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.

SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96–100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.

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. Clinically relevant sub-variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, and BA.4/5) 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 153 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 21.9-fold for BA.4/5; in boosted participants fold-reduction was similar for all sub-variants (5.9-fold to 7.1-fold) except for BA.4/5 which was 12.7-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 1.2-fold) except for BA.4/5 which was higher (2.0-fold). Omicron sub-variant specific responder rates were low post-primary vaccination (range median 33.5% to 56.7%) compared to the prototype (median 96.0%), but improved post-booster (range median 85.4% to 92.6%).

SummaryBackgroundMass COVID-19 vaccination and the continuous introduction of new viral variants of SARS-CoV-2, especially of Omicron subvariants, has resulted in an increase in the proportion of the population with hybrid immunity at various stages of waning protection. We systematically reviewed waning of post-vaccination neutralizing antibody titers in different immunological settings to investigate potential differences.MethodsWe searched for studies providing data for post-vaccination neutralizing antibody responses against SARS-CoV-2 in PubMed, bioRxiv, and medRxiv from Dec 15, 2021, to Jan 31, 2023, using keywords related to COVID-19, vaccination, and antibody neutralization. We used random effects meta-regression to estimate the average fold-reduction in post-vaccination neutralizing antibody titers against the Index strain or Omicron BA.1. from month 1 to month 6 post last dose, stratified by vaccination regimen (primary or booster) and infection-naïve vs hybrid-immune status.FindingsIn total, 26 studies reporting longitudinal post-vaccination neutralizing antibody titers were included. Neutralization titers against the Index variant were available from all studies for infection-naïve participants, and from nine for hybrid-immune participants. Against Omicron BA.1, nine and eight studies were available for infection-naïve and hybrid-immune cohorts, respectively. In infection-naïve cohorts, post-vaccination neutralization titers against the Index strain waned 5.1-fold (95% CI 3.4-7.8) from month 1 to month 6 following primary regimen and 3.8-fold (95% CI 2.4-5.9) following the booster. Titers against Omicron BA.1 waned 5.9-fold (95% CI 3.8-9.0) in infection-naïve, post-booster cohorts. In hybrid-immune, post-primary vaccination cohorts, titers waned 3.7-fold (95% CI 1.7-7.9) against the Index strain and 5.0-fold (95% CI 1.1-21.8) against Omicron BA.1.InterpretationNo obvious differences in waning between post-primary or post-boost vaccination were observed for vaccines used widely to date, nor between infection-naïve and hybrid-immune participants. Titers against Omicron BA.1 may wane faster compared to Index titers, which may worsen for more recent Omicron sub-variants and should be monitored. Relatively small datasets limit the precision of our current analysis; further investigation is needed when more data become available. However, based on our current findings, striking differences in waning for the analyzed and future comparisons are unlikely.