Contains Nonbinding Recommendations

Emergency Use Authorization for 

Vaccines to Prevent COVID-19

Guidance for Industry

This guidance is intended to remain in effect until November 7, 2023, 

unless superseded by a revised final guidance before that date. For 

further information, refer to 85 FR 15417, March 13, 2023, and

https://www.federalregister.gov/documents/2023/03/13/2023-

05094/guidance-documents-related-to-coronavirus-disease-2019-covid19.
Contains Nonbinding Recommendations

Emergency Use Authorization for 

Vaccines to Prevent COVID-19

Guidance for Industry 

Document issued on March 31, 2022. 

This document supersedes the guidance of the same title issued on 

May 25, 2021.

U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Biologics Evaluation and Research 

March 2022 
Contains Nonbinding Recommendations

Preface

Public Comment

This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public 

health emergency. This guidance is being implemented without prior public comment because 

the Food and Drug Administration (FDA or Agency) has determined that prior public 

participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 

Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 

10.115(g)(2)). This guidance document is being implemented immediately, but it remains 

subject to comment in accordance with the Agency’s good guidance practices. 

Comments may be submitted at any time for Agency consideration. Submit written comments to 

the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 

Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov. 

All comments should be identified with the docket number FDA-2020-D-1137 and complete 

title of the guidance in the request.

Additional Copies

Additional copies are available from the FDA webpage titled “COVID-19-Related Guidance 

Documents for Industry, FDA Staff, and Other Stakeholders,” available at 

https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-relatedguidance-documents-industry-fda-staff-and-other-stakeholders, and from the FDA webpage 

titled “Search for FDA Guidance Documents” available at https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents. 

Additional copies of this guidance are also available from the Office of Communication, 

Outreach and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver 

Spring, MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email 

ocod@fda.hhs.gov, or from the Internet at https://www.fda.gov/vaccines-bloodbiologics/guidance-compliance-regulatory-information-biologics/biologics-guidances. 

Questions

For questions on the content of this guidance, contact OCOD at the phone numbers or email 

address listed above. 
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Table of Contents

I. INTRODUCTION................................................................................................................... 1

II. BACKGROUND...................................................................................................................... 2

III. CRITERIA AND CONSIDERATIONS FOR THE ISSUANCE OF AN EUA FOR A 

COVID-19 VACCINE............................................................................................................. 3

IV. KEY LOGISTIC RECOMMENDATIONS FOR THE REQUEST FOR AN EUA FOR 

A COVID-19 VACCINE......................................................................................................... 4

V. PRIORITIZATION OF REQUESTS FOR ISSUANCE OF AN EUA FOR A COVID-19 

VACCINE ................................................................................................................................ 5

VI. RECOMMENDATIONS REGARDING INFORMATION AND DATA TO BE 

INCLUDED IN A REQUEST FOR AN EUA FOR A COVID-19 VACCINE.................. 6

A. Regulatory .................................................................................................................... 6

B. Chemistry, Manufacturing, and Controls................................................................. 7

C. Safety and Effectiveness Information...................................................................... 10

VII. CONSIDERATIONS FOR CONTINUING CLINICAL TRIALS FOLLOWING 

ISSUANCE OF AN EUA FOR A COVID-19 VACCINE ................................................. 12

VIII. CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA 

ADVISORY COMMITTEE................................................................................................. 12

IX. REFERENCES...................................................................................................................... 14

APPENDIX 1: SUBMISSION OF INFORMATION IN PREPARATION FOR A VRBPAC 

MEETING.............................................................................................................................. 16

A. Preparation and submission of briefing materials for the Advisory Committee 

meeting........................................................................................................................ 16

B. Process ........................................................................................................................ 16

APPENDIX 2: Evaluation of Vaccines to Address Emerging SARS-CoV-2 Variants .............. 18

A. Background................................................................................................................ 18

B. Introduction ............................................................................................................... 18
Contains Nonbinding Recommendations

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Emergency Use Authorization for 

Vaccines to Prevent COVID-19

Guidance for Industry

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) 

on this topic. It does not establish any rights for any person and is not binding on FDA or the public. 

You can use an alternative approach if it satisfies the requirements of the applicable statutes and 

regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance 

as listed on the title page. 

I. INTRODUCTION 

FDA plays a critical role in protecting the United States (U.S.) from threats such as emerging 

infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is 

committed to providing timely guidance to support response efforts to this pandemic. 

FDA is issuing this guidance to provide sponsors of requests for Emergency Use Authorization 

(EUA) for COVID-19 vaccines with recommendations regarding the data and information needed to 

support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an 

investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health 

emergency. This document supersedes the guidance of the same title issued in May 2021 (which 

superseded the guidance of the same title issued October 2020 and reissued February 2021).

This policy is intended to remain in effect only for the duration of the public health emergency 

related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 31, 

2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance 

with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)). 

Given this public health emergency, and as discussed in the Notice published in the Federal Register

of March 25, 2020, titled “Process for Making Available Guidance Documents Related to 

Coronavirus Disease 2019,” (85 FR 16949) available at https://www.govinfo.gov/content/pkg/FR2020-03-25/pdf/2020-06222.pdf, this guidance is being implemented without prior public comment 

because FDA has determined that prior public participation for this guidance is not feasible or 

appropriate (see section 701(h)(1)(C) of the FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 

10.115(g)(2)). This guidance document is being implemented immediately, but it remains subject to 

comment in accordance with the Agency’s good guidance practices. 

The contents of this document do not have the force and effect of law and are not meant to bind the 

public in any way, unless specifically incorporated into a contract. This document is intended only to 

provide clarity to the public regarding existing requirements under the law. FDA guidance 
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2 

documents, including this guidance, should be viewed only as recommendations, unless specific 

regulatory or statutory requirements are cited. The use of the word should in FDA guidances means 

that something is suggested or recommended, but not required. 

II. BACKGROUND

There is currently a respiratory disease pandemic caused by a novel coronavirus. The virus has been 

named “SARS-CoV-2” and the disease it causes has been named “Coronavirus Disease 2019” 

(COVID-19). On January 31, 2020, HHS issued a declaration of a public health emergency related 

to COVID-19 and mobilized the Operating Divisions of HHS. 1 In addition, on March 13, 2020, 

there was a Presidential declaration of a national emergency in response to COVID-19. 2 

The COVID-19 pandemic presents an extraordinary challenge to global health. Commercial vaccine 

manufacturers and other entities are developing COVID-19 vaccine candidates using different 

technologies including RNA, DNA, protein, and viral vectored vaccines. 

This guidance was first developed prior to issuance of an EUA or license for a COVID-19 vaccine 

but has been revised to take into account the EUAs currently in place for COVID-19 vaccines and 

the U.S.-licensed vaccines for the prevention of COVID-19. This guidance describes FDA’s current 

recommendations regarding the data and information needed to support the issuance of an EUA 

under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent 

COVID-19, including chemistry, manufacturing, and controls information (CMC); nonclinical data 

and information; and clinical data and information, as well as administrative and regulatory 

information. In addition, the guidance provides recommendations regarding key information and 

data that should be submitted to a relevant investigational new drug application (IND) or crossreferenced master file (MF) prior to submission of an EUA request in order to facilitate FDA’s 

complete and timely review of such a submission, including convening the Vaccines and Related 

Biological Products Advisory Committee (VRBPAC). This guidance also discusses FDA’s current 

thinking regarding the circumstances under which the issuance of an EUA for a COVID-19 vaccine 

would be appropriate, providing additional context to the discussion regarding EUAs in the guidance 

for industry entitled “Development and Licensure of Vaccines to Prevent COVID-19” (Ref. 1). 

These recommendations are specific to COVID-19 vaccines, which are complex biological products 

that are intended to be administered to millions of individuals, including healthy people, to prevent 

disease. These vaccines have the potential for broad use under an EUA. The recommendations in 

this guidance are not necessarily applicable to drugs and biological products intended for treatment 

of COVID-19, for which there may be significantly different considerations under the standard set 

forth in section 564 of the FD&C Act (21 U.S.C. 360bbb-3), reflecting the products’ characteristics 

1 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued Jan. 

