Post-Vaccination Neutralization Responses to Omicron Sub-Variants

Background: The emergence of the Omicron variant (B.1.1.529), which correlated with dramatic losses in cross-neutralization capacity of post-vaccination sera, raised concerns about the effectiveness of COVID-19 vaccines against infection and disease. Several clinically relevant sub-variants subsequently emerged rapidly. Methods: We evaluated published and pre-print studies reporting sub-variant specific reductions in cross-neutralization compared to the prototype strain of SARS-CoV-2 and between sub-variants. Median fold-reduction across studies was calculated by sub-variant and vaccine platform. Results: Among 178 studies with post-vaccination data, after primary vaccination the sub-variant specific fold-reduction in neutralization capacity compared to the prototype antigen varied widely, from median 4.2-fold for BA.3 to 40.1-fold for BA.2.75; in boosted participants fold-reduction was similar for most sub-variants (5.3-fold to 7.0-fold); however, a more pronounced fold-change was observed for sub-variants related to BA.4 and BA.5 (10.4-fold to 14.2-fold). Relative to BA.1, the other Omicron sub-variants had similar neutralization capacity post-primary vaccination (range median 0.8-fold to 1.1-fold) and post-booster (0.9-fold to 1.4-fold) except for BA.4/5-related sub-variants which was higher (2.1-fold to 2.7-fold). Omicron sub-variant-specific responder rates were low post-primary vaccination (range median 28.0% to 65.9%) compared to the prototype (median 100%) but improved post-booster (range median 73.3% to 100%). Conclusions: Fold-reductions in neutralization titers were comparable post-booster except for sub-variants related to BA.4 and BA.5, which had higher fold-reduction. Assessment after primary vaccination was not possible because of overall poor neutralization responses causing extreme heterogeneity. Considering large fold-decreases in neutralization titers relative to the parental strain for all Omicron sub-variants, vaccine effectiveness is very likely to be reduced against all Omicron sub-variants, and probably more so against variants related to BA.4 or BA.5.