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MEMORANDUM

TO: File

FROM: Peter Marks, MD, PhD, Acting Director, Office of Vaccines Research and 

Review (OVRR), Center for Biologics Evaluation and Research (CBER)

DATE: June 30, 2022

RE: Fall 2022 COVID-19 Vaccine Strain Composition Selection Recommendation

The purpose of this memorandum is to document considerations behind the Food and Drug 

Administration’s (FDA, the Agency, or we) recommendation to vaccine manufacturers seeking 

to update their COVID-19 vaccine that they should develop a bivalent prototype + Omicron

BA.4/5 spike protein COVID-19 vaccine for use as a booster dose in potentially eligible 

populations during a possible fall 2022 vaccination campaign. Specifically, this memorandum 

delineates information relevant to the advice that we have provided to the manufacturers. 

I. Background 

The response to the ongoing COVID-19 pandemic has been complicated by the rapid evolution 

of the virus. The current circulating SARS-CoV-2 virus variants are antigenically distinct from 

the strain included in current authorized and approved vaccines. As a result, available FDAapproved and -authorized COVID-19 vaccines are less effective against currently circulating 

virus variants than against previously circulating strains of virus. It is our expectation that 

candidate vaccines with an updated strain composition that is more closely matched to currently 

circulating virus can be manufactured according to requirements for quality and consistency and 

in sufficient quantity to meet public health needs to be used as booster doses in the United States 

(U.S.) this fall. Additionally, candidate vaccines with such an updated strain composition may be 

more effective against circulating and potentially emerging virus variants and consequently may 

have a more favorable benefit-risk balance than currently available COVID-19 vaccines.1

1 For more information see FDA’s Briefing document for the June 28, 2022 Vaccines and Related Biological 

Products Advisory (VRBPAC) meeting, available at https://www.fda.gov/media/159452/download. 
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A. SARS-CoV-2 Variants of Concern (VOC) 

Since the original Omicron variant (designated as the BA.1 variant) spread rapidly around the 

world, the virus has continued to evolve and at the present time, several sublineages of Omicron 

are in circulation in various parts of the world. In the U.S., by late December 2021 Omicron 

BA.1 had become the dominant virus variant, replacing the previously dominant Delta variant. 

By early April 2022, Omicron BA.2 became the dominant virus strain in the U.S, but by late 

April to early May, Omicron BA.2.12.1 began rapidly spreading and became the dominant strain 

in the U.S. for a time. Most recently, two other Omicron sublineages, BA.4 and BA.5, which 

appeared in South Africa in March 2022, have spread to the U.S. and as of June 25, 2022, when 

combined constitute the majority of the circulating SARS-CoV-2 virus in the U.S.. 

Compared to the prototype strain spike (S) antigen used in currently available COVID-19 

vaccines (referred to here as prototype vaccines), the Omicron S protein has more than 

30 mutations, 15 of which are in the spike receptor binding domain (RBD), the predominant 

target of neutralizing antibodies elicited by infection and vaccination. The large number of 

mutations is of particular concern, including the mutations in the RBD known to be important for 

ACE2 receptor binding and antibody recognition. Several studies documented that sera from 

previously infected or vaccinated individuals had substantially reduced neutralization titers to 

Omicron BA.1 and BA.2 compared to previously circulating virus strains (e.g., D614G) and 

most approved or authorized monoclonal antibodies have reduced activity to Omicron.2

Neutralization titers against recent Omicron sublineages (e.g., BA.2.12.1 and BA.4/BA.5) 

elicited by current COVID-19 vaccines appear to be further reduced.3

 In addition, Omicron 

infection of previously unvaccinated individuals results in a neutralizing antibody response that 

is not extensively cross-reactive for other SARS-CoV-2 VOCs. On the other hand, however, 

Omicron infection following vaccination appears to improve neutralizing antibody titers against 

2 See Mannar D, James W Saville JW, Zhu X et al. SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM 

structure of spike protein-ACE2 complex. Science 2022. DOI: 10.1126/science.abn7760; Zhou T, Wang L, Misasi J 

et al. Structural basis for potent antibody neutralization of SARS-CoV-2 variants including B.1.1.529. Science 2022. 

