Strong cross immune responses against sarbecoviruses but not merbecoviruses in SARS-CoV-2 BA.5/BF.7-infected individuals with or without inactivated COVID-19 vaccination
Authors: Lujia Sun, Qiuhong Man, Hui Zhang, Shuai Xia, Lu Lu, Xinling Wang, Lize Xiong, Shibo Jiang
Journal: Journal of Infection (2024)

•SARS-CoV-2-infected persons have strong cross immune response against sarbecovirus.•SARS-CoV-2-infected persons have weak cross immune response against merbecovirus.•Inactivated COVID-19 vaccination enhances immune response against sarbecovirus.•People in a post-COVID-19 world may not be very sensitive to sarbecovirus infection. Dear Editor, We note with interest the occurence of COVID-19 disease despite previous MERS-CoV infection, as reported in this Journal.1Maani A.A. Al-Jardani A. Karrar H. et al.COVID-19 in a case previously infected with MERS-CoV: No cross immunity.J Infect. 2021; 82: e28-e29https://doi.org/10.1016/j.jinf.2020.11.035Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Even as COVID-19 remains a continuing worldwide threat, concerns over emerging new sarbecoviruses (SARS-CoV, SARS-CoV-2 and SARS-related coronavirus (SARSr-CoV)) and merbecoviruses (MERS-CoV and MERS-related coronavirus (MERSr-CoV)) have arisen. In particular, we envision a high risk of recombination between SARS-CoV-2 and MERS-CoV in patients with SARS-CoV-2 and MERS-CoV coinfection, possibly causing the emergence of a novel coronavirus with strong transmissibility like SARS-CoV-2 and high pathogenicity like MERS-CoV.2Wang Q. Sun L. Jiang S. Potential recombination between SARS-CoV-2 and MERS-CoV: calls for the development of Pan-CoV vaccines.Signal Transduct Target Ther. 2023; 8https://doi.org/10.1038/s41392-023-01396-6Crossref Scopus (1) Google Scholar Many recent studies have reported the potential transmission of bat-derived coronaviruses to humans, such as SARSr-CoV-WIV1, NEO-CoV, and MjHKU4r-CoV-1, using either ACE2 or hDPP4 as a cell entry receptor.3Menachery V.D. Yount B.L. Sims A.C. et al.SARS-like WIV1-CoV poised for human emergence.Proc Natl Acad Sci U S A. 2016; 113: 3048-3053https://doi.org/10.1073/pnas.1517719113Crossref PubMed Scopus (276) Google Scholar, 4Xiong Cao Q. Ma L. et al.Close relatives of MERS-CoV in bats use ACE2 as their functional receptors.Nature. 2022; 612: 748-757https://doi.org/10.1038/s41586-022-05513-3Crossref PubMed Scopus (31) Google Scholar, 5Chen J. Yang X. Si H. et al.A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry.Cell. 2023; 186 (e16): 850-863https://doi.org/10.1016/j.cell.2023.01.019Abstract Full Text Full Text PDF Scopus (16) Google Scholar This means that SARS-CoV-2-infected individuals might or might not have antibodies able to cross-neutralize the current SARS- and MERS-related CoVs. Such determination is worthy of further research as these individuals may or may not possess immunity against future emerging and re-emerging sarbecovirus and merbecoviruses. To investigate this question, we first performed phylogenetic analysis of the nucleotide sequences of sarbecovirus and merbecovirus spike (S) proteins (Fig. 1A). Results showed that SARSr-CoV-WIV1 is, indeed, a close relative of SARS-CoV and formed a sister clade to it. In contrast, the same analysis of MERS-CoV spike protein showed that the genetic relationship between MjHKU4r-CoV-1 and MERS-CoV was more distant than that between MERS-CoV and NEO-CoV. However, after receptor-binding domain (RBD) sequence alignment (Fig. 1B) and similarity analysis (Fig. 1C), MjHKU4r-CoV-1 and MERS-CoV still showed higher receptor-binding domain similarity, explaining why they used the same receptor to enter cells. Next, to determine the cross-reactive antibody responses in BA.5/BF.7-infected