Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination

Abstract

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and its numerous spike mutations, which have the potential to evade neutralizing antibodies elicited by COVID-19 vaccines. Here we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants who had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that a heterologous CoronaVac prime vaccination of two doses followed by a BNT162b2 booster induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and the Delta variant, resembling the titers obtained after two doses of mRNA vaccines. Although neutralization of Omicron was undetectable in participants who had received a two-dose regimen of CoronaVac, the BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron compared with the two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 7.1-fold and 3.6-fold for Omicron compared with the ancestral strain and the Delta variant, respectively. These findings have immediate implications for multiple countries that previously used a CoronaVac regimen and reinforce the idea that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.

Fig. 1. Characterization of vaccine-induced immunity after heterologous CoronaVac–BNT162b2 vaccination.

Dominican Republic (DR) participants received two doses of CoronaVac followed by a heterologous booster with BNT162b2 mRNA vaccine. Plasma samples were collected at baseline, before the booster (CoronaVac (2x) DR), and at 7 and 28 days after the booster (CoronaVac (2x) + Pfizer (1x)). The HCW participants from Yale-New Haven Hospital received two doses of the mRNA vaccine and the plasma samples were used for comparison (mRNAVac (2x) Yale). a,b, Plasma reactivity to the spike (S) protein (a) and RBD (b) measured with ELISA (DR n = 101 and Yale n = 32 at each respective time point). Horizontal lines indicate the mean values. c–f, Neutralization assay using wild-type SARS-CoV-2. c,d, Plasma neutralization capacity against the ancestral strain (WA1, USA) (c) and the Delta variant (d) by time (DR, n = 101 in each group; Yale, n = 32). The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. e, Plasma neutralization capacity against the ancestral strain and the Delta and Omicron variants at baseline (left) and at 28 days after the booster (right) (n = 64 for baseline Omicron variant, n = 101 in other group). f, Plasma neutralization capacity against Omicron by time. CoronaVac (2x) DR, n = 64; CoronaVac (2x) + Pfizer (1x) DR, n = 101; mRNAVac (2x) Yale, n = 32. Significance was assessed with one-way ANOVA corrected for multiple comparisons using Tukey’s method. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. Each circle represents a single individual. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant.

Fig. 2. Comparison of neutralizing activity in CoronaVac–BNT162b2-vaccinated participants by SARS-CoV-2 infection status.

a,b, Plasma neutralization titers against ancestral lineage A virus and variants of concern in HCW participants from Yale-New Haven Hospital who received two doses of the mRNA vaccine. a, Plasma neutralization titers measured at 28 days after the second dose in non-previously infected (left) and previously infected participants (right). Significance was measured using one-way ANOVA corrected using Dunnett’s test. Boxes represent the mean ± s.d. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. b, Neutralization titers from the participants in a by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 16; (+) vaccinated–previously infected, n = 14. c–g, Plasma neutralization titers from Dominican Republic participants who received two doses of CoronaVac followed by BNT162b2 booster. c, Neutralization titers against the ancestral virus and the Delta and Omicron variants at 28 days after the booster in non-previously infected (left; ancestral, n = 75; Delta, n = 75; Omicron, n = 75) and SARS-CoV-2-previously infected participants (right; ancestral, n = 26; Delta, n = 26; Omicron, n = 26). Significance was measured using one-way ANOVA corrected using Tukey’s test. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. d, Neutralization titers from the participants in c by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 57; (+) vaccinated–previously infected, n = 24. e, Plasma neutralization titers at 28 days after the booster dose by time from the second CoronaVac vaccination (n = 101 in each group). f,g, Plasma neutralization titers measured before (f) and 28 days after the booster dose (g) by time from SARS-CoV-2 infection. Ancestral, n = 26; Delta, n = 26; Omicron, n = 26. The lines indicate the cross-sectional average from each group and the shading represents the 95% CI. Each dot represents a single individual. A multivariable linear regression modeling was used to access significance. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Extended Data Fig. 1. Impact of SARS-CoV-2 Omicron on neutralization capacity of in mRNA-vaccinated participants.

Plasma neutralization titers against ancestral lineage A virus, (WA1, USA) and VOCs: Alpha, Beta, Delta and Omicron. SARS-CoV-2 variants were isolated from nasopharyngeal swabs of infected individuals and ancestral (WA1, USA) isolate was obtained from BEI. Neutralization capacity was accessed using plasma samples from HCW participants that received 2 doses of the mRNA vaccine (mRNAVac (2x) Yale), 28 days post second vaccination dose at the experimental sixfold serial dilutions (from 1:3 to 1:2430). Significance was assessed by One-way ANOVA corrected for multiple comparisons using Dunnett’s method. Neutralization capacity to the variants was compared to neutralization capacity against the ancestral strain. Boxes represent mean values ± standard deviations. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared to ancestral strain. n = 32/group Each dot represents a single individual. ****p < 0.0001 **p < 0.005.

Extended Data Fig. 2. Plasma antibody kinetics post CoronaVac vaccination.

a, Vaccinated participants plasma reactivity to RBD measured by ELISA. b, Plasma neutralization titers measured at baseline, previously to BNT162b2 booster shot against ancestral virus, Delta and Omicron variants. Regression lines are shown over time as days post 2 CoronaVac dose vaccination, as purple (ancestral), dark green (Delta) and light green (Omicron). Lines indicates cross-sectional averages from each group, with shading representing 95% CI and colored accordingly. Each dot represents a single individual. n = 101 (Ancestral); n = 101 (Delta); n = 80 (Omicron).