Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates

TLDR: In this article, the effect of mRNA-1273 vaccination against B.1.351 was evaluated in NHP using qRT-PCR for sgRNA and histopathology and viral antigen quantification on lung tissue post-challenge.

Abstract: BackgroundVaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. MethodsNonhuman primates received 30 or 100 {micro}g of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 {micro}g at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. ResultsEight weeks post-boost, 100 {micro}g x2 of mRNA-1273 induced reciprocal ID50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 {micro}g x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 {micro}g. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 {micro}g x2 of mRNA-1273, and there was a [~]2-log reduction in sgRNA in NHP that received two doses of 30 {micro}g compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 {micro}g x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. ConclusionsImmunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

Figures

Figure 4. Antibody correlates of protection. Rhesus macaques were immunized and challenged as described

Figure 1. Antibody responses following mRNA-1273 immunization. Rhesus macaques were immunized with

Figure 2. T cell responses following mRNA-1273 immunization. Rhesus macaques were immunized

Figure 3. Efficacy of mRNA-1273 against upper and lower respiratory B.1.351 viral replication. Rhesus

Full text

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates 1
2
Kizzmekia S. Corbett, PhD
1
, Anne P. Werner, BS
1
, Sarah O’ Connell, MS
1
, Matthew Gagne, 3
PhD
1
, Lilin Lai, MD
2
, Juan I. Moliva, PhD
1
, Barbara Flynn, MS
1
, Angela Choi, PhD
3
, Matthew 4
Koch, BS
3
, Kathryn E. Foulds, PhD
1
, Shayne F. Andrew, BS
1
, Dillon R. Flebbe, BS
1
, Evan 5
Lamb, BS
1
, Saule T. Nurmukhambetova, MS
1
, Samantha J. Provost, BS
1
, Kevin W. Bock, MS
4
, 6
Mahnaz Minai, MS
4
, Bianca M. Nagata, MS
4
, Alex Van Ry, BS
5
, Zackery Flinchbaugh, BS
5
, 7
Timothy S. Johnston, BS
1
,
Elham Bayat Mokhtari, PhD
1
, Prakriti Mudvari, PhD
1
, Amy R. 8
Henry, MS
1
, Farida Laboune, MS
1
, Becky Chang, BS
5
, Maciel Porto, BS
5
, Jaclyn Wear, BS
5
, 9
Gabriela S. Alvarado, PhD
1
, Seyhan Boyoglu-Barnum, PhD
1
, John-Paul M. Todd, BS
1
, Bridget 10
Bart
5
, Anthony Cook, DVM
5
, Alan Dodson
5
, Laurent Pessaint, MS
5
, Katelyn Steingrebe
5
, Sayda 11
Elbashir, PhD
3
, Hanne Andersen, PhD
5
, Kai Wu, PhD
3
, Darin K. Edwards, PhD
3
, Swagata Kar, 12
PhD
5
,
Mark G. Lewis, PhD
5
, Eli Bortiz, MD
1
, Ian N. Moore, PhD
4
, Andrea Carfi, PhD
3
, Mehul 13
S. Suthar, PhD
2,6
, Adrian McDermott, PhD
1
, Mario Roederer, PhD
1
, Martha C. Nason, PhD
7
, 14
Nancy J. Sullivan, PhD
1
, Daniel C. Douek, MD
1
, Barney S. Graham, MD
1
*, and Robert A. 15
Seder, MD
1
* 16
17
1
Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National 18
Institutes of Health; Bethesda, Maryland, 20892; United States of America 19
2
Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department 20
of Pediatrics, Department of Microbiology and Immunology, Emory Vaccine Center, Emory 21
University, Atlanta, Georgia, 30322, United States of America 22
3
Moderna Inc., Cambridge, MA, 02139; United States of America 23
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.21.445189doi: bioRxiv preprint

4
Infectious Disease Pathogenesis Section;
National Institute of Allergy and Infectious Diseases; 24
National Institutes of Health; Bethesda, Maryland, 20892; United States of America 25
5
Bioqual, Inc.; Rockville, Maryland, 20850; United States of America 26
6
Department of Microbiology and Immunology; Atlanta, Georgia, 30329, United States of 27
America 28
7
Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and 29
Infectious Diseases, National Institutes of Health; Bethesda, Maryland, 20892; United States of 30
America 31
32
*Correspondence: rseder@mail.nih.gov and bgraham@nih.gov 33
34
35
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.21.445189doi: bioRxiv preprint

