1

Booster Doses of Moderna COVID-19 Vaccines in Adults, 

Adolescents & Children

ACIP

September 1, 2022

Jacqueline Miller, MD
2

Indication 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 monovalent1 COVID-19 vaccine, or

▪ Receipt of the most recent booster dose with any 

authorized or approved monovalent COVID-19 

vaccine.

1 Monovalent 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).
4

Moderna 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

Betacontaining vaccine

(mRNA-1273.211)

25 μg 

Beta Variant

(B.1.351)

BA.1 Omicroncontaining vaccine 

(mRNA-1273.214)

25 μg 

Original SARS-CoV-2

25 μg

Omicron Variant 

(BA.1)

BA.4/BA.5 Omicroncontaining 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 3

rd dose (50 μg) of mRNA-1273

▪ Part G enrolled Mar 8-23, 2022; Part H enrolled Aug 10-23, 2022

Bivalent Vaccine Study (Part) Dose N

Median 

Follow-up

Beta 

(mRNA-1273.211) 205 (A) 3

rd (1st 

booster) 300 245 days

BA.1 Omicron 

(mRNA-1273.214) 205 (G) 4

th (2nd 

booster) 437 43 days

BA.4/BA.5 Omicron 

(mRNA- 1273.222) 205 (H) 4

th (2nd 

booster) 512 Ongoing

Total 1249

Chalkias et al. Research Square 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
7 Study of 4th Dose (2nd Booster) in Adults Using BA.1 Omicron 

Bivalent Vaccine (mRNA-1273.214) -

Demographics and Baseline Characteristics

Study 205, Safety Set

Characteristic

4

th Dose (2nd Booster)

Original 

(mRNA-1273)

N = 377

BA.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 2nd and 3rd Dose 

(months) – median (range) 8.0 (5.6, 14.4) 8.0 (4.7, 15.0)

Interval between 3rd and 4th Dose

(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.

2

nd dose mRNA-1273 (Baden et al, NEJM 2021); 3rd dose mRNA-1273 (Choi et al, Nat Med 2022); 4th dose 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 4th Dose 

Similar to 2nd Dose of Primary Series and 3rd Dose 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 1-2

Grade 3

Axillary Swelling 

or Tenderness

4

th Dose (2nd booster) using BA.1 Omicron

(mRNA-1273.214)

N = 437

Swelling

3

rd Dose (1st booster) Original 

(mRNA-1273)

N = 167

2

nd Dose Original

(mRNA-1273)

N = 14,677
9

Systemic Reactogenicity of BA.1 Omicron Bivalent (mRNA-1273.214) as 4th

Dose Generally Lower than 2nd Dose of Primary Series and 3rd Dose 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 Arthralgia Nausea /

Vomiting Chills

Solicited systemic adverse reactions within 7 days after injection. a) Grade 4 systemic reactions only with 2nd dose of mRNA-1273 (<0.1%).

2

nd dose mRNA-1273 (Baden et al, NEJM, 2021); 3rd dose mRNA-1273 (Choi et al, Nat Med, 2022); 4th dose mRNA-1273.214 (Chalkias et al. medRxiv, 2022; in press New Engl J Med).

Grade 1-2

Grade 3a

4

th Dose (2nd booster) using BA.1 

Omicron bivalent (mRNA-1273.214)

N = 437

3

rd Dose (1st booster) Original 

(mRNA-1273)

N = 167

2

nd Dose Original

(mRNA-1273)

N = 14,677
10

Similar Overall Safety Profile of BA.1 Omicron Bivalent 

(mRNA-1273.214) and Original mRNA-1273 as 4th Dose (2nd Booster)

Study 205, Safety Set

Unsolicited AEs within 28 Days After Any Injection

n (%)

Original 

(mRNA-1273)

N = 377

BA.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%)
Omicron BA.1 Neutralizing Titers Were Significantly Higher Following 4th Dose 11

(2nd Booster) 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

2 Common 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 Med

Success 

Criteria Met

Parameter 

4

th Dose (2nd Booster)

Original 

(mRNA-1273)

N = 260

Omicron BA.1 Bivalent

(mRNA-1273.214)

(N = 334)

GMT Pre-booster 

95% CI

332

(282, 391)

298

(259, 343)

GMT at Day 291

95% CI

1421

(1283, 1574)

2480

(2264, 2716)

GMT Ratio1(Bivalent vs Original)

97.5% CI

1.75 

(1.49, 2.04)

Seroresponse rate at Day 29

95% CI

99.2%

(97.2, 99.9)

100%

(98.9, 100)

Difference in seroresponse rates2

97.5% CI

1.5 

(-1.1, 4.0)

Superiority of GMTs: Lower 97.5% CI of GMT Ratio > 1.0

Non-inferiority of Seroresponse Rates: Lower 97.5% CI of difference > -10%
Original Strain (D614G) Neutralizing Titers Were Higher Following 4th Dose (2nd Booster) 12

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

2 Common risk difference and 97.5% CI (Miettinen-Nurminen) cannot be calculated when SRR in both group is 100%, absolute difference is reported.

