Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine

Makda S. Gebre, Susanne Rauch (), Nicole Roth, Jingyou Yu, Abishek Chandrashekar, Noe B. Mercado, Xuan He, Jinyan Liu, Katherine McMahan, Amanda Martinot, David R. Martinez, Victoria Giffin, David Hope, Shivani Patel, Daniel Sellers, Owen Sanborn, Julia Barrett, Xiaowen Liu, Andrew C. Cole, Laurent Pessaint, Daniel Valentin, Zack Flinchbaugh, Jake Yalley-Ogunro, Jeanne Muench, Renita Brown, Anthony Cook, Elyse Teow, Hanne Andersen, Mark G. Lewis, Adrianus C. M. Boon, Ralph S. Baric, Stefan O. Mueller, Benjamin Petsch and Dan H. Barouch ()
Additional contact information
Makda S. Gebre: Harvard Medical School
Susanne Rauch: CureVac AG
Nicole Roth: CureVac AG
Jingyou Yu: Harvard Medical School
Abishek Chandrashekar: Harvard Medical School
Noe B. Mercado: Harvard Medical School
Xuan He: Harvard Medical School
Jinyan Liu: Harvard Medical School
Katherine McMahan: Harvard Medical School
Amanda Martinot: Tufts University Cummings School of Veterinary Medicine
David R. Martinez: University of North Carolina at Chapel Hill
Victoria Giffin: Harvard Medical School
David Hope: Harvard Medical School
Shivani Patel: Harvard Medical School
Daniel Sellers: Harvard Medical School
Owen Sanborn: Harvard Medical School
Julia Barrett: Harvard Medical School
Xiaowen Liu: Beth Israel Deaconess Medical Center
Andrew C. Cole: Beth Israel Deaconess Medical Center
Laurent Pessaint: Bioqual
Daniel Valentin: Bioqual
Zack Flinchbaugh: Bioqual
Jake Yalley-Ogunro: Bioqual
Jeanne Muench: Bioqual
Renita Brown: Bioqual
Anthony Cook: Bioqual
Elyse Teow: Bioqual
Hanne Andersen: Bioqual
Mark G. Lewis: Bioqual
Adrianus C. M. Boon: Washington University School of Medicine
Ralph S. Baric: University of North Carolina at Chapel Hill
Stefan O. Mueller: CureVac AG
Benjamin Petsch: CureVac AG
Dan H. Barouch: Harvard Medical School

Nature, 2022, vol. 601, issue 7893, 410-414

Abstract: Abstract The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 μg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.

Date: 2022
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DOI: 10.1038/s41586-021-04231-6

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