Potential of conserved antigenic sites in development of universal SARS-like coronavirus vaccines.

Given pandemic risks of zoonotic SARS-CoV-2 variants and other SARS-like coronaviruses in the future, it is valuable to perform studies on conserved antigenic sites to design universal SARS-like coronavirus vaccines. By using antibodies obtained from convalescent COVID-19 patients, we succeeded in functional comparison of conserved antigenic sites at multiple aspects with each other, and even with SARS-CoV-2 unique antigenic sites, which promotes the cognition of process of humoral immune response to the conserved antigenic sites. The conserved antigenic sites between SARS-CoV-2 and SARS-CoV can effectively induce affinity maturation of cross-binding antibodies, finally resulting in broadly neutralizing antibodies against multiple variants of concern, which provides an important basis for universal vaccine design, however they are subdominant, putatively due to their lower accessibility relative to SARS-CoV-2 unique antigenic sites. Furthermore, we preliminarily design RBDs to improve the immunogenicity of these conserved antigenic sites. Our study focusing on conserved antigenic sites provides insights for promoting the development of universal SARS-like coronavirus vaccines, thereby enhancing our pandemic preparedness.

Longitudinal analysis of SARS-CoV-2 reinfection reveals distinct kinetics and emergence of cross-neutralizing antibodies to variants of concern.

The ongoing evolution of SARS-CoV-2 continues to raise new questions regarding the duration of immunity to reinfection with emerging variants. To address these knowledge gaps, controlled investigations in established animal models are needed to assess duration of immunity induced by each SARS-CoV-2 lineage and precisely evaluate the extent of cross-reactivity and cross-protection afforded. Using the Syrian hamster model, we specifically investigated duration of infection acquired immunity to SARS-CoV-2 ancestral Wuhan strain over 12 months. Plasma spike- and RBD-specific IgG titers against ancestral SARS-CoV-2 peaked at 4 months post-infection and showed a modest decline by 12 months. Similar kinetics were observed with plasma virus neutralizing antibody titers which peaked at 2 months post-infection and showed a modest decline by 12 months. Reinfection with ancestral SARS-CoV-2 at regular intervals demonstrated that prior infection provides long-lasting immunity as hamsters were protected against severe disease when rechallenged at 2, 4, 6, and 12 months after primary infection, and this coincided with the induction of high virus neutralizing antibody titers. Cross-neutralizing antibody titers against the B.1.617.2 variant (Delta) progressively waned in blood over 12 months, however, re-infection boosted these titers to levels equivalent to ancestral SARS-CoV-2. Conversely, cross-neutralizing antibodies to the BA.1 variant (Omicron) were virtually undetectable at all time-points after primary infection and were only detected following reinfection at 6 and 12 months. Collectively, these data demonstrate that infection with ancestral SARS-CoV-2 strains generates antibody responses that continue to evolve long after resolution of infection with distinct kinetics and emergence of cross-reactive and cross-neutralizing antibodies to Delta and Omicron variants and their specific spike antigens.

Significant neutralizing escapes of Omicron and its sublineages in SARS-CoV-2-infected individuals vaccinated with inactivated vaccines.

In China, most SARS-CoV-2-infected individuals had been vaccinated with inactivated vaccines. However, little is known about their immune resistances to the previous variants of concerns (VOCs) and the current Omicron sublineages. Here, we collected convalescent serum samples from SARS-CoV-2-infected individuals during the ancestral, Delta, and Omicron BA.1 waves, and evaluated their cross-neutralizing antibodies (nAbs) against the previous VOCs and the current Omicron sublineages using VSV-based pseudoviruses. In the convalescents who had been unvaccinated and vaccinated with two doses of inactivated vaccines, we found infections from either the ancestral or the Delta strain elicited moderate cross-nAbs to previous VOCs, but very few cross-nAbs to the Omicron sublineages, including BA.1, BA.2, BA.3, and BA.4/5. The individuals who had been vaccinated with two doses of inactivated vaccines before Omicron BA.1 infection had moderate nAbs to Omicron BA.1, but weak cross-nAbs to the other Omicron sublineages. While three doses of inactivated vaccines followed Omicron BA.1 infection induced elevated and still weak cross-nAbs to other Omicron sublineages. Our results indicate that the Omicron sublineages show significant immune escape in the previously SARS-CoV-2-infected individuals and thus highlights the importance of vaccine boosters in this population.