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1
Booster Doses of Moderna COVID -19 Vaccines in Adults,
Adolescents & Children
ACIP
September 1, 2022
Jacqueline Miller, MD
2Indication for Use of Moderna COVID -19 Vaccine, Bivalent
(Original And Omicron BA.4/BA.5)
EUA of Aug 31, 2022
Moderna COVID -19 Vaccine, Bivalent (Original And
Omicron BA.4/BA.5) is authorized for use in individuals 18
years of age and older as a single booster dose
administered at least 2 months after either:
▪Completion of primary vaccination with any authorized
or approved monovalent1COVID -19 vaccine, or
▪Receipt of the most recent booster dose with any
authorized or approved monovalent COVID -19
vaccine.
1Monovalent refers to any authorized or approved COVID -19 vaccine that contains or encodes the spike protein of only the Original SARS -CoV-2.
3
Rationale for Variant -Containing Booster Vaccines
▪Goals of variant -containing booster vaccines1,2
▪Retain neutralization for Original SARS -CoV-2
▪Stronger immune response against current variants
▪Broader cross -neutralization against future variants
▪Extend durability of protection
1. FDA Briefing Document for June 26, 2022 VRBPAC Meeting.
2. WHO Interim Statement on the Composition of Current COVID -19 Vaccines (June 17, 2022).
4Moderna COVID -19 Investigational Variant -containing
Vaccine Candidates Evaluated In Clinical Trials
▪Extensive evaluation of 3 monovalent and 4 bivalent investigational variant vaccines in
past year
▪>7,000 individuals boosted across all variant vaccine candidates
▪Bivalent vaccine candidates include :
25 µg
Original SARS -CoV-2
Beta -
containing vaccine
(mRNA -1273.211)
25 µg
Beta Variant
(B.1.351)
BA.1 Omicron -
containing vaccine
(mRNA -1273.214)
25 µg
Original SARS -CoV-2
25 µg
Omicron Variant
(BA.1)
BA.4/BA.5 Omicron -
containing vaccine
(mRNA -1273.222)
25 µg
Original SARS -CoV-2
25 µg
Omicron Variant
(BA.4/BA.5)
5
Clinical Studies of Booster Doses of Bivalent
Vaccines in Adults
6
Clinical Studies with Moderna COVID -19 Investigational
Bivalent Vaccine Candidates in Adults (≥ 18 Years of Age)
▪All participants previous received a primary series of mRNA -1273 (100 g); participants in Parts G & H
also previously received a 3rddose (50 µg) of mRNA -1273
▪Part G enrolled Mar 8 -23, 2022; Part H enrolled Aug 10 -23, 2022Bivalent Vaccine Study (Part) Dose NMedian
Follow -up
Beta
(mRNA -1273.211)205 (A)3rd (1st
booster)300 245 days
BA.1 Omicron
(mRNA -1273.214)205 (G)4th (2nd
booster)437 43 days
BA.4/BA.5 Omicron
(mRNA -1273.222)205 (H)4th (2nd
booster) 512 Ongoing
Total 1249
Chalkias et al. Research Squa re 2022, doi: 10.21203/rs.3.rs -1555201/v1; in press Nat Med
Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703; in press New Engl J Med
7Study of 4thDose (2ndBooster) in Adults Using BA.1 Omicron
Bivalent Vaccine (mRNA -1273.214) -
Demographics and Baseline Characteristics
Study 205, Safety Set
Characteristic4thDose (2ndBooster)
Original
(mRNA -1273)
N = 377BA.1 Omicron
Bivalent
(mRNA -1273.214)
N = 437
Mean Age -Years (range) 57.5 (20, 96) 57.3 (20, 88)
≥ 65 years 39.8% 39.8%
Female 50.7% 59.0%
Non-White Race 14.6% 12.8%
Hispanic / Latino Ethnicity 9.8% 10.5%
Interval between 2ndand 3rdDose
(months) –median (range)8.0 (5.6, 14.4) 8.0 (4.7, 15.0)
Interval between 3rdand 4thDose
(months) –median (range)4.4 (3.0, 10.2) 4.5 (2.9, 13.4)
Prior SARS -CoV-2 Infection 26.8% 22.0%
Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703; in press New Engl J Med
8
Solicited local adverse reactions within 7 days after injection. No Grade 4 events reported.