individuals against sarbecovirus and merbecovirus, we collected 61 serum samples from elderly patients over 60 years of age hospitalized in Shanghai Fourth People's Hospital during the BA.5/BF.7-wave between December 2022 and January 2023. During this time, a total of 59,938 deaths related to SARS-CoV-2 infection occurred in Chinese medical institutions of which about 90.1% were aged 65 and above.6Transcript of Press Conference of Joint Defense and Joint Control Mechanism of the State Council on January 14, 2023: National Health Commission of the People's Republic of China Web; 2023 (Available from: 〈http://www.nhc.gov.cn/xcs/yqfkdt/202301/a68301ee500b436b989ec5be2a35cad2.shtml〉).Google Scholar Among these 61 samples, 47 were collected about 2 weeks after BA.5/BF.7 infection and defined as BA.5/BF.7-infected sera. The history of inactivated vaccination and SARS-CoV-2 nucleic acid test reports during hospitalization of these participants were presented in Supplemental Table 1. As the first step in this study, we detected BA.5-RBD- and BF.7-RBD-binding antibody (IgG) titers and found that they reached 20,156 and 18,356 in BA.5/BF.7-infected individuals, respectively (Fig. 1D-F). SARS-CoV-RBD- and SARSr-CoV-WIV1-RBD-binding antibody titers in BA.5/BF.7-infected sera were 1,614 and 1,220, respectively, both higher than those in sera from uninfected individuals (Fig. 1G-H). Meanwhile, the titers of RBD-binding antibodies specific to MERSr-CoVs in BA.5/BF.7-infected and uninfected sera were very low with no significant difference in titers of antibodies specific for MERS-CoV-RBD and NEO-CoV (T510F)-RBD (Fig. 1I-J). However, the titer of anti-MjHKU4r-CoV-1-RBD antibody in infected sera reached 388, a value significantly higher than that of uninfected patients (Fig. 1K). In the second step, titers of neutralizing antibodies in sera from BA.5/BF.7-infected individuals against SARS-CoV-2 BA.5 and BF.7 pseudovirus (PsV), respectively, were detected. No neutralizing activity against BA.5/BF.7 PsV was detected in 14 serum samples from uninfected participants at the detection limit of 1:50 dilution (Fig. 1M). Similar to the results for RBD-binding antibodies, sera from individuals after BA.5/BF.7 infection showed high NT50 (50% neutralization titer) against BA.5 and BF.7 PsV with geometric mean neutralizing titers (GMT) of 3,979 and 6,568, respectively (Fig. 1L). Eight of them were immunized with the inactivated vaccines BBIBP or CoronaVac, but no significant difference was observed between vaccinated and unvaccinated individuals (Fig. 1N-O). Next, we detected the cross-neutralizing antibodies in sera from BA.5/BF.7-infected participants against SARS-CoV and SARS-related CoV (SARSr-CoV). The sera samples showed detectable NT50 against SARS-CoV and SARSr-CoV-WIV1 PsV with GMTs of 951 and 802, about 6.6-fold and 6.8-fold higher than uninfected sera, respectively (Fig. 1P-Q). Interestingly, the neutralizing activity of sera from vaccinated participants against SARS-CoV and SARSr-CoV-WIV1 PsV was significantly higher than sera from unvaccinated participants by 1.6-fold and 4-fold, respectively (Table 1). Collectively, these results suggest that inactivated vaccine can improve immune responses against SARS-CoV and SARSr-CoVs.Table 1Effect of vaccination with inactivated vaccine on the titers of neutralizing antibodies in sera of elderly convalescents.CharacteristicsAll convalescents N=47Vaccination statusUnvaccinated N=39Vaccinated N=8P valueMedian age-yr (range)82 (64-99)83 (64-99)78.5 (69-85)-Male (%, n/N)70.2 (33/47)71.8 (28/39)62.5 (5/8)-GMTsBA.5/BF.75689540470380.879SARS-CoV95181020900.024SARSr-CoV WIV18026063053<0.001MERS-CoV6160630.379NEO-CoV(T510F)92861320.195MjHKU4r-CoV-183731500.289 Open table