31, 2020, and subsequently renewed), available at

https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. 2 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak 

(Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-declaring-nationalemergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. On February 24, 2021, there was a Presidential 

Declaration continuing the national emergency concerning the COVID-19 pandemic beyond March 1, 2021. See

Continuation of the National Emergency Concerning the Coronavirus Disease 2019 (COVID-19) Pandemic (Feb. 24, 

2021), available at https://www.federalregister.gov/documents/2021/02/26/2021-04173/continuation-of-the-nationalemergency-concerning-the-coronavirus-disease-2019-covid-19-pandemic. 
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and anticipated clinical uses.

Sponsors engaged in the development of vaccines to prevent COVID-19 should refer to the guidance 

for industry entitled “Development and Licensure of Vaccines to Prevent COVID-19” (Ref. 1), the 

guidance for industry and investigators entitled “COVID-19 Public Health Emergency: General 

Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological 

Products” (Ref. 2), and the guidance for industry and other stakeholders entitled “Emergency Use 

Authorization of Medical Products and Related Authorities” (Ref. 3).

III. CRITERIA AND CONSIDERATIONS FOR THE ISSUANCE OF AN EUA FOR A 

COVID-19 VACCINE

On February 4, 2020, pursuant to section 564(b)(1)(C) of the FD&C Act (21 U.S.C. 360bbb3(b)(1)(C)), the Secretary of HHS determined that there is a public health emergency that has a 

significant potential to affect national security or the health and security of U.S. citizens living 

abroad, and that involves the virus that causes COVID-19. On the basis of such determination, on 

March 27, 2020, the Secretary then declared that circumstances exist justifying the authorization of 

emergency use of drugs and biological products during the COVID-19 pandemic, pursuant to section 

564(b)(1) of the FD&C Act (21 U.S.C. 360bbb-3(b)(1)).

3

Based on this declaration and determination, FDA may issue an EUA after FDA has determined that 

the following statutory requirements are met (section 564 of the FD&C Act (21 U.S.C. 360bbb-3)) 

(Ref. 3):

• The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the March 27, 

2020, EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or lifethreatening disease or condition.

• Based on the totality of scientific evidence available, including data from adequate and wellcontrolled trials, if available, it is reasonable to believe that the product may be effective to 

prevent, diagnose, or treat such serious or life-threatening disease or condition that can be 

caused by SARS-CoV-2.

• The known and potential benefits of the product, when used to diagnose, prevent, or treat the 

identified serious or life-threatening disease or condition, outweigh the known and potential 

risks of the product. 

• There is no adequate, approved, and available alternative to the product for diagnosing, 

preventing, or treating the disease or condition. 4

3 This EUA declaration is distinct from, and is not dependent on, the declaration by the Secretary of HHS of a public 

health emergency related to COVID-19, issued on January 31, 2020, and subsequently renewed, under section 319 of the 

PHS Act. See supra note 1. The issuance of an EUA for a COVID-19 vaccine is not based on that January 2020 

declaration of a public health emergency and, therefore, an EUA may remain in effect beyond the duration of the public 

health emergency declaration if all other statutory conditions are met.

4 For example, a potential alternative product may be considered “unavailable” if there are insufficient supplies of the 

approved alternative to fully meet the emergency need. See section III.B.1.d of “Emergency Use Authorization of 

Medical Products and Related Authorities” guidance (Ref. 3).
Contains Nonbinding Recommendations

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In the case of investigational vaccines being developed for the prevention of COVID-19, any 

assessment regarding an EUA will be made on a case-by-case basis considering the target 

population, the characteristics of the product, the preclinical and human clinical study data on the 

product, and the totality of the available scientific evidence relevant to the product.

FDA acknowledges that an EUA for a COVID-19 vaccine may be requested to allow for the 

vaccine’s rapid and widespread deployment for administration to millions of individuals, including 

healthy people, potentially following interim results from one or more clinical trials meeting prespecified success criteria described in the analysis plan submitted to FDA. In this scenario, for a 

COVID-19 vaccine for which there is adequate manufacturing information to ensure quality and 

consistency, issuance of an EUA would require a determination by FDA that the vaccine’s benefits 

outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that 

demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.

It is FDA’s expectation that, following submission of an EUA request and issuance of an EUA, a 

sponsor would continue to collect data in any ongoing trials and would also work towards 

submission of a Biologics License Application (BLA) as soon as possible 5. FDA’s 

recommendations regarding the safety and effectiveness data and information outlined in section VI

of this guidance are essential to ensure that clinical development of a COVID-19 vaccine has 

progressed far enough that issuance of an EUA for the vaccine would not interfere with the ability of 

an ongoing Phase 3 trial to demonstrate effectiveness of the vaccine to support licensure and to 

continue safety assessments, including investigating the potential for vaccine-associated enhanced 

respiratory disease (ERD). The ability of a sponsor to accrue this information about a COVID-19 

vaccine is critical to ongoing assessment of its benefits and risks. FDA notes that there would need 

to be an adequate plan for safety data collection among individuals vaccinated under an EUA.

IV. KEY LOGISTIC RECOMMENDATIONS FOR THE REQUEST FOR AN EUA FOR 

A COVID-19 VACCINE

A sponsor 6 considering the submission of an EUA request for an investigational COVID-19 vaccine

should contact the Center for Biologics Evaluation and Research’s (CBER’s) Office of Vaccines

Research and Review (OVRR) as early in development as possible to discuss expectations and 

considerations for the sponsor’s particular vaccine.

FDA also recommends that vaccine sponsors engage in early communication with CBER’s Office of 

Compliance and Biologics Quality (OCBQ), Division of Manufacturing and Product Quality to 

discuss facility issues related to manufacturing of the particular vaccine.

5 In earlier versions of this guidance, FDA included language stating that it expected sponsors to continue to collect 

placebo-controlled data in an ongoing trial for as long as feasible after submission of an EUA request and issuance of an 

EUA. FDA has modified this language because access to a safe and effective authorized or approved COVID-19 vaccine 

may preclude the ethical continuation of blinded, placebo-controlled follow-up in ongoing clinical trials. Additionally, 

trial participants may choose to withdraw from trial follow-up for any reason, including to receive a vaccine available to 

them under an EUA.

6 For purposes of this guidance, the term “sponsor” is used when referring to the applicant, submitter, or person 

requesting an EUA.
Contains Nonbinding Recommendations

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In order to facilitate a complete and timely review of a request for an EUA for a COVID-19 vaccine, 

including scheduling of a meeting of FDA’s VRBPAC, the following information should be 

submitted in advance of submission of an EUA request:

• A detailed description of the chemistry, manufacturing, and controls information and data 

described in section VI.B of this guidance should be submitted to a relevant IND or crossreferenced MF(s) at least one month prior to submission of an EUA request.

• FDA strongly encourages the vaccine sponsor to provide FDA with notice within 24 hours 

after any interim analysis has been completed, on the basis of which submission of an EUA 

request is planned, by contacting OVRR, and to discuss proposed timelines for submission of 

an EUA request.

V. PRIORITIZATION OF REQUESTS FOR ISSUANCE OF AN EUA FOR A COVID-19 

VACCINE

The issuance of an EUA is discretionary. FDA’s decision to review and process an EUA request,

and ultimately issue an EUA if the relevant statutory criteria are met, is based on a determination, on 

a case-by-case basis, that such action is necessary to protect the public health in an emergency. It is 

an authorization that the government “may” issue when necessary to protect the public health in an 

emergency (see section 564 FD&C Act (21 U.S.C. 360bbb-3(a)(1)), which states, in relevant part, 

“subject to the provisions of this section, the Secretary may authorize the introduction into interstate 

commerce...a drug, device, or biological product intended for use in an actual or potential 

emergency”). FDA’s January 2017 guidance entitled, “Emergency Use Authorization of Medical 

Products and Related Authorities,” (Ref. 3) describes factors that FDA intends to use in its 

prioritization of EUA requests, such as the public health need for the product, the availability and 

adequacy of the information concerning the likelihood that the product may be safe and effective in 

preventing, treating, or diagnosing the condition, and whether the product is included in government 

stakeholder stockpiles.