2nddose mRNA -1273 (Baden et al, NEJM 2021); 3rddose mRNA -1273 (Choi et al, Nat Med 2022); 4thdose mRNA -1273.214 ( Chalkias et al. medRxiv 2022; in press New Engl J Med ).Local Reactogenicity of BA.1 Omicron Bivalent (mRNA -1273.214) as 4thDose
Similar to 2ndDose of Primary Series and 3rdDose of Original (mRNA -1273) in
Adults
Study 205, Safety Set
88%84%
77%
9%5% 7%12%
5% 7%14%20%17%
0%20%40%60%80%100%Pain Erythema
Grade 1 -2Grade 3Axillary Swelling
or Tenderness
4thDose (2ndbooster) using BA.1 Omicron
(mRNA -1273.214)
N = 437Swelling
3rdDose (1stbooster) Original
(mRNA -1273)
N = 1672ndDose Original
(mRNA -1273)
N = 14,677
9Systemic Reactogenicity of BA.1 Omicron Bivalent (mRNA -1273.214) as 4th
Dose Generally Lower than 2ndDose of Primary Series and 3rdDose of
mRNA -1273 in Adults
Study 205, Safety Set
16%
7%4%59%55%
44%65%
59%55%58%
49%
40%43% 41%
31%
19%
11% 10%44%
35%
24%
0%20%40%60%80%100%Fever Headache Fatigue Myalgia ArthralgiaNausea /
VomitingChills
Solicited systemic adverse reactions within 7 days after injection. a) Grade 4 systemic reactions only with 2nddose of mRNA -1273 (<0.1%).
2nddose mRNA -1273 (Baden et al, NEJM , 2021); 3rddose mRNA -1273 (Choi et al, Nat Med , 2022); 4thdose mRNA -1273.214 ( Chalkias et al. medRxiv, 2022; in press New Engl J Med ).Grade 1 -2Grade 3a
4thDose (2ndbooster) using BA.1
Omicron bivalent (mRNA -1273.214)
N = 4373rdDose (1stbooster) Original
(mRNA -1273)
N = 1672ndDose Original
(mRNA -1273)
N = 14,677
10
Similar Overall Safety Profile of BA.1 Omicron Bivalent
(mRNA -1273.214) and Original mRNA -1273 as 4thDose (2ndBooster)
Study 205, Safety Set
Unsolicited AEs within 28 Days After Any Injectionn (%)
Original
(mRNA -1273)
N = 377BA.1 Omicron
Bivalent
(mRNA -1273.214)
N = 437
Any AE 78 (20.7%) 81 (18.5%)
SAE 1 (0.3%) 2 (0.5%)
Fatal AE 0 0
Medically Attended AE 52 (13.8%) 43 (9.8%)
AE Leading to Discontinuation from Study 0 0
Severe AE 3 (0.8%) 4 (0.9%)
11 Omicron BA.1 Neutralizing Titers Were Significantly Higher Following 4thDose
(2ndBooster) Using Omicron BA.1 Bivalent (mRNA -1273.214) than with mRNA -1273
Study 205, Per -Protocol Immunogenicity Set with No Prior Infection
1Based on ANCOVA model adjusting for age group (<65, ≥65 years) and pre -booster titer
2Common risk difference and 97.5% CI were calculated by Miettinen -Nurminen method adjusted for age group (<65, ≥65 years)
Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703 –in press New Engl J MedSuccess
Criteria MetParameter 4thDose (2ndBooster)
Original
(mRNA -1273)
N = 260Omicron BA.1 Bivalent
(mRNA -1273.214)
(N = 334)
GMT Pre -booster
95% CI332
(282, 391)298
(259, 343)
GMT at Day 291
95% CI1421
(1283, 1574)2480
(2264, 2716)
GMT Ratio1(Bivalent vs Original)
97.5% CI1.75
(1.49, 2.04)
Seroresponse rate at Day 29
95% CI99.2%
(97.2, 99.9)100%
(98.9, 100)
Difference in seroresponse rates2
97.5% CI1.5
(-1.1, 4.0)
Superiority ofGMTs: Lower 97.5% CI of GMT Ratio > 1.0
Non-inferiority ofSeroresponse Rates: Lower 97.5% CI of difference > -10%
12 Original Strain (D614G) Neutralizing Titers Were Higher Following 4thDose (2ndBooster)
Using Omicron BA.1 Bivalent (mRNA -1273.214) than with mRNA -1273
Study 205, Per -Protocol Immunogenicity Set with No Prior Infection
1 Based on ANCOVA model adjusting for age group (<65, ≥65 years) and pre -booster titer
2Common risk difference and 97.5% CI (Miettinen -Nurminen) cannot be calculated when SRR in both group is 100%, absolute differen ce is reported.
Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703 –in press New Engl J MedSuccess
Criteria MetParameter4thDose (2ndBooster)
Original
(mRNA -1273)
N = 260Omicron BA.1 Bivalent
(mRNA -1273.214)
(N = 334)
GMT Pre -booster
95% CI1521
(1353, 1710)1267
(1120, 1432)
GMT at Day 291
95% CI5287
(4887, 5719)6422
(5990, 6886)
GMT Ratio1(Bivalent vs Original)
97.5% CI1.22
(1.08,1.37)
Seroresponse rate at Day 29
95% CI100%
(98.9, 100)100%
(98.6, 100)
Difference in seroresponse rates2
97.5% CI0
Non-inferiority ofGMTs: Lower 97.5% CI of GMT Ratio >0.67
Non-inferiority ofSeroresponse Rates: Lower 97.5% CI of difference > -10%
13
3.8-fold
rise
7.1-fold
rise
4.4-fold
rise
8.0-fold
rise
2.5-fold
rise
4.8-fold
rise
512
3321558 1933
14733886
432
29816153070
23727676
2002,00020,000
All Participants SARS-CoV-2 Negative Pre-Booster SARS-CoV-2 Positive Pre-BoosterOmicron BA.1 Neutralizing Titers After 4thDose (2ndBooster) Significantly
Higher with BA.1 Omicron Bivalent (mRNA -1273.214) than mRNA -1273 in Adults
Study 205, Per -Protocol Immunogenicity Set
Omicron
Neutralizing
Antibody
ID50 GMT
(95% CI)
All Participants
No Prior Infection
Prior Infection
Omicron BA.1 Bivalent
(mRNA -1273.214)Original
(mRNA -1273) (N = 367) (N = 428) (N = 260) (N = 334) (N = 98) (N = 94)Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29
GMR: 1.78
95% CI: 1.56, 2.04
GMR: 1.75
95% CI: 1.49, 2.04
GMR: 1.90
95% CI: 1.50, 2.40
Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703;
in press New Engl J Med
14
18 –< 65 years
≥ 65 years
18 –< 65 years
≥ 65 yearsOmicron BA.1 and Original Strain (D614G) Neutralizing Titers After 4thDose (2nd
Booster) of BA.1 Omicron Bivalent Were Consistent in Persons ≥65 Years of Age
Study 205, Per -Protocol Immunogenicity Set with No Prior Infection
13041820
30037344947378
12351811
11111522
28431951987272
22292590
1001,00010,000
18-<65 - Ancestral 65+ - Ancestral 18-<65 - Omicron 65+ - OmicronNeutralizing
Antibody
ID50 GMT
(95% CI)
Original SARS -CoV-2
Pre
BoostDay
29Pre
BoostDay
29
BA.1 Omicron Bivalent
(mRNA -1273.214)Original
(mRNA -1273) (N = 120) (N = 139)Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29Pre
BoostDay
29
Omicron BA.1
(N = 120) (N = 139) (N = 140) (N = 195) (N = 140) (N = 195)
VRBPAC, June 28, 2022 https://www.fda.gov/media/159492/download
15
Omicron B.1 and Original Strain (D614G) Neutralizing Antibodies After 4th
Dose (2ndBooster) Comparable Across Racial Groups
Study 205, Per -Protocol Immunogenicity Set with No Prior Infection
(N=316) (N=376) (N=316) (N=376) (N=26) (N=30) (N=26) (N=30) (N=25) (N=22) (N=25) (N=22)
PBD29PBD29 PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29101001,00010,000100,000
3092333
207699
3403352
3232114
2942308
3431520 12346086
14585639
12236988
10354685
12735894
15535700Neutralizing Antibody
(GM Titer, 95%CI)Black/African
AmericanOther White
N=234 N=291 N=11 N=24 N=15 N=19 N=234 N=291 N=11 N=24 N=15 N=19
Prototype (mRNA-1273) Vaccine 50 μg BA.1 Omicron Bivalent Vaccine (mRNA-1273.214) 50 μg Omicron Original SARS-CoV-2
Black/African
AmericanOther White
Pre-booster ( PB), Day 29 post -boost ( D29)
164thDose (2ndBooster) with BA.1 Omicron Bivalent Booster (mRNA -
