature 
of research. The parent(s)/legal guardian(s) will provide permission for the minor participant to 
participate by signing the consent form. The consent/assent process will be documented in the 
child’s medical record, including the assessment of the child’s ability to provide written assent as 
applicable.

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Remote Consent Process: The informed consent/assent document(s) will be sent via secure 
email or file transfer to the potential participant and their parents (as applicable) prior to the 
consent discussion. An explanation of the study will be provided over the telephone or video 
conference (e.g., Microsoft Teams) after the participant and parents (as applicable) has had the 
opportunity to read the consent/assent form(s). During the consent process, participants and 
investigators will view individual copies of the approved consent document on screens at their 
respective locations. The participant and parents (as applicable) can print the form(s) to sign and 
date in ink, or they can sign and date digitally with a finger, stylus, or mouse in iMed or Adobe. 
The participant will return the signed and dated consent/assent form(s) to the consenting 
investigator, who will sign and date it with the date it was received. The consent/assent form(s) 
can either be printed and signed and dated in ink, or signed and dated digitally as described 
above. A fully executed copy will be sent to the participant for their records.
The informed consent process will be documented on a progress note by the consenting 
investigator. The investigator will confirm that written consent has been obtained prior to 
initiating any study interventions.
9.1.2
Considerations for Consent of NIH Staff
Consent for NIH staff will be obtained as detailed above and will comply with the requirements 
of NIH Human Research Protections Program (HRPP) Policy 404 Research Involving NIH Staff 
as Subjects.
Consent from NIH staff for whom this research is taking place within their own work unit or is 
conducted by any of their supervisors will, when possible, be obtained by an individual in a non-
supervisory relationship with that staff member. When consent of that staff member is 
conducted, a third party will be present to observe the consent process in order to minimize the 
risk of undue pressure on the staff member.
9.1.3
Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained.
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The research could not practicably be carried out without the waiver or alteration.
a.
Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 

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them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a.
Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies.  Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority.
The informed consent process will be documented in the medical record.
The investigator will confirm that, when required, written legally effective consent has been 
obtained prior to initiating any study interventions.
9.1.4
Consent of Subjects who are/become Decisionally Impaired
Not applicable. No such subjects will be enrolled.
9.2
Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the principal investigator. 
If the study is prematurely terminated or suspended, the principal investigator will promptly 
inform the study participants, IRB, and sponsor, as applicable, and will provide the reason(s) for 
the termination or suspension. Study participants will be informed of changes to study visit 
schedule, if applicable.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants.

Insufficient compliance to protocol requirements.

Data that are not sufficiently complete and/or evaluable.
In the case of a temporary suspension, the study may resume once concerns about safety, 
protocol compliance, and data quality are addressed, and satisfy the IRB.

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9.3
Confidentiality and Privacy
All records will be kept confidential to the extent provided by federal, state, and local law. 
Authorized representatives of the NIAID may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records. Records will be 
kept locked and data will be coded. Any personally identifiable information maintained for this 
study will be kept on restricted-access computers and networks. Personally identifiable 
information will only be shared with individuals authorized to receive it under this protocol. 
Individuals not authorized to receive personally identifiable information will be provided with 
coded information only, as needed. Clinical information will not be released without written 
permission of the participant, except as necessary for monitoring by the IRB, NIAID, and the 
Office for Human Research Protections (OHRP).
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the NIH. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants.
9.4
Future Use of Stored Specimens and Data
Coded specimens and data will be stored at the NIH indefinitely for future research after the 
study is complete. Human genetic testing may be performed. Plans for future use of specimens 
and data will be described in the informed consent document. Samples are stored in NML 
laboratories at the NIH campus in Frederick, MD or in the DLM, LCIM, or IE laboratories on the 
NIH main campus in Bethesda, MD located in secure buildings with limited access. Data will be 
kept in password-protected computers. Samples and data will be tracked using Biological 
Specimen Inventory (BSI) software and Clinical Research Information Management System of 
NIAID (CRIMSON). Only investigators or their designees will have access to the samples and 
data. 
Other investigators (at NIH and elsewhere) may wish to study these specimens and data. If the 
planned research falls within the category of “human subjects research” on the part of the 
investigators, NIH IRB review and approval will be obtained. This includes the investigators 
sending out coded and linked specimens or data and getting results that they can link back to 
their participants.
9.5
Safety Oversight
All data will be collected in a timely manner and reviewed by the principal investigator and/or a 
designee on a regular basis (at least weekly). Events meeting requirements for expedited 
reporting as described in HRPP Policy 801 will be submitted within the required timelines. 
The principal investigator will review all data on each subject to ensure safety and data accuracy. 
The principal investigator will personally conduct or supervise the investigation and provide 
appropriate delegation of responsibilities to other members of the research staff.

