Document text
cdc.gov/coronavirus
Considerations for Bivalent Primary Series
Sara Oliver, MD, MSPH
ACIP MeetingFebruary 24, 2023
Does ACIP support h armonizing 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
2Mono-
valent Mono-
valent BivalentPeople ages 6 months and older*
Bivalent Bivalent BivalentPeople 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 doseBooster dose
(in most ages) Primary seriesBooster dose
(in most ages) Primary series
Policy considerations for bivalent primary series
3Policy on bivalent primary series will be coordinated with F DAfor
regulatory action, and CDC/ACIP for recommendations for use
Review data
Discuss
considerations FDA
Regulatory
allowanceCDC/ACIP
Recommendations
for use
4Public
Health
ProblemConsiderations 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 1stand 2nddose 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
01020304050607080Rate per 100,000 population
Week Ending DateAugust 2022– February 2023
01020304050607080Rate per 100,000 population
Week Ending DateMarch 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
2.62.2
02468101214Weighted % 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
050100150200250300
0-5
months6-11
months1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17COVID -19 deaths
Age in yearsCOVID -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, 2023In 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- 19Considerations for Bivalent Primary Series
Public Health Problem
Benefits
and
HarmsConsiderations for Bivalent Primary Series
12
Ongoing, Phase 3, open- l abel study (unpublished, data obtained from sponsor)
Children ages 6 months –5 y ears in United States
–
–Original primary series (historical control): 4,792 participants received 25 ug of
m
RNA- 1273
BA.1 bivalent primary series: 179 participants received 25 ug of mRNA -1 273.214
(12.5 ug original strain and 12.5 ug Omicron BA.1 strain)
Median follow- up f or the original vaccine was 102 days post Dose 1 and for the BA.1
bivalent vaccine was 85 days post Dose 1
Baseline SAR -Co V-2 positive was 8% for the original vaccine and 63% for the BA.1
bivalent vaccineModerna 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
14Bivalent Vaccine Original Vaccine
Outcome Time point NGMTa(95% CI)N GMTa(95% CI)GMRb(95% CI) –
Bivalent vs. Original
BA.1
Neutralizing AntibodyPre Dose 1
5849.2 (30.4, 79.6)
4025.9 (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 AntibodyPre Dose 1
6635.6 (24.0, 52.7)
5949.6 (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 investigatorSafety 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 –36months
Systemic reactions 37 months –5 years
Concern that initial exposure to one virus strain may primes B -c ell 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 oc curs: the ability of memory B cells to mature over time, especially
when exposed to newer strains4-5
–Variant -s pecific 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
i
nfection and vaccine, requires additional research
Vaccines continue to be able to provide a b road boost in antibody responses
Imprinting concerns related to in cremental benefit of updated variant- specific vaccinesConsiderations 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 185.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- l ineages for both the bivalent
and monovalent vaccines; most studies ranging from ~21 -42 days after bivalent vaccine
Ratio o f antibody titers from bivalent vaccine to monovalent vaccine shownComparing 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-x19Wang, et al1Collier, et al2 Davis -Gardner4 Kurhade, et al5 Miller, et al3012345678910
BA.4/5 BA.4/5 XBB.1 BA.4/5 XBB.1Bivalent to Monovalent Ratio of Antibody Titers
Pseudovirus neutralization assays Live virus neutralization assaysOverall, most studies show improvement
i
n neutralizing antibodies for Omicron
sub- lineages with a bivalent vaccine
(ratio >1 )
Clinical impact is unknown for specific r
atios or antibody levels
Neutralizing antibodies at a single time do no
t 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 ~1 0%
increase in relative VE for COVID- 19
infections
Unable to estimate differential i
mpact for prevention of severe
COVID -19
Considerations for Bivalent Primary Series
Benefits and Harms
21Bivalent COVID-1 9 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 -1 9 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
22Feasibility
and
ImplementationConsiderations 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 s torage space
–
–
–
–
–Providers have limited storage space
In addition to monovalent and bivalent products, Vaccines for Children (VFC) stock required
t
o be duplicate and separate
Reduce errors
Would eliminate ‘look -alike’ vials
Currently, one of the most common administration errors reported is providers giving a bi
valent vaccine as a primary series
Allow for c ontinued access to primary series
Majority of current monovalent vaccine stock expires within the next few monthsConsiderations 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 useConsiderations for Bivalent Primary Series
Resource Use
Summary
Considerations for Bivalent Primary Series
Summary
28Receiving a C OVID- 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- 1 9
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,
r
educe administration errors, and allow continued access to primary series for
unvaccinated populations
The Work Group was su pportive 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 WolickiHeather 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
D
iseasesAcknowledgments
Question for ACIP
30Transition to bivalent primary series can only occur after FDA regulatory action
an
d updates to CDC recommendations
What are ACIP thoughts on a tr ansition 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
32Pseudovirus neutralization assayBivalent BA.4/BA.5
N=19Monovalent
N=21Ratio
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 assayBivalent BA.4/BA.5
N=15Monovalent
N=18Ratio
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 assayBivalent BA.4/BA.5
N=12Monovalent
N=12Ratio
Ancestral SARS -CoV -2 antibody titers (ID50) 2312 1812 1.27
BA.5 neutralizing antibody titers (ID50) 576 142 4.06
Live virus neutralization assayBivalent BA.4/BA.5
WITH infection
N=23Monovalent
N=25Ratio
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 8.58Wang, et al1
Collier, et al2
Davis -Gardner, et al4
Kurhade , et al5Pseudovirus neutralization assayBivalent BA.4/BA.5
N=15Monovalent
N=18Ratio
Ancestral SARS -CoV -2 antibody titers (ID50) 40515 21507 1.89
XBB.1 neutralizing antibody titers (ID50) 170 175 0.97Miller, et al3References for data:
Live virus neutralization assayBivalent BA.4/BA.5
Without infection
N=29Monovalent
N=25Ratio
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 2.33Antibody 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)