RESEARCH ARTICLES
◥CORONAVIRUS
Protection against SARS-CoV-2 Beta variant in
mRNA-1273 vaccineÐboosted nonhuman primates
Kizzmekia S. Corbett^1 †‡, Matthew Gagne^1 †, Danielle A. Wagner^1 , Sarah O’Connell^1 ,
Sandeep R. Narpala^1 , Dillon R. Flebbe^1 , Shayne F. Andrew^1 , Rachel L. Davis^1 , Barbara Flynn^1 ,
Timothy S. Johnston^1 , Christopher D. Stringham^1 §, Lilin Lai^2 , Daniel Valentin^3 , Alex Van Ry^3 ,
Zackery Flinchbaugh^3 , Anne P. Werner^1 , Juan I. Moliva^1 , Manjari Sriparna^1 ¶, Sijy O’Dell^1 ,
Stephen D. Schmidt^1 , Courtney Tucker^1 #, Angela Choi^4 , Matthew Koch^4 , Kevin W. Bock^5 ,
Mahnaz Minai^5 , Bianca M. Nagata^5 , Gabriela S. Alvarado^1 , Amy R. Henry^1 , Farida Laboune^1 ,
Chaim A. Schramm^1 , Yi Zhang^1 , Eun Sung Yang^1 , Lingshu Wang^1 , Misook Choe^1 ,
Seyhan Boyoglu-Barnum^1 , Shi Wei^1 , Evan Lamb^1 , Saule T. Nurmukhambetova^1 , Samantha J. Provost^1 ,
Mitzi M. Donaldson^1 , Josue Marquez^1 , John-Paul M. Todd^1 , Anthony Cook^3 , Alan Dodson^3 ,
Andrew Pekosz^6 , Eli Boritz^1 , Aurélie Ploquin^1 , Nicole Doria-Rose^1 , Laurent Pessaint^3 ,
Hanne Andersen^3 , Kathryn E. Foulds^1 , John Misasi^1 , Kai Wu^4 , Andrea Carfi^4 , Martha C. Nason^7 ,
John Mascola^1 , Ian N. Moore^5 , Darin K. Edwards^4 , Mark G. Lewis^3 , Mehul S. Suthar^2 , Mario Roederer^1 ,
Adrian McDermott^1 , Daniel C. Douek^1 , Nancy J. Sullivan^1 , Barney S. Graham^1 , Robert A. Seder^1
Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after
vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger
RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a
primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous
mRNA-1273 or heterologous mRNA-1273.b, which encompasses the spike sequence of the B.1.351 Beta
variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was
sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the
SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and
significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may
be required to sustain immunity and protection.
S
evere acute respiratory syndrome coro-
navirus 2 (SARS-CoV-2) vaccines, such
as mRNA-1273, BNT162b2, AD26.COV2.
S, AZD1222, and NVX-CoV2373, which
deliver the Wuhan-1 Spike (S) protein,
are between 70 and 94% effective against
symptomatic D614G or B.1.1.7 Alpha (a) SARS-
CoV-2 variant infection ( 1 – 5 ). Several SARS-
CoV-2 variants of concern (VOCs) show reduced
sensitivity to neutralizing antibodies induced
by vaccination or prior infection. The B.1.617.2
Delta (d) variant is notable for its high trans-
missibility and an intermediate level of reduced
neutralization by WA-1 immune sera ( 6 , 7 ). The
B.1.351 Beta (b) variant and the P.1 Gamma (g)
variant show the greatest reduction in neutra-
lizability by the vaccine recipient or convales-
cent patient sera ( 8 – 13 ).
