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. 2022 Oct 3:9:994160.
doi: 10.3389/fmed.2022.994160. eCollection 2022.

Comparison of vaccine-induced antibody neutralization against SARS-CoV-2 variants of concern following primary and booster doses of COVID-19 vaccines

Astrid K Hvidt  1   2 , Eva A M Baerends  1   2 , Ole S Søgaard  1   2 , Nina B Stærke  1   2 , Dorthe Raben  3 , Joanne Reekie  3 , Henrik Nielsen  4   5 , Isik S Johansen  6   7 , Lothar Wiese  8 , Thomas L Benfield  9   10 , Kasper K Iversen  10   11 , Ahmed B Mustafa  9   10 , Maria R Juhl  4   5 , Kristine T Petersen  4   5 , Sisse R Ostrowski  10   12 , Susan O Lindvig  6   7 , Line D Rasmussen  6   7 , Marianne H Schleimann  1   2 , Sidsel D Andersen  1   2 , Anna K Juhl  1   2 , Lisa L Dietz  1   2 , Signe R Andreasen  1   2 , Jens Lundgren  3   10   13 , Lars Østergaard  1   2 , Martin Tolstrup  1   2 ; ENFORCE Study Group
Affiliations

Comparison of vaccine-induced antibody neutralization against SARS-CoV-2 variants of concern following primary and booster doses of COVID-19 vaccines

Astrid K Hvidt et al. Front Med (Lausanne). .

Abstract

The SARS-CoV-2 pandemic has, as of July 2022, infected more than 550 million people and caused over 6 million deaths across the world. COVID-19 vaccines were quickly developed to protect against severe disease, hospitalization and death. In the present study, we performed a direct comparative analysis of four COVID-19 vaccines: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford/AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), following primary and booster vaccination. We focused on the vaccine-induced antibody-mediated immune response against multiple SARS-CoV-2 variants: wildtype, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and B.1.1.529 (Omicron). The analysis included the quantification of total IgG levels against SARS-CoV-2 Spike, as well as the quantification of antibody neutralization titers. Furthermore, the study assessed the high-throughput ACE2 competition assay as a surrogate for the traditional pseudovirus neutralization assay. The results demonstrated marked differences in antibody-mediated immune responses. The lowest Spike-specific IgG levels and antibody neutralization titers were induced by one dose of the Ad26.COV2.S vaccine, intermediate levels by two doses of the BNT162b2 vaccine, and the highest levels by two doses of the mRNA-1273 vaccine or heterologous vaccination of one dose of the ChAdOx1 vaccine and a subsequent mRNA vaccine. The study also demonstrated that accumulation of SARS-CoV-2 Spike protein mutations was accompanied by a marked decline in antibody neutralization capacity, especially for B.1.1.529. Administration of a booster dose was shown to significantly increase Spike-specific IgG levels and antibody neutralization titers, erasing the differences between the vaccine-induced antibody-mediated immune response between the four vaccines. The findings of this study highlight the importance of booster vaccines and the potential inclusion of future heterologous vaccination strategies for broad protection against current and emerging SARS-CoV-2 variants.

Keywords: COVID-19; SARS-CoV-2; antibodies; booster; immunity; neutralization; omicron; vaccines.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared parent affiliation with several of the authors AH, EB, OS, NS, MS, SA, AJ, LD, and SRA at the time of the review.

