key: cord-0714818-zsqzonje
authors: Peng, Qiaoli; Zhou, Runhong; Wang, Yuewen; Zhao, Meiqing; Liu, Na; Li, Shuang; Huang, Haode; Yang, Dawei; Au, Ka-Kit; Wang, Hui; Man, Kwan; Yuen, Kwok-Yung; Chen, Zhiwei
title: Waning immune responses against SARS-CoV-2 among vaccinees in Hong Kong
date: 2021-12-23
journal: bioRxiv
DOI: 10.1101/2021.12.22.473934
sha: 760d36b77486c8b21effe4550d246e1fc313aae1
doc_id: 714818
cord_uid: zsqzonje

Background Nearly 4 billion doses of the BioNTech-mRNA and Sinovac-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 BioNTech and Sinovac 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 Sinovac-vaccinees than BioNTech-vaccinees. Against VOCs, NAb response rate and geometric mean IC50 against B1.351 and B.1.617.2 were significantly lower for Sinovac (14.3%, 15 and 50%, 23.2) than BioNTech (79.4%, 107 and 94.1%, 131). Three months after vaccinations, NAbs to VOCs dropped near to detection limit, along with waning memory T cell responses, mainly among Sinovac-vaccinees. Interpretation Our results indicate that Sinovac-vaccinees may 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 to Z.C and C1134-20GF); 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).

To measure antigen-specific T cell response, PBMCs were stimulated with 2 µg/mL of 169 indicated COVID-19 antigen peptide pools (RBD or Spike or NP) in the presence of 0.5 170 µg/mL anti-CD28 and anti-CD49d mAbs (Biolegend). Cells were incubated at 37 overnight, 171 and BFA (Sigma) was added at 2 h post incubation, as previously described (13). CMV (pp65) 172 peptide pool was included as an internal positive control. Stimulation alone with anti-CD28 173 and anti-CD49d was used as negative control. After overnight incubation, cells were washed 174 with staining buffer (PBS containing 2% FBS) and stained with mAbs against surface 175 markers (Zombie Aqua, Pacific blue anti-CD3, Percp-Cy5.5 anti-CD4, APC-Fire750 anti-176 CD8, BV711 anti-CD45RA and APC anti-CCR7) (Biolegend). For intracellular staining, 177 cells were fixed and permeabilized with BD Cytofix/Cytoperm (BD Biosciences) prior to 178 staining with the mAbs against cytokines (PE anti-IFN-γ, AF488 anti-TNF-α and PE-Cy7 179 anti-IL-2) (Biolegend) with Perm/Wash buffer (BD Biosciences). After gating on CD4 + T 180 and CD8 + T cells, intracellular IFN-γ/TNF-α/IL-2 were calculated (Fig. S1 ). All percentages 181 of antigen-specific CD4 + and CD8 + T cells were reported as background subtracted data from 182 the same sample stimulated with negative control (anti-CD28/CD49d only). The LOQ for 183 antigen-specific CD4 + (0.01%) and CD8 + T cell responses (0.02%) was calculated using a 184 twofold median value of all negative controls. Responses >LOQ and a stimulation index >2 185 for CD4 + and CD8 + T cells were considered positive responder. Values higher than the 186 threshold of positive responders after spike peptide pool stimulation were considered for the 187 analysis of multifunctional antigen-specific T cell responses. Phenotype profiles were further 188 analyzed by gating on IFN-γ + CD4 or IFN-γ + CD8 T cells for expression of CCR7 and/or 189 Besides humoral immune response, we also measured antigen-specific T cell response 248 because it may play an important role in protection against SARS-CoV-2 infection (13, 18). 249

Vaccine-specific T cell responses were determined by ICS after stimulation by the peptide 250 pools covering RBD, spike and NP antigen ( 2E). Spike-specific CD8 + T cells were consistently detected in 81.8% of our BioNTech-263 vaccinees similar to recent reports by others (19-21). BioNTech, however, did not elicited 264 significantly higher frequencies of spike-specific IFN-γ + CD8 + T cells (P=0.6376) as 265 compared with the Sinovac group ( Fig. 2D and 2E) . Surprisingly, Sinovac did not induce 266 measurable levels of NP-specific IFN-γ + CD4 + T or IFN-γ + CD8 + T cells compared with the 267 non-vaccinated group (Fig. 2D ). As expected, CMV-specific IFN-γ + CD4 + and CD8 + T cells 268

were comparable between these two vaccinated groups ( After gating on CD4 or CD8 + T cells, single cytokine (IFN-γ + or TNF-α + or IL-2 + ), double 588 cytokines (IFN-γ + TNF-α + or IFN-γ + IL-2 + or TNF-α + IL-2 + ), and triple cytokines (IFN-γ + 589 TNF-α + IL-2 + ) producing cells were analyzed in response to spike-specific ex vivo peptide 590 pool stimulation, respectively. Background-subtracted data was analyzed in all cases in D and 

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