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9.6
Clinical Monitoring
Monitors under contract to the NIAID Office of Clinical Research Policy and Regulatory 
Oversight (OCRPRO) will visit the clinical research site to monitor several aspects of the study 
in accordance with the appropriate regulations and the approved protocol. Only pediatric subjects 
will be monitored and the objectives of a monitoring visit will be: 1) to verify the existence of 
signed informed consent documents and documentation of the consent process for each 
monitored pediatric subject; 2) to verify AEs and serious adverse events (SAEs), including the 
prompt reporting of all SAEs; 3) to compare applicable CRIMSON data abstracts with individual 
subjects’ records and source documents (subjects’ charts, laboratory analyses and test results, 
physicians’ progress notes, nurses’ notes, and any other relevant original subject information); 
and 4) to help ensure investigators are in compliance with the protocol. 
The investigator (and/or designee) will make study documents (eg, consent forms, CRIMSON 
data abstracts) and pertinent hospital or clinical records, including CRIMSON, readily available 
for inspection by the local IRB, the site monitors, and the NIAID staff for confirmation of the 
study data. 
A specific protocol monitoring plan will be discussed with the principal investigator and study 
staff prior to enrollment. The plan will outline the frequency of monitoring visits based on such 
factors as study enrollment, data collection status, and regulatory obligations.
9.7
Quality Assurance and Quality Control
To help ensure that NIH Office of Research Support and Compliance procedures and GCP are 
being carried out, a Clinical Trials Management designee within the OCRPRO Regulatory 
Compliance and Human Subjects Protection Program will conduct a study initiation visit before 
study enrollment begins. The purpose of this meeting is to review with the principal investigator 
and study team designees the roles and responsibilities concerning their commitment to adhere to 
the requirements of the protocol, especially in terms of NIH Office of Human Subjects Research 
Protections (OHSRP) reporting requirements for reportable events. In addition, the quality 
management and data management plan for the study will be reviewed.
9.8
Data Handling and Record Keeping
9.8.1
Data Collection and Management Responsibilities
Study data will be maintained in REDCap and CRIMSON and collected directly from 
participants during study visits and telephone calls or via REDCap online questionnaire or will 
be abstracted from participants’ medical records. Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary to confirm 
the data abstracted for this study. Data entry into REDCap and CRIMSON will be performed by 
authorized individuals. The investigator is responsible for assuring that the data collected are 
complete, accurate, and recorded in a timely manner. Study data, including cumulative subject 
accrual numbers, should be generated via the chosen data capture method and submitted to study 
oversight bodies as needed.