When FDA assesses investigational COVID-19 vaccines for use under EUA, FDA’s review includes:

stringent evaluation of product quality, including a determination that the facilities producing the 

product meet appropriate standards; evaluation of the conduct of clinical trials; and assessment of 

trial data integrity. As noted in section IV of this guidance, early interaction with the Agency is 

critical. FDA intends to decline to review and process EUA requests in cases where it is not feasible

for the Agency to verify any one of these characteristics. Additionally, given the need to address 

urgent public health priorities, FDA may need to further prioritize among the EUA requests it 

receives for COVID-19 vaccine candidates. For the remainder of the current pandemic, FDA may 

decline to review and process further EUA requests other than those for vaccines whose developers 

have engaged in an ongoing manner with the Agency during the development of their manufacturing 

process and clinical trials program as described in this guidance, “Emergency Use Authorization for 

Vaccines to Prevent COVID-19.” These COVID-19 vaccine developers will have had the benefit of 

FDA feedback early and throughout the development process. Therefore, their EUA requests are 

more likely to contain the comprehensive data and information needed to demonstrate that issuance 

of an EUA is appropriate, and the Agency is more likely to be able to confirm the validity of the 

clinical and manufacturing information submitted in the EUA request.
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VI. RECOMMENDATIONS REGARDING INFORMATION AND DATA TO BE 

INCLUDED IN A REQUEST FOR AN EUA FOR A COVID-19 VACCINE

As stated in the “Emergency Use Authorization of Medical Products and Related Authorities” 

January 2017 guidance (Ref. 3), FDA recommends that a request for an EUA include a wellorganized summary of the available scientific evidence regarding the product’s safety and 

effectiveness, risks (including an adverse event profile) and benefits, and any adequate, approved, 

available alternatives to the product. FDA recommends that the following information be submitted 

in a request for an EUA for a COVID-19 vaccine or, as applicable, that this information be submitted 

in a relevant IND or cross-referenced MF before an EUA request is submitted.

A. Regulatory

The following information should be submitted in a request for an EUA for a COVID-19 

vaccine:

1. A description of the product and its intended use (e.g., identification of the serious or 

life-threatening disease or condition for which the product may be effective; where, 

when, and how the product is anticipated to be used; and/or the population(s) for 

which the product may be used). The submission should address the following 

details:

• Proposed use(s) under EUA 

• Proposed dosing regimen(s) and method(s) of administration for use under EUA

• Rationale for dosing regimen

• Information to support the use, dosing and administration of the vaccine in the 

following populations, as applicable:

o Adults

o Pediatric age groups

o Other specific populations (e.g., geriatric individuals, pregnant or lactating 

individuals, immunodeficient individuals);

2. Available safety and effectiveness information for the product;

3. A discussion of risks and benefits, including available information concerning the 

threat posed by SARS-CoV-2 and how that threat would be addressed by the product 

under the proposed use under the EUA. As noted above, for a preventive COVID-19 

vaccine to be potentially administered to millions of individuals, including healthy 

individuals, data adequate to inform an assessment of the vaccine’s benefits and risks 

and support issuance of an EUA would include not only meeting the prespecified 

success criteria for the study’s primary efficacy endpoint, but also additional safety 

and effectiveness data as described below in section VI.C.3 of this guidance. The

discussion of the risks and benefits in the EUA request should include an assessment 

of the risks and benefits for the proposed use under the EUA, including a discussion 

of the following:

• Any steps taken to mitigate risk or optimize benefit

• Any recommended restrictions to ensure safe use

• Any situations under which the product should not be used (i.e., contraindications)

• Important information that should be considered prior to use of the EUA product;
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4. The need for the product, including identification of any approved alternative 

product(s) and their availability and adequacy for the proposed use;

5. A description of the product’s FDA approval status; whether the product is under an 

investigational application (e.g., if an IND is in effect or has been submitted); whether 

the product is approved in a foreign country for either the proposed use or another 

use; and information on the use of the medical product by either a foreign country or 

an international organization (e.g., the World Health Organization (WHO)). The 

submission of the EUA request should include a brief summary of any related 

submissions to FDA and indicate which one(s) were cross-referenced in a letter to this 

file. This information may include:

• Related IND number(s) and a brief description of the stage of clinical testing 

• Related Pre-IND number(s)

• Related MF number(s) and brief description of the contents;

6. Information comparable to an FDA-approved package insert; drafts of the “Fact 

Sheets” to be furnished to health care professionals or authorized vaccine 

administrators, as well as those to be furnished to recipients of the product, which are 

described in section E of the “Emergency Use Authorization of Medical Products and 

Related Authorities” guidance (Ref. 3) and typically are part of pre-EUA discussions; 

and plans for providing such information in an emergency;

7. Information regarding the supply chain, which will help FDA to assess anticipated 

availability of the vaccine for its intended recipients and whether anticipated storage

and distribution conditions will affect the vaccine’s safety and effectiveness, including

the following details:

• Whether the product will be supplied to the U.S. Government or Vendor Managed 

Inventory (VMI)

• Anticipated quantity of finished product on hand and the surge capabilities of the 

manufacturing site(s)

• Details of the distributor(s) for the vaccine and plans for distribution.

B. Chemistry, Manufacturing, and Controls

The EUA request should include information on chemistry, manufacturing, and controls; a 

list of each site where the product, if authorized, is or would be manufactured, relevant 

information about each site, and the current status of the manufacturing site(s) with respect to 

current good manufacturing practice (CGMP) requirements (Refs. 4, 5).

As noted above, in order to facilitate a complete and timely review of an EUA request, FDA

expects that a detailed description of the manufacturing process and controls will be provided 

in a relevant IND or cross-referenced MF(s) as it becomes available but not less than one

month prior to submission of an EUA request. Any manufacturing and process control data 

that will not be available at the time of submission of an EUA request should be discussed 

with FDA well in advance of the submission of the EUA request and identified in the 

submission.
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Following notice by a sponsor of intent to submit an EUA request as noted above, FDA will 

continue to work with the sponsor regarding resolution of any necessary manufacturing site

issues resulting from a site visit or other information submitted. FDA will assess CGMP 

compliance for each manufacturing site using all available tools and information.

1. Manufacturing

Sufficient data should be submitted to support drug substance (DS) and drug product (DP) 

manufacturing to ensure the quality and consistency of the vaccine product that is 

produced. FDA generally expects a minimum of three Process Performance Qualification 

(PPQ) lots per manufacturing facility to support the consistency of vaccine quality. In 

addition, critical process parameters and in-process controls of specific unit operations 

should be qualified/validated. Evidence should be provided that all DS and DP 

manufacturing sites, including testing sites, are adequately qualified/validated to ensure 

that the equipment/process meets all predetermined specifications/intended purposes, and 

the production process is controlled and operates with quality oversight consistent with 

CGMP requirements. If more than one manufacturing facility is used to produce DS and 

DP, data should be provided to support the consistency of vaccine quality between 

manufacturing sites. 

2. Control of Drug Substance and Drug Product

Product data as described below should be provided to support FDA’s determination 

regarding the safety and effectiveness of the vaccine: 

a. Documentation establishing that critical source materials used in manufacturing 

are adequately controlled, including history and qualification of cell banks and 

virus banks, identification of all animal-derived materials used for cell culture and 

virus growth, and DP excipients.

b. An evaluation and mitigation plan for potential adventitious agents.

c. Data to demonstrate that the DS is sufficiently characterized in order to identify 

and understand the critical properties that impact performance and stability.

d. A detailed description of the quality control system for all stages of 

manufacturing, including the testing program for in-process/intermediate product 

quality and DS and DP quality for release. 

e. Analytical methods and qualification/validation data for all quality-indicating 

assays. Validation data for assays used to evaluate critical vaccine qualities such 

as purity, identity, and potency are expected.

f. The DS and DP development history and manufacturing changes introduced in 

Phase 1, 2, 3 and EUA lots, including analytical comparability of DS lots with 

these changes. Quality release data and supplementary characterization tests to 

assess the impact of the changes on the DS quality attributes should be provided.
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g. A tabular listing of all clinical studies and DP lot numbers used in each study 

including DS lot genealogy, manufacturing processes used, and the manufacturing 

site, as well as the Certificates of Analysis (CoAs) for all clinical lots used in 

clinical studies and information on any lots that were initiated but not accepted for 

release.

h. A stability plan including safety and stability-indicating tests and available 

stability data from all developmental, clinical, and commercial lots. Data to 

support short-term stability, reflecting storage conditions during transport and 

distribution and in clinics and covering the time from dose preparation to 

administration expected.

i. Appropriate quality specifications should be established for all DP lots used under 

EUA and testing results for the final vaccine lots should be submitted to the IND 

at the time of product distribution.

j. Aseptic-process information, including the appropriate validation studies.

k. A description of sterile filtration and sterilization processes, as well as validation 

studies. Depyrogenation of container-closure systems, if applicable, should also 

be provided.

l. Storage conditions, including the container-closure integrity, should be validated 

and this information should be provided.