1273.214) Resulted in Higher Neutralizing Antibody Titers against Omicron
BA.4 & BA.5 than mRNA -1273 in Adults
Pre-booster ( PB), Day 29 post -boost ( D29)
PBD29PBD29PBD29PBD29 PBD29PBD29101001,00010,000
7202337
6091271
116727
140492
173941
209645Neutralizing Antibody
(GM Titer, 95%CI)No Prior InfectionPrior Infection All Participants
N=367 N=428 N=260 N=334 N=98 N=94
Original (mRNA-1273) 50 μg BA.1 Omicron Bivalent Vaccine (mRNA-1273.214) 50 μg
174th Dose (2ndBooster) with BA.1 Omicron Bivalent Booster (mRNA -1273.214)
Resulted in Higher Neutralizing Antibody Titers against Omicron BA.4/BA.5
Across Age Groups, Including ≥65 Year Olds, than mRNA -1273
Pre-booster ( PB), Day 29 post -boost ( D29)
PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29PBD29101001,00010,000
8442783
5321375
6582118
6311245
132817
161588
105670
123422
1901039
192679
162879
222624Neutralizing Antibody
(GM Titer, 95%CI)No Prior Infection Prior Infection All Participants
Original (mRNA-1273) 50 μg BA.1 Omicron Bivalent Vaccine (mRNA-1273.214) 50 μgN=221 N=255 N=146 N=173 N=140 N=195 N= 120 N= 139 N=78 N=60 N=20 N=3418-64 yrs ≥65 yrs 18-64 yrs ≥65 yrs 18-64 yrs ≥65 yrs
18
GMR –ratio of GMT of BA.1 Omicron bivalent/GMT of mRNA -1273 at day 29
VOC –Variant of Concern
Meso Scale Discovery (MSD) Assay. Nominal alpha = 0.05.
mRNA -1273 N = 350 -351; mRNA -1273.214 N = 398 -402Binding Antibody Titers Against VOCs Are Significantly Higher after 4thDose
(2ndBooster) with BA.1 Omicron Bivalent (mRNA -1273.214) than mRNA -1273 in
Adults
Study 205, Per -Protocol Immunogenicity Set
569
353502
384652
403546
442
1001,000
Alpha Beta Delta GammaBinding
Antibody
Titer GMT
(AU/mL) at
Day 29
(95% CI)
GMR: 1.17
95% CI: 1.09, 1.24
Alpha
GMR: 1.14
95% CI: 1.07, 1.22
Beta
GMR: 1.10
95% CI: 1.03, 1.16
Delta
GMR: 1.16
95% CI: 1.09, 1.24
Gamma
500
BA.1 Omicron Bivalent
(mRNA -1273.214)Original
(mRNA -1273) Thousands
19
19
Bivalent Beta Vaccine (mRNA -1273.211) as 3rd Dose Elicited Higher
Neutralizing Antibody Responses in Adults through 6 Months Compared to
mRNA -1273
Study 205 Part A & Study 201 Part B, Per -Protocol Immunogenicity Set, No Prior Infection
Geometric Mean Ratio –GMT of bivalent beta vaccine (mRNA.1273.211)/GMT of original mRNA -1273 vaccine ofvramRNA -
1273 N = 149; Bivalent Beta vaccine (mRNA -1273.211) N = 295
Chalkias et al. Research Square 2022, doi: 10.21203/rs.3.rs -1555201/v1 –in press Nature Medicine
20
Pre-Clinical Studies of Booster Doses of Bivalent
BA.4/5 -Containing Vaccine (mRNA -1273.222) in
Mice
21
Increased Immunogenicity after Booster Dose of the BA.1 & BA.4/BA.5
Omicron Bivalent Vaccines (mRNA -1273.214 & mRNA -1273.222) in Mice
BA.1, pre and post boost comparison•K18 hACE2 mice previously vaccinated with primary series of mRNA -1273 (n = 8 -10 per group)
•Boosted with Original (mRNA -1273), BA.1 Omicron Bivalent (mRNA -1273.214), or BA.4/BA.5 Bivalent (mRNA -
1273.222
•~31 weeks between primary series & booster
•Low 0.25 µg dose used to allow for differences between dose regimens to be captured
Neutralization (before and 4 weeks after booster)
Scheaffer et al, manuscript under preparationBA.1 neuts:
