cdc.gov/coronavirus

Considerations for Bivalent Primary Series 

Sara Oliver, MD, MSPH

ACIP Meeting

February 24, 2023
 Does ACIP support harmonizing the vaccine strain composition for mRNA COVID-19 

vaccines across both primary series and booster doses:

Changing the primary series from monovalent (Original) to bivalent (Original plus Omicron 

BA.4/5) for all ages?

Question for consideration

2

Monovalent 

Monovalent Bivalent

People ages 6 months and older*

Bivalent Bivalent Bivalent

People ages 6 months and older*

Current recommendations 

(Simplified representation) Future proposed recommendations

*Ages and vaccines as authorized by FDA and recommended by ACIP/CDC

For children ages 6 months-4 years of age who start a Pfizer-BioNTech 

primary series, 3-dose primary series still needed

*Ages and vaccines as authorized by FDA and recommended by ACIP/CDC

For children ages 6 months-4 years of age who start a Pfizer-BioNTech 

primary series, the third dose in a 3-dose primary series is a bivalent dose

Booster dose

Primary series (in most ages)

Booster dose

Primary series (in most ages)
Policy considerations for bivalent primary series

3

 Policy on bivalent primary series will be coordinated with FDA for 

regulatory action, and CDC/ACIP for recommendations for use 

Review data 

Discuss 

considerations 

FDA

Regulatory 

allowance

CDC/ACIP

Recommendations 

for use
4

Public 

Health 

Problem

Considerations for Bivalent Primary Series 
Coverage / Age (years) <2 2–4 5–11 12–17 18–24 24–49 50–64 >65

At least 1-dose 7.6 10.3 39.7 71.9 81.9 85.2 95.0 95.0

Completed primary series 3.7 5.5 32.6 61.6 66.5 72.0 83.7 94.2

1st monovalent booster* - - 3.3 16.6 27.2 45.3 64.6

2nd monovalent booster * - - - - - - 10.6 25.3

Bivalent booster** 0.2 0.3 4.0 7.0 6.7 11.2 20.3 40.8

Unvaccinated 92.4 89.7 60.3 28.1 18.1 14.8 —† —†

U.S. COVID-19 Vaccination Coverage (%) of Total Population by 

Age Group — February 8, 2023

*Monovalent booster dose coverage as of August 26, 2022

** Bivalent booster coverage is independent of 1st and 2nd dose monovalent coverage

†Note: Coverage is capped at 95%

Source: https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trends Updated February 10, 2023 5
Gray boxes indicate potential reporting delays. Interpretation of trends should be excluded from these weeks. 

Weekly Population-Based Rates of COVID-19-Associated Hospitalizations among 

Children and Adolescents Ages ≤17 Years — COVID-NET, March 2020–February 2023

0

10

20

30

40

50

60

70

80

Rate per 100,000 population

Week Ending Date

August 2022–February 2023

0

10

20

30

40

50

60

70

80

Rate per 100,000 population

Week Ending Date

March 2020–February 2023 (entire pandemic period)

<6 months 6 months–<2 years 2–4 years 5–11 years 12–17 years

Gray boxes indicate potential reporting delays. Interpretation of trends should be excluded from these weeks. 
Underlying Medical Conditions among Children and Adolescents Ages ≤17 Years 

— COVID-NET, June–November 2022

13.1

11.2

8.8 8.8

7.9

6.7 6.6 6.4

5.3

3.5 3.4

2.6 2.2

0

2

4

6

8

10

12

14

Weighted % of hospitalizations

Data are limited to hospitalizations where COVID-19 is a likely primary reason for admission.

49% of hospitalized children and 

adolescents have no underlying 

medical conditions.
Age-adjusted rates of COVID-19-associated hospitalization by vaccination status and 

receipt of booster dose in children and adolescents

COVID-NET, December 2021 - December 2022

CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination Accessed February 10, 2023 8

Hospitalization rates by vaccination status

Adolescents ages 12-17 years

Hospitalization rates by vaccination status

Children ages 5-11 years
0

50

100

150

200

250

300

0-5

months

6-11

months

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

COVID-19 deaths

Age in years

COVID-19 deaths in children and adolescents by age based on death certificate 

data, National Center for Health Statistics

January 1, 2020–February 11, 2023

Source: https://data.cdc.gov/NCHS/Provisional-COVID-19-Deaths-Counts-by-Age-in-Years/3apk-4u4f/data. Accessed February 16, 2023 

Children 6 months–17 years: 

1489 COVID-19 deaths

1.4% of all deaths in this age group
Death rates by vaccination status and receipt of bivalent booster doses among 

people ages 5 years and older April 3 – December 3, 2022 (23 U.S. Jurisdictions)

