Omicron BA.1 neutralizing antibody response following Delta breakthrough infection compared with booster vaccination of BNT162b2

Abstract

Background: Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron.

Methods: Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups.

Results: Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients.

Conclusions: Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

Keywords: Booster effect; Delta variant; Neutralizing antibody; Omicron variant; SARS-CoV-2 breakthrough infection.

Fig. 1

Flowchart for the case-control matching Infection-naïve were defined as having no history of COVID-19 and being negative with anti-SARS-CoV-2 nucleocapsid protein assays (both Abbott and Roche assays) Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 2

Change in the neutralizing and spike antibody titers in individuals who experienced breakthrough infection, received the booster vaccine, or were unboosted during follow-up Shown are NAb titers against the original Wild-type strain (A), the Delta variant (B), and the Omicron BA.1 variant (C) determined by 50% focus reduction neutralization test (FRNT₅₀) using the serum at baseline and follow-up. Also shown are anti-spike antibody titers measured with the Abbott reagent (D) and the Roche reagent (E) at baseline and follow-up. Box plots show the median, interquartile range, and full range. The dushed horizontal lines indicate the LOD in the present analysis (NT₅₀ < 40 in FRNT₅₀ and U/mL > 25,000 in Roche assay) The fold-change values are estimated ratios of geometric means for antibody titers based on the GEE model (ns: not significant; *P < 0.05; **P < 0.01; ***P < 0.001) Abbreviations: AU, arbitrary units; B, baseline; F, follow-up; GEE, generalized estimating equation; LOD, limits of detection; NT₅₀, 50% neutralization titer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 3

Neutralizing and spike antibody titers after three vaccine doses, symptomatic and asymptomatic breakthrough infections Shown are NAb titers against the original Wild-type strain (A), the Delta variant (B), and the Omicron BA.1 variant (C) determined by 50% focus reduction neutralization test (FRNT₅₀) using the serum at follow-up. Also shown are anti-spike antibody titers measured with the Abbott reagent (D) and the Roche reagent (E) using the serum at follow-up Patients with PCR-confirmed infection were all symptomatic (n = 7), while those with seropositive on any of anti-SARS-CoV-2 nucleocapsid protein assays (Abbott or Roche assays) at follow-up were all asymptomatic (n = 4) The bars indicate geometric mean titers, and I-shaped bars indicate its geometric standard deviations. The dushed horizontal lines indicate the LOD for FRNT₅₀ (NT₅₀ < 40) and Roche assay (U/mL > 25,000) in the present analysis Statistical significance was determined by Kruskal-Wallis and Dunn’s multiple comparison test (ns: not significant; *P < 0.05; **P < 0.01; ***P < 0.001) Abbreviations: AU, arbitrary units; COVID-19, coronavirus disease 2019; LOD, limits of detection; NT50, 50% neutralization titer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 4

Comparison of neutralizing antibody titers against Wild-type, Delta, and Omicron BA.1 strains Shown are the NAb titers against the original Wild-type strain, the Delta variant, and the Omicron BA.1 variant as determined by the 50% focus reduction neutralization test (FRNT₅₀). The bars indicate geometric mean titers, and I-shaped bars indicate its geometric standard deviations. The dushed horizontal lines indicate the LOD (NT₅₀ titer < 40) Statistical significance was determined by the GEE model (ns: not significant; *P < 0.05; **P < 0.01; ***P < 0.001) Abbreviations: GEE, generalized estimating equation; LOD, limits of detection; NT₅₀, m: months, 50% neutralization titer; 2 doses + 2 m, two months following the two doses; 2 doses + 8 m, eight months following the two doses; 95% CI, 95% confidence interval.