Waning immune responses against SARS-CoV-2 variants of concern among vaccinees in Hong Kong

Qiaoli Peng, Runhong Zhou, Yuewen Wang, Meiqing Zhao, Na Liu, Shuang Li, Haode Huang, Dawei Yang, Ka-Kit Au, Hui Wang, Kwan Man, Kwok-Yung Yuen, Zhiwei Chen, Qiaoli Peng, Runhong Zhou, Yuewen Wang, Meiqing Zhao, Na Liu, Shuang Li, Haode Huang, Dawei Yang, Ka-Kit Au, Hui Wang, Kwan Man, Kwok-Yung Yuen, Zhiwei Chen

Abstract

Background: Nearly 4 billion doses of the BNT162b2-mRNA and CoronaVac-inactivated vaccines have been administrated globally, yet different vaccine-induced immunity against SARS-CoV-2 variants of concern (VOCs) remain incompletely investigated.

Methods: We compare the immunogenicity and durability of these two vaccines among fully vaccinated Hong Kong people.

Findings: Standard BNT162b2 and CoronaVac vaccinations were tolerated and induced neutralizing antibody (NAb) (100% and 85.7%) and spike-specific CD4 T cell responses (96.7% and 82.1%), respectively. The geometric mean NAb IC50 and median frequencies of reactive CD4 subsets were consistently lower among CoronaVac-vaccinees than BNT162b2-vaccinees. CoronaVac did not induce measurable levels of nucleocapsid protein-specific IFN-γ+ CD4+ T or IFN-γ+ CD8+ T cells compared with unvaccinated. Against VOCs, NAb response rates and geometric mean IC50 titers against B.1.617.2 (Delta) and B.1.1.529 (Omicron) were significantly lower for CoronaVac (50%, 23.2 and 7.1%, <20) than BNT162b2 (94.1%, 131 and 58.8%, 35.0), respectively. Three months after vaccinations, NAbs to VOCs dropped near to detection limit, along with waning memory T cell responses, mainly among CoronaVac-vaccinees.

Interpretation: Our results indicate that vaccinees especially CoronaVac-vaccinees with significantly reduced NAbs may probably face higher risk to pandemic VOCs breakthrough infection.

Funding: This study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20GF and C1134-20GF); the Wellcome Trust (P86433); the National Program on Key Research Project of China (Grant 2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); Shenzhen Science and Technology Program (JSGG20200225151410198 and JCYJ20210324131610027); HKU Development Fund and LKS Faculty of Medicine Matching Fund to AIDS Institute; Hong Kong Innovation and Technology Fund, Innovation and Technology Commission and generous donation from the Friends of Hope Education Fund. Z.C.'s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).

Keywords: Cellular immune response; Humoral immune response; Inactivated vaccine; SARS-CoV-2; mRNA vaccine.