DOI: 10.1126/science.abn8897; Iketani S, Liu L, Guo Y et al. Antibody evasion properties of SARS-CoV-2 

Omicron sublineages. Nature 2022. DOI: 10.1038/s41586-022-04594-4; Lusvarghi S, Pollett SD, Neerukonda SN et 

al. SARS-CoV-2 BA.1 variant is neutralized by vaccine booster-elicited serum but evades most convalescent serum 

and therapeutic antibodies. Sci Transl Med 2022. DOI: 10.1126/scitranslmed.abn8543. 

3 See Qu P, Faraone J, Evans JP et al. Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 

Subvariants. N Engl J Med 2022. DOI: 10.1056/NEJMc2206725; Hachmann NP, Miller J, Collier AY et al. 

Neutralization Escape by the SARS-CoV-2 Omicron Variants BA.2.12.1 and BA.4/BA.5 medRxiv 2022. DOI: 

https://doi.org/10.1101/2022.05.16.22275151 Preprint.
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other VOCs.

4 Although the sublineages of Omicron are antigenically closer to each other than 

Omicron is to previously circulating variants, the amino acid changes among the different 

sublineages may still be significant in the context of cross-protection. 

Within the S protein, BA.2 has an additional six amino acid changes relative to BA.1, two in the 

N-terminal domain (NTD) (T19I and V213G) and four in the RBD (S371F, T376A, D405N, and 

R408S).5 There is also a nine-nucleotide deletion in the NTD of BA.2 that results in deletions of 

amino acids 24-26 and mutation A27S. The more recently characterized Omicron sublineages 

BA.2.12.1 and BA.4 and BA.5 share many of the S protein mutations present in BA.2. For 

example, BA.2.12.1 is identical to BA.2 with the exception of two additional amino acid changes 

at L452Q (in the RBD) and S704L (not in the RBD). The BA.4/BA.5 S protein sequence is also 

similar to that of BA.2 except that the Q493R change is absent, and additional changes are 

present at L452R and F486V (both in the RBD). The BA.4/BA.5 sublineages also share the 

deletions at H69 and V70 present in Omicron BA.1. Numerous studies to compare and contrast 

the cross-protection afforded by Omicron sublineages are ongoing. It should be noted that the S 

protein amino acid sequences of BA.4 and BA.5 used for vaccine production are identical and 

can be considered together.

B. World Health Organization (WHO) Recommendations for COVID-19 Vaccine 

Strain Composition 

The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC)

issued an updated interim statement on June 17, 2022.6 The key recommendations in the recent 

interim statement stated:

• The use of currently available vaccines based on protype virus strains from early in the 

pandemic provide a high level of protection against severe disease outcomes for all virus 

variants, including Omicron, if the primary vaccination series is supplemented with a 

booster vaccine dose. 

4 See Richardson SI, Madzorera VS, Spencer H et al. SARS-CoV-2 Omicron triggers cross-reactive neutralization 

and Fc effector functions in previously vaccinated, but not unvaccinated, individuals. Cell Host Microbe 2022. DOI: 

10.1016/j.chom.2022.03.029.

5 See Covariants website: https://covariants.org/. 

6 See WHO’s Interim statement on the composition of current COVID-19 vaccines, dated June 17, 2022, available at 

https://www.who.int/news/item/17-06-2022-interim-statement-on--the-composition-of-current-COVID-19-vaccines. 
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• Broader immunity against recent circulating virus variants may be achieved by including 

an Omicron component in a booster vaccine dose to those who have previously received 

a COVID-19 vaccination primary series.

• The use of an Omicron-specific monovalent vaccine as a primary series was not advised 

because of the uncertainty of whether such a vaccine would elicit the same level of 

protection against severe illness as previously demonstrated for prototype COVID-19 

vaccines.

The TAG-CO-VAC statement acknowledged the limited amount of data currently available and 

the considerable uncertainties that remain, including the course of SARS-CoV-2 evolution and 

the relative performance of variant-specific vaccine formulations. The TAG-CO-VAC continued 

to strongly encourage the generation of additional clinical immunogenicity data from Omicronspecific candidate vaccines from a variety of vaccine platforms.