•7-and 3 -fold increase from bivalent
vaccines
BA.5 neuts:
•4.2-and 4.5 -fold increase from
bivalent vaccines
Limited boost from mRNA -1273 ns –not significant
* p <0.05
** p <0.01
PBS = 1273 primary series + PBS boosterBA.5, pre and post boost comparison
22
Increased Protection from BA.5 Challenge after Booster Dose of BA.4/BA.5
& BA.1 Omicron Vaccines (mRNA -1273.214 & mRNA -1273.222) in Mice
Scheaffer et al, manuscript under preparationBivalent vaccines
better protect from
BA.5 infection in lungs
ns –not significant
* p <0.05
** p <0.01
*** p <0.001
**** p <0.0001
Control = PBS primary series & booster
PBS = 1273 primary series + PBS booster•Mice challenged with 104PFU of BA.5 virus 4 weeks after booster dose
23
Ongoing Studies of Booster Doses in Adolescents
and Children, 6 Months -17 Years of Age
24
24Studies of Booster Dose of Original (mRNA -1273) Vaccine
inAdolescents & Children, 6 -17 Years
Studies 203 & 204
•3rddose (1stbooster) administered after completion of primary series
Study AgeBooster
DoseMonths between
2ndDose &
Booster (range) N
203 12-17 years 50 g 10.4 (9.0, 13.9) 1346
204 6-11 years 25 g 7.4 (4.1, 12.4) 1294
•Submission of data to the FDA is ongoing
25
25Ongoing Study of BA.1 Omicron Bivalent Vaccine (mRNA -1273.214)
Primary Series & Booster Dose in Infants & Children, 6 Months -5 Years
Study 306
•Open -label, Phase 3 study to evaluate safety & immunogenicity
Part History Vaccine Series Vaccine
Dose N Status
1 Vaccine
naive2-dose
primary series25 g 480
(320 2 -5 years;
160 6 -23 months)Enrollment ongoing
2 Previously
received
primary
series1 booster dose 10 g 480
(320 2 -5 years;
160 6 -23 months) 2-5 year olds fully
enrolled
Enrollment ongoing
for 6-23 month olds
26
Summary of Moderna COVID -19 Vaccine Booster Program
Immunogenicity
Safety ▪Vaccine boosters generally well tolerated in adults ≥18 years
▪Local and systemic reactogenicity of BA.1 Omicron bivalent as 4th dose similar to or lower
than 2nd dose of primary series & 3rd dose of original vaccine (mRNA -1273) in adults
▪No new safety concerns identified
▪Pre-specified immunogenicity objectives met for booster doses in adults
▪BA.1 Omicron bivalent in adults demonstrated:
▪Superior responses against BA.1 Omicron compared to Original mRNA -1273 booster in subjects
who were antibody negative pre -booster
▪Significantly higher neutralizing GMT against both BA.4/BA.5 Omicron & Original (D614G) in
subjects who were anti -N negative pre -booster
▪Significantly higher binding titers against Alpha, Beta, Delta and Gamma, confirming a broad
immune response regardless of VOC
▪Consistent immunogenicity across all ages (including ≥65 year olds)
▪Beta-containing bivalent in adults demonstrated improved durability of neutralizing
antibodies against VOC through 6 months compared to the original vaccine
▪Studies of BA.4/BA.5 Omicron bivalent booster in adults & BA.1 Omicron bivalent booster
in children 6 months -5 years ongoing
27
THANK YOU to Our Study Collaborators,
Investigators, and Participants
•All investigators
•Study site personnel
•Most importantly, the individuals who participated in these trials and
their families