A SARS-CoV-2 Wuhan spike virosome vaccine induces superior neutralization breadth compared to one using the Beta spike

Abstract

Current SARS-CoV-2 vaccines are effective, but long-term protection is threatened by the emergence of virus variants. We generated a virosome vaccine containing the Beta spike protein and compared its immunogenicity in mice to a virosome vaccine containing the original Wuhan spike. Two administrations of the virosomes induced potent SARS-CoV-2 neutralizing antibodies in both vaccine groups. The level of autologous neutralization in Beta-vaccinated mice was similar to the level of autologous neutralization in Wuhan-vaccinated mice. However, heterologous neutralization to the Wuhan strain in Beta-vaccinated mice was 4.7-fold lower than autologous neutralization, whereas heterologous neutralization to the Beta strain in Wuhan-vaccinated mice was reduced by only 1.9-fold compared to autologous neutralization levels. In addition, neutralizing activity against the D614G, Alpha and Delta variants was also significantly lower after Beta spike vaccination than after Wuhan spike vaccination. Our results show that Beta spike vaccination induces inferior neutralization breadth. These results are informative for programs aimed to develop broadly active SARS-CoV-2 vaccines.

Figure 1

Binding and neutralizing antibody responses elicited by Wuhan and Beta spike virosome vaccines. (A) Schematic representation of a virosome with coupled SARS-CoV-2 spike protein. (B) SARS-CoV-2 spike structure, with the amino acid mutations in the Beta spike highlighted, compared to the parental Wuhan spike. Amino acid mutations in the N-terminal domain are indicated in pink, mutations in the receptor binding domain in blue and mutations in the S2 domain in green. The beta immunogen contains the L242H and R246I substitutions that were present in early Beta strains, and not the the 242–244 deletion that later became dominant in the beta lineage. (C) Vaccination schedule. Blood droplets indicate the weeks at which blood was collected. In all subfigures, Wuhan-vaccinated animals are depicted in blue and Beta-vaccinated animals in magenta. Crosses indicate time of sacrifice for the indicated number of animals. The pre-vaccine is a virosome vaccine without spike protein. (D) Autologous SARS-CoV-2 pseudovirus neutralization titers at week 8 (n = 16 per group) for Wuhan pseudovirus and Beta pseudovirus. (E) Paired comparison of autologous and heterologous SARS-CoV-2 pseudovirus neutralization titers for Wuhan pseudovirus and Beta pseudovirus at week 8 (n = 16 per group). (F) SARS-CoV-2 pseudovirus neutralization titers against Wuhan, D614G and all variants of concern at week 8 (n = 16 per group). Median and 25th to 75th percentiles are indicated by the box, whiskers indicate the minimum and maximum value. (G) Spiderweb representation of the median ID₅₀ values from (F). (H) Anti-SARS-CoV-2 spike IgG levels in plasma measured by Luminex assay using beads coated with spike proteins of Wuhan and all variants of concern at week 8 (n = 16 per group). Median and 25th to 75th percentiles are indicated by the box, whiskers indicate the minimum and maximum value. (I) Spiderweb representation of the median IgG levels from (H). Mann–Whitney U-tests were used for unpaired comparisons and Wilcoxon matched-pairs signed rank test for paired comparisons (* = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001, ns = not significant). The dotted lines are the assay cut-off for the pseudovirus neutralization assay. HA = hemagglutinin, NA = neuraminidase.