key: cord-0746343-7ada9d29 authors: Hoffmann, Donata; Corleis, Björn; Rauch, Susanne; Roth, Nicole; Mühe, Janine; Halwe, Nico Joel; Ulrich, Lorenz; Fricke, Charlie; Schön, Jacob; Kraft, Anna; Breithaupt, Angele; Wernike, Kerstin; Michelitsch, Anna; Sick, Franziska; Wylezich, Claudia; Müller, Stefan O.; Mettenleiter, Thomas C.; Petsch, Benjamin; Dorhoi, Anca; Beer, Martin title: CVnCoV protects human ACE2 transgenic mice from ancestral B BavPat1 and emerging B.1.351 SARS-CoV-2 date: 2021-03-22 journal: bioRxiv DOI: 10.1101/2021.03.22.435960 sha: 7f1d38ddde2cc5407dfa1bb05dc95aab28914afb doc_id: 746343 cord_uid: 7ada9d29 The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic necessitates the fast development of vaccines as the primary control option. Recently, viral mutants termed “variants of concern” (VOC) have emerged with the potential to escape host immunity. VOC B.1.351 was first discovered in South Africa in late 2020, and causes global concern due to poor neutralization with propensity to evade preexisting immunity from ancestral strains. We tested the efficacy of a spike encoding mRNA vaccine (CVnCoV) against the ancestral strain BavPat1 and the novel VOC B.1.351 in a K18-hACE2 transgenic mouse model. Naive mice and mice immunized with formalin-inactivated SARS-CoV-2 preparation were used as controls. mRNA-immunized mice developed elevated SARS-CoV-2 RBD-specific antibody as well as neutralization titers against the ancestral strain BavPat1. Neutralization titers against VOC B.1.351 were readily detectable but significantly reduced compared to BavPat1. VOC B.1.351-infected control animals experienced a delayed course of disease, yet nearly all SARS-CoV-2 challenged naïve mice succumbed with virus dissemination and high viral loads. CVnCoV vaccine completely protected the animals from disease and mortality caused by either viral strain. Moreover, SARS-CoV-2 was not detected in oral swabs, lung, or brain in these groups. Only partial protection was observed in mice receiving the formalin-inactivated virus preparation. Despite lower neutralizing antibody titers compared to the ancestral strain BavPat1, CVnCoV shows complete disease protection against the novel VOC B.1.351 in our studies. Coronavirus disease 2019 (COVID-19) severely affects human health and societies worldwide. 45 It has accounted for more than 116 million morbidities and 2.5 million fatalities by early March 46 2021 (WHO, https://covid19.who.int). The responsible pathogen, severe acute respiratory 47 syndrome coronavirus type 2 (SARS-CoV-2), has rapidly spread globally despite stringent 48 intervention strategies (1) . To control pandemic spread and disease, vaccination is considered 55 and Brazil (B.1.1.28; P1) (https://www.ecdc.europa.eu/en/publications-data/covid-19-risk-56 assessment-variants-vaccine-fourteenth-update-february-2021). These "variants of concern 57 (VOC)" acquired numerous mutations, particularly in the spike protein encoding gene (S), most 58 frequently within the S1 and the receptor binding domain (RBD) (7-9). These mutations confer 59 higher binding affinities and allow some VOC to evade pre-existing immunity (10), resulting 60 in increased transmissibility, including epidemiologic scenarios where "herd immunity" was 61 expected (11 Strong antibody responses in mRNA-vaccinated mice 74 We used the K18-hACE2 transgenic mouse model (21) to determine the protective efficacy of (Fig. 2B) . In the CVnCoV-vaccinated group 131 challenged with BavPat1, only 3/10 animals showed low genome copy numbers in the conchae. No animal was positive in the LRT or the brain, indicating complete protection from infection 133 by BavPat1 (Fig. 2C-F) . For VOC B.1.351, 6/10 CVnCoV-vaccinated animals exhibited 134 residual viral replication in the conchae, but viral levels were reduced without reaching 135 statistical significance (Fig. 2B) . In contrast, CVnCoV prevented any detectable replication of 136 this VOC in the LRT and the brain, with low viral copy numbers close to the limit of detection 137 in the lung of only 2/10 animals, and in the cerebrum for only 1/10 animals (Fig. 2C-F) . 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