ABSTRACT
ARCoV is a candidate mRNA vaccine encoding receptor-binding domain of SARS-CoV-2. Its safety, tolerability, and immunogenicity profile have been confirmed in the phase 1 clinical trial in China. A multi-regional phase 3 clinical trial is currently underway to test the efficacy of ARCoV (NCT04847102). Here, we tested the cross-neutralization against SARS-CoV-2 variants of concern (VOCs) of a panel of serum samples from participants in the phase 1 clinical trial of ARCoV by pesudo- and authentic SARS-CoV-2. Our data suggest the immunity induced by the ARCoV vaccine reduced but still has significant neutralization against the Alpha and Delta variants. Moreover, ARCoV maintained activity against the Beta variant, despite of its obvious reduction in neutralizing titers. Our findings further support the solid protective neutralization activity against VOCs induced by ARCoV vaccine.
KEYWORDS: SARS-CoV-2, mRNA vaccine, ARCoV, Variants of concern, Neutralization
Dear Editor
ARCoV, which is developed by the Academy of Military Medical Sciences and Suzhou Abogen Biosciences in China, is a candidate mRNA vaccine encoding the receptor binding domain (RBD) of SARS-CoV-2 (Wuhan-Hu-1 strain).1 Its safety, tolerability, and immunogenicity profile have been confirmed in the randomized, double-blind, and placebo-controlled phase 1 clinical trial in healthy adults aged 18–59 years old in China.2 A multi-regional phase 3 clinical trial is currently underway to test the efficacy of ARCoV (NCT04847102).
The continuous global circulation of SARS-CoV-2 has resulted in emergence of SARS-CoV-2 variants of concern (VOCs) including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). In November 2021, a new VOC Omicron (B.1.1.529) emerged in South Africa with highly transmissibility. These VOCs contain multiple mutations in the spike protein of SARS-CoV-2, especially in neutralizing antibody binding sites3 (Table S1). These mutations have been reported to confer neutralization resistance to mAbs, a modest loss of susceptibility to convalescent plasma, and sera from vaccinated individuals in comparison with the wild-type Wuhan-01 bearing D614 G.4–6
Herein, a set of sera of 11 participants in the phase 1 clinical trial of ARCoV was tested for neutralization of VOCs. All samples were collected on day 43 post initial immunization with 15 μg of ARCoV.2 The cross-neutralizing activity of these serum samples against all pesudo-SARS-CoV-2 VOCs except the Gamma and Omicron variants was assayed by a 50% neutralization assay. The VSV-based pseudovirus neutralization assay showed that all 11 serum samples still potently neutralized the Alpha variant with geometric mean titer (GMT) of 826.7 (1.7-fold reduction) in comparison with WT with GMT of 1440.9 (Figure 1a and Tables S1 and S2). We also observed 2.6-fold average reduction of the plasma neutralizing activity against the Delta (GMT: 548.9) variant. However, compared with the WT pseudovirus, the neutralization activity significantly reduced 2.4-fold for the Beta variant (GMT: 610.4) (Figure 1a, Tables S1 and S2, p < .05).
Figure 1.
Human serum neutralization of SARS-CoV-2 variant following the second dose of ARCoV.
Shown are the results of 50% neutralization titer with the use of 11 serum samples obtained from 11 trial participants 2 weeks following the administration of the second dose of ARCoV. Results from individual participant sera are represented as dots. (a) The 50% neutralization titer against pseudovirus. (b) The 50% SARS-CoV-2 neutralizing geometric mean titers. The numbers above the bars show the geometric mean titer in the group. Fold reduction is shown above the geometric mean titer. Statistical analysis was performed using unpaired t test (*p < 0.05, **p < 0.01).
By the authentic virus neutralization assay, we further assessed the cross-neutralizing activity of the serum samples to the VOCs including Alpha (strain BJ202101), Beta (strain GDPCC), and Delta (strain CQ0077). The prototypic SARS-CoV-2 (strain 131, WT) was used as the control.1 As shown in Figure 1b and Table S3, the Alpha and Delta variants were 1.6- and 1.4-fold less sensitive to the sera than the WT, respectively. Notably, the neutralization activity significantly reduced 4.5-fold for the Beta variant (GMT: 105.7) in comparison with the WT strain (Figure 1b, Tables S1 and S3, p < .01).