C. The June 28, 2022 VRBPAC Meeting 

On June 28th, 2022, a meeting of the Vaccines and Related Biological Products Advisory 

(VRBPAC) convened in an open session to discuss whether and how the SARS-CoV-2 strain 

composition of COVID-19 vaccines should be modified. The committee heard presentations on: 

the current epidemiology of the COVID-19 Pandemic and SARS-CoV-2 variants (H Scobie, 

CDC); COVID-19 vaccine effectiveness (R Link-Gelles, CDC); modeling future epidemiology 

of the COVID-19 pandemic (J T Lessler, University of North Carolina); vaccine manufacturer 

presentations on clinical data regarding variant vaccines (ModernaTX, Pfizer, Inc., Novavax 

Inc.); considerations for vaccine strain composition from the WHO TAG-Co-VAC (K Subbarao, 

WHO Collaborating Center for Reference and Research on Influenza, Melbourne, Australia); 

and the FDA perspective on the considerations for strain composition modifications of COVID19 vaccines.7

 

After these presentations and the committee discussion, the VRBPAC voted 19-2 in favor of the 

inclusion of a SARS-CoV-2 Omicron component for COVID-19 booster vaccines in the U.S. 

Although there was not a vote on the topic, there was general preference among committee 

7 See FDA’s website for background materials on the June 28, 2022 VRBPAC meeting, available at 

https://www fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-productsadvisory-committee-june-28-2022-meeting-announcement. 
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members for a bivalent vaccine with an ancestral strain and an Omicron strain. Specifically, there 

seemed to be a preference for vaccine coverage of Omicron sublineages BA.4 and BA.5. 

II. Discussion 

Several key issues will need to be addressed for any recommendation to modify the composition 

of COVID-19 vaccines. These issues include the current epidemiology of circulating virus 

variants, the antigenic relatedness of currently circulating virus variants to the strain included in 

current vaccines composition, whether there is evidence that current vaccines are less effective 

against new circulating virus variants than against previous strains of virus, and whether there is 

data that indicates a candidate vaccine with an updated strain composition will be more effective 

against new circulating virus variants and provide an improved clinical benefit. The FDA has 

reviewed a variety of data relevant to each of these issues that informed our advice to vaccine

manufacturers seeking to update their COVID-19 vaccine composition for a potential fall 2022 

booster vaccination campaign. 

As noted above, epidemiological data indicates that the SARS-CoV-2 Omicron variant has 

become dominant globally. The Omicron VOC poses a higher risk of re-infection than previous 

virus strains and has further evolved into sub-lineages that are also antigenically distinct but 

much more closely related to each other than to previous circulating variants. Because of their 

antigenic relatedness, these sub-lineages are not classified as separate VOCs. Virus surveillance 

data indicates that almost all SARS-CoV-2 viruses in the world are currently descended from the 

Omicron variant lineage, and there is no evidence to suggest that earlier strains of virus such as 

the original prototype strain represented in current vaccines, nor the previously identified VOC

(Alpha, Beta, Gamma and Delta), are in existence. Modeling data such as that presented in the 

April 6th VRBPAC and phylogenetic analysis strongly suggest that future strains of virus will 

evolve from the Omicron VOC. As of June 25, 2022, the Omicron sublineages BA.4 and BA.5 

constitute the majority of circulating Omicron sublineages in the U.S.

As noted in the Agency’s VRBPAC briefing document,8 the current authorized and approved 

COVID-19 vaccines in the U.S. are based on the original prototype strain, and the recent and 

current circulating SARS-CoV-2 variants harbor mutations in the S protein that confer at least 

partial antigenic escape from vaccine-elicited immunity. Results from observational studies that 

have investigated the effectiveness of primary vaccination with authorized and approved 

8 See Briefing document, available at https://www fda.gov/media/159452/download. 
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vaccines have shown decreased effectiveness against certain variants (notably Omicron, for 

which neutralizing antibody titers are decreased compared with the prototype strain) and waning 

effectiveness over time.

9

 Although first booster doses have restored waning vaccine 

effectiveness (VE), including against severe disease and hospitalization associated with 

Omicron,

10 observational studies have also indicated waning effectiveness of the first booster 

dose over time, mainly against mild disease, with some studies also suggesting waning 

effectiveness against hospitalization11 and lower effectiveness among the 

immunocompromised.

12 Taken together the data suggest that current COVID-19 vaccines are 

less effective against new circulating virus variants than against previous strains of virus. 

