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Updated: Aug 23, 2025
Author Spotlight: A Pseudotype Virus System for Assessing Omicron Subvariants and Neutralizing Antibodies in SARS-CoV-2 Research
Published on: September 8, 2023
Post-Vaccination Neutralization Responses to Omicron Sub-Variants
Henning Jacobsen1, Maeva Katzmarzyk1, Melissa M Higdon2
1Department of Viral Immunology, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
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.
Insights
COVID-19 vaccine effectiveness is reduced against Omicron sub-variants, especially BA.4 and BA.5. Booster doses improve neutralization but significant reductions persist, indicating lower protection against infection and disease.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- The Omicron variant (B.1.1.529) and its sub-variants have raised concerns regarding COVID-19 vaccine effectiveness due to significant reductions in neutralization capacity.
- Rapid emergence of clinically relevant Omicron sub-variants necessitates an evaluation of vaccine-induced immune responses.
Purpose of the Study:
- To evaluate the reduction in SARS-CoV-2 neutralization capacity against Omicron sub-variants after primary vaccination and booster doses.
- To compare neutralization capacity across different Omicron sub-variants and vaccine platforms.
Main Methods:
- Systematic review and meta-analysis of published and pre-print studies reporting neutralization data.
- Calculation of median fold-reduction in neutralization capacity compared to the prototype strain and between sub-variants.
- Analysis of responder rates post-primary vaccination and post-booster doses.
Main Results:
- Fold-reduction in neutralization capacity varied widely by sub-variant after primary vaccination (e.g., 4.2-fold for BA.3 to 40.1-fold for BA.2.75).
- Boosted participants showed similar fold-reductions for most sub-variants (5.3-fold to 7.0-fold), but higher reductions for BA.4/BA.5-related sub-variants (10.4-fold to 14.2-fold).
- Responder rates were low post-primary vaccination (28.0%–65.9%) but improved significantly post-booster (73.3%–100%).
Conclusions:
- Neutralization titers showed comparable fold-reductions post-booster, except for BA.4/BA.5-related sub-variants, which exhibited higher fold-reductions.
- Primary vaccination alone resulted in poor and heterogeneous neutralization responses, making assessment difficult.
- Reduced vaccine effectiveness against all Omicron sub-variants, particularly BA.4/BA.5, is highly likely due to significant decreases in neutralization titers.
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