Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice

Alexandra C Walls, Laura A VanBlargan, Kai Wu, Angela Choi, Mary Jane Navarro, Diana Lee, Laura Avena, Daniela Montes Berrueta, Minh N Pham, Sayda Elbashir, John C Kraft, Marcos C Miranda, Elizabeth Kepl, Max Johnson, Alyssa Blackstone, Kaitlin Sprouse, Brooke Fiala, Megan A O'Connor, Natalie Brunette, Prabhu S Arunachalam, Lisa Shirreff, Kenneth Rogers, Lauren Carter, Deborah H Fuller, Francois Villinger, Bali Pulendran, Michael S Diamond, Darin K Edwards, Neil P King, David Veesler, Alexandra C Walls, Laura A VanBlargan, Kai Wu, Angela Choi, Mary Jane Navarro, Diana Lee, Laura Avena, Daniela Montes Berrueta, Minh N Pham, Sayda Elbashir, John C Kraft, Marcos C Miranda, Elizabeth Kepl, Max Johnson, Alyssa Blackstone, Kaitlin Sprouse, Brooke Fiala, Megan A O'Connor, Natalie Brunette, Prabhu S Arunachalam, Lisa Shirreff, Kenneth Rogers, Lauren Carter, Deborah H Fuller, Francois Villinger, Bali Pulendran, Michael S Diamond, Darin K Edwards, Neil P King, David Veesler

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.

Trial registration: ClinicalTrials.gov NCT05007951.

Keywords: COVID-19; CP: Immunology; CP: Microbiology; SARS-CoV-2; antibodies; humans; mouse; non-human primates; vaccines.

Conflict of interest statement

Declaration of interests A.C.W., N.P.K., and D.V. are named as inventors on patent applications filed by the University of Washington based on the RBD-NP presented in this paper. N.P.K. is a co-founder, shareholder, paid consultant, and chair of the scientific advisory board of Icosavax, Inc., and the King lab has received an unrelated sponsored research agreement from Pfizer. M.S.D. is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Kaleido, and Emergent BioSolutions and past support from Moderna not related to these studies. K.W., A.C., and D.K.E are employees of Moderna and hold stock/stock options in the company. D.H.F. has equity interest in HDT Bio.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Vaccine-elicited serum neutralizing activity against VOCs in mice does not recapitulate observations in NHPs and humans Results from mice in (A)–(E), NHPs in (F), and humans in (G)–(H). (A) Neutralizing activity of sera from BALB/c mice immunized with RBD-NP, S2P, or HexaPro 2 weeks post-prime, 2 weeks after boost (5 weeks post-prime), or 5 weeks after boost (8 weeks post-prime with RBD-NP and Hexapro only) with VSV pseudotyped with SARS-CoV-2 G614 S, Beta S, or Gamma S on VeroE6-TMPRSS2 cells. Data from one out of at least two representative experiments shown; vaccination experiment performed once; n = 5 mice. Schematic above the figure shows animal model, antigen, dosing, and timeline of bleeds. (B) Neutralizing activity of sera from BALB/c mice immunized with RBD-NP, S2P, or HexaPro 2 weeks post-prime or 2 weeks after boost (5 weeks post-prime) with VSV pseudotyped with SARS-CoV-2 G614 S, Beta S, or Gamma S on HEK-293T-ACE2 cells. Data from one out of at least two representative experiments shown; vaccination experiment performed once; n = 5 mice. Schematic above the figure shows organism, antigen, dosing, and timeline of bleeds. (C) Neutralizing activity of sera from BALB/c mice immunized with different doses (ranging from 1.66–0.0001μg) RBD-NP analyzed 2 weeks after boost (6 weeks after prime) with VSV pseudotyped with SARS-CoV-2 G614 S, Beta S, or Gamma S on VeroE6-TMPRSS2 cells. Data from one of three representative experiments shown; vaccination experiment performed once; n = 5 mice/group. Schematic above the figure shows organism, antigen, dosing, and timeline of bleeds. (D) Neutralizing activity of sera from BALB/c mice immunized with mRNA-1273 2 or 5 weeks after boost with VSV pseudotyped with SARS-CoV-2 G614 S, Beta S, or Gamma S on A549-ACE2-TMPRSS2 cells. Data from one out of at least two representative experiments shown; n = 8 or 104 mice. (E) Neutralization of sera from 129S2 or K18-hACE2 mice immunized with mRNA-1273 3 weeks after boost with authentic SARS-CoV-2 G614 or Beta on VeroE6-TMPRSS2 cells. Data shown are from two independent experiments; vaccination experiment performed once; n = 16 mice. (F) Neutralizing activity of sera from NHPs immunized with RBD-NP formulated in various adjuvants or HexaPro at peak titer (day 42 post-prime) with VSV pseudotyped with SARS-CoV-2 G614 S, Beta S, or Gamma S on HEK-293T-ACE2 cells. Data from one out of at least two representative experiments shown; vaccination experiment performed once; n = 2 pigtail macaques, n = 5 rhesus macaques. (G) Neutralizing activity of sera from humans vaccinated either with Pfizer/BioNTech Comirnaty or Moderna mRNA-1273 on HEK-293T-ACE2 cells (Table S1). Data from one out of at least two representative experiments shown; vaccination experiment performed once; n = 10 Moderna mRNA-1273 vaccinees, n = 11 Pfizer/BioNTech Comirnaty vaccinees. Normalized curves and data fits for (A)–(G) are shown in Data S1. (H) Fold change data from the SARS-CoV-2 resistance database (https://covdb.stanford.edu/page/susceptibility-data/) for sera obtained from humans vaccinated with either Pfizer/BioNTech Comirnaty or Moderna mRNA-1273 and assayed with G614 compared with either Beta (n = 62 Pfizer/BioNTech Comirnaty, n = 29 Moderna mRNA1273) or Gamma (n = 34 Pfizer/BioNTech Comirnaty, n = 15 Moderna mRNA-1273). Box plot shows mean with the standard deviation described by bars. Kruskal-Wallis with Dunn’s multiple comparisons or Mann Whitney statistical tests were used within a comparison group (i.e., comparing RBD-NP bleed 1 G614-Beta and G614-Gamma) and shown when significant (∗p = 0.033; ∗∗p = 0.002; ∗∗∗p < 0.0002).

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