Our data show the immunity induced by the ARCoV vaccine still has relative potent neutralization against the Alpha and Delta variants. This finding is consistent with the other recent reports assessing neutralization activity of two leading SARS-CoV-2 mRNA vaccines BNT162b2 and mRNA-1273 developed by Pfrzier and Moderna, respectively.7,8 There is growing body of evidence that both humoral and cellular immune responses induced by SARS-CoV-2 mRNA vaccines play an important role in protection against VOCs.9,10 Therefore, the ARCoV-elicited cross-reactive T cell response is likely to be able to provide solid protection against the Beta variant despite of obvious reduction in neutralization activity. Of note, for Delta variant, the pseudovirus was less sensitive to neutralization of serum samples than that of authentic variant in comparison with WT. This discrepancy in neutralization activity is possibly due to the absent of the G142D mutation in the S protein of the authentic virus (Table S2). Despite this, pseudovirus titers still represent a good prediction for the neutralization activity to the authentic viruses. A potential limitation of this study may be absent of data on neutralization activity to the authentic Omicron variant, which will be performed in the future study. Overall, our findings support the solid protective neutralization activity against VOCs induced by ARCoV vaccine, although the vaccine effectiveness against these variants must be validated by the undergoing phase 3 clinical trial.
Supplementary Material
Funding Statement
This study was supported by the National Key Research and Development Project of China (2020YFC0842200, 2020YFA0707801) and the National Natural Science Foundation of China (82171820). C.F.Q. was supported by the National Science Fund for Distinguished Young Scholar (number 81925025) and the Innovative Research Group (number 81621005) from the National Natural Science Foundation China.
Disclosure statement
C.F.Q. is an inventor on pending patent applications related to the ARCoV mRNA vaccine. All other authors declare no competing interests.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2022.2094142.
References
- 1.Zhang N-N, Li X-F, Deng Y-Q, Zhao H, Huang Y-J, Yang G, Huang W-J, Gao P, Zhou C, and Zhang R-R, et al. A thermostable mRNA vaccine against COVID-19. Cell. 2020;182(5):1–2. doi: 10.1016/j.cell.2020.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Chen GL, Li X-F, Dai X-H, Li N, Cheng M-L, Huang Z, Shen J, Ge Y-H, Shen Z-W, Deng Y-Q, et al. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Microbe. 2022;3(3):e193–2. doi: 10.1016/S2666-5247(21)00280-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, Ludden C, Reeve R, Rambaut A, Peacock SJ, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021;19(7):409–424. doi: 10.1038/s41579-021-00573-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, Wang M, Yu J, Zhang B, Kwong PD, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021;593(7857):130–135. doi: 10.1038/s41586-021-03398-2. [DOI] [PubMed] [Google Scholar]
- 5.Kuzmina A, Khalaila Y, Voloshin O, Keren-Naus A, Boehm-Cohen L, Raviv Y, Shemer-Avni Y, Rosenberg E, Taube R.. SARS-CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera. Cell Host Microbe. 2021;29(4):522–528 e522. doi: 10.1016/j.chom.2021.03.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shen X, Tang H, McDanal C, Wagh K, Fischer W, Theiler J, Yoon H, Li D, Haynes BF, Sanders KO, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines. Cell Host Microbe. 2021;29(4):529–539 e523. doi: 10.1016/j.chom.2021.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Liu Y, Liu J, Xia H, Zhang X, Fontes-Garfias CR, Swanson KA, Cai H, Sarkar R, Chen W, Cutler M, et al. Neutralizing activity of BNT162b2-elicited serum. N Engl J Med. 2021;384(15):1466–1468. doi: 10.1056/NEJMc2102017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pegu A, O’-Connell SE, Schmidt SD, O’-Dell S, Talana CA, Lai L, Albert J, Anderson E, Bennett H, Corbett KS, et al. Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants. Science. 2021;373(6561):1372–1377. doi: 10.1126/science.abj4176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Liu J, et al. Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron. Nature. 2022. doi: 10.1038/s41586-022-04465-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Keeton R, Tincho MB, Ngomti A, Baguma R, Benede N, Suzuki A, Khan K, Cele S, Bernstein M, Karim F, et al. T cell responses to SARS-CoV-2 spike cross-recognize Omicron. Nature. 2022;603(7901):488–492. doi: 10.1038/s41586-022-04460-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.