Conflict of interest statement

Declaration of interest The authors declare no competing interests.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Immune responses measured at the acute phase after the second dose among BNT162b2 and CoronaVac vaccinees. (a) The area under curve (AUC) of anti-Spike and anti-RBD IgG in BNT162b2 (orange) (n=34), CoronaVac (green) (n=28) and non-vaccinated volunteers (grey) (n=16). The AUC represents the total peak area calculated from ELISA OD values by the GraphPad Prism v8. (b) Percentage inhibition and IC50/IC90 values against wild type SARS-CoV-2 pseudoviruses in BNT162b2 and CoronaVac vaccinees. (c) The neutralization antibody potency index defined by the ratio of IC50/AUC of anti-Spike IgG and anti-RBD IgG in BNT162b2 and CoronaVac group. Data showed geometric mean values in each group in a-c. (d) Quantified results depict the percentage of RBD, spike and NP-specific IFN-γ+ CD4+ T (top) and IFN-γ+ CD8+ T (bottom) cells in BNT162b2 (n=33), CoronaVac (n=28) and non-vaccinated volunteers (n=15), respectively. Fresh PBMC were subjected to T cell response measurement by ICS after RBD-, spike- and NP-specific ex vivo peptide pool stimulation, respectively. Numbers under the x-axis in a and d indicate the rate of positive responders. (e) The proportions of spike-specific polyfunctional CD4+ T (top) and CD8+ T (bottom) cells were compared in BNT162b2 and CoronaVac-vaccinated responders. After gating on IFN-γ+CD4+/CD8+ T cells and IFN-γ−CD4+/CD8+ T cells, single cytokine (IFN-γ+ or TNF-α+ or IL-2+only), double cytokines (IFN-γ+ TNF-α+ or IFN-γ+ IL-2+ or TNF-α+ IL-2+), and triple cytokines (IFN-γ+ TNF-α+ IL-2+) producing cells were analyzed in response to spike-specific ex vivo peptide pool stimulation, respectively. Background-subtracted data was analyzed in all cases in d and e. The bars in D and E indicated median value. (f) Phenotypic analysis depicted antigen-specific T cell subsets of BNT162b2 and CoronaVac vaccinees. After gating on IFN-γ+ CD4+ or IFN-γ+ CD8+ T cells, T cell subsets expressing CCR7 and/or CD45RA were analyzed in response to spike-specific ex vivo peptide pool stimulation. Data were analyzed for statistical significance using Mann-Whitney U test. Dotted black lines indicate the limit of quantification (LOQ). **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 2
Figure 2
Neutralizing antibody activity against SARS-CoV-2 variants of concerns elicited by BNT162b2 and CoronaVac. (a) Neutralizing antibody titers (NAbTs) against seven SARS-CoV-2 strains from BNT162b2 (orange) (n=34) and CoronaVac (green) (n=28) participants at acute phase after the second vaccination. NAbTs represent serum dilution required to achieve 50% virus neutralization (IC50). Numbers under the x-axis indicate the fold difference of BNT162b2 to CoronaVac. (b) shows neutralizing IC50 of four response levels from BNT162b2 (orange) and CoronaVac (green) recipients. Grey bars indicate the percentage of non-responders. Numbers in the top right corner represent the percentage of responders for each VOC. Neutralizing IC50 against wild type compared to D614G, B.1.1.7, B.1.351, P1, B.1.617.2, B.1.429 and B.1.1529 in BNT162b2 (c) and CoronaVac (d) vaccinees. Numbers under the x-axis indicate the fold change of different VOC relative to Wuhan-Hu-1wild type. Mann-Whitney U test was used for between-group comparison in a, c and d. Two-sided chi-square test was used in b. The bars represent geometric mean in a, c, d. Dotted black lines indicate the limit of quantification (LOQ). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 3
Figure 3
Changes of humoral and cellular responses from the acute phase to the memory phase among BNT162b2- and CoronaVac-vaccinees. Longitudinal samples from 27 BNT162b2 (orange) and 16 CoronaVac (green) vaccinees were available to track immune response from acute phase to memory phase. Longitudinal binding antibodies to anti-Spike (a) and RBD IgG (b), neutralizing IC50 to wild type (c) and different VOCs including D614G (d), B.1.1.7 (e), B.1.351 (f), P1 (g), B.1.617.2 (h), B.1.429 (i), B.1.1.529 (j) and spike-specific IFN-γ+ CD4+ (k) or CD8+ (l) T cells were measured and compared. Significant differences between acute phase and memory phase of both vaccine groups were determined by Wilcoxon signed-rank test. Dotted black lines indicate the limit of quantification (LOQ) . *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 4
Figure 4
Correlation analysis of vaccine-induced humoral and cellular immune responses. Correlation analysis of anti-Spike (a) and RBD IgG (b) (Iog10), IC50 against different VOCs including D614G (c), B.1.1.7 (d), B.1.351 (e), P1 (f), B.1.617.2 (g), B.1.429 (h), B.1.1.529 (i) and spike-specific IFN-γ+ CD4+ (j) or CD8+ T cells (k) to IC50 against wild type (WT) as well as spike-specific IFN-γ+ CD4+ and CD8+ T cells (l) . The non-parametric Spearman test was used for correlation analysis. P and r values were indicated.

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