3. Facilities 

a. Facility information should be submitted to demonstrate that the facilities are of 

suitable size and adequately designed to prevent contamination, crosscontamination, and mix-ups.

b. Utility information, including validation information, should be provided for all 

utilities. For the heating, ventilation, and air conditioning (HVAC) system, it is 

important to demonstrate control by including area classifications, pressure 

differentials, and containment features where needed.

c. Manufacturing equipment should be qualified, and a list of critical equipment for 

DS and DP should be submitted.

d. Facility and equipment cleaning should be validated, and the validation should be 

submitted for review.

e. A quality control unit should be established and have the responsibility for 

oversight of manufacturing, and review and release of components, containers and 

closures, labeling, in-process material, and final products. The quality control unit 

should have the responsibility for approving validation protocols and reports, 

investigating deviations, and instituting corrective and preventive actions.
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C. Safety and Effectiveness Information

The EUA request should include the following safety and effectiveness information, which 

will inform FDA’s determination regarding the product’s benefit-risk profile:

1. Bioassays for assessment of clinical endpoints

The diagnostic bioassays that were used to assess study endpoints of clinical studies 

supportive of the EUA request should be identified. FDA expects that the standard 

operating procedures (SOPs) and validation reports for the final assay methods, and a list 

of all laboratories where the clinical samples have been tested, will be submitted to 

support the EUA request.

2. Nonclinical: 

a. A list of the nonclinical studies conducted to support vaccine effectiveness and 

safety (e.g., characterization of markers associated with enhanced disease, 

biodistribution, shedding, and attenuation) should be provided, along with the 

timelines for study completion and submission of final study reports for all 

ongoing nonclinical studies as applicable.

b. A final study report, if available, for a Developmental and Reproductive 

Toxicology (DART) study, or the timeline for study completion and submission of 

the final study report, should be provided in order to inform potential emergency 

use of the vaccine in pregnant women.

3. Clinical

a. FDA acknowledges the potential to request an EUA for a COVID-19 vaccine 

based on an interim analysis of a clinical endpoint from a Phase 3 efficacy study. 

Issuance of an EUA requires a determination that the known and potential benefits 

of the vaccine outweigh the known and potential risks. For a preventive COVID19 vaccine to be potentially administered to millions of individuals, including 

healthy individuals, data adequate to inform an assessment of the vaccine’s 

benefits and risks and support issuance of an EUA would include not only meeting 

the prespecified success criteria for the study’s primary efficacy endpoint as 

described in the guidance for industry entitled “Development and Licensure of 

Vaccines to Prevent COVID-19” (Ref. 1) (i.e., a point estimate for a placebocontrolled efficacy trial of at least 50%, with a lower bound of the appropriately 

alpha-adjusted confidence interval around the primary efficacy endpoint point 

estimate of >30%), but also additional safety and effectiveness data as described 

below in this section. The timing of interim analyses planned for a Phase 3 study

would thus ideally be aligned with the ability of the analyses to meet these criteria.

b. An EUA request for a COVID-19 vaccine should include all safety data 

accumulated from Phase 1 and 2 studies conducted with the vaccine, with focus on 

serious adverse events (SAEs), adverse events of special interest, and cases of 

severe COVID-19 among study subjects. We recognize that the Phase 1 and 2 
Contains Nonbinding Recommendations

11

safety data likely will be of a longer duration than the available safety data from 

the Phase 3 trial at the time of submission of an EUA request. The Phase 1 and 2 

data are intended to complement the available data from safety follow-up from 

ongoing Phase 3 studies.

c. Data from Phase 3 studies should include a median follow-up duration of at least 

two months after completion of the full vaccination regimen to help provide 

adequate information to assess a vaccine’s benefit-risk profile, including: adverse 

events; cases of severe COVID-19 disease among study subjects; and cases of 

COVID-19 occurring during the timeframe when adaptive (rather than innate) and 

memory immune responses to the vaccine would be responsible for a protective 

effect.

In addition, FDA does not expect to be able to make a favorable benefit-risk 

determination that would support an EUA without Phase 3 data that include the 

following, which will help the Agency to assess the safety of the vaccine:

i. Local and systemic solicited adverse reactions collected for the protocoldefined duration of follow-up in an adequate number of subjects to 

characterize reactogenicity in each protocol-defined age cohort 

participating in the trial;

ii. All safety data collected up to the point at which the database is locked to 

prepare the submission of the EUA request, including a high proportion of 

enrolled subjects (numbering well over 3,000 vaccine recipients) followed 

for SAEs and adverse events of special interest for at least one month after 

completion of the full vaccination regimen; 7 and

iii. Sufficient cases of severe COVID-19 among study subjects to support low 

risk for vaccine-induced ERD (a total of 5 or more severe COVID-19 cases 

in the placebo group would generally be sufficient to assess whether the 

severe COVID-19 case split between vaccine vs. placebo groups supports 

a favorable benefit-risk profile or conversely raises a concern about ERD).

d. Vaccine safety and COVID-19 outcomes in individuals with prior SARS-CoV-2 

infection, who might have been asymptomatic, are important to examine because 

screening for prior infection is unlikely to occur prior to administration of 

COVID-19 vaccines under EUA. An EUA request should therefore include 

subgroup analyses of safety and efficacy endpoints stratified by prior infection 

status at study entry, as determined by pre-vaccination serology or medical 

history.

7 As noted in FDA’s guidance for industry entitled “Development and Licensure of Vaccines to Prevent COVID-19” 

(Ref. 1), the pre-licensure safety database for preventive vaccines for infectious diseases typically consists of at least 

3,000 study participants vaccinated with the dosing regimen intended for licensure. FDA anticipates that adequately 

powered efficacy trials for COVID-19 vaccines will be of sufficient size to provide an acceptable safety database for each 

of the younger adult and elderly populations, provided that no significant safety concerns arise during clinical 

development that would warrant further evaluation.
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12

e. The EUA request should include a plan for active follow-up for safety (including

deaths and hospitalizations, and other serious or clinically significant adverse 

events) among individuals administered the vaccine under an EUA in order to 

inform ongoing benefit-risk determinations to support continuation of the EUA.

VII. CONSIDERATIONS FOR CONTINUING CLINICAL TRIALS FOLLOWING 

ISSUANCE OF AN EUA FOR A COVID-19 VACCINE

FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds 

for stopping blinded follow-up in an ongoing clinical trial. An EUA request should include strategies 

that will be implemented to ensure that ongoing clinical trials of the vaccine are able to assess longterm safety and efficacy (including evaluating for vaccine-associated ERD as well as decreased 

effectiveness as immunity wanes over time) in sufficient numbers of subjects to support vaccine 

licensure. These strategies should address how ongoing trial(s) will handle loss of follow-up 

information for study participants who choose to withdraw from the study in order to receive the

vaccine under an EUA. 

VIII. CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA 

ADVISORY COMMITTEE

FDA expects to convene an open session of FDA’s VRBPAC prior to the issuance of any EUA for a 

COVID-19 vaccine, to discuss whether the available safety and effectiveness data support 

authorization of an EUA for the specific request under review. This discussion, which will be 

specific to the particular vaccine that is the subject of the EUA request, will be separate from, and in 

addition to, any general discussion by the VRBPAC regarding the development, authorization, and/or 

licensure of vaccines to prevent COVID-19. A VRBPAC meeting may also include a closed session, 

if it is deemed necessary, to discuss proprietary CMC issues.

FDA expects to convene the VRBPAC for consideration of an EUA request for a COVID-19 vaccine 

that, on its face, contains the information required under section 564 of the FD&C Act (21 U.S.C. 

360bbb-3) and includes the recommended data and information described above. FDA intends to

provide briefing materials to the VRBPAC members as far in advance of any scheduled meeting as 

practicable and intends to post a publicly available version of the briefing materials on the FDA 

webpage no later than two full business days before the day the advisory committee meeting is 

scheduled to occur.

To facilitate discussion by the VRBPAC, an EUA request should be accompanied by briefing 

materials summarizing data to support the safety and effectiveness of the vaccine to be considered at 

the open session of the VRBPAC, and if requested by FDA, separate briefing materials related to

manufacturing of the vaccine for a closed session. The purpose of any closed session would be 

limited to the review and discussion of manufacturing information that is considered confidential

commercial or trade secret information exempt from public disclosure.

