key: cord-0970408-6ls2l0b7
authors: Wanlapakorn, N.; Yorsaeng, R.; Phowatthanasathian, H.; Suntronwong, N.; Kanokudom, S.; Sudhinaraset, N.; Poovorawan, Y.
title: Immunogenicity of heterologous prime/boost inactivated and mRNA COVID-19 vaccine
date: 2021-11-21
journal: nan
DOI: 10.1101/2021.11.20.21266644
sha: 2ca8dc6817488c767f5708336ba40baf2516ce78
doc_id: 970408
cord_uid: 6ls2l0b7

Introduction: In August 2021, Thailand imported the BNT162b2 mRNA COVID-19 vaccine. The prioritised group to receive the BNT162b2 vaccine were health professionals. The BNT162b2 vaccine scheduled for healthcare workers were two-dose regimen administered three weeks apart, the third dose booster in two-dose inactivated CoronaVac vaccine recipients or as a second dose in health professionals who had received the CoronaVac or adenoviral-vectored (ChAdOx1-S) vaccine as the first dose regardless of the interval between the first and second dose. Methods: This study aims to evaluate the immunogenicity of the heterologous prime boost CoronaVac followed by BNT162b2 in health professionals. Results: The CoronaVac/BNT162b2 vaccine recipients elicited higher neutralizing activity against the original Wuhan and all variants of concern than in the recipients of the two-dose CoronaVac. Conclusions: The heterologous CoronaVac/BNT162b2 could be used as an alternative regimen in countries experiencing the vaccine shortages and in individuals experiencing the adverse events following CoronaVac.

In August 2021, Thailand imported the BNT162b2 mRNA COVID-19 vaccine. The 45 prioritised group to receive the BNT162b2 vaccine were health professionals. The BNT162b2 46 vaccine scheduled for healthcare workers were two-dose regimen administered three weeks 47 apart, the third dose booster in two-dose inactivated CoronaVac vaccine recipients or as a 48 second dose in health professionals who had received the CoronaVac or adenoviral-vectored 49 (ChAdOx1-S) vaccine as the first dose regardless of the interval between the first and second 50 dose. 51

It is possible to mix and match vaccines in specific situations such as a vaccine 52 shortage or adverse reactions following vaccine administration. The interval between the first 53 and the second dose may vary according to the availability of a vaccine. This study aims to 54 assess and provide preliminary data on the immunogenicity of heterologous prime/boost 55 inactivated vaccine followed by the BNT162b2 mRNA vaccine at different intervals amongst 56 Thai health professionals. 57 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Switzerland), and anti-spike protein 1 (S1) IgA by an enzyme-linked immunosorbent assay 73 (ELISA) (Euroimmun, Lübeck, Germany). 74

The neutralizing activity was tested against the original Wuhan strain and variants of 75 concern, B.1.1.7, B.1.617.2, and B.1.351, by an ELISA-based surrogate virus neutralization 76 test (sVNT); cPass TM SARS-CoV-2 neutralizing antibody detection kit (GenScript Biotech, 77

Piscataway, NJ). The methods were described in a previous study [1] . 78

The differences in antibody responses between groups were calculated using the 79

Mann-Whitney U test. A p-value <0.05 was considered statistically significant. 80 81 82 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint There were significantly more women in the CV/BNT162b2 group (Table 1) due to 84 the fact that healthcare professionals enrolled in this study were mostly female nurses. 85 Furthermore, the CV/BNT162b2 group was younger than the CV/CV group (χ 2 test p-value 86 <0.001). Unlike the homologous CV/CV and BNT162b2/BNT162b2 vaccination cohorts, 87 there were variations in intervals between the first and second dose vaccinations among the 88 heterologous CV/BNT162b2 vaccinees. We analysed the immunogenicity data of the 89 heterologous CoronaVac/BNT162b2 vaccinees in two sets. The first set were those who 90 received two vaccines 21-28 days apart, now termed the short-interval CV/BNT162b2 91 regimen, and the second set were those who received two vaccines for more than 7 weeks 92 apart, now the termed long-interval CV/BNT162b2 regimen (Table 2) . 93