ABSTRACT 36
Background: Vaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination 37
in humans has not been determined. Nonhuman primates (NHP) are a useful model for 38
demonstrating whether mRNA-1273 mediates protection against B.1.351. 39
Methods: Nonhuman primates received 30 or 100 µg of mRNA-1273 as a prime-boost vaccine 40
at 0 and 4 weeks, a single immunization of 30 µg at week 0, or no vaccine. Antibody and T cell 41
responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral 42
replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and 43
histopathology and viral antigen quantification were performed on lung tissue post-challenge. 44
Results: Eight weeks post-boost, 100 µg x2 of mRNA-1273 induced reciprocal ID
50
neutralizing 45
geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, 46
respectively, and 430 and 84 for the 30 µg x2 group. There were no detectable neutralizing 47
antibodies against B.1351 after the single immunization of 30 µg. On day 2 following B.1.351 48
challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 µg x2 of mRNA-49
1273, and there was a ~2-log reduction in sgRNA in NHP that received two doses of 30 µg 50
compared to controls. In nasal swabs, there was a 1-log
10
reduction observed in the 100 µg x2 51
group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-52
challenge. 53
Conclusions: 54
Immunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls 55
lower and upper airway viral replication against the B.1.351 variant in NHP.
56
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.21.445189doi: bioRxiv preprint

INTRODUCTION 57
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has led to more 58
than 3.4 million deaths worldwide
1
. Vaccination with two 100 µg doses of mRNA-1273, a lipid 59
nanoparticle (LNP) encapsulated messenger RNA-based vaccine encoding a stabilized full-60
length SARS-CoV-2 Wuhan-Hu-1 spike (S) glycoprotein, proved 94% efficacious against 61
symptomatic COVID-19 in the United States (US)
2
. mRNA-1273 is authorized by the US Food 62
and Drug Administration for Emergency Use (EUA). 63
The emergence of SARS-CoV-2 variants of concern (VOC)
3
that show reduced neutralization by 64
sera from Wu-1 strain convalescent subjects or vaccinees
4-6
has created uncertainty about the 65
efficacy of current SARS-CoV-2 vaccines against VOC infection
. To date,
the most concerning 66
variants contain
combinations
of mutations and deletions in the S receptor-binding domain
67
(RBD) and N-terminal domain (NTD), respectively.
Acquisition
of
amino acid substitutions in 68
the S RBD-- namely K417N, E484K, and N501Y—and in the NTD, such as L18F, D80A, 69
D215G, and
Δ
242-244, is associated with increased transmissibility and reduction in 70
neutralization sensitivity
7-17
. Variants containing these substitutions originally isolated in the 71
United Kingdom (UK) (B.1.1.7), Republic of South Africa (B.1.351), Brazil (P.1 lineage), New 72
York (B.1.526), and California (B.1.427/B.1.429), have shown varying reduction in 73
neutralization by convalescent and vaccine serum, and are resistant to some monoclonal 74
antibodies
14,18-24
.
Among these variants, B.1
.
351
contains
the most concerning set of
75
mutations in the RBD and NTD
subdomains
25
. 76
We and others recently reported that sera from mRNA-1273-immunized human and nonhuman 77
primates (NHP) showed the greatest reduction of neutralization against B.1.351 compared to 78
B.1.1.7, P.1, B.1.427/B.1.429, and B.1.1.7+E484K variants
7-17,26
. In UK- or US-based clinical 79
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.21.445189doi: bioRxiv preprint

studies, NVX-CoV2373 (Novavax), AZD1222 (University of Oxford/AstraZeneca), and 80
Ad26.COV2.S (Janssen/Johnson & Johnson) vaccines show between ~70 and 90% protection 81
against the circulating D614G or B.1.1.7 variants
11,27-29
, and vaccine efficacy against mild 82
symptomatic COVID-19 caused by B.1.351 was up to 60% for Ad26.CoV2
29
and NVX-83
CoV2373
30
and ~10% for AZD122
31
. A recent report showed BNT162b2, Pfizer’s mRNA 84
vaccine, conferred ~75% protection against confirmed B.1.351 infection in Qatar
32
. While 85
immunological assessments for all vaccine trials are underway and correlates of protection are 86
not yet determined, these data highlight the potential impact that reduced neutralization capacity 87
to B.1.351 may have on protection against mild symptomatic COVID-19 across various 88
platforms. Though comparable to BNT162b2 in other settings, human efficacy trials with 89
mRNA-1273 have not been conducted in regions where B.1.351 circulates as a dominant variant. 90
Vaccine development for COVID-19 has benefitted from clinically translatable data from the 91
NHP
33-39
. As there have been no published studies on vaccine protection in NHP challenged with 92
the B.1.351 variant, we evaluated the impact of the dose and number of immunizations with 93
mRNA-1273 on immunogenicity and protection against B.1.351 challenge in NHP. 94
95
METHODS 96
Pre-clinical mRNA-1273 mRNA and Lipid Nanoparticle Production Process 97
A sequence-optimized mRNA encoding prefusion-stabilized SARS-CoV-2 S-2P
40,41
protein was 98
synthesized in vitro. The mRNA was purified by oligo-dT affinity purification and encapsulated 99
in a lipid nanoparticle through a modified ethanol-drop nanoprecipitation process described 100
previously
42
. 101
Rhesus Macaque Model 102
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
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36 Background: Vaccine efficacy against the B. 1. 351 variant following mRNA-1273 vaccination 37 in humans has not been determined. 53 Conclusions: 54 Immunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls 55 lower and upper airway viral replication against the B. 1. 351 variant in NHP. 56 was not certified by peer review ) is the author/funder.