Figures

FIGURE 1
FIGURE 1
Levels of SARS-CoV-2-S IgG after COVID-19 vaccination: Levels of total SARS-CoV-2-S IgG in U/mL induced by primary COVID-19 vaccination with BNT162b2 (n = 22), mRNA-1273 (n = 24), ChAdOx1/mRNA (n = 20) or Ad26.COV2.S (n = 19) quantified by the MSD platform (serum 1:5,000). Data from convalescent comparators (n = 25) are also displayed, but are not included in the statistical analysis. From left to right: SARS-CoV-2-S wt (Wuhan-Hu-1) and the following SARS-CoV-2-S VOCs: B.1.1.7 (Alpha), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529; BA.1 (Omicron). The boxplots present the lower quartile, median and upper quartile, and the error bars indicate 95% CI. P-values were indicated as follows: ***p < 0.001 and ****p < 0.0001.
FIGURE 2
FIGURE 2
Neutralizing antibody responses to pseudoviral SARS-CoV-2-S after COVID-19 vaccination: (A) The 50% neutralization titers (NT50) induced by primary COVID-19 vaccination with BNT162b2 (n = 22), mRNA-1273 (n = 24), ChAdOx1/mRNA (n = 20) or Ad26.COV2.S (n = 19) quantified by the pseudovirus neutralization assay. Data from convalescent comparators (n = 25) are also displayed, but are not included in the statistical analysis. (B) NT50 values merged for all vaccine types. (C) The frequency of quantifiable (> 25) and non-quantifiable (≤ 25) NT50 values merged for all vaccine types. From left to right: SARS-CoV-2-S wt (Wuhan-Hu-1 including D614G) and the following SARS-CoV-2-S VOCs: B.1.1.7 (Alpha), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529; BA.1 (Omicron) (B.1.1.529; BA.1, n = 32: eight individuals per vaccine group). All boxplots present the lower quartile, median and upper quartile, and the error bars indicate 95% CI. P-values were indicated as follows: *p ≤ 0.05, **p < 0.01, and ****p < 0.0001.
FIGURE 3
FIGURE 3
ACE2 competition assay as a surrogate for quantifying COVID-19 vaccine-induced antibody neutralization capacity: (A) SARS-CoV-2-S ACE2 receptor-blocking antibodies in U/mL and (B) ACE2 receptor blocking in percentage for SARS-CoV-2-S wt induced by primary COVID-19 vaccination with BNT162b2 (n = 22), mRNA-1273 (n = 24), ChAdOx1/mRNA (n = 20) or Ad26.COV2.S (n = 19) quantified by the MSD platform (serum 1:100). Data from convalescent comparators (n = 25) are also displayed, but are not included in the statistical analysis. The boxplots present the lower quartile, median and upper quartile, and the error bars indicate 95% CI. P-values were indicated as follows: **p < 0.01 and ****p < 0.0001. (C) Spearman’s correlation between SARS-CoV-2-S wt NT50 values quantified by the pseudovirus neutralization assay and ACE2 receptor-blocking antibodies in U/mL and (D) ACE2 receptor blocking in percentage quantified by the MSD ACE2 competition assay.
FIGURE 4
FIGURE 4
Percentage of ACE2 receptor blocking after COVID-19 vaccination: (A) Percentage of ACE2 receptor blocking induced by primary COVID-19 vaccination with BNT162b2 (n = 22), mRNA-1273 (n = 24), ChAdOx1/mRNA (n = 20) or Ad26.COV2.S (n = 19) quantified by the MSD platform (serum 1:10). Data from convalescent comparators (n = 25) are also displayed, but are not included in the statistical analysis. From left to right: SARS-CoV-2-S wt (Wuhan-Hu-1) and B.1.1.529; BA.1, BA.2 and BA.3 (Omicron). (B) Percentage of ACE2 receptor blocking merged for all vaccine types. From left to right: SARS-CoV-2-S wt, B.1.1.7 (Alpha), B.1.617.2 (Delta), B.1.351 (Beta), and B.1.1.529; BA.1, BA.2 and BA.3 (Omicron). All boxplots present the lower quartile, median and upper quartile, and the error bars indicate 95% CI. P-values were indicated as follows: ***p < 0.001 and ****p < 0.0001.
FIGURE 5
FIGURE 5
Levels of SARS-CoV-2-S IgG and percentage of ACE2 receptor blocking after COVID-19 booster vaccination: (A) Levels of total SARS-CoV-2-S IgG in U/mL and (B) ACE2 receptor blocking in percentage at the third study visit (after primary vaccination) and at the Xc study visit (after booster vaccination) merged for all vaccine types quantified by the MSD platform (after primary = serum and after booster = plasma, IgG = 1:5,000 and ACE2 = 1:10). From left to right: SARS-CoV-2-S wt (Wuhan-Hu-1) and B.1.1.529; BA.1, BA.2 and BA.3 (Omicron). (C) ACE2 receptor blocking in percentage after booster vaccination with BNT162b2 (n = 11), mRNA-1273 (n = 12), ChAdOx1/mRNA (n = 5) and Ad26.COV2.S/mRNA (n = 6) quantified by the MSD platform (plasma 1:10). From left to right: SARS-CoV-2-S wt and B.1.1.529; BA.1, BA.2, and BA.3. All boxplots present the lower quartile, median and upper quartile, and the error bars indicate 95% CI. P-values were indicated as follows: ns = p > 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.
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