COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

Abstract

As SARS-CoV-2 has been circulating for over a year, dozens of vaccine candidates are under development or in clinical use. The BNT162b2 mRNA COVID-19 vaccine induces spike protein-specific neutralizing antibodies associated with protective immunity. The emergence of the B.1.1.7 and B.1.351 variants has raised concerns of reduced vaccine efficacy and increased re-infection rates. Here we show, that after the second dose, the sera of BNT162b2-vaccinated health care workers (n = 180) effectively neutralize the SARS-CoV-2 variant with the D614G substitution and the B.1.1.7 variant, whereas the neutralization of the B.1.351 variant is five-fold reduced. Despite the reduction, 92% of the seronegative vaccinees have a neutralization titre of >20 for the B.1.351 variant indicating some protection. The vaccinees' neutralization titres exceeded those of recovered non-hospitalized COVID-19 patients. Our work provides evidence that the second dose of the BNT162b2 vaccine induces cross-neutralization of at least some of the circulating SARS-CoV-2 variants.

Fig. 1. Antibody responses against SARS-CoV-2 S1 and N proteins in BNT162b2 vaccinated health care workers and non-hospitalized recovered COVID-19 patients.

A Anti-S1 and B anti-N IgG, IgA, IgM, and total Ig antibody levels were measured with EIA. Serum samples from BNT162b2 vaccinated initially seronegative participants (n = 169) were collected before vaccination (0d), and three (3wk) and six (6wk) weeks after the first dose of the vaccine. All vaccinees received the second dose of the vaccine three weeks after the first dose. Convalescent phase patient samples (Conv, n = 50) were collected 14 days–6 weeks after the positive RT-qPCR test result. Data are represented as geometric means and geometric standard deviations (SD). Cut-off values are indicated with dashed lines.

Fig. 2. Genetic analysis of virus variants and spike protein structure prediction.

A Schematic presentation of S gene and amino acid changes in FIN-25 (B.1 lineage), SR121 (B.1.463), 85HEL (B.1.1.7), and HEL12-102 (B.1.351) virus isolates used in the present study. B Trimeric SARS-CoV-2 S protein, referred to as the spike, structure in the closed conformation (pdb: 6VXX). Amino acid substitutions (yellow) and deletions (green) as compared to the original spike structure. C Collective presentation of all amino acid changes found in virus isolates. Space-filling model indicating amino acids changes (yellow) and deletions (green) on the surface of a trimeric S protein. Side and top views are shown.

Fig. 3. Neutralization of B.1.1.7 and B.1.351 variants by BNT162b2 vaccinees’ sera and COVID-19 patient sera.

A Neutralization titres of initially seronegative vaccinees (n = 169) for D614G variants FIN-25 and SR121, and 85HEL (B.1.1.7) and HEL12-102 (B.1.351) variants before (0d), three (3wk), and six weeks (6wk) after the first dose of BNT162b2 vaccine and neutralization titres of convalescent sera of non-hospitalized patients (Conv, n = 50). Values above the groups indicate geometric mean titres (GMTs) and data are shown as geometric means and geometric SDs. Neutralization titres <20 were plotted as 10. B Neutralization titres 3 weeks (3wk) and six weeks (6wk) after the first dose of the vaccine. Statistical differences between the virus isolates were analyzed with Wilcoxon matched-pairs signed-rank test. Two-tailed p-values <0.05 were considered significant. Exact p-values were *=0.0201, **=0.0015, ****<0.0001 for 3wk and 6wk. Values above the groups indicate geometric mean titres (GMTs) and data are shown as geometric means and geometric SDs. Neutralization titres <20 were plotted as 10.

Fig. 4. Correlation of MNT titres against SARS-CoV-2 isolates.

MNT titres of BNT162b2 vaccinees (initially seronegative, n = 169) against FIN-25 were compared with MNT titres against 85HEL (B.1.1.7) and HEL12-102 (B.1.351) variants including 0d, 3wk, and 6wk samples. Comparison between two D614G virus isolates, FIN-25 and SR121, was done with sera from 86 BNT162b2 vaccinees. Correlation co-efficient (r) was calculated with Pearsons correlation test and two-tailed p-values < 0.05 were considered significant. Each dot may represent multiple samples.

Fig. 5. Antibody responses against SARS-CoV-2 S1 protein and neutralization of FIN-25 by age and gender.

A BNT162b2 vaccinated health care workers (initially seronegative, n = 169) were divided into four age groups. Age specific differences of anti-S1 IgG antibody levels and neutralization titres against FIN-25 virus isolate were analyzed. Sera was collected three weeks (3w) and six weeks (6wk) after the first vaccine dose. Differences between age groups were tested with two-tailed Mann–Whitney U test. Two-tailed p-values < 0.05 were considered significant. Exact p-values were **=0.0078, ***=0.0007, and ****<0.0001 for 3wk EIA, **=0.0021 (age group 35–44 vs. 55–65), *= 0.0.231, and **=0.0041 for 6wk EIA, and *=0.0133 and ***=0.0005 for 3wk MNT. B Gender-specific differences in S1 specific IgG antibody responses and neutralization titres against FIN-25 were analyzed. Differences between age and gender groups were tested with two-tailed Mann–Whitney U test. Two-tailed p-values <0.05were considered significant. Exact p-values were *=0.0412. The data in A and B are presented as geometric means and geometric SDs. Neutralization titres <20 were plotted as 10.

Fig. 6. Correlation of anti-S1 antibody levels with SARS-CoV-2 neutralization titres.

Anti-S1 IgG and total Ig antibody levels were determined with EIA and neutralization titres of BNT162b2 vaccinated health care workers (initially seronegative, n = 169) against FIN-25 virus isolate were obtained with microneutralization test (MNT). All sequential serum samples (0d, 3wk, and 6wk) were included in the analysis. Spearman’s rank correlation coefficient (r) is indicated.