Humoral immune response characteristics of the susceptible populations after the infection of SARS-CoV-2 BA.5 strain

Humoral immune response characteristics of the susceptible populations after the infection of SARS-CoV-2 BA.5 strain | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Humoral immune response characteristics of the susceptible populations after the infection of SARS-CoV-2 BA.5 strain Huan Zhang, Shi Ouyang, Zhuolin Li, Yushan Jiang, Tingting Peng, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4185718/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This study compared the humoral immune characteristics of children, elderly people, pregnant women, and adults infected with BA.5 and XBB strains in Guangzhou, China. It was found that binding and neutralizing antibodies the titers against distinct SARS-CoV-2 strains were low in the acute-phase sera of BA.5 infected patients, while the corresponding titers were significantly increased in the convalescent phase, the antibody titers against the Wuhan strain were the highest. Regardless of whether they were vaccinated, BA.5 infection did not induce high neutralizing antibodies against XBB. During the recovery phase, the titers of antiviral antibodies in the vaccinated population are more robust than those in the unvaccinated population. For BA.5 infections, the specific binding and neutralizing antibody titers in the children group were lower compared to other population groups. In the convalescence period of the disease, the titers of neutralizing antibodies against Wuhan, BA.5 and XBB strains induced by BA.5 infections are significantly correlated in pairs. XBB can induce a broader and balanced antiviral humoral immune response than BA.5 as a first-time infected strain. This finding can provide a reference for the judgment of the future epidemic law of SARS-CoV-2, and provide a scientific basis for developing novel COVID-19 vaccines, especially for discovering customized vaccines and immune strategies for different populations. Humoral immune characteristics COVID-19 Susceptible populations BA.5 Neutralizing antibody Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Even though most of the world's population has been vaccinated against COVID-19, multiple variants of SARS-CoV-2 are still circulating the world 1 , and SAR-CoV-2 continues to mutate and can infect the same person multiple times over different periods 2 , it is worth noting that although the virulence of SARS-CoV-2 has decreased, its infection can still cause severe illness or death 3 . Right after lifting the dynamic zero-COVID policy in China, there have been at least two waves of SARS-CoV-2 outbreaks. The first wave was caused by Omicron BA.5 and BF.7 variants from December 2022 to February 2023 4,5 . The second wave occurred between April 2023 and July 2023 due to the Omicron XBB variant 6 . The primary vaccine used in China is the inactivated COVID-19 vaccine, which can induce high titers of SARS-CoV-2 neutralizing antibodies 7 . While after a certain period following vaccination, the antibody titers in the body decline 8 . Research has demonstrated that vaccination can mitigate the severity and reduce mortality rates during the two epidemic waves in China 9 . However, due to the pronounced immune escape of the Omicron variants and the decrease in anti-SARS-CoV-2 antibody titers in vaccine recipients, COVID-19 vaccination has not been very effective in preventing infections by these two waves of Omicron pandemic viruses 10,11 . The decision to receive the COVID-19 vaccine may potentially influence the strength and breadth of antibody responses following Omicron infection 12 . Variations may occur in the specific immune responses to SARS-CoV-2 among individuals based on their vaccine type, prior SARS-CoV-2 infection history, age group, or exposure to different SARS-CoV-2 strains 13 . SARS-CoV-2 infection can be analogized to a robust vaccination event, triggering the host's production of SARS-CoV-2-specific neutralizing antibodies 14 . The strength and breadth of these neutralizing antibodies may affect an individual's susceptibility to SARS-CoV-2 in subsequent infections, thereby influencing the severity of the next wave of COVID-19 in the human population 15 . A systematic evaluation of neutralizing antibody patterns induced by BA.5 infections in both unvaccinated and vaccinated individuals is essential. This data will significantly contribute to COVID-19 pandemic control and the advancement of next-generation vaccines. The elderly population faces a heightened risk of severe illness and death following SARS-CoV-2 infection compared to other groups. Furthermore, special attention should be given to vulnerable populations, such as children and pregnant women, concerning their clinical characteristics and antiviral immune response patterns following SARS-CoV-2 infection 16 . At present, there is limited research on humoral immune responses in susceptible populations to BA.5 infections, highlighting the need for additional data in this domain. This study, initiated in December 2022 in Guangzhou, China, aims to bridge existing research gaps. It involves the recruitment of 177 individuals from three vulnerable groups: children, pregnant women, and the elderly, alongside 78 adult participants. These participants were infected with either the BA.5 variant between December 2022 and March 2023 or the XBB variant between April 2023 and June 2023, with diverse histories of inactivated vaccine administration. Serum samples were collected during both the acute and recovery phases of COVID-19 to assess the strength and spectrum of their SARS-CoV-2-specific humoral immune responses. The primary objectives of this study are to investigate and compare the humoral immune responses induced by BA.5 and XBB infections, with a particular focus on response patterns in distinct vulnerable populations. This research, in conjunction with vaccination data, will provide valuable scientific insights into the ability of susceptible individuals to effectively respond to new SARS-CoV-2 variants following various SARS-CoV-2 infections. Ultimately, it will contribute to the development of the next generation of COVID-19 vaccines, including tailored vaccines and immunization strategies for diverse populations, all grounded in robust scientific evidence. Methods Study design The clinical serum samples in this study were obtained from the following COVID-19 patients. The first wave of COVID-19 patients in Guangzhou after the termination of China's COVID-19 dynamic zero clearing and control policy from December 2022 to March 2023, these patients were from the Baiyun Branch of Nanfang Hospital of Southern Medical University which was the designated hospital for pregnant women, children and elderly people. The second wave of COVID-19 patients in Guangzhou after the termination of China's COVID-19 dynamic zero clearing and control policy from April 2023 to June 2023, these patients were enrolled from the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University. The COVID-19 susceptible population in this study refers to children (0–11 years old), the elderly (60–100 years old), and pregnant women, while adults refer to the population aged 18–59. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. All the individuals had no history of earlier COVID-19 infection. Vaccinated individuals who had 2 or 3 doses of vaccination had infection with BA.5 after 6 to 15 months, while had infection with XBB after 6 to 18 months in this study. The acute phase of infection in this study is defined as the 0–7 days after the onset of COVID-19, and the convalescent period is defined as the 14–90 days after the onset of COVID-19. The patient's sera was collected and placed in a -20°C refrigerator on the same day until it was used. This study has passed relevant ethical reviews at the Baiyun Branch of Southern Medical University and the Fifth Affiliated Hospital of Guangzhou Medical University. This research protocol has passed the relevant ethical review of the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University. Protein expression and purification The SARS-CoV-2 RBD recombinant protein was expressed in human HEK293F cells as a soluble protein. The RBD were purified by HisTrap HP column (GE Healthcare) and were further purified by size-exclusion chromatography with a Superdex 200 column (GE Healthcare) in 20mM Tris, pH 8.0 Enzyme-linked immunosorbent assay (ELISA), 150mM NaCl and then analyzed by reducing sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). Enzyme-linked immunosorbent assays (ELISAs) Microtiter plates (Sangon Biotech) were coated with 100 ng of each recombinant receptor binding protein of SARS-CoV-2 overnight at 4°C. The plates were then washed twice with 1*PBS (phosphate buffer saline) containing 0.1% v/v Tween-20 (PBST) and blocked with blocking solution (1*PBS containing 5% w/v bovine serum albumin) overnight at 4°C. On the day of the experiment, the plates were then washed once with PBST. The serially diluted sera were added to the wells and incubated at 37°C for 60 min. Then the plates were washed five times using PBST and added 100 µL horseradish peroxidase (HRP)-conjugated goat anti-human IgG antibody solution (Sangon Biotech) to each plate, respectively, and incubated at 37°C for 60 min. Wash each plate with PBST five times, and 100 µL of tetramethylbenzidine (TMB) substrate (Sangon Biotech) was added to each plate at room temperature in the dark and reacted for 15 min. After the reaction, the plate was stopped with a 2 M H 2 SO 4 solution. The absorbance was measured at 450 nm using a microplate reader. All samples were run in triplicate. The ELISA titers were determined by endpoint dilution. Serum-neutralization assay The day before the infection, the 6-well cell culture plates (Costar) were seeded with 10 4 Vero cells, and then the cells were washed twice with a cell culture medium on the day of infection. Sera from individuals thawed at room temperature and were incubated at 56°C for 30 min, and then diluted from 20-fold to 5120-fold. 40 µL aliquots of each diluted sera were added to a cell culture medium containing 100 tissue culture infective dose (TCID 50 ) of each SARS-CoV-2 virus strain in 40 µL on a 96-well cell culture plate and incubated at 37°C for 2 h in CO 2 5% v ⁄ v, all the SARS-CoV-2 virus strains were isolated from Guangdong Provincial Center for Disease Control