Timely consideration of the EUA request by the VRBPAC would be further facilitated by submission 

of briefing materials for the open session that the sponsor states are fully releasable. For additional 

information regarding the process for preparation and review of briefing materials for open FDA 
Contains Nonbinding Recommendations

13

advisory committee meetings, sponsors should consult the guidance for industry entitled “Advisory 

Committee Meetings – Preparation and Public Availability of Information Given to Advisory 

Committee Members” (Ref. 6), although the time frames set forth in the appendix of that guidance 

may not be applicable to a meeting of the VRBPAC for a COVID-19 vaccine. Please see Appendix 

1 for more information regarding submission of information in preparation for a VRBPAC meeting 

to consider a request for an EUA for a COVID-19 vaccine.
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IX. REFERENCES

1. Development and Licensure of Vaccines to Prevent COVID-19; Guidance for Industry, June 

2020, https://www.fda.gov/media/139638/download.

2. COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting 

Requests for COVID-19 Related Drugs and Biological Products; Guidance for Industry and 

Investigators, May 2020, https://www.fda.gov/media/137927/download. 

3. Emergency Use Authorization of Medical Products and Related Authorities; Guidance for 

Industry and Other Stakeholders, January 2017, https://www.fda.gov/media/97321/download. 

4. Guidance for Industry: Process Validation: General Principles and Practices, January 2011, 

https://www.fda.gov/media/71021/download.

5. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls 

Information and Establishment Description Information for a Vaccine or Related Product, 

January 1999, https://www.fda.gov/media/73614/download. 

6. Advisory Committee Meetings – Preparation and Public Availability of Information Given to 

Advisory Committee Members; Guidance for Industry, August 2008, 

https://www.fda.gov/media/75436/download.

7. Polack, F.P., et al., 2020, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, N. 

Engl. J. Med., 383:2603-2615, https://www.nejm.org/doi/full/10.1056/NEJMoa2034577. 

8. Baden, L.R., et al., 2021, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, 

384:403-416, N. Engl. J. Med., https://www.nejm.org/doi/full/10.1056/NEJMoa2035389. 

9. Rambaut, A., et al., 2020, Preliminary Genomic Characterization Of An Emergent SARSCov-2 Lineage In The UK Defined By A Novel Set Of Spike Mutations, 

https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-

lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563.

10. Li, J., et al., 2021, The Emergence, Genomic Diversity and Global Spread of SARS-CoV-2, 

Nature, 600: 408-419, https://doi.org/10.1038/s41586-021-04188-6.

11. SARS-CoV-2 Variant Classifications and Definitions, 

https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. 

12. Cao, Y., et al., 2021, Omicron Escapes the Majority of Existing SARS-CoV-2 Neutralizing 

Antibodies, Nature, https://doi.org/10.1038/s41586-021-04385-3; 

https://www.nature.com/articles/s41586-021-04385-3_reference.pdf. 
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13. Branal, L.T., et al., 2021, Outbreak Caused by the SARS-CoV-2 Omicron Variant in Norway, 

November to December 2021, Euro Surveill, https://doi.org/10.2807/1560-

7917.ES.2021.26.50.2101147. 

14. Wu, K., et al., 2021, mRNA-1273 Vaccine Induces Neutralizing Antibodies Against Spike 

Mutants From Global SARS-Cov-2 Variants, BioRxiv, 

https://www.biorxiv.org/content/10.1101/2021.01.25.427948v1. 
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APPENDIX 1: SUBMISSION OF INFORMATION IN PREPARATION FOR A VRBPAC 

MEETING

A. Preparation and submission of briefing materials for the Advisory Committee 

meeting

For an open session of the VRBPAC, please plan to submit final and fully releasable briefing 

materials at the time of submission of an EUA request for a COVID-19 vaccine. 

As noted in section VIII of this guidance, for certain EUA requests, FDA may determine that 

a closed session of the VRBPAC to discuss proprietary CMC information would be 

appropriate. In such circumstances, sponsors would not be expected to submit fully 

releasable briefing materials and should consult with OVRR regarding the submission of 

briefing materials for the closed session.

B. Process

Final sponsor-prepared and FDA-prepared briefing documents will be made available to the 

public no later than two full business days prior to the meeting date on the FDA webpage

under the respective Advisory Committee Meeting.

Publications need not be submitted with the briefing materials. If you choose to submit 

publications, the electronic submission should contain your actual briefing materials in one 

file and the publications in a separate file. The briefing materials should include a references 

section that lists these publications. Only the briefing materials will be posted on the FDA 

webpage; the file of publications will be sent to the committee members but will not be

posted.

In addition to the fully releasable briefing materials, to facilitate timely consideration of the 

EUA request by the VRBPAC, the following additional information should be provided by 

the sponsor at the time of submission of the EUA request:

1. Point of Contact for Advisory Committee Related Matters

At the time of submission of the EUA request, please provide primary and alternative

points of contact’s name, title, address, e-mail address and phone numbers.

2. List of Investigators

At the time of submission of the EUA request, please provide as a searchable electronic 

copy, a list of investigators, and the clinical sites for all clinical trials supporting the 

submission(s) under review.

3. Meeting Participants

At the time of submission of the EUA request, please provide a list of all presenters and 

responders who will be representing you at the meeting, along with their affiliation(s). 
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Representational activities include presenting, responding to questions, and/or sitting in 

the Sponsor/Industry section at the meeting. 

Please note that there are restrictions for any current or former advisory committee

members, or other past or present Special Government Employees (SGEs), to attend the 

meeting representing the sponsors before the Agency (5 CFR Part 2635). 

The goal is to avoid situations in which a current or former advisory committee member 

and/or consultant might inadvertently violate the law concerning representational 

activities. It is a violation of ethics statute 18 U.S.C. 208 for a Federal Employee 

(including but not limited to full-time and part-time employees of the National Institutes 

of Health, Centers for Disease Control and Prevention, Department of Defense, and 

Veterans Affairs) to represent a third party before another Agency. Please note that 

Federal Employees will not be permitted to represent your company at the meeting. 

4. Meeting Day Presentation Materials (slides)

It is recommended that your planned speakers’ slides be numbered for ease of reference 

during the meeting by the committee members. Please provide us with an electronic 

version of the slide presentation five business days prior to the Advisory Committee 

meeting. If back-up slides are presented, we ask that you provide the backup slides in the 

same file as your core presentation. All slides will be also posted on FDA’s webpage. 

Therefore, they must meet the requirements of section 508 of the Rehabilitation Act. 8

8 Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794(d)). See also Requirements Checklists for Section 508, 

available at https://www.fda.gov/about-fda/internet-accessibility/requirements-checklists-section-508. 
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APPENDIX 2: EVALUATION OF VACCINES TO ADDRESS EMERGING SARS-COV-2 

VARIANTS 

A. Background 

In the U.S. there are currently two licensed COVID-19 vaccines (Comirnaty (COVID-19 

Vaccine, mRNA) and Spikevax (COVID-19 Vaccine, mRNA)); three COVID-19 vaccines 

are currently authorized for emergency use (Janssen COVID-19 Vaccine, Moderna COVID19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine). Additionally, numerous COVID-19 

vaccines are in development in the U.S. and globally, many in advanced clinical trials. The 

U.S.-licensed and authorized vaccines and many investigational COVID-19 vaccines are 

designed to elicit a protective immune response to the SARS-CoV-2 Spike (S) protein, the 

major structural protein of the virus that has an essential role in attachment and infection of 

host cells. Several COVID-19 vaccines (e.g., mRNA vaccines and adenovirus-vectored 

vaccines expressing the S protein) have been shown to be effective in clinical studies (Refs. 

7-8). Evidence has accumulated from laboratory studies, pre-clinical animal studies, and 

clinical studies that indicates a neutralizing antibody response, primarily directed to the S 

protein, makes an important contribution to the protective response elicited by COVID-19 

vaccines based on S protein antigens. Nevertheless, the relative contribution of neutralizing 

antibody to protection elicited by current vaccines is not defined, and it is likely that the role 

of neutralizing antibody in protection may differ depending on the type of vaccine. Further, 

the level of neutralizing antibody that reliably predicts protection has not been established. 

Like most RNA viruses, SARS-CoV-2 is constantly evolving, and new variants have emerged 

that improve virus fitness for transmission. SARS-CoV-2 variants that include mutations in 

the S protein were identified within a few months after the start of the pandemic. 