Since mRNA-1273 was granted Emergency
Use Authorization (EUA) in December 2020
and deployed globally, many months have
elapsed since the first individuals were vacci-
nated, and the durability of vaccine protection
remains a concern. Additionally, the question
of whether an additional booster vaccination
is necessary, particularly as new VOCs become
more prevalent, is clinically relevant. mRNA-
1273 vaccination in humans reportedly indu-
ces antibody responses that persist beyond
6 months ( 14 ), but serum-neutralizing activity
was significantly reduced againstbanddvar-
iants ( 7 , 15 , 16 ). Recent data show that boosting
fully vaccinated individuals with mRNA-1273
several months after initial vaccine priming
with mRNA-1273, mRNA-1273.b(S sequencebased on thebvariant), or a 1:1 combination of
both vaccines (mRNA-1273.211) showed signif-
icantly increased neutralizing titers against
the prototypic D614G virus and all variants,
includingb( 17 ). Although these in vitro func-
tional data are promising, there are no available
efficacy data to define the level of antibodies
that is sufficient to mediate protection against
infection because the correlates of protection
against VOCs are undetermined. Moreover, in
nonhuman primates (NHPs), a higher thresh-
old of neutralizing antibodies was reportedly
needed for upper compared with lower airway
protection ( 18 ), suggesting that a boost could
be important to reach this threshold and con-
tribute to reducing virus transmission.
NHPs have proven useful for vaccine devel-
opment by facilitating the analysis of immu-
nogenicity and protection against SARS-CoV-2
( 19 – 24 ). Here, NHPs immunized with the clin-
ically relevant mRNA-1273 vaccine regimen
(100mg × 2) were boosted ~6 months later
with either mRNA-1273 (homologous) or mRNA-
1273.b(heterologous) vaccines. Antibody, B cell,
and T cell responses were assessed temporally
after vaccination and infection to determine
how boosting with mRNA-1273 or mRNA-1273.b
influences the magnitude and quality of anti-
body responses against WA-1-,b-, andd-specific
responses and protection against SARS-CoV-2
bchallenge. The data show that an additional,
delayed boost with mRNA vaccines matched
to either the original vaccine strain or to the
heterologous challenge strain can have a marked
and sustained effect on increasing the breadth
of neutralization against all VOCs tested and
protection in both the lower and upper airways
against thebvariant.Results
Boosting increases mRNA-1273Ðinduced serum
antibody responses
The primary focus of this study was to assess
the effect of homologous or heterologous boost-
ing with the original WA-1 mRNA-1273 or
mRNA-1273.bvaccines, respectively, on immu-
nogenicity and protection against infection
with thebvariant. NHPs that received the
clinically relevant primary regimen of mRNA-
1273 (100mg at weeks 0 and 4) were boosted
with either mRNA-1273 or mRNA-1273.bvac-
cines ~6 months later (fig. S1). WA-1 andb
S-specific or receptor-binding domain (RBD)–
specific serum antibody responses were assessed
at weeks 6, 29, 31, and 37. These time points
were selected because they correspond to
peak ( 19 ), memory before boost, 2 weeks after
boost, and time of challenge (“prechallenge”)
responses, respectively. WA-1 andbS-specific
immunoglobulin G (IgG) geometric mean titers
(GMTs) were 53,000 and 39,000 area under
the curve (AUC), respectively, at the peak time
point after a primary regimen of mRNA-1273.
These responses dropped fourfold and sixfold,RESEARCHSCIENCEscience.org 10 DECEMBER 2021•VOL 374 ISSUE 6573 1343
(^1) Vaccine Research Center, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda,
MD 20892, USA.^2 Center for Childhood Infections and
Vaccines of Children’s Healthcare of Atlanta, Department of
Pediatrics, Department of Microbiology and Immunology,
Emory Vaccine Center, Emory University, Atlanta, GA 30322,
USA.^3 BIOQUAL Inc., Rockville, MD 20850, USA.^4 Moderna
Inc., Cambridge, MA 02139, USA.^5 Infectious Disease
Pathogenesis Section, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda,
MD 20892, USA.^6 Department of Microbiology and
Immunology, Johns Hopkins University, Bloomberg School of
Public Health, Baltimore, MD 21205, USA.^7 Biostatistics
Research Branch, Division of Clinical Research, National
Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD 20892, USA.
*Corresponding author. Email: [email protected] (R.A.S.);
[email protected] (B.S.G.)
†These authors contributed equally to this work.‡Present address:
Department of Immunology and Infectious Diseases, Harvard T. H.
Chan School of Public Health, Boston, MA 02115, USA. §Present
address: Duke University School of Medicine, Medical Scientist
Training Program, Durham, NC 27705, USA. ¶Present address:
Medical College of Virginia, Richmond, VA 23223, USA. #Present
address: Division of Intramural Research, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD 20892, USA.