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9.8.2
Study Records Retention
Study documents will be retained in accordance with regulatory and institutional requirements, 
ICH GCP guidelines, and the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the principal investigator and sponsor, as applicable. 
Should the investigator wish to assign the study records to another party and/or move them to 
another location, the investigator will provide written notification of such intent to 
OCRPRO/NIAID with the name of the person who will accept responsibility for the transferred 
records and/or their new location. Relocation of research records will not proceed without 
written permission from OCRPRO/NIAID.
9.9
Unanticipated Problems
9.9.1
Definition of Unanticipated Problems (UP)
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and
•
Suggests that the research places participants or others (which may include research staff, 
family members or other individuals not directly participating in the research) at a greater 
risk of harm (including physical, psychological, economic, or social harm) than was 
previously known or expected.
9.9.2
Unanticipated Problem Reporting 
The investigator will report UPs to the NIH IRB according to Policy 801.
9.10 Protocol Deviations and Non-Compliance
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH IRB as per Policy 801. All deviations must be 
addressed in study source documents and reported as specified in the protocol quality 
management plan and/or monitoring plan. The investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.
9.10.1 NIH Definition of Protocol Deviation
A protocol deviation is any change, divergence, or departure from the IRB-approved research 
protocol. 

Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.

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
Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study.
9.11 Reporting to the NIAID Clinical Director
The principal investigator will report UPs, major protocol deviations, and deaths to the NIAID 
clinical director according to institutional timelines. 
9.12 Publication and Data Sharing Policy
9.12.1 Human Data Sharing Plan
We will comply with NIH policies on data access, sharing, and dissemination, and clinical trials 
registration, as applicable. Human data generated in this study may be made available for future 
research as follows:

De-identified data in an NIH-funded or approved public repository.

De-identified data in another public repository.  

De-identified data with approved outside collaborators under appropriate agreements.

De-identified data in publications and/or public presentations.
Data will be shared at the time of or shortly after publication.
9.12.2  Genomic Data Sharing Plan
This study is not expected to generate the amount of genetic data that triggers the NIH Genomic 
Data Sharing Policy, which applies to all NIH-funded research that generates large-scale human 
or non-human genomic data, as well as the use of these data for subsequent research. However, 
viral genomic data will be shared in GenBank, as described above (section 7.3.1).
9.13 Conflict of Interest Policy
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial. The study leadership in 
conjunction with NIAID has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest.
ABBREVIATIONS
ACE2
Angiotensin-converting enzyme 2
ADA
Adenosine deaminase
AE
Adverse event

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APDS1/2
Activated PI3K delta syndrome 1/2
APECED
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
ARDS
Acute respiratory distress syndrome
BSI
Biological Specimen Inventory
CARD11
Caspase recruitment domain-containing protein 11
CBC
Complete blood count
CC
Clinical Center
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
COVID-19
Coronavirus disease 2019
CRIMSON
Clinical Research Information Management System of NIAID
CRIS
Clinical Research Information System
CVID
Common variable immune deficiency
DLM
Department of Laboratory Medicine
DNA
Deoxyribonucleic acid
DOCK8
Dedicator of cytokinesis 8 (protein)
ELISA
Enzyme-linked immunosorbent assay
EUA
Emergency use authorization
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GOF
Gain-of-function
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HRPP
Human Research Protections Program

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ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IE
Section on Immunoengineering
IFNg
Interferon gamma 
Ig (IgG, IgE, etc.)
Immunoglobulin (immunoglobulin G, immunoglobulin E, etc.)
IGHC
Immunoglobulin heavy chain
IL-12
Interleukin 12
IRB
Institutional Review Board
LCIM 
Laboratory of Clinical Immunology and Microbiology
MMRM
Mixed model repeated measures
mRNA
Messenger ribonucleic acid
N
Nucleocapsid (protein)
NEMO
Nuclear factor-kappa B essential modulator
NIH 
National Institutes of Health
NIAID
National Institute of Allergy and Infectious Diseases
NIBIB
National Institute of Biomedical Imaging and Bioengineering
NML
Neutrophil Monitoring Laboratory
OCRPRO
Office of Clinical Research Policy and Regulatory Oversight
OHRP
Office for Human Research Protections
OHSRP
Office of Human Subjects Research Protections
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PI3K
Phosphoinositide 3-kinase
RAC2
Ras-related C3 botulinum toxin substrate 2

