Vaccine- and Breakthrough Infection-Elicited Pre-Omicron Immunity More Effectively Neutralizes Omicron BA.1, BA.2, BA.4 and BA.5 Than Pre-Omicron Infection Alone.

Since the emergence of SARS-CoV-2 Omicron BA.1 and BA.2, several Omicron sublineages have emerged, supplanting their predecessors. Here we compared the neutralization of Omicron sublineages BA.1, BA.2, BA.4 and BA.5 by human sera collected from individuals who were infected with the ancestral B.1 (D614G) strain, who were vaccinated (3 doses) or with breakthrough infection with pre-Omicron strains (Gamma or Delta). All Omicron sublineages exhibited extensive escape from all sera when compared to the ancestral B.1 strain and to Delta, albeit to different levels depending on the origin of the sera. Convalescent sera were unable to neutralize BA.1, and partly neutralized BA.2, BA.4 and BA.5. Vaccinee sera partly neutralized BA.2, but BA.1, BA.4 and BA.5 evaded neutralizing antibodies (NAb). Some breakthrough infections (BTI) sera were non-neutralizing. Neutralizing BTI sera had similar neutralizing ability against all Omicron sublineages. Despite similar levels of anti-Spike and anti-Receptor Binding Domain (RBD) antibodies in all groups, BTI sera had the highest cross-neutralizing ability against all Omicron sublineages and convalescent sera were the least neutralizing. Antibody avidity inferred from the NT50:antibody titer ratio was highest in sera from BTI patients, underscoring qualitative differences in antibodies elicited by infection or vaccination. Together, these findings highlight the importance of vaccination to trigger highly cross-reactive antibodies that neutralize phylogenetically and antigenically distant strains, and suggest that immune imprinting by first generation vaccines may restrict, but not abolish, cross-neutralization.

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone.

SARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here, we compared the neutralizing abilities of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of concern (VOCs) and of 16 vaccine breakthrough infection (BTI) cases infected with Gamma or Delta against the ancestral B.1 strain, the Gamma, Delta and Omicron BA.1 VOCs using live virus. We further determined antibody levels against the Nucleocapsid (N) and full Spike proteins, the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the Spike protein. Convalescent sera featured considerable variability in the neutralization of B.1 and in the cross-neutralization of different strains. Their neutralizing capacity moderately correlated with antibody levels against the Spike protein and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease had higher antibody levels and displayed a higher neutralizing ability against all strains than patients with mild or severe forms of the disease. The sera from BTI cases fell into one of two categories: half the sera had a high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or a very low neutralizing activity against all strains. Although antibody levels against the spike protein and the RBD were lower in BTI sera than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, suggestive of a better cross-neutralization and higher affinity of vaccine-elicited antibodies over virus-induced antibodies. Accordingly, the IC50: antibody level ratios were comparable for BTI and convalescent sera, but remained lower in the neutralizing convalescent sera from patients with moderate disease than in BTI sera. The neutralizing activity of BTI sera was strongly correlated with antibodies against the Spike protein and the RBD. Together, these findings highlight qualitative differences in antibody responses elicited by infection in vaccinated and unvaccinated individuals. They further indicate that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross-neutralizing antibodies against different strains, including Omicron BA.1.

Case series of four re-infections with a SARS-CoV-2 B.1.351 variant, Luxembourg, February 2021.

We describe four SARS-CoV-2 re-infections with a B.1.351 variant in 2021, in healthcare workers (HCWs) previously infected in 2020, before detection of this variant in Europe. Cases live in France, near the border with Luxembourg, where variants B.1.351 and B.1.1.7 circulated. All work in the same hospital unit where a cluster of COVID 19 with B1.351 variant occurred, affecting patients and HCWs. Before the cluster onset, HCWs used surgical masks, as per recommendations. After cluster onset, HCWs used FFP2 masks.