Neutralization of ancestral SARS-CoV-2 and variants Alpha, Beta, Gamma, Delta, Zeta and Omicron by mRNA vaccination and infection-derived immunity through homologous and heterologous variants

Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. Here, we have assessed a total of 104 blood specimens, consisting of convalescent samples after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination samples after double-dose mRNA-vaccination as well as samples after vaccine break-through infections with Delta or Omicron. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, Omicron) was assessed by plaque-reduction neutralization assay. We found highest neutralization titers against the homologous (previously infecting) variant, with lower neutralization efficiency against heterologous variants. Loss of neutralization against heterologous variants showed considerably variability between convalescent groups suggesting that a variant-specific infection background influences immune escape characteristics. Convalescent samples from pre-VOC SARS-CoV-2, Alpha, Beta, Gamma and Delta-infected individuals all showed a significant loss of neutralization for Omicron but to a varying degree (23.0-fold in Beta-convalescent up to 56.1-fold in Alpha-convalescent samples), suggesting that infection-derived immunity, independent of the infecting variant is most likely only poorly protective against Omicron. Of note, former variant of concern Zeta showed also a pronounced escape form neutralization of up to 28.2-fold in Alpha convalescent samples. Two-dose vaccinated individuals showed robust neutralization against B.1 and only slightly lower neutralization titers for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction for heterologous virus between 2.8 (for Alpha) to 6.9 (for Beta). In contrast to convalescent specimens, escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron showed a strongly reduced neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2. Robust neutralization titers were observed in double-vaccinated individuals with subsequent Delta break-through infections, that also neutralized Omicron with a loss of only 12.5-fold. Individuals with an Omicron breakthrough infection showed high neutralization titers for both Delta and Omicron, with only a 1.5-fold loss for Delta neutralization. This suggests that infection with antigenically different variants can boost immunity against variants that are antigenically similar to the vaccine strain. We conclude that for the assessment of escape from neutralization by new VOCs such as Omicron, the complexity of background immunity due to individual and regional differences needs to be taken into account. Geographic variation in the proportion of individual with infection- or vaccination-derived immunity or a combination of both could have substantial influence on the course of the pandemic. Combined infection/vaccination immunity after break-through infections could ultimately lead to broad immunity also against non-homologous variants.