Understanding the potential risk of SARS-CoV-2 variants to those previously unexposed to 

the virus, to previously infected individuals, and to recent vaccinees, is an area of intense 

research focus. The emergence of SARS-CoV-2 variants with multiple mutations in the S 

protein (e.g., Alpha (B.1.1.7 lineage), Delta (B.1.617.2 and AY lineages) and Omicron 

(B.1.1.529 and BA lineages)) have raised concerns because of their increased transmission 

rates and because of evidence that current COVID-19 vaccines (herein referred to as 

prototype vaccines) licensed or authorized under EUA or otherwise in clinical development 

provide reduced protection against these variants (Refs. 9-11), at least with respect to mild 

disease (Refs. 12-14). With the expectation that new SARS-CoV-2 variants will continue to 

emerge over time, available COVID-19 vaccines may need to be modified to adequately 

protect against disease caused by these variants. 

B. Introduction

The following describes FDA’s current thinking regarding the CMC, nonclinical data, and 

clinical data needed to support an amendment to an EUA under section 564 of the FD&C Act 

(21 U.S.C. 360bbb-3) for a vaccine for the prevention of COVID-19. These 

recommendations pertain to modified COVID-19 vaccines for the prevention of COVID-19, 

where the vaccine is made by the same process and manufacturer as an authorized or 

approved prototype vaccine but is modified in order to enhance efficacy against COVID-19 
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19 

caused by a SARS-CoV-2 variant(s). It should be recognized that FDA’s thinking regarding 

data needed to authorize a modified COVID-19 vaccine may evolve as additional information 

is accrued with SARS-CoV-2 variants and corresponding vaccines. 

Of note, the recommendations detailed below are specifically for pandemic COVID-19 

vaccines that express the S protein and are made under the assumptions that neutralizing 

antibody to SARS-CoV-2 S is a major component of the vaccine protective response (or for a 

given vaccine construct, is likely to vary in proportion to the protective response), that an 

immune marker predictive of protection has not been established, and that it is not feasible to 

conduct clinical disease endpoint efficacy studies rapidly enough to respond to the emergence 

of SARS-CoV-2 variants that may escape immunity conferred by prototype vaccines. 

Assuming the prototype vaccine has been authorized under an EUA or is approved, it is 

expected that the modified COVID-19 vaccine against a SARS-CoV-2 variant made by the 

same manufacturer and process as the prototype COVID-19 vaccine would be authorized 

through an EUA amendment to the EUA for the prototype COVID-19 vaccine.

This Appendix does not address how it will be determined that a vaccine based on a new viral 

sequence is needed, determining which protein sequences should be expressed by such a 

vaccine, or approaches to follow-up of modified vaccines to ensure that they retain adequate 

effectiveness, and do not lose efficacy due to evolution of new viral variants. This document 

also does not address considerations for multivalent COVID-19 vaccines. 

Other issues that FDA continues to consider, but are not discussed in this Appendix, include, 

and are not limited to:

• data indicating the need for a modified vaccine,

• what entity evaluates, decides and recommends whether a modified vaccine is 

needed, and

• the role of FDA’s VRBPAC in determining the need for a modified vaccine in the 

U.S. 

A request for an EUA amendment for the modified vaccine should address the following: 

1. Chemistry, Manufacturing, and Controls

The EUA amendment should include information on CMC; a list of each site where the 

modified product, if authorized, is or would be manufactured, relevant information about 

each site and the current status of the manufacturing site(s) with respect to CGMP 

requirements.

FDA expects that much of the manufacturing process and controls, as well as the facilities 

for vaccine production, for the modified COVID-19 vaccine will be identical to that of the 

prototype COVID-19 vaccine. However, updated CMC data will need to be generated for 

the modified COVID-19 vaccine, as a scientific matter. The CMC data to support the 

modified vaccine formulation may differ depending on the vaccine platform, but at a 

minimum should include critical aspects of product characterization, a potency assay, and 

data on stability generated using the modified COVID-19 vaccine. Any changes made to 

the manufacturing process and process control should be discussed with FDA in advance 

of the EUA amendment submission. 
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2. Nonclinical 

A list of the nonclinical studies conducted to support vaccine effectiveness and safety 

(e.g., characterization of markers associated with enhanced disease, biodistribution, 

shedding, and attenuation) obtained with the prototype COVID-19 vaccine made by the 

same manufacturer and process should be provided. 

In general, for a modified COVID-19 vaccine directed against a SARS-CoV-2 variant and 

made by the same manufacturer and process, conducting additional repeat dose toxicity 

studies or DART studies may not be warranted. Data from the vaccine platform or from 

the prototype vaccine will be considered in making this decision. 

Data from studies in a relevant animal model receiving the prototype COVID-19 vaccine 

and the modified COVID-19 vaccine directed against SARS-CoV-2 variant(s) and 

subsequently challenged with wild-type viruses representing clinically relevant circulating 

variants, including the variant(s) of interest, are encouraged as they contribute to the 

totality of the evidence supporting the authorization of a modified COVID-19 vaccine. 

Vaccine manufacturers may submit the draft protocols for such studies to FDA. It should 

be recognized that conduct of challenge studies with any live SARS-CoV-2 requires a 

BSL-3 containment facility. These challenge/protection studies may be performed in 

parallel with the clinical immunogenicity studies described below. 

3. Clinical data

a. Clinical data to support effectiveness of a modified vaccine

The effectiveness of a modified COVID-19 vaccine against a particular SARS-CoV-2 

variant of concern (VOC) can be evaluated based on:

• The efficacy of primary vaccination with the manufacturer’s authorized or 

approved prototype COVID-19 vaccine made by the same process and for 

which a clinical disease endpoint efficacy study has been conducted that met 

FDA pre-specified success criteria, AND

• Comparison of immune responses (assessed by neutralizing antibody) induced 

by the modified vaccine and the prototype vaccine. 

The immunogenicity studies to assess the effectiveness of a modified COVID-19 

vaccine against a particular VOC administered as primary vaccination, a first booster 

dose and a second booster dose are described below in this section (Appendix 2 

B.3.a.). Each of these studies is described as having a contemporaneous comparator 

group who receive the prototype vaccine; however, serum samples from study 

subjects administered the prototype vaccine in a previously conducted study, if 

available, may be used in lieu of a contemporaneous comparator group if evaluated 

using the same assay(s) and provided that the prototype vaccine and modified vaccine 

groups are well-balanced with respect to factors that may affect interpretation of the 

immune response. Ideally, the modified vaccine would be evaluated in subjects 

spanning the age range for the authorized use of the prototype vaccine for primary and 

booster vaccination. If a more limited age range is studied it may, in certain 

situations, be reasonable to extrapolate the data to other age groups for which the 
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21 

prototype is authorized or approved. We acknowledge that certain aspects of the

immunogenicity evaluations outlined below in this section (Appendix 2 B.3.a.) may 

be challenging, and in situations where available data support that certain studies or 

analyses would be infeasible, we would consider alternative approaches with 

appropriate justification. The assessment of effectiveness of a modified COVID-19 

vaccine will take into account the totality of the immunogenicity data from the 

primary, secondary and descriptive analyses.

Primary Vaccination: Sponsors should conduct an immunogenicity study in which 

previously unvaccinated persons are randomized to receive either the modified 

COVID-19 vaccine or the prototype COVID-19 vaccine. The modified vaccine dose 

and dosing regimen should be the same as authorized (or approved) for the prototype 

vaccine. If high SARS-CoV-2 seroprevalence precludes conducting studies in a 

SARS-CoV-2 naïve population, the prototype vaccine and modified vaccine groups 

should ideally be well balanced with respect to SARS-CoV-2 infection history based 

on baseline serostatus (presence of nucleocapsid antibody) and/or laboratory 

confirmed COVID-19, and with respect to neutralizing antibody titer prior to 

vaccination. Subgroup analyses should be conducted to evaluate immunogenicity 

based on these variables. 

Immune response comparisons and analyses to demonstrate effectiveness of a 

modified COVID-19 vaccine administered for primary vaccination are outlined below 

and in Table 1. 

