High-Throughput Neutralization and Serology Assays Reveal Correlated but Highly Variable Humoral Immune Responses in a Large Population of Individuals Infected with SARS-CoV-2 in the US between March and August 2020

Shuting Zhang; Peijun Ma; Marek Orzechowski; Allison Lemmer; Kara Rzasa; Josephine Bagnall; Sulyman Barkho; Michael Chen; Lorri He; Raymond Neitupski; Victoria Tran; Ross Ackerman; Emily Gath; Austin Bond; Giana Frongillo; Thomas Cleland; Aaron Golas; Anthony Gaca; Michael Fitzgerald; Kathleen Kelly; Kelsey Hazegh; Larry Dumont; Corey Hoffman; Mary Homer; Peter Marks; Ann Woolley; Sharon Wong; James Gomez; Jonathan Livny; Deborah Hung

doi:10.1128/mbio.03523-22

mBio (Apr 2023)

High-Throughput Neutralization and Serology Assays Reveal Correlated but Highly Variable Humoral Immune Responses in a Large Population of Individuals Infected with SARS-CoV-2 in the US between March and August 2020

Shuting Zhang,
Peijun Ma,
Marek Orzechowski,
Allison Lemmer,
Kara Rzasa,
Josephine Bagnall,
Sulyman Barkho,
Michael Chen,
Lorri He,
Raymond Neitupski,
Victoria Tran,
Ross Ackerman,
Emily Gath,
Austin Bond,
Giana Frongillo,
Thomas Cleland,
Aaron Golas,
Anthony Gaca,
Michael Fitzgerald,
Kathleen Kelly,
Kelsey Hazegh,
Larry Dumont,
Corey Hoffman,
Mary Homer,
Peter Marks,
Ann Woolley,
Sharon Wong,
James Gomez,
Jonathan Livny,
Deborah Hung

Affiliations

Shuting Zhang: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Peijun Ma: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Marek Orzechowski: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Allison Lemmer: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Kara Rzasa: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Josephine Bagnall: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Sulyman Barkho: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Michael Chen: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Lorri He: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Raymond Neitupski: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Victoria Tran: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Ross Ackerman: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Emily Gath: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Austin Bond: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Giana Frongillo: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Thomas Cleland: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Aaron Golas: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Anthony Gaca: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Michael Fitzgerald: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Kathleen Kelly: Vitalant Research Institute, Denver, Colorado, USA
Kelsey Hazegh: Vitalant Research Institute, Denver, Colorado, USA
Larry Dumont: Vitalant Research Institute, Denver, Colorado, USA
Corey Hoffman: Biomedical Advanced Research and Development Authority, Administration for Strategic Preparedness and Response, Department of Health and Human Services, Washington, DC, USA
Mary Homer: Biomedical Advanced Research and Development Authority, Administration for Strategic Preparedness and Response, Department of Health and Human Services, Washington, DC, USA
Peter Marks: Center for Biologics Evaluation and Research, US FDA, Silver Spring, Maryland, USA
Ann Woolley: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Sharon Wong: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
James Gomez: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Jonathan Livny: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Deborah Hung: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

DOI: https://doi.org/10.1128/mbio.03523-22
Journal volume & issue: Vol. 14, no. 2

Abstract

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ABSTRACT The ability to measure neutralizing antibodies on large scale can be important for understanding features of the natural history and epidemiology of infection, as well as an aid in determining the efficacy of interventions, particularly in outbreaks such as the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Because of the assay’s rapid scalability and high efficiency, serology measurements that quantify the presence rather than function of serum antibodies often serve as proxies of immune protection. Here, we report the development of a high-throughput, automated fluorescence-based neutralization assay using SARS-CoV-2 virus to quantify neutralizing antibody activity in patient specimens. We performed large-scale testing of over 19,000 COVID-19 convalescent plasma (CCP) samples from patients who had been infected with SARS-CoV-2 between March and August 2020 across the United States. The neutralization capacity of the samples was moderately correlated with serological measurements of anti-receptor-binding domain (RBD) IgG levels. The neutralizing antibody levels within these convalescent-phase serum samples were highly variable against the original USA-WA1/2020 strain with almost 10% of individuals who had had PCR-confirmed SARS-CoV-2 infection having no detectable antibodies either by serology or neutralization, and ~1/3 having no or low neutralizing activity. Discordance between neutralization and serology measurements was mainly due to the presence of non-IgG RBD isotypes. Meanwhile, natural infection with the earliest SARS-CoV-2 strain USA-WA1/2020 resulted in weaker neutralization of subsequent B.1.1.7 (alpha) and the B.1.351 (beta) variants, with 88% of samples having no activity against the BA.1 (omicron) variant. IMPORTANCE The ability to directly measure neutralizing antibodies on live SARS-CoV-2 virus in individuals can play an important role in understanding the efficacy of therapeutic interventions or vaccines. In contrast to functional neutralization assays, serological assays only quantify the presence of antibodies as a proxy of immune protection. Here, we have developed a high-throughput, automated neutralization assay for SARS-CoV-2 and measured the neutralizing activity of ~19,000 COVID-19 convalescent plasma (CCP) samples collected across the United States between March and August of 2020. These data were used to support the FDA’s interpretation of CCP efficacy in patients with SARS-CoV-2 infection and their issuance of emergency use authorization of CCP in 2020.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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