Protein Nanoparticle Vaccines Induce Potent Neutralizing Antibody Responses Against MERS-CoV

Overview

Journal bioRxiv

Date 2024 Apr 1

PMID 38558973

Authors

Cara W Chao

Kaitlin R Sprouse

Marcos C Miranda

Nicholas J Catanzaro

Miranda L Hubbard

Amin Addetia

Cameron Stewart

Jack T Brown

Annie Dosey

Adian Valdez

Rashmi Ravichandran

Grace G Hendricks

Maggie Ahlrichs

Craig Dobbins

Alexis Hand

Catherine Treichel

Isabelle Willoughby

Alexandra C Walls

Andrew T McGuire

Elizabeth M Leaf

Ralph S Baric

Alexandra Schafer

David Veesler

Neil P King

Affiliations

Soon will be listed here.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.

References

McCallum M, Walls A, Sprouse K, Bowen J, Rosen L, Dang H . Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science. 2021; 374(6575):1621-1626. DOI: 10.1126/science.abl8506. View

Wang C, van Haperen R, Gutierrez-Alvarez J, Li W, Okba N, Albulescu I . A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies. Nat Commun. 2021; 12(1):1715. PMC: 7969777. DOI: 10.1038/s41467-021-21968-w. View

Goddard T, Huang C, Meng E, Pettersen E, Couch G, Morris J . UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein Sci. 2017; 27(1):14-25. PMC: 5734306. DOI: 10.1002/pro.3235. View

McCallum M, De Marco A, Lempp F, Tortorici M, Pinto D, Walls A . N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell. 2021; 184(9):2332-2347.e16. PMC: 7962585. DOI: 10.1016/j.cell.2021.03.028. View

Folegatti P, Bittaye M, Flaxman A, Lopez F, Bellamy D, Kupke A . Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial. Lancet Infect Dis. 2020; 20(7):816-826. PMC: 7172901. DOI: 10.1016/S1473-3099(20)30160-2. View

Robbiani D, Gaebler C, Muecksch F, Lorenzi J, Wang Z, Cho A . Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. 2020; 584(7821):437-442. PMC: 7442695. DOI: 10.1038/s41586-020-2456-9. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Low J, Jerak J, Tortorici M, McCallum M, Pinto D, Cassotta A . ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies. Science. 2022; 377(6607):735-742. PMC: 9348755. DOI: 10.1126/science.abq2679. View

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

10.

Park Y, Walls A, Wang Z, Sauer M, Li W, Tortorici M . Structures of MERS-CoV spike glycoprotein in complex with sialoside attachment receptors. Nat Struct Mol Biol. 2019; 26(12):1151-1157. PMC: 7097669. DOI: 10.1038/s41594-019-0334-7. View

11.

Dalvie N, Rodriguez-Aponte S, Hartwell B, Tostanoski L, Biedermann A, Crowell L . Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice. Proc Natl Acad Sci U S A. 2021; 118(38). PMC: 8463846. DOI: 10.1073/pnas.2106845118. View

12.

Kariko K, Buckstein M, Ni H, Weissman D . Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005; 23(2):165-75. DOI: 10.1016/j.immuni.2005.06.008. View

13.

Pallesen J, Wang N, Corbett K, Wrapp D, Kirchdoerfer R, Turner H . Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. 2017; 114(35):E7348-E7357. PMC: 5584442. DOI: 10.1073/pnas.1707304114. View

14.

Song J, Choi W, Heo J, Kim E, Lee J, Jung D . Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial. EClinicalMedicine. 2023; 64:102140. PMC: 10498190. DOI: 10.1016/j.eclinm.2023.102140. View

15.

Douglas M, Kocher J, Scobey T, Baric R, Cockrell A . Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease. Virology. 2017; 517:98-107. PMC: 5869108. DOI: 10.1016/j.virol.2017.12.006. View

16.

Cohen A, van Doremalen N, Greaney A, Andersen H, Sharma A, Starr T . Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models. Science. 2022; 377(6606):eabq0839. PMC: 9273039. DOI: 10.1126/science.abq0839. View

17.

Wang L, Shi W, Chappell J, Joyce M, Zhang Y, Kanekiyo M . Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape. J Virol. 2018; 92(10). PMC: 5923077. DOI: 10.1128/JVI.02002-17. View

18.

Pierre C, Adams L, Higgins J, Anasti K, Goodman D, Mielke D . Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions. PLoS Pathog. 2024; 20(6):e1011569. PMC: 11218955. DOI: 10.1371/journal.ppat.1011569. View

19.

McCallum M, Bassi J, De Marco A, Chen A, Walls A, di Iulio J . SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern. Science. 2021; 373(6555):648-654. PMC: 9835956. DOI: 10.1126/science.abi7994. View

20.

Read B, Won L, Kraft J, Sappington I, Aung A, Wu S . Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens. Cell Rep. 2022; 38(2):110217. PMC: 8805147. DOI: 10.1016/j.celrep.2021.110217. View