Primary immunogenicity analyses: The primary analysis should be a comparison of 

Geometric Mean Titer (GMT) against the particular VOC, elicited by the modified 

and prototype vaccine. The study should be designed and adequately powered to 

demonstrate statistical superiority of the GMT elicited by the modified vaccine as 

compared to the prototype vaccine. Ideally, the primary analysis would test for 

“super” superiority (margin of >1.5-fold for GMT ratio) to statistically exclude noninferiority of the prototype vaccine compared with the modified vaccine. However, it 

would be acceptable to test for “simple” superiority (margin of >1-fold for GMT 

ratio) in the primary analysis and to test for “super” superiority as a secondary 

immunogenicity analysis. 

A second co-primary analysis should be a comparison of seroresponse rates against 

the particular VOC, elicited by the modified and prototype vaccine. The study should 

be designed and adequately powered to demonstrate non-inferiority of the 

seroresponse rate elicited by the modified vaccine as compared to the prototype 

vaccine, using a non-inferiority margin of <5% for seroresponse rate difference. 

Alternatively, the co-primary analysis of seroresponse rates could test for superiority 

(“simple” superiority margin of >0% or “super” superiority margin of >10% for 

seroresponse rate difference). If the co-primary analysis of seroresponse rates will 

test for non-inferiority, FDA would expect that additional descriptive analyses of 

seroresponses against clinically relevant variants, including the particular VOC, 

support the benefit of the modified vaccine over the prototype vaccine. Determination 

of an appropriate seroresponse definition should be based on available data. 
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Additional immunogenicity analyses: A secondary analysis should evaluate noninferiority of seroresponse rates and GMTs against the particular VOC that are 

induced by the modified vaccine relative to seroresponse rates and GMTs against the 

virus upon which the prototype was based that are induced by the prototype vaccine. 

Non-inferiority margins should be 10% for seroresponse rates and 1.5-fold for GMTs, 

respectively. Alternate non-inferiority margins may be considered, with adequate 

justifications, on a case-by-case basis. Additional descriptive analyses should 

compare the seroresponse rates and GMTs in each group against other clinically 

relevant VOCs (e.g., currently or recently circulating variants) and against the virus 

upon which the prototype was based. 

Table 1: Immune Response Comparisons and Analyses to Demonstrate Effectiveness 

of a Modified COVID-19 Vaccine Administered for Primary Vaccination

Immune response 

analyses Modified Vaccine Group Prototype Vaccine Group

Primary: Superiority* GMTV GMTV

Primary: Noninferiority** SRRV SRRV

Secondary: Noninferiority IRV IRO

Secondary: “Super” 

Superiority 

(if not primary)

IRV IRV

Additional Descriptive IRO IRO

Additional Descriptive IRR-V IRR-V

*Ideally the primary analyses will test for “super” superiority (margin of >1.5-fold for 

GMT ratio). However, it would be acceptable to test for “simple” superiority (margin 

of >1-fold for GMT ratio) in the primary analysis and to test for “super” superiority as 

a secondary immunogenicity analysis.

**Non-Inferiority margin of <5% for SRR difference. Alternatively, the co-primary 

analysis of SRR could test for superiority (“simple” superiority margin of >0% or “super” 

superiority margin of >10% for SRR difference).

GMTV = GMT against the particular VOC targeted by the modified vaccine 

SRRV = Seroresponse rate against the particular VOC targeted by the modified 

vaccine

IRV= seroresponse rate and GMT against the particular VOC targeted by the modified 

vaccine

IRO= seroresponse rate and GMT against the virus upon which the prototype is based 

IRR-V= seroresponse rate and GMT against other clinically relevant VOCs

First Booster Dose: Sponsors should conduct an immunogenicity study in which 

persons who have previously completed primary vaccination with the prototype 
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COVID-19 vaccine, administered according to the authorized (or approved) dose and 

dosing regimen, are randomized to receive a booster dose of either the modified 

COVID-19 vaccine or the prototype COVID-19 vaccine. Alternate study designs can 

be considered, for example a study in which subjects who have completed primary 

vaccination with other authorized (or approved) prototype vaccines are randomized to 

receive a booster dose with either the prototype vaccine or the modified vaccine. If 

the study population is heterogeneous with respect to previous vaccines received, the 

design should take into consideration factors that may affect interpretation of the 

immune response to the booster dose (i.e., the prototype vaccine and modified vaccine 

groups should ideally be well balanced with respect to vaccination history and SARSCoV-2 infection history based on baseline serostatus (presence of nucleocapsid 

antibody), laboratory confirmed COVID-19, and neutralizing antibody titer prior to 

the booster dose). Subgroup analyses should be conducted to evaluate 

immunogenicity based on these variables. 

Immune response comparisons and analyses to demonstrate effectiveness of a 

modified COVID-19 vaccine administered as a first booster dose are outlined below 

and in Table 2. 

Primary immunogenicity analyses: The primary analysis should be a comparison of 

GMTs against the particular VOC, elicited by the modified and prototype vaccine. 

The study should be designed and adequately powered to demonstrate statistical 

superiority of the GMT elicited by the modified vaccine as compared to the prototype 

vaccine. Ideally, the primary analysis would test for “super” superiority (margin of 

>1.5-fold for GMT ratio) to statistically exclude non-inferiority of the prototype 

vaccine compared with the modified vaccine. However, it would be acceptable to test 

for “simple” superiority (margin of >1-fold for GMT ratio) in the primary analysis 

and to test for “super” superiority as a secondary immunogenicity analysis.

A second co-primary analysis should be a comparison of seroresponse rates against 

the particular VOC, elicited by the modified and prototype vaccine. The study should 

be designed and adequately powered to demonstrate non-inferiority of the 

seroresponse rate elicited by the modified vaccine as compared to the prototype 

vaccine, using a non-inferiority margin of <5% for seroresponse rate difference. 

Alternatively, the co-primary analysis of seroresponse rates could test for superiority 

(“simple” superiority margin of >0% or “super” superiority margin of >10% for 

seroresponse rate difference). If the co-primary analysis of seroresponse rates will 

test for non-inferiority, FDA would expect that additional descriptive analyses of 

seroresponses against clinically relevant variants, including the particular VOC, 

support the benefit of the modified vaccine over the prototype vaccine. Determination 

of an appropriate seroresponse definition for a first booster dose should be based on 

available data.

Additional immunogenicity analyses: The following descriptive analyses should be 

conducted: 

• Comparison of the seroresponse rates and GMTs following the booster dose in 

each group against the virus upon which the prototype was based. 
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24 

• Comparison of the seroresponse rates and GMTs following the booster dose in 

each group against other clinically relevant VOCs (e.g., currently or recently 

circulating variants). 

• Comparison of the immune response elicited by a booster dose of the modified 

vaccine against the particular VOC to that elicited following primary vaccination 

with the prototype vaccine against the virus upon which the prototype was based. 

• Comparison of the immune response elicited by a booster dose of the modified 

vaccine to that elicited following primary vaccination with the prototype vaccine 

against the virus upon which the prototype was based. 

• Comparison of the immune response elicited by a booster dose of the modified 

vaccine to that elicited following primary vaccination with the prototype vaccine 

against other clinically relevant VOCs. 

The descriptive comparisons to the immune response after primary vaccination may 

be limited to a comparison of GMTs. 

Table 2: Immune Response Comparisons and Analyses to Demonstrate Effectiveness 

of a Modified COVID-19 Vaccine Administered as a First Booster Dose

Immune response 

analyses 

Modified Booster 

Vaccine Group

Prototype Booster 

Vaccine Group

Prototype Primary 

Vaccination Vaccine 

Group*

Co-Primary:

Superiority** GMTV GMTV NA

Co-Primary: Noninferiority*** SRRV SRRV NA

Secondary: “Super” 

Superiority 

(if not primary) GMTV GMTV NA

Additional Descriptive IRO IRO NA

Additional Descriptive IRR-V IRR-V NA

Additional Descriptive IRV NA IRO

Additional Descriptive IRO NA IRO

Additional Descriptive IRR-V NA IRR-V

*Comparisons to the immune response following primary vaccination may be comparisons to sera 

obtained in different studies and may be limited to GMTs. 
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25 

**Ideally the primary analysis of GMTs will test for “super” superiority (margin of >1.5-fold for 

GMT ratio). However, it would be acceptable to test for “simple” superiority (margin of >1-fold for 

GMT ratio) in the primary analyses and to test for “super” superiority as secondary analysis of GMT. 

***Non-Inferiority margin of <5% for SRR difference. Alternatively, the co-primary analysis of 

SRR could test for superiority (“simple” superiority margin of >0% or “super” superiority margin of 

>10% for SRR difference).

