Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice

Martinez, David R.; Schäfer, Alexandra; Leist, Sarah R.; Cruz, Gabriela De la; West, Ande; Atochina‐Vasserman, Elena N.; Lindesmith, Lisa C.; Pardi, Norbert; Parks, Robert; Barr, Maggie; Li, Dapeng; Yount, Boyd; Saunders, Kevin O.; Weissman, Drew; Haynes, Barton F.; Montgomery, Stephanie A.; Baric, Ralph S.

doi:10.1126/science.abi4506

Cited by 170 publications

(146 citation statements)

References 43 publications

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“…2b). One week following the week 4 Live-virus NAb titers 18 were largely consistent with pseudovirus NAb titers. Live virus NAb responses elicited by CV2CoV were higher than CVnCoV against the WA1/2020 and B.1.617.2 (delta) variants (P=0.0466 and P=0.0152, respectively), with similar trends for B.1.1.7 (alpha) and B.1.351 (beta) (P=0.0628 and 0.1450, respectively) (Fig.…”

Section: Vaccine Immunogenicitymentioning

confidence: 55%

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

Gebre

Rauch

Roth

et al. 2021

Nature

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102

107

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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.

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Section: Vaccine Immunogenicitymentioning

confidence: 55%

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

Gebre

Rauch

Roth

et al. 2021

Nature

Self Cite

102

107

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“…The SARS-CoV-2 RBD accounts for most serum neutralizing activity in both COVID-19 convalescent (11,37) and vaccinated individuals (12) and comprises antigenic sites targeted by broadly neutralizing sarbecovirus Abs (13)(14)(15)(16)(17)(18)(19). A few RBD-based subunit vaccines and mRNA vaccines based on chimeric S glycoproteins were recently shown to elicit broadly neutralizing sarbecovirus Abs and heterotypic protection in vivo (38)(39)(40)(41)(42). Most of these Abs with broad neutralizing activity are expected to target conserved RBD epitopes, due to their much greater potency and protection efficacy compared to known fusion machinery-directed Abs (43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Park

Marco

Starr

et al. 2021

Preprint

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Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures effective against SARS-CoV-2 variants and future spillovers of other sarbecoviruses. Here we describe the isolation and characterization of a human monoclonal antibody, designated S2K146, broadly neutralizing viruses belonging to all three sarbecovirus clades known to utilize ACE2 as entry receptor and protecting therapeutically against SARS-CoV-2 beta challenge in hamsters. Structural and functional studies show that most of the S2K146 epitope residues are shared with the ACE2 binding site and that the antibody inhibits receptor attachment competitively. Viral passaging experiments underscore an unusually high barrier for emergence of escape mutants making it an ideal candidate for clinical development. These findings unveil a key site of vulnerability for the development of a next generation of vaccines eliciting broad sarbecovirus immunity.

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“…Full-length SARS-CoV-2 Seattle, a mouse-adapted SARS-CoV-2 2AA Q498Y/P499T, SARS-CoV-2 D614G, SARS-CoV-2 B.1.351, SARS-CoV-2 B.1.1.7, SARS-CoV, WIV-1, and RsSHC014 viruses were designed to express nanoluciferase (nLuc) (8). Virus titers were measured in Vero E6 (C1008) cells, as defined by plaque forming units (PFU) per ml, in a 6-well plate format in quadruplicate technical replicates for accuracy.…”

Section: Measurement Of Neutralizing Antibodies Against Live Virusesmentioning

confidence: 99%

A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice

et al. 2022

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Severe acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants D614G, B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, B.1.617.1, and B.1.617.2 by a receptor binding domain (RBD)–specific human antibody, DH1047. Prophylactic and therapeutic treatment with DH1047 was protective against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B.1.351 infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among sarbecoviruses. Thus, DH1047 is a broadly protective antibody that can prevent infection and mitigate outbreaks caused by SARS-related strains and SARS-CoV-2 variants. Our results also suggest that the conserved RBD epitope bound by DH1047 is a rational target for a universal sarbecovirus vaccine.

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Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice

Cited by 170 publications

References 43 publications

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

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

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice

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