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

Abstract

Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. As the population immunity to SARS-CoV-2 has become more complex due to prior infection and/or vaccination, understanding the antigenic relationship between variants is needed. Here, we have assessed in total 104 blood specimens from convalescent individuals after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination after double-dose mRNA-vaccination and break through infections due to 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. Significant loss of neutralization for Omicron was observed but to a varying degree depending on previously infecting variant (23.0-fold in Beta-convalescence up to 56.1-fold in Alpha-convalescence), suggesting that infection-derived immunity varies, but independent of the infecting variant is only poorly protective against Omicron. Of note, Zeta VOI showed also pronounced escape from neutralization of up to 28.2-fold in Alpha convalescent samples. Antigenic mapping reveals both Zeta and Omicron as separate antigenic clusters. Double dose vaccination showed robust neutralization for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction of only 2.8 (for Alpha) up to 6.9 (for Beta). Escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron still showed a loss of neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2. Combined immunity from infection followed by vaccination or vaccine breakthrough infection showed highest titers and most robust neutralization for heterologous variants. Breakthrough infection with Delta showed only 12.5-fold reduced neutralization for Omicron, while breakthrough infection with Omicron showed only a 1.5-fold loss for Delta, suggests that infection with antigenically different variants can boost immunity for antigens closer to the vaccine strain. Antigenic cartography showed also a tendency towards broader neutralizing capacity for heterologous variants. We conclude that the complexity of background immunity needs to be taken into account when assessing new VOCs. Development towards separate serotypes such as Zeta was already observed before Omicron emergence, thus other factors than just immune escape must contribute to Omicrons rapid dominance. However, combined infection/vaccination immunity could ultimately lead to broad neutralizing capacity also against non-homologous variants.

BA.2 omicron differs immunologically from both BA.1 omicron and pre-omicron variants

“…The antigenic map visualizes the substantial difference of the two omicron sub-lineages BA.1 and BA.2 compared to the previously circulating variants (Figure 2) and corresponds well with previous maps. 14,15,18,25 Wu-1 like variants (D614G, alpha, alpha+E484K), beta and gamma occupy a small space in the map and the delta variant is in roughly the same area. Barely detectable neutralization titers against BA.1 omicron in all but the BA.1 omicron convalescent serum group resulted in its positioning far away from the other variants.…”

SARS-CoV-2 Omicron Variant, Lineage BA.1, Is Associated with Lower Viral Load in Nasopharyngeal Samples Compared to Delta Variant

“…Complete mechanisms driving the higher transmissibility of the Omicron variant are still unknown. Infectiousness could be multifactorial and related to background immunity, respiratory symptoms (cough, sneeze), duration of viral excretion, age and viral parameters such as new viral entry mechanism [ 11 , 14 , 15 ].…”

Omicron infection induces low-level, narrow-range SARS-CoV-2 neutralizing activity

“…Omicron differs from previously prevalent SARS-CoV-2 variants at more than thirty amino acid positions within Spike, the protein responsible for mediating viral entry through recognition of the ACE2 receptor and targeted by SARS-CoV-2 neutralizing antibodies. Accordingly, Omicron escapes neutralization by most monoclonal antibodies available for the treatment of COVID19 or by pre-Omicron convalescent sera and can readily cause infections in individuals who have been either previously infected with other SARS-CoV-2 variants or subjected to full vaccination regimens, all current vaccines being derived from the original SARS-CoV-2 strain or from close relatives 2–7 .…”