*Includes either a booster or additional dose. Updated booster = Bivalent booster 

CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status Accessed February 10, 2023

In November 2022, people ages 

5 years and older with 

bivalent booster had 

12.7 times lower risk of dying 

from COVID-19, compared 

to unvaccinated people and 

2.4 times lower risk of dying from 

COVID-19 than people 

vaccinated without 

a bivalent booster

10
 Children and adolescents can develop severe COVID-19. Nearly 1500 children and 

adolescents have died from COVID-19 since the beginning of the pandemic

 Half of the hospitalized children and adolescents had no underlying medical 

conditions 

 During all periods, COVID-19 hospitalizations and mortality were consistently higher

among unvaccinated persons than among persons who had completed a primary 

series and/or an updated booster

 Many children remain unvaccinated for COVID-19

Considerations for Bivalent Primary Series 

Public Health Problem 
Benefits 

and 

Harms

Considerations for Bivalent Primary Series

12
 Ongoing, Phase 3, open-label study (unpublished, data obtained from sponsor)

 Children ages 6 months – 5 years in United States

–

–

Original primary series (historical control): 4,792 participants received 25 ug of 

mRNA-1273

BA.1 bivalent primary series: 179 participants received 25 ug of mRNA-1273.214 

(12.5 ug original strain and 12.5 ug Omicron BA.1 strain) 

 Median follow-up for the original vaccine was 102 days post Dose 1 and for the BA.1 

bivalent vaccine was 85 days post Dose 1 

 Baseline SAR-CoV-2 positive was 8% for the original vaccine and 63% for the BA.1 

bivalent vaccine

Moderna BA.1 bivalent primary series among children 

ages 6 months – 5 years 

13
Immunogenicity of Moderna BA.1 bivalent primary series 

among children ages 6 months – 5 years 

14

Bivalent Vaccine Original Vaccine

Outcome Time point N GMTa (95% CI) N GMTa (95% CI) GMRb (95% CI) –

Bivalent vs. Original

BA.1 

Neutralizing 

Antibody

Pre Dose 1

58

49.2 (30.4, 79.6)

402

5.9 (5.5, 6.2)

Day 57 1889.7 (1430.0, 2497.2) 74.3 (67.7, 81.7) 25.42 (20.14, 32.07)c

Original Strain 

Neutralizing 

Antibody

Pre Dose 1

66

35.6 (24.0, 52.7)

594

9.6 (8.9, 10.4)

Day 57 1432.9 (1054.5, 1947.0) 1732.5 (1611.5, 1862.5) 0.83 (0.67, 1.02)d

GMT = geometric mean titer; GMR = geometric mean ratio; CI=confidence interval

a GMTs were estimated using an analysis of covariance (ANCOVA) model with neutralizing antibody values at Day 57 as the depend 

variable and a group variable (mRNA-1273.214 vs mRNA-1273) as the fixed variable, adjusted by age group and by baseline SARS-CoV-2 

infection status. The GMT value at Day 57 was estimated by the geometric least square mean (GLSM) from the model.

b GMRs were estimated by the ratio of the GLSMs with a 2-sided 95% CI from the model

c Met the pre-specified superiority success criterion (lower bound of the 95% CI > 1.0)

d Met the pre-specified non-inferiority success criterion (lower bound of the 95% CI > 0.667)
 142 patients received two doses of the bivalent vaccine

 Percentage of patients reporting solicited local or systemic events was similar to or 

less than percentages seen after original vaccine, however this may be a result of the 

larger percent of seropositive participants in the bivalent vaccine group

 Pain, axillary (or groin) swelling or tenderness, and erythema were the most common 

local events

 Irritability/crying, sleepiness, and fatigue were the most common systemic events

 There were no Grade 4 solicited adverse events reported

 There was one serious adverse events (SAE) of asthma exacerbation reported after 

the first dose that was assessed as unrelated to vaccination by the investigator

Safety of Moderna BA.1 bivalent primary series among 

children ages 6 months – 5 years 
Safety of Moderna BA.1 bivalent primary series among 

children ages 6 months – 5 years 

From Jan 26, 2022 VRBPAC meeting: https://www.fda.gov/media/164810/download
Safety of Moderna BA.1 bivalent primary series among 

children ages 6 months – 5 years 

From Jan 26, 2022 VRBPAC meeting: https://www.fda.gov/media/164810/download

Systemic reactions 6–36 months

Systemic reactions 37 months–5 years
 Concern that initial exposure to one virus strain may primes B-cell memory and limit the 

development of memory B cells and neutralizing antibodies against new strains

 Prior infection and/or vaccine history likely has impact on subsequent immune response1-3