Analysis of RBD-specific total Ig following a two-dose vaccination showed that 94 regimens including BNT162b2 elicited higher responses compared to the homologous 95

CoronaVac regimen ( Figure 1A ). Within the CV/BNT162b2 regimen, the long-interval 96 regimen elicited higher RBD total Ig following the second dose vaccination compared to the 97 short-interval regimen. 98

When only considering anti-RBD IgG, all BNT162b2-incorporated regimens also 99 showed higher anti-RBD IgG levels compared to the homologous CoronaVac regimen 100 ( Figure 1B) . The long-interval CV/BNT162b2 regimen elicited higher anti-RBD IgG than the 101 short-interval CV/BNT162b2 and homologous BNT162b2 regimens. 102

In addition, anti-S1 IgA was detected in only BNT162b2-incorporated vaccination 103 schedules at similar levels, while no significant amount of anti-S1 IgA was detected in 104 homologous inactivated CV/CV regimen ( Figure 1C ). 105

Comparison of neutralizing activities (presented as percent inhibition) showed that the 106 long-interval CV/BNT162b2 regimen elicited higher neutralizing activities against the wild-107 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint type and all variants of concerns than the short-interval CV/BNT162b2 regimen (Figure 2A -108 D). The long-interval CV/BNT162b2 regimen also elicited higher neutralizing activities 109 against the alpha and beta SARS-CoV-2 variants compared to the BNT162b2/BNT162b2 110 regimens ( Figure 2B-C) . 111

Our study found that both the short and long-interval heterologous regimens with 113

CoronaVac followed by BNT162b2 induced higher SARS-CoV-2 RBD-specific antibody 114 responses and neutralizing activities against wild type and variants of concern than that of the 115 perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint Aside from heightened immunoglobulin titters and inhibition percentages of 133 neutralizing activities in BNT162b2-incorporated regimens compared to the 134 CoronaVac/CoronaVac regimen, a notable discrepancy of anti-S1 IgA was observed. Serum 135 anti-spike-1 protein-specific IgA OD/CO ratios were detected only in the BNT162b2-136 incorporated regimen. Limited data is available on the clinical benefit of serum IgA in 137 protection; however, a recent in vitro experimental study has shown that serum IgA 138 contributed to the neutralization of the SARS-CoV-2 [8-10]. 139

Our study had a few noteworthy limitations. Firstly, the demographic discrepancies of 140 the short and long-interval heterologous regimen cohorts heavily favour young females. 141

Cohort sizes were relatively small, therefore requiring further studying with a larger sample 142 size. Secondly, this study did not investigate the reactogenicity of the heterologous schedule. 143

Lastly, efficacy data from more extensive trials are needed to comprehensively determine the 144 benefits of heterologous CoronaVac followed by BNT162b2 regimen across all age groups in 145 different countries facing different emerging SARS-CoV-2 variants. 146

In low-and middle-income countries experiencing a vaccine shortage and emerging 148 variants, heterologous COVID-19 vaccine schedules have the potential to accelerate vaccine 149 rollout. Additionally, adverse events following vaccination called into question whether a 150 different combination would be advantageous in reducing the chance of adverse reactions 151 following the second dose of some vaccines, for example, mRNA vaccine which is related to 152 myocarditis more frequently after the second than first dose vaccination [11] . Results of this 153 preliminary investigation call for a larger safety and efficacy trial especially in males between 154 16-29 years of age, due to possible cases of myocarditis following the second dose of mRNA 155 vaccine [12] . Further experimentation into T-cells responses is also of interest to fully 156 elucidate immunological response to the heterologous regimen. 157 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint 

Correlates of protection against symptomatic and 185 asymptomatic SARS-CoV-2 infection

Longer intervals and extra doses of ChAdOx1 188 nCoV-19 vaccine

SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, 192 placebo-controlled, phase 1/2 clinical trial

Effectiveness of an Inactivated SARS-CoV-2 196

IgA dominates the early neutralizing antibody 199 response to SARS-CoV-2

Role of Immunoglobulin M and A Antibodies in the 202

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2

Enhanced SARS-CoV-2 neutralization by 205 dimeric IgA

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 21, 2021. ; https://doi.org/10.1101/2021.11.20.21266644 doi: medRxiv preprint