Abstract
Although mRNA vaccines encoding the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevent COVID-19, the emergence of new viral variants jeopardizes their efficacy. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike protein) or modified (mRNA-1273.351, designed for B.1.351 spike protein) Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Mice were immunized with either high-dose or low-dose formulations of the mRNA vaccines, where low-dose vaccination modeled suboptimal immune responses. Immunization with formulations at either dose induced neutralizing antibodies in serum against ancestral SARS-CoV-2 WA1/2020 and several virus variants, although serum titers were lower against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. However, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, showed breakthrough lung infections with B.1.617.2 and development of pneumonia in K18-hACE2 mice. Thus, in individuals with reduced immunity after mRNA vaccination, breakthrough infection and disease may occur with some SARS-CoV-2 variants.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the Coronavirus Disease 2019 (COVID19)
We first tested preclinical versions of the Moderna mRNA-1273 and mRNA-1273.351 vaccines encoding sequenced-optimized prefusion-stabilized spike proteins of Wuhan-1 and B.1.351, respectively, in immunocompetent 129S2 mice. These animals are permissive to infection by some SARS-CoV-2 variants or mouse-adapted strains [15,16,17] that encode an N501Y mutation, which enables engagement of endogenous murine angiotensin converting enzyme 2 (ACE2) [18]
Responses to different spike proteins for each vaccine generally were similar. Both doses and all spike protein-based mRNA vaccines generated anti-spike protein IgG responses in 129S2 mice
Summary
CoV-2) is the cause of the Coronavirus Disease 2019 (COVID19). More than 256 million infections and 5.1 million deaths have been recorded worldwide (https://covid19.who.int) since the start of the pandemic. The extensive morbidity and mortality associated with the COVID-19 pandemic made the development of SARS-CoV-2 vaccines a global health priority. In a period of less than one year, several highly effective vaccines targeting the SARS-CoV-2 spike protein encompassing multiple platforms (lipid nanoparticle encapsulated mRNA, inactivated virion, or viral-vectored vaccine platforms [1]) gained Emergency Use Authorization or Food and Drug Administration approval and were deployed with hundreds of millions of doses given worldwide (https://covid19.who.int). In localities with high rates of vaccination, markedly reduced numbers of infections, hospitalizations, and deaths were initially observed
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