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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The SARS-CoV-2 Omicron (B.1.1.529) variant has proven highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4-10% weight loss by day 4 and 10-17% weight loss by day 6, as expected. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection still led to substantial viral replication in both the upper and lower respiratory tracts and pulmonary pathology, but with a trend towards higher viral loads in nasal turbinates and lower viral loads in lung parenchyma compared with WA1/2020 infection. These data suggest that the SARS-CoV-2 Omicron variant may result in more robust upper respiratory tract infection but less severe lower respiratory tract clinical disease compared with prior SARS-CoV-2 variants.

Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against SARS-CoV-2 infection. Recently, robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for virologic control. However, direct data demonstrating a role of CD8 + T cells in vaccine protection has not yet been reported. In this study, we show that vaccine-elicited CD8 + T cells contribute substantially to virologic control following SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector-based vaccine Ad26.COV2.S or sham and then challenged them with 5x10 5 TCID 50 SARS-CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but showed rapid virologic control in nasal swabs and bronchoalveolar lavage by day 4 following challenge. However, administration of an anti-CD8α or anti-CD8β depleting monoclonal antibody in vaccinated animals prior to SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8 + T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.

corresponding to the B.1.351 variant in South Africa. These data and the emergence of new circulating strains globally support the importance of developing animal models to study of the impact of variants on vaccine-mediated protection. RESULTS SARS-CoV-2 variant strains induce disease in a hamster challenge model.We expanded stocks of WA1/2020, B.1.1.7, and B.1.351 SARS-CoV-2 variants through in vitro passage in either VeroE6 or Calu-3 cells. Deep sequencing confirmed the expected corresponding sequences for each challenge stock and revealed no unexpected or additional mutations; in particular, no mutations or deletions with >2.5% frequency in the Spike furin cleavage site were detected (NCBI SRA Accession Numbers SRR 14313077 and 14313078). We inoculated groups of Syrian hamsters by the intranasal route with each variant at 5 × 10 5 , 5 × 10 4 , and 5 × 10 3 median tissue culture infectious dose (TCID 50 ) of these stocks. Challenge with the WA1/2020 variant led to severe (greater than 15%) weight loss by day 6, consistent with our prior published data (Fig. 1A, fig. S1) (9). Challenge with the B.1.1.7 (Fig. 1B, fig. S1) and B.1.351 (Fig. 1C, fig. S1) variants led to comparable kinetics and extent of weight loss, with no statistically significant differences observed in peak weight loss across variants or challenge doses (p > 0.08, Fig. 1D). Natural immunity confers protection against rechallenge with heterologous variants.We next explored the potential of natural immunity from a primary WA1/2020 infection to protect against re-challenge with either homologous or heterologous variants. 18 hamsters were infected with 5 × 10 4 TCID 50 WA1/2020 strain and monitored for five weeks post-challenge. All hamsters exhibited substantial body weight loss (Fig. 2A), which peaked approximately one week post-challenge and was followed by a gradual recovery. At week 5, hamsters were divided into three groups with similar body weight loss (fig. S2) and re-challenged with 5 × 10 4 TCID 50 of WA1/2020, B.1.1.7, or B.1.351 SARS-CoV-2 (Fig. 2B).At the time of re-challenge (week 5 post initial challenge), three additional groups of naïve, age-matched hamsters were also challenged as internal positive controls. Severe weight loss was observed in these naïve animals with all three viruses, similar to the results of the previous experiment (Fig. 2C open symbols, fig. S3). Mean maximum weight loss of 16.9%, 16.5%, and 17.0% was observed following primary challenge with WA1/2020, B.1.1.7, and B.1.351, respectively (Fig. 2D). In contrast, hamsters that had recovered from WA1/2020 infection and were re-challenged maintained body weight with minimal signs of disease for all three viruses (Fig. 2C closed symbols, fig. S3). Mean maximum weight loss of 0.1%, 0.6%, and 1.5% was observed in groups re-challenged with WA1/2020, B.1.1.7, and B.1.351 (Fig. 2D).