 Affinity maturation occurs: the ability of memory B cells to mature over time, especially 

when exposed to newer strains4-5

– Variant-specific vaccines can also initiate new variant-specific immune responses6-7

 Clinical impact of different immune responses by prior exposure, or how it may differ by 

infection and vaccine, requires additional research

 Vaccines continue to be able to provide a broad boost in antibody responses 

 Imprinting concerns related to incremental benefit of updated variant-specific vaccines

Considerations for Bivalent Primary Series: 

Imprinting

1. Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure | Science

2. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution (nature.com)

3. Protective Effect of Previous SARS-CoV-2 Infection against Omicron BA.4 and BA.5 Subvariants | NEJM

4. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations – ScienceDirect 18

5. The germinal centre B cell response to SARS-CoV-2 | Nature Reviews Immunology

6. SARS-CoV-2 Omicron boosting induces de novo B cell response in humans | bioRxiv

7. Molecular fate-mapping of serum antibody responses to repeat immunization (nature.com)
 Several studies compared antibody titers with recent Omicron sub-lineages for both the bivalent 

and monovalent vaccines; most studies ranging from ~21-42 days after bivalent vaccine

 Ratio of antibody titers from bivalent vaccine to monovalent vaccine shown

Comparing monovalent and bivalent vaccines

Antibody data

1. https://www.biorxiv.org/content/10.1101/2022.10.22.513349v1.full.pdf

2. https://www.nejm.org/doi/full/10.1056/NEJMc2213948

3. https://www.nejm.org/doi/full/10.1056/NEJMc2214314

4. https://www.biorxiv.org/content/10.1101/2022.10.31.514636v1

5. https://www.nature.com/articles/s41591-022-02162-x

19 Wang, et al1 Collier, et al2 Davis-Gardner4 Kurhade, et al Miller, et al3 5

0

1

2

3

4

5

6

7

8

9

10

BA.4/5 BA.4/5 XBB.1 BA.4/5 XBB.1

Bivalent to Monovalent Ratio of Antibody Titers

Pseudovirus neutralization assays Live virus neutralization assays

 Overall, most studies show improvement 

in neutralizing antibodies for Omicron 

sub-lineages with a bivalent vaccine 

(ratio >1)

 Clinical impact is unknown for specific 

ratios or antibody levels 

 Neutralizing antibodies at a single time do 

not convey the entire immune response
 Unable to directly compare clinical outcomes for monovalent and bivalent vaccines in 

the U.S. due to timing of authorizations 

Comparing monovalent and bivalent vaccines

Clinical data

https://www.fda.gov/media/164810/download

A Randomized Trial Comparing Omicron-Containing Boosters with the Original Covid-19 Vaccine mRNA-1273 | medRxiv 20

 Study in the UK found ~10% 

increase in relative VE for COVID-19 

infections 

 Unable to estimate differential 

impact for prevention of severe 

COVID-19
Considerations for Bivalent Primary Series 

Benefits and Harms 

21

 Bivalent COVID-19 vaccines are able to induce an immune response when given 

either as a primary series or a booster dose

 Limited data to directly compare COVID-19 outcomes after receipt of a 

monovalent or bivalent vaccine 

 COVID-19 vaccines have a high degree of safety. Initial safety data from bivalent 

primary series trial are encouraging but study was not powered to assess rare 

adverse events
22

Feasibility 

and 

Implementation

Considerations for Bivalent Primary Series
Number of mRNA COVID-19 vaccine products currently

Moderna: 5 products Pfizer-BioNTech: 6 products 

11 TOTAL Products!
Possible number of mRNA COVID-19 vaccine products with a 

bivalent primary series

Moderna: 2 products Pfizer-BioNTech: 3 products 

Could be reduced to 

5 total products

Would eliminates look-alike vials for 

Moderna and Pfizer-BioNTech
Transition to bivalent primary series could: 

 Improve storage space

–

–

–

–

–

Providers have limited storage space

In addition to monovalent and bivalent products, Vaccines for Children (VFC) stock required 

to be duplicate and separate

 Reduce errors

Would eliminate ‘look-alike’ vials

Currently, one of the most common administration errors reported is providers giving a 

bivalent vaccine as a primary series

 Allow for continued access to primary series

Majority of current monovalent vaccine stock expires within the next few months

Considerations for Bivalent Primary Series 

Feasibility and Implementation 

25
 Work is ongoing to evaluate cost effectiveness in preparation for a transition to 

commercialization of COVID-19 vaccine 

 Bivalent COVID-19 vaccines already purchased and delivered; transition of current 