Chalkias et al. medRxiv 2022, doi: 10.1101/2022.06.24.22276703 – in press New Engl J Med

Success 

Criteria Met

Parameter

4

th Dose (2nd Booster)

Original 

(mRNA-1273)

N = 260

Omicron BA.1 Bivalent

(mRNA-1273.214)

(N = 334)

GMT Pre-booster 

95% CI

1521 

(1353, 1710)

1267

(1120, 1432)

GMT at Day 291

95% CI

5287 

(4887, 5719)

6422

(5990, 6886)

GMT Ratio1(Bivalent vs Original)

97.5% CI

1.22 

(1.08,1.37)

Seroresponse rate at Day 29

95% CI

100%

(98.9, 100)

100%

(98.6, 100)

Difference in seroresponse rates2

97.5% CI

0

Non-inferiority of GMTs: Lower 97.5% CI of GMT Ratio > 0.67

Non-inferiority of Seroresponse 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

332

1933 1558

1473

3886

432

298

1615

3070

2372

7676

200

2,000

20,000

All Participants SARS-CoV-2 Negative Pre-Booster SARS-CoV-2 Positive Pre-Booster

Omicron BA.1 Neutralizing Titers After 4th Dose (2nd Booster) 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

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

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 years

Omicron BA.1 and Original Strain (D614G) Neutralizing Titers After 4th Dose (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

1304

1820

300

373

4494

7378

1235

1811

1111

1522

284 319

5198

7272

2229

2590

100

1,000

10,000

18-<65 - Ancestral 65+ - Ancestral 18-<65 - Omicron 65+ - Omicron

Neutralizing 

Antibody 

ID50 GMT

(95% CI)

Original SARS-CoV-2

Pre

Boost

Day 

29

Pre

Boost

Day 

29

BA.1 Omicron Bivalent 

(mRNA-1273.214)

Original

(mRNA-1273) 

(N = 120) (N = 139)

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Pre

Boost

Day 

29

Omicron BA.1

(N = 140) (N = 195) (N = 120) (N = 139) (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 (2nd Booster) Comparable Across Racial Groups

Study 205, Per-Protocol Immunogenicity Set with No Prior Infection

(N=316) (N=376) (N=26) (N=30) (N=25) (N=22) (N=316) (N=376) (N=26) (N=30) (N=25) (N=22) PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29 PBD29

10

100

1,000

10,000

100,000

309

2333

207

699

340

3352

323

2114

294

2308

343

1234 1520

6086

1458

5639

1223

6988

1035

4685

1273

5894

1553

5700

Neutralizing Antibody

(GM Titer, 95%CI)

Black/African American White Other

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

Original SARS-CoV-2 Omicron

Black/African American White Other

Pre-booster (PB), Day 29 post-boost (D29) 
16 4

th Dose (2nd Booster) with BA.1 Omicron Bivalent Booster (mRNA1273.214) 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) PB D29 PB D29 PB D29 PB D29 PB D29 PB D29

10

100

1,000

10,000

720

2337

609

1271

116

727

140

492

173

941

209

645

Neutralizing Antibody

(GM Titer, 95%CI)

All Participants No Prior Infection Prior Infection

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
17

4th Dose (2nd Booster) 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) 

PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29 PB D29

10

100

1,000

10,000

844

2783

532

1375

658

2118

631

1245

132

817

161

588

105

670

123

422

190

1039

192

679

162

879

222

624

Neutralizing Antibody

(GM Titer, 95%CI)

All Participants No Prior Infection Prior Infection

Original (mRNA-1273) 50 μg BA.1 Omicron Bivalent Vaccine (mRNA-1273.214) 50 μg N=221 N=255 N=146 N=173 N=140 N=195 N= 120 N= 139 N=78 N=60 N=20 N=34

18-64 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 = 398-402

Binding Antibody Titers Against VOCs Are Significantly Higher after 4th Dose 

(2nd Booster) with BA.1 Omicron Bivalent (mRNA-1273.214) than mRNA-1273 in 

Adults

Study 205, Per-Protocol Immunogenicity Set

569

353

502

384

652

403

546

442

100

1,000

Alpha Beta Delta Gamma

Binding 

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 ofvramRNA1273 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 (mRNA1273.222

• ~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 preparation

BA.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 booster

BA.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 preparation

Bivalent 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 104 PFU 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

24

Studies of Booster Dose of Original (mRNA-1273) Vaccine 

in Adolescents & Children, 6 - 17 Years 

Studies 203 & 204

• 3

rd dose (1st booster) administered after completion of primary series

Study Age

Booster

Dose

Months between 

2

nd Dose & 

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

25

Ongoing 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 

naive

2-dose 

primary series

25 g 480

(320 2-5 years; 

160 6-23 months)

Enrollment ongoing

2 Previously 

received 

primary 

series

1 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