As outlined in Guidance for Industry “Emergency Use Authorization for Vaccines to Prevent 

COVID-19,” FDA recommends that the effectiveness of a modified COVID-19 vaccine against a 

particular VOC can be evaluated based on: efficacy of primary vaccination with the 

manufacturer’s authorized or approved prototype COVID-19 vaccine made by the same process 

9 See Tseng HF, Ackerson BK, Luo Y, et al. Accepted, Nature Medicine. Effectiveness of mRNA-1273 against 

SARS-CoV-2 Omicron and Delta variants. Nature Medicine, 2022. https://doi.org/10.1038/s41591-022-01753-y.;

Andrews N, Stowe J, Kirsebom F, et al. NEJM 2022. DOI: 10.1056/NEJMoa2119451; Taylor CA, Whitaker M, 

Anglin O, et al. COVID-19–Associated Hospitalizations Among Adults During SARS-CoV-2 Delta and Omicron 

Variant Predominance, by Race/Ethnicity and Vaccination Status — COVID-NET, 14 States, July 2021–January 

2022. MMWR Morb Mortal Wkly Rep 2022;71:466–473. DOI: 

https://www.cdc.gov/mmwr/volumes/71/wr/mm7112e2 htm. 

10 See Tseng, et al, ibid; Andrews, et al, ibid; Taylor et al, ibid; Korves C, Izurieta HS, Smith J, Zwain GM, Powell 

EI, Balajee A, Ryder K, Young-Xu Y. Relative effectiveness of booster vs. 2-dose mRNA Covid-19 vaccination in 

the Veterans Health Administration: Self-controlled risk interval analysis. medRxiv 2022.03.17.22272555; Preprint. 

DOI: https://doi.org/10.1101/2022.03.17.22272555. 

11 See Tseng, et al, ibid; Stowe J, Andrews N, Kirsebom F et al. Effectiveness of COVID-19 vaccines against 

Omicron and Delta hospitalisation: test negative case-control study. Preprint. 

https://khub net/documents/135939561/430986542/Effectiveness+of+COVID19+vaccines+against+Omicron+and+Delta+hospitalisation+-+test+negative+case-control+study.pdf/d0e803c0-

3dd2-0c1b-03b8-0a12fd211980; ; Ferdinands JM, Rao S, Dixon BE, et al. Waning 2-Dose and 3-Dose Effectiveness 

of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and 

Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 

10 States, August 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:255–263. DOI: 

https://www.cdc.gov/mmwr/volumes/71/wr/mm7107e2 htm; Chemaitelly H, Hussein H, Ayoub H, et al. Duration of 

mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar. medRxiv 

2022.03.13.22272308; doi: https://doi.org/10.1101/2022.03.13.22272308 Preprint.

12 See Tenforde MW, Patel MM, Gaglani M, et al. Effectiveness of a Third Dose of Pfizer-BioNTech and Moderna 

Vaccines in Preventing COVID-19 Hospitalization Among Immunocompetent and Immunocompromised Adults — 

United States, August–December 2021. MMWR Morb Mortal Wkly Rep 2022; 71:118–124. DOI: 

https://www.cdc.gov/mmwr/volumes/71/wr/mm7104a2 htm. 
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and for which a clinical disease endpoint efficacy study has been conducted that met FDA prespecified success criteria, and a comparison of immune responses (assessed by neutralizing 

antibody) induced by the modified vaccine and the prototype vaccine.13 The evaluation of 

modified vaccines for the purpose of vaccine strain composition decisions will need to rely on 

comparative immunogenicity data due to the time constraints involved in vaccine manufacturing 

and clinical efficacy evaluation. Toward that end, several manufacturers have prepared modified 

vaccine candidates for immunogenicity evaluation in clinical trials. Among COVID-19 vaccines 

currently authorized or approved for use in the U.S., clinical immunogenicity data for modified 

versions including an Omicron (BA.1) component are available for the Pfizer-BioNTech and 

Moderna COVID-19 vaccines. 

A superior Omicron (BA.1) neutralizing antibody response was elicited to a candidate bivalent 

vaccine from Moderna containing 25 μg each of mRNA encoding prototype and Omicron (BA.1 

sub-lineage) S protein compared to the response elicited by the approved Moderna booster 

vaccine (50 μg mRNA encoding prototype S protein). In addition, the neutralizing antibody 

response to the ancestral SARS-CoV-2 strain elicited by both vaccine boosters was similar.

Pfizer-BioNTech has studied two Omicron-containing candidate vaccines, a monovalent version 

and a bivalent version. In one study, a superior Omicron (BA.1) neutralizing antibody response 

was elicited to a candidate monovalent vaccine containing 30 μg of mRNA encoding Omicron 

(BA.1 sub-lineage) S protein compared to the response elicited by the authorized PfizerBioNTech booster vaccine (30 μg mRNA encoding prototype S protein). In a second study, 

bivalent candidate vaccines containing mRNA encoding prototype and Omicron (BA.1 sublineage) S protein at 2 different doses and monovalent vaccines containing mRNA encoding 

Omicron at 2 doses were compared to the authorized Pfizer-BioNTech booster vaccine. All 

tested candidate vaccines containing an Omicron component elicited a superior Omicron (BA.1) 

neutralizing antibody response. 

