D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Drew Weissman; Mohamad-Gabriel Alameh; Thushan de Silva; Paul Collini; Hailey Hornsby; Rebecca Brown; Celia C LaBranche; Robert J Edwards; Laura Sutherland; Sampa Santra; Katayoun Mansouri; Sophie Gobeil; Charlene McDanal; Norbert Pardi; Nick Hengartner; Paulo J C Lin; Ying Tam; Pamela A Shaw; Mark G Lewis; Carsten Boesler; Uğur Şahin; Priyamvada Acharya; Barton F Haynes; Bette Korber; David C Montefiori

doi:10.1016/j.chom.2020.11.012

D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Cell Host Microbe. 2021 Jan 13;29(1):23-31.e4. doi: 10.1016/j.chom.2020.11.012. Epub 2020 Dec 1.

Authors

Drew Weissman¹, Mohamad-Gabriel Alameh², Thushan de Silva³, Paul Collini³, Hailey Hornsby⁴, Rebecca Brown⁴, Celia C LaBranche⁵, Robert J Edwards⁶, Laura Sutherland⁷, Sampa Santra⁸, Katayoun Mansouri⁷, Sophie Gobeil⁷, Charlene McDanal⁵, Norbert Pardi², Nick Hengartner⁹, Paulo J C Lin¹⁰, Ying Tam¹⁰, Pamela A Shaw¹¹, Mark G Lewis¹², Carsten Boesler¹³, Uğur Şahin¹³, Priyamvada Acharya⁷, Barton F Haynes⁷, Bette Korber⁹, David C Montefiori¹⁴

Affiliations

¹ Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: dreww@pennmedicine.upenn.edu.
² Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; South Yorkshire Regional Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
⁴ Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
⁵ Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
⁶ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Duke University, Department of Medicine, Durham, NC, USA.
⁷ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
⁸ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁹ T6: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM USA.
¹⁰ Acuitas Therapeutics, Vancouver, BC, CA.
¹¹ Department of Biostatistics, Epidemiology and Informatics University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹² Bioqual Inc., Rockville, MD, USA.
¹³ BioNTech, Mainz, Germany.
¹⁴ Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD "up" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.

Keywords: COVID-19; D614G; LNP; SARS-CoV-2; Spike; electron micrograph; mRNA; neutralization; nucleoside-modified; vaccine.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Randomized Controlled Trial

MeSH terms

Adolescent
Adult
Animals
Antibodies, Monoclonal / immunology
Binding Sites
COVID-19 / immunology
COVID-19 / therapy*
COVID-19 Serotherapy
COVID-19 Vaccines / immunology
Female
HEK293 Cells
Humans
Immunization, Passive / methods
Macaca mulatta
Male
Mice
Mice, Inbred BALB C
Middle Aged
Mutation*
Neutralization Tests
SARS-CoV-2 / genetics*
SARS-CoV-2 / pathogenicity
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / genetics*
Spike Glycoprotein, Coronavirus / immunology*
Young Adult

Substances

Antibodies, Monoclonal
COVID-19 Vaccines
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding