Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2

Alexandra C Walls,Claire Sydeman,Ralph S Baric,Cassandra Ogohara,E-Chiang Lee,Thomas B Lewis,Deborah H Fuller,Samuel Wrenn,Minh N Pham,Brieann Brown,Sarah R Leist,Kelly K Lee,Rashmi Ravichandran,Alexandra Schäfer,Chengbo Chen,Deleah Pettie,Mary Jane Navarro,Neil P King,Kenneth H Dinnon,Helen Y Chu,Michael Murphy,Elizabeth Kepl,Marcos C Miranda,Lisa E Gralinski,John C Kraft,Megan A O’Connor,Longping V Tse,Cameron M Chow,Brooke Fiala,Timothy P Sheahan,Paul Kellam,Marion Pepper,Lauren Carter,Laila Shehata,David Veesler,Edgar A Hodge,Sara Chalk,Kendra L Gully ,Kathryn A Guerriero ,Jim Fuller ,Miklós Guttman ,Anne L Palser

doi:10.1016/j.cell.2020.10.043

Abstract

SummaryA safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.

Highlights

The recent emergence of a previously unknown virus in Wuhan, China has resulted in the ongoing coronavirus disease 2019 (COVID-19) pandemic that has caused more than 34,000,000 infections and 1,000,000 fatalities as of October 2, 2020 (WHO)
Structures of the SARS-CoV-2 S receptor-binding domain (RBD) in complex with angiotensin-converting enzyme 2 (ACE2) defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity (Lan et al, 2020; Shang et al, 2020; Starr et al, 2020; Wang et al, 2020b; Yan et al, 2020)
These findings showed that the RBD is a prime target of neutralizing Abs upon natural CoV infection, in agreement with other reports of the isolation of RBD-targeted neutralizing Abs from COVID-19 convalescent patients (Barnes et al, 2020; Brouwer et al, 2020; Liu et al, 2020; Robbiani et al, 2020; Seydoux et al, 2020; Tortorici et al, 2020; Wang et al, 2020a; Wu et al, 2020) and the demonstration that they provide in vivo protection against SARS-CoV-2 challenge in small animals and nonhuman primates (Alsoussi et al, 2020; Tortorici et al, 2020; Wu et al, 2020; Zost et al, 2020)

Summary

Introduction

The recent emergence of a previously unknown virus in Wuhan, China has resulted in the ongoing coronavirus disease 2019 (COVID-19) pandemic that has caused more than 34,000,000 infections and 1,000,000 fatalities as of October 2, 2020 (WHO). Cryoelectron microscopy structures of SARS-CoV-2 S revealed its shared architecture with SARS-CoV S and provided a blueprint for the design of vaccines and antivirals (Walls et al, 2020; Wrapp et al, 2020) Both SARS-CoV-2 S and SARS-CoV S bind to angiotensin-converting enzyme 2 (ACE2), which serves as entry receptor (Hoffmann et al, 2020; Letko et al, 2020; Li et al, 2003; Walls et al, 2020; Wrapp et al, 2020; Zhou et al, 2020c). Structures of the SARS-CoV-2 S receptor-binding domain (RBD) in complex with ACE2 defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity (Lan et al, 2020; Shang et al, 2020; Starr et al, 2020; Wang et al, 2020b; Yan et al, 2020)

Methods

Results

Discussion

Conclusion