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RAG
Recombination-activating gene
RBD
Receptor binding domain (protein)
REDCap
Research Electronic Data Capture (system)
RNA
Ribonucleic acid
S
Spike (protein)
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
SCID
Severe combined immunodeficiency
SNP
Single nucleotide polymorphism
STAT3
Signal transducer and activator of transcription 3 (protein)
TCR
T-cell receptor
UP
Unanticipated problem
US
United States
XLA
X-linked agammaglobulinemia
XMEN
X-linked immunodeficiency with magnesium defect, Epstein-Barr virus 
infection, and neoplasia
REFERENCES
1.         Hoffmann M, Kleine-Weber H, Schroeder S, Mü MA, Drosten C, Pö S. SARS-CoV-2 
Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven 
Protease Inhibitor. Cell. 2020;181:271-280. doi:10.1016/j.cell.2020.02.052
2.         Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-
nCoV. Biochemical and Biophysical Research Communications. 2020;525(1):135-140. 
doi:10.1016/j.bbrc.2020.02.071
3.         World Health Organization. COVID-19 Weekly Epidemiological Update Global 
Epidemiological Situation.; 2021.
4.         Berlin DA, Gulick RM, Martinez FJ. Severe COVID-19. The New England Journal of 
Medicine. 2020;383(25):2451-2460. doi:10.1056/NEJMcp2009575

Abbreviated Title: COVID vaccine immune response
38
Version Date: June 13, 2022
5.         Szczawinska-Poplonyk A, Breborowicz A, Samara H, Ossowska L, Dworacki G. 
Impaired Antigen-Specific Immune Response to Vaccines in Children with Antibody 
Production Defects. Published online 2015. doi:10.1128/CVI.00148-15
6.         Hanitsch LG, Löbel M, Mieves JF, et al. Cellular and humoral influenza-specific immune 
response upon vaccination in patients with common variable immunodeficiency and 
unclassified antibody deficiency. Vaccine. 2016;34(21):2417-2423. 
doi:10.1016/j.vaccine.2016.03.091
7.         Bonilla FA. Vaccines in Patients with Primary Immune Deficiency. Immunology and 
Allergy Clinics of North America. 2020;40(3):421-435. doi:10.1016/j.iac.2020.03.004
8.         Klumpp-Thomas C, Kalish H, Drew M, et al. Standardization of ELISA protocols for 
serosurveys of the SARS-CoV-2 pandemic using clinical and at-home blood sampling. 
Nature Communications. 2021;12(1):1-13. doi:10.1038/s41467-020-20383-x
9.         Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 
— Preliminary Report. New England Journal of Medicine. 2020;383(20):1920-1931. 
doi:10.1056/nejmoa2022483
10.        Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2019 
Update on the Classification from the International Union of Immunological Societies 
Expert Committee. Journal of Clinical Immunology. 2020;40(1):24-64. 
doi:10.1007/s10875-019-00737-x
11.        Sobh A, Bonilla FA. Vaccination in Primary Immunodeficiency Disorders. Journal of 
Allergy and Clinical Immunology: In Practice. 2016;4(6):1066-1075. 
doi:10.1016/j.jaip.2016.09.012
12.        Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination 
in primary immunodeficiency: A working group report of the Basic and Clinical 
Immunology Interest Section of the American Academy of Allergy, Asthma & 
Immunology. Journal of Allergy and Clinical Immunology. 2012;130(3 SUPPL.):S1-S24. 
doi:10.1016/j.jaci.2012.07.002
13.        Molenberghs G. Analyzing incomplete longitudinal clinical trial data. Biostatistics. 
2004;5(3):445-464. doi:10.1093/biostatistics/5.3.445
14.        Mallinckrodt CH, Clark WS, Carroll RJ, Molenberghs G. Assessing response profiles 
from incomplete longitudinal clinical trial data under regulatory considerations. Journal of 
Biopharmaceutical Statistics. 2003;13(2):179-190. doi:10.1081/BIP-120019265