in a new tab SARS-CoV-2 is distantly related to MERS-CoV, nonetheless, in the third step, we proceeded to investigate if antibodies in sera from BA.5/BF.7-infected individuals could cross-neutralize infection of MERS-CoV and MERSr-CoV (Fig. 1R-T). We found that titers of cross-neutralizing antibodies against MERSr-CoVs were higher in sera from vaccinated participants with GMTs of 63, 132, and 150 when compared to those in sera from unvaccinated individuals with GMTs of 60, 86, and 73 against MERS-CoV, NEO-CoV(T510F), and MjHKU4r-CoV-1, respectively, despite the absence of significant difference between vaccinated and unvaccinated groups (Table 1). The heatmap displayed the neutralizing profiles of sera from all infected participants (Fig. 1U). These results indicate that BA.5/BF.7-infected sera contain high titer of cross-neutralizing antibodies against SARS-CoV and SARSr-CoV-WIV1, but not MERS-CoV and MERSr-CoVs. In summary, our results showed that naive infections with BA.5 or BF.7 subvariants induced cross-neutralizing responses against SARS-CoV and SARSr-CoV-WIV1 and that inactivated vaccine can significantly improve the production of cross-neutralizing antibodies. Also, the sera from BA.5/BF.7-infected individuals who received the inactivated vaccine seem to have higher titers of cross-neutralizing antibodies than those without vaccination, despite the absence of significant difference between the two groups. Of note, a retrospective cohort study by Khan et al. found that individuals infected with MERS-CoV possessed cross-reactive immune response against SARS-CoV-2.7Khan A.A. Alahmari A.A. Almuzaini Y. et al.Potential Cross-Reactive Immunity to COVID-19 Infection in Individuals With Laboratory-Confirmed MERS-CoV Infection: A National Retrospective Cohort Study From Saudi Arabia.Front Immunol. 2021; 12https://doi.org/10.3389/fimmu.2021.727989Crossref Scopus (7) Google Scholar Moreover, our previous studies showed that vaccines derived from SARS-CoV-2 S2 subunit could elicit cross-neutralizing antibodies in mice against merbecovirus,8Wang X. Sun L. Liu Z. et al.An engineered recombinant protein containing three structural domains in SARS-CoV-2 S2 protein has potential to act as a pan-human coronavirus entry inhibitor or vaccine antigen.Emerg Microbes Infect. 2023; 12https://doi.org/10.1080/22221751.2023.2244084Crossref Scopus (0) Google Scholar suggesting the possible presence of broad-spectrum neutralizing antibodies in sera, the epitopes of which are outside the RBD. The limitations in this study include 1) small sample size, 2) no consideration of the potential effect of basal metabolic disease on the production of antibodies, and 3) failure to detect cross-cellular immune response against infection of sarbecoviruses and merbecoviruses.9Guan X. Huang Q. Dong M. et al.SARS-CoV-2–specific antibody and T-cell immunity in convalescents after infection wave in Beijing in late 2022.J Infect. 2023; 87: 413-419https://doi.org/10.1016/j.jinf.2023.08.010Abstract Full Text Full Text PDF Scopus (1) Google Scholar Overall, however, our study did confirm the presence of cross-neutralizing antibodies against sarbecoviruses and merbecoviruses in humans, providing inspiration for the development of broad-spectrum anti-coronavirus vaccines to combat potential cross-species transmission of emerging and re-emerging sarbecoviruses and merbecoviruses that may cause future outbreaks. This work was supported by grants from the National Natural Science Foundation of China (grant numbers 92169112 to S.J.; 82202491 to X.W.), Shanghai Municipal Science and Technology Major Project (ZD2021CY001 to S.J, L.L and S.X.), and Science and Technology Commission of Shanghai Municipality (23JC1404302 to X.W.).