NA = Not Applicable

GMTV = GMT against the particular VOC targeted by the modified vaccine 

SRRV = Seroresponse rate against the particular VOC targeted by the modified vaccine 

IRV= seroresponse rates and GMT against the particular VOC targeted by the modified vaccine 

IRO= seroresponse rates and GMT against the virus upon which the prototype is based 

IRR-V= seroresponse rates and GMT against other clinically relevant VOCs

Second booster dose: Sponsors should conduct an immunogenicity study in which 

persons who have completed primary and first booster vaccination with the prototype 

COVID-19 vaccine, administered according to the authorized or approved (primary 

vaccination) and authorized (booster vaccination) dose and dosing regimen, are 

randomized to receive a second booster dose of either the modified COVID-19 vaccine or 

the prototype COVID-19 vaccine. Alternate study designs can be considered, for 

example a study in which subjects who have completed primary vaccination and first 

booster with any combination of authorized or approved (primary vaccination) and 

authorized (booster vaccination) prototype vaccines are randomized to receive a second 

booster dose with either the prototype vaccine or the modified vaccine. If the study 

population is heterogeneous with respect to previous vaccines received, the design should 

take into consideration factors that may affect interpretation of the immune response to 

the second booster dose (i.e., the prototype vaccine and modified vaccine groups should 

ideally be well balanced with respect to vaccination history and SARS-CoV-2 infection 

history based on baseline serostatus (presence of nucleocapsid antibody), laboratory 

confirmed COVID-19, and neutralizing antibody titer prior to the second booster dose). 

Subgroup analyses should be conducted to evaluate immunogenicity based on these 

variables. 

Immune response comparisons and analyses to demonstrate effectiveness of a modified 

COVID-19 vaccine administered as a second booster dose are outlined below and in 

Table 3.

Primary immunogenicity analyses: One co-primary analysis should be a comparison of 

GMTs against the particular VOC, elicited by the modified and prototype vaccine. The 

study should be designed and adequately powered to demonstrate statistical superiority of 

the GMT elicited by the modified vaccine as compared to the prototype vaccine. Ideally, 

the primary analysis would test for “super” superiority (margin of >1.5-fold for GMT 

ratio) to statistically exclude non-inferiority of the prototype vaccine compared with the 

modified vaccine. However, it would be acceptable to test for “simple” superiority 

(margin of >1-fold for GMT ratio) in the primary analyses and to test for “super” 

superiority as a secondary immunogenicity analysis. 
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26 

A second co-primary analysis should be a comparison of seroresponse rates against the 

particular VOC, elicited by the modified and prototype vaccine. The study should be 

designed and adequately powered to demonstrate non-inferiority of the seroresponse rate 

elicited by the modified vaccine as compared to the prototype vaccine, using a noninferiority margin of <5% for seroresponse rate difference. Alternatively, the co-primary 

analysis of seroresponse rates could test for superiority (“simple” superiority margin of 

>0% or “super” superiority margin of >10% for seroresponse rate difference). If the 

coprimary analysis of seroresponse rates will test for non-inferiority, FDA would expect 

that additional descriptive analyses of seroresponses against clinically relevant variants, 

including the particular VOC, support the benefit of the variant vaccine over the prototype 

vaccine. Determination of an appropriate seroresponse definition for a second booster 

dose should be based on available data 

Additional Immunogenicity Analyses: The following descriptive analyses should be 

conducted: 

• Comparison of the seroresponse rates and GMTs following the second booster 

dose in each group against the virus upon which the prototype was based. 

• Comparison of the seroresponse rates and GMTs following the second booster 

dose in each group against other clinically relevant VOCs (e.g., currently or 

recently circulating variants). 

• Comparison of the immune response elicited by a second booster dose of the 

modified vaccine against to that elicited following a first booster dose with the 

prototype vaccine against the particular VOC. 

• Comparison of the immune response elicited by a second booster dose of the 

modified vaccine to that elicited following a first booster dose with the prototype 

vaccine against the virus upon which the prototype was based. 

• Comparison of the immune response elicited by a second booster dose of the 

modified vaccine to that elicited following a first booster dose with the prototype 

vaccine against other clinically relevant VOCs. 

The descriptive comparisons to the immune response after the first booster dose may be 

limited to a comparison of GMTs. 
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Table 3: Immune Response Comparisons and Analyses to Demonstrate Effectiveness of a 

Modified COVID-19 Vaccine Administered as a Second Booster Dose

Immune response 

analysis

Modified Booster #2 

Vaccine Group

Prototype Booster #2 

Vaccine Group

Prototype Booster #1 

Vaccine Group*

Co-Primary:

Superiority** GMTV GMTV NA

Co-Primary: Noninferiority*** SRRV SRRV NA

Secondary: “Super” 

Superiority 

(if not primary) GMTV GMTV NA

Additional Descriptive IRO IRO NA

Additional Descriptive IRR-V IRR-V NA

Additional Descriptive IRV NA IRV

Additional Descriptive IRO NA IRO

Additional Descriptive IRR-V NA IRR-V

*Comparisons to the immune response following the first booster dose may comparisons to sera 

obtained in different studies and may be limited to GMTs. 

**Ideally the primary analyses will test for “super” superiority (margin of >1.5-fold for GMT 

ratio). However, it would be acceptable to test for “simple” superiority (margin of >1-fold for 

GMT ratio) in the primary analysis and to test for “super” superiority as a secondary 

immunogenicity analysis.

NA = Not Applicable

***Non-Inferiority margin of <5% for seroresponse rate difference. Alternatively, the co-primary 

analysis of SRR could test for superiority (“simple” superiority margin of >0% or “super” superiority 

margin of >10% for seroresponse rate difference).

GMTV = geometric mean titer against the particular VOC targeted by the modified vaccine 

SRRV = seroresponse rate against the particular VOC targeted by the modified vaccine 

IRV= SRR and GMT against the particular VOC targeted by the modified vaccine 

IRO= SRR and GMT against the virus upon which the prototype is based 

IRR-V= SRR and GMT against other clinically relevant VOCs

b. Clinical data to support safety of a modified vaccine 

Safety assessments, including solicited local and systemic adverse events assessed 

daily for at least 7 days after each study vaccination as well as serious and other 
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unsolicited adverse events assessed during the immunogenicity evaluation period, 

may be sufficient to support EUA of the modified COVID-19 vaccine. However, 

evaluation of the modified COVID-19 vaccine in a larger safety database than initially 

planned for immunogenicity studies may be warranted if safety signals arise, and 

studies should also plan for longer-term assessments of serious and other medically 

attended adverse events.

Assays for assessment of immunogenicity endpoints

The assays used to assess immunogenicity endpoints of clinical studies should be 

identified. Even though an immune marker predictive of protection against COVID19 has not been established to date, depending on the vaccine construct, neutralizing 

antibody may be considered a relevant measure of immunogenicity. 

Data demonstrating the ability of the modified COVID-19 vaccine to induce a 

neutralizing antibody response are needed, as a scientific matter. These may be 

derived from virus neutralization assays (using pseudovirus or wildtype virus) 

assessing neutralization of SARS-CoV-2 viruses (including the virus from which the 

prototype vaccine was derived as well as variants of interest) with clinical serology 

samples obtained from persons immunized with the prototype and/or the modified 

COVID-19 vaccine construct. 

FDA expects that the SOPs and validation reports for the final assay methods, and a 

list of all laboratories where the clinical samples have been tested, will be submitted 

to support the EUA amendment. 

4. Additional considerations

Currently, it is not known whether the immunogenicity and safety profiles of vaccines 

against SARS-CoV-2 variants will be comparable to those of vaccines against the original 

SARS-CoV-2 virus and whether regular (e.g., annual) modifications will be needed. 

Thus, manufacturers should generate the data to support authorization of a modified 

COVID-19 vaccine as outlined above. Further discussions will be necessary to decide 

whether in the future, certain or all modified COVID-19 vaccines may be authorized 

without the need for clinical studies. 

Developers are encouraged to perform exploratory studies regarding the ability of 

modified vaccines to boost immune responses to an appropriate level, even if the viral 

sequence being evaluated may not ultimately be selected for use in a modified vaccine. 

Such studies may provide important dose-finding and safety information. 

If a manufacturer plans to develop a modified monovalent vaccine against a variant, it 

will be important to ensure that the modified vaccine can be clearly distinguished from 

vaccines made by the manufacturer that target the original virus.