key: cord-0312681-pb4ddae7
authors: Zhao, Xin; Zheng, Anqi; Li, Dedong; Zhang, Rong; Sun, Huan; Wang, Qihui; Gao, George F.; Han, Pengcheng; Dai, Lianpan
title: Neutralization of recombinant RBD-subunit vaccine ZF2001-elicited antisera to SARS-CoV-2 variants including Delta
date: 2021-07-16
journal: bioRxiv
DOI: 10.1101/2021.07.15.452504
sha: f491a96e7d00c998952fbdef0810923eae77c83e
doc_id: 312681
cord_uid: pb4ddae7

SARS-CoV-2 variants brought new waves of infection worldwide. In particular, Delta variant (B.1.617.2 lineage) has become predominant in many countries. These variants raised the concern for their potential immune escape to the currently approved vaccines. ZF2001 is a subunit vaccine received emergency use authorization (EUA) in both China and Uzbekistan, with more than 100-million doses administrated with a three-dose regimen. The tandem-repeat dimer of SARS-CoV-2 spike protein receptor binding domain (RBD) was used as the antigen. In this work, we evaluated the neutralization of ZF2001-elicited antisera to SARS-CoV-2 variants including all four variants of concern (Alpha, Beta, Gamma and Delta) and other three variants of interest (Epsilon, Eta and Kappa) by pseudovirus-based assay. We found antisera preserved majority of the neutralizing activity against these variants. E484K/Q substitution is the key mutation to reduce the RBD-elicited sera neutralization. Moreover, ZF2001-elicited sera with a prolonged intervals between the second and third dose enhanced the neutralizing titers and resilience to SARS-CoV-2 variants.

SARS-CoV-2 variants brought new waves of infection worldwide. In particular, Delta variant (B.1.617.2 lineage) has become predominant in many countries. These variants raised the concern for their potential immune escape to the currently approved vaccines. ZF2001 is a subunit vaccine received emergency use authorization (EUA) in both China and Uzbekistan, with more than 100-million doses administrated with a three-dose regimen. The tandem-repeat dimer of SARS-CoV-2 spike protein receptor binding domain (RBD) was used as the antigen. In this work, we evaluated the neutralization of ZF2001-elicited antisera to SARS-CoV-2 variants including all four variants of concern (Alpha, Beta, Gamma and Delta) and other three variants of interest (Epsilon, Eta and Kappa) by pseudovirus-based assay. We found antisera preserved majority of the neutralizing activity against these variants. E484K/Q substitution is the key mutation to reduce the RBD-elicited sera neutralization. Moreover, ZF2001elicited sera with a prolonged intervals between the second and third dose enhanced the neutralizing titers and resilience to SARS-CoV-2 variants. SARS-CoV-2 variants are continually emerging and becoming the circulating strains in many countries. Several highly transmissible variants of concern (VOCs) showed altered pathogenicity and become dominant worldwide, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) lineages (www.who.int). Some variants were reported to escape the immunity acquired by natural infection or vaccination, bringing a global concern for the effectiveness of the currently approved Table S1 . We found all 28 serum samples efficiently neutralized pseudotyped virus expressing wild-type spike (Wuhan-1 reference strain), with the pVNT50 higher than 1:20. We found the neutralizing titer did not decline, but Further, the volunteers with an extended interval between the second and third doses (0-1-(4-6) regimen) showed higher neutralizing activity and resilience to variants than those with shorter interval (0-1-2 regimen) (Fig.2) , which is consistent with a prior work for neutralization of B.1.351 lineage virus by the ZF2001-elicited antisera 15 . In the 0-1-2 group, the antisera neutralization titers were significant reduced against six of the seven variants except B.1.1.7 ( Figs.2A and 2C ). In contrast, in the 0-1-(4-6) group, significant reduction of neutralization titer was only detected against the B.1.617.1spike lineage virus (double mutations at L452R and E484Q in RBD) ( Fig.2A, C and   Fig. S1 ). The better performance of the 0-1-(4-6) regimen is likely due to the benefit from the prolonged antibody maturation in individuals 14 . Our data are consistent with the fact that the 0-1-6 regimen has been widely used for other subunit vaccines, such as Hepatitis B virus vaccine, and provide guidance to further optimize the vaccination regimen.

In this work, we provide preliminary evidence of the approved RBD-based protein subunit vaccine for its neutralization profile to SARS-CoV-2 variants. Given the positive correlation between neutralizing titer and protection efficacy 20 , the sera neutralization variation between variants should be taken into account for the vaccine effectiveness. The high susceptibility of these newly emerged variants to ZF2001 vaccine supports the current mass immunization to build a herd immunity. However, the vaccine effectiveness against these variants must be validated by phase 3 clinical trials and real-world evidences. The dashed line indicates the lower limit of detection. The GMT lower than 20 were considered negative and calculated as 10 in the statistical analysis. c: Summarization the fold-change and p value of the pVNT50 for the variants from the wild type.

Background color in pink indicates significant GMT increase and in light blue indicates significant GMT decrease, compare with the GMT to the wild type. White means no significant change. Neutralization values between different variants were analyzed with two-tailed Wilcoxon matched-pairs signed rank test. pVNT50 of each sample is tested by two repeats.

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We thank all the volunteers for providing blood samples. This work was supported by