The results from these 3 studies indicate that an improved Omicron antibody response results 

from inclusion of the Omicron component in the vaccine. While all tested vaccines included a 

BA.1 Omicron strain, the data suggests that candidate vaccines containing other Omicron sublineages (BA.2, BA.4/BA.5) would be similarly immunogenic and provide improved neutralizing 

13 See FDA’s Guidance for Industry, entitled “Emergency Use Authorization for Vaccines to Prevent COVID-19,” 

available at https://www fda.gov/media/142749/download. 
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antibody responses to Omicron sub-lineage viruses because of the relatedness of S protein

among the various Omicron sub-lineages.

In addition to clinical immunogenicity data from candidate vaccines containing an Omicron 

component, additional data relevant to the potential effectiveness of an updated vaccine 

composition as a booster was reviewed. Several studies have shown that vaccination followed by 

infection with a VOC leads to an enhanced and broadened antibody response to SARS-CoV-2 

VOCs. While infection is different from vaccination, the results from such studies suggest that 

vaccination with a current vaccine followed by booster vaccination with a VOC vaccine might 

also lead to a broadened antibody response. The WHO-TAG-Co-VAC presented several 

examples of such data in their June 11th interim statement. Those examples, as well as more 

recent data, including unpublished studies that reported the improved neutralizing antibody 

responses to multiple Omicron sub-lineages following Omicron BA.4 or BA.5 infection, support 

the conclusion that an Omicron S protein exposure, either through vaccination or infection, 

increases and broadens the neutralizing antibody response to more recently circulating strains of 

virus.

Taken together, the data indicate that a modified booster vaccine composition is now warranted. 

Note that at this time we are not advising manufacturers to change the primary vaccination 

series, as right now there are inadequate clinical data to make such a recommendation.

The preponderance of evidence indicate that an improved antibody response to SARS-CoV-2 

Omicron variants results from inclusion of an Omicron component and suggests the potential for 

improved vaccine effectiveness for a modified booster formulation. In considering the 

recommended Omicron strain to be included in a modified vaccine formulation, it is appropriate 

to be guided by current epidemiological data as well as the breadth of protection that a modified 

vaccine might offer. The subvariants BA.4 and BA.5 are now dominant in the United States, and 

BA.1 is no longer circulating. Preliminary laboratory and epidemiologic evidence indicate that 

vaccines with a BA.1 spike may not be as effective against the BA.4 and BA.5 variants. As there 

is evidence for an increased breath of cross-reactive neutralizing antibodies elicited by modified 

vaccines containing an Omicron component, we expect that variants with a BA.4/5 component 

will provide a cross-reactive neutralizing antibody response that will more likely match the 

variant strains that may evolve to circulate during fall 2022 and after. 

Toward this end, FDA has recommended that vaccine manufacturers considering updating their 

vaccines for a potential fall 2022 booster campaign add a BA.4/5 component. In addition, 

because the currently authorized and approved COVID-19 vaccines provide protection against 

COVID-19, we are recommending that vaccine manufacturers maintain a component of the
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prototype strain. Should we receive requests to authorize modified COVID-19 vaccines, in 

evaluating such requests we expect that it will be appropriate to consider that available clinical 

immunogenicity data from clinical studies of vaccines containing Omicron BA.1 components, 

among other data potentially applicable to the safety and effectiveness of modified vaccines.

III.Conclusion 

For the reasons noted above, to optimize protection during a potential fall 2022 booster 

vaccination campaign, FDA is recommending that vaccine manufacturers develop a bivalent 

(prototype + Omicron BA.4/5 S protein) COVID-19 vaccine for use as a booster dose. 

Specifically, FDA is requesting that vaccine manufacturers expediently conduct clinical studies 

in relevant populations (inclusive of different age groups and vaccination history) to generate 

clinical safety and immunogenicity data with a bivalent (prototype + Omicron BA.4/5 S protein) 

booster composition of its authorized COVID-19 vaccines. The Agency considers the current 

year to be transitional, and data becoming available from clinical studies over the coming months 

may inform any future recommendation for primary series strain composition.