primary series recommendations from monovalent to bivalent vaccines unlikely 

to have significant impact on resource use

Considerations for Bivalent Primary Series 

Resource Use 
Summary 
Considerations for Bivalent Primary Series 

Summary

28

 Receiving a COVID-19 vaccine primary series continues to be important for 

prevention of COVID-19 severe disease, hospitalization, and death

 Many children and adolescents remain unvaccinated for COVID-19

 COVID-19 vaccines recommendations that are simple to implement may remove 

some barriers to uptake

 Harmonizing the primary series and booster doses could simplify the presentations, 

reduce administration errors, and allow continued access to primary series for 

unvaccinated populations

 The Work Group was supportive of a transition of the mRNA COVID-19 vaccine 

primary series from monovalent (original) to bivalent (original plus Omicron BA.4/5)
 Monica Godfrey

 Megan Wallace 

 Danielle Moulia

 Evelyn Twentyman

 Hannah Rosenblum

 Lauren Roper

 Katherine Fleming-Dutra

 Sarah Meyer

 Susan Goldstein

 Mary Chamberland

 Elisha Hall

 Julianne Gee

 Valerie Morelli

 JoEllen Wolicki

 Heather Scobie

 Ruth Link-Gelles

 Megan Lindley

 Sierra Scarbrough

 Jefferson Jones

 Aron Hall

 Barbara Mahon

 Data Analytics and Visualization Task Force

 Coronavirus and other Respiratory Viruses Division

 National Center for Immunization and Respiratory 

Diseases

Acknowledgments
Question for ACIP

30

 Transition to bivalent primary series can only occur after FDA regulatory action 

and updates to CDC recommendations 

 What are ACIP thoughts on a transition of the mRNA COVID-19 vaccine primary 

series from monovalent (original) to bivalent (original plus Omicron BA.4/5)?

Note: “Monovalent” and “bivalent” designations are based on the currently authorized products. 

For future vaccines, focus would be harmonization of products across primary series and booster doses. 
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

Thank you
Comparing monovalent and bivalent vaccines

Antibody data

1. https://www.biorxiv.org/content/10.1101/2022.10.22.513349v1.full.pdf

2. https://www.nejm.org/doi/full/10.1056/NEJMc2213948

3. https://www.nejm.org/doi/full/10.1056/NEJMc2214314

4. https://www.biorxiv.org/content/10.1101/2022.10.31.514636v1

5. https://www.nature.com/articles/s41591-022-02162-x

32

Pseudovirus neutralization assay Bivalent BA.4/BA.5

N=19

Monovalent

N=21 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 8488 12054 0.70

BA.4/BA.5 neutralizing antibody titers (ID50) 1649 1366 1.2

Pseudovirus neutralization assay Bivalent BA.4/BA.5

N=15

Monovalent

N=18 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 40575 21507 1.89

BA.4/BA.5 neutralizing antibody titers (ID50) 3693 2829 1.31

Live virus neutralization assay Bivalent BA.4/BA.5

N=12

Monovalent

N=12 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 2312 1812 1.27

BA.5 neutralizing antibody titers (ID50) 576 142 4.06

Live virus neutralization assay

Bivalent BA.4/BA.5

WITH infection

N=23

Monovalent

N=25 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 5776 1533 3.77

BA.4/BA.5 neutralizing antibody titers (ID50) 1558 95 16.4

XBB.1 neutralizing antibody titers (ID50) 103 15 8.58

Wang, et al1

Collier, et al2

Davis-Gardner, et al4

Kurhade, et al5

Pseudovirus neutralization assay Bivalent BA.4/BA.5

N=15

Monovalent

N=18 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 40515 21507 1.89

XBB.1 neutralizing antibody titers (ID50) 170 175 0.97

Miller, et al3

References for data: 

Live virus neutralization assay

Bivalent BA.4/BA.5

Without infection

N=29

Monovalent

N=25 Ratio

Ancestral SARS-CoV-2 antibody titers (ID50) 3620 1533 2.36

BA.4/BA.5 neutralizing antibody titers (ID50) 298 95 3.14

XBB.1 neutralizing antibody titers (ID50) 35 15 2.33

Antibody titers measured 24-26 days after vaccine

Antibody titers measured ~21 days post-dose for bivalent and ~32 days post-dose for monovalent group 

Timing post-vaccine differed (monovalent: 70-100 days post vaccine; bivalent: 16-42 days post vaccine) 

Antibody titers measured ~21 days post-dose for bivalent and ~32 days post-dose for monovalent group 

Antibody titers measured at different time points (monovalent: 23-94 days post vaccine; bivalent: 14-32 days post vaccine)