and Prevention). The mixture containing the virus and serum was then added to cells in 96-well plates and were incubated at 37°C for 5-day incubation. Microscopic examination for cytopathic effect (CPE) was conducted after the incubation. The highest dilution of serum that showed inhibition activity of SARS-CoV-2 was estimated as the neutralization titer. Neutralization titer assays were performed in triplicate with negative control sera. The threshold of neutralization activity is NT ≥ 4. Statistical analysis The two-tailed Wilcoxon signed-rank matched-pairs test was used to compare paired comparisons (α = 0.05). In 2-tailed testing, P < 0.5 was deemed statistically significant. Two-tailed Wilcoxon signed-rank matched-pairs test was used to compare paired comparisons. P < 0.5 was considered to be statistically significant in 2-tailed tests. The Spearman rank correlation coefficient was used for linear correlation analysis between the expression level of plasma cytokine and Murray's score. All statistical analysis was conducted in GraphPad Prism 6.0. p values reported in the figures and figure legends indicate the following significance levels: *p < 0.05, **p < 0.01, and ***p < 0.001. Results At the end of 2022, after adjusting the prevention and control policy of the COVID-19 epidemic in China, the first wave of the nationwide epidemic virus was the BA.5 strain of SARS-CoV-2. Baiyun branch of Nanfang Hospital of Southern Medical University was the designated hospital for pregnant women, children and elderly people. In the first wave of the COVID-19 epidemic, 56 SARS-CoV-2 susceptible people were enrolled in this study, and their humoral immune response characteristics in the acute and convalescent phases were determined. Table 1 displayed the demographic characteristics of the participants in the first COVID-19 wave, including 33 elderly people, 18 children, 5 pregnant women and 30 adults who had not received any vaccines or had received two or three doses of inactivated SARS-CoV-2 vaccines. First, the ELISA binding reactivity of the sera from susceptible patients against the receptor binding domain (RBD) proteins of different SARS-CoV-2 strains (Wuhan, Delta, BA.5 and XBB) was evaluated. In the acute phase of COVID-19 (0–7 days post onset), the IgG titers against all SARS-CoV-2 RBDs in the sera were at low levels. In contrast, in the convalescent phase of COVID-19 (14–90 days post onset), the SARS-CoV-2-specific IgG titers were significantly increased, when compared to the sera in the acute stage, the IgG titer against Delta, BA.5 and XBB increased by 22.2, 20.3, 11.6 and 6.4 times, respectively; The IgG antibody titer against the Wuhan strain was the highest, for the convalescent sera, the IgG titers against Delta, BA.5, and XBB decreased by 1.2, 2.3, and 5.6 times compared with those against the Wuhan strain, respectively (Fig. 1 A). The neutralization titer of COVID-19 susceptible people's sera against the SARS-CoV-2 virus showed the same trend as the titer of the IgG antibody, only a few sera samples in the acute phase showed a low level of neutralization titer against the SARS-CoV-2 virus. Compared with the sera in the acute phase, the neutralization titer of convalescent sera against Wuhan, Delta, BA.5 and XBB increased by 6.5, 6.3, 3.8 and 1.5 times, respectively. The geometric mean (GM) values of neutralization titers of sera against Wuhan, Delta, BA.5 and XBB during the convalescent stage were 82.6, 76.3, 46.8 and 15.1, respectively, of concern, all sera had low neutralization titers against XBB (Fig. 1 B). In this COVID-19 wave, before infection with BA.5, most people had been vaccinated with two or three doses of the COVID-19 vaccine, and the difference in humoral immune response between vaccinated and unvaccinated people after infection with BA.5 was compared further. In the acute phase of BA.5 infection, the neutralizing antibody levels against SARS-CoV-2 in the sera of vaccinated and unvaccinated patients were comparable (Fig. 1 C), while in the convalescent phase of BA.5 infection, the neutralizing antibody titer against various SARS-CoV-2 strains in the sera of vaccinated patients was significantly higher than that of unvaccinated patients, and the neutralizing antibody titers in the sera of vaccinated population against Wuhan, Delta, BA.5 and XBB were 6.9, 6.7, 2.5 and 1.3 times higher than those of the unvaccinated population, respectively (Fig. 1 D). Next, this study compared the differences in neutralizing antibody titers against SARS-CoV-2 in the sera of the SARS-CoV-2 susceptible population (elderly, children and pregnant women) and adults (18–60 years-old population), the results showed that there was no significant difference in the titers of neutralizing antibodies between SARS-CoV-2 susceptible population and adults in the acute phase and convalescent phase of COVID-19 (Fig. 1 E and 1 F), although, in the convalescent phase, the neutralizing antibody titer of sera in the adult's group is higher than that of the susceptible population (Fig. 1 F). Excluding the unvaccinated population, there was also no significant difference in the titers of neutralizing antibodies against different SARS-CoV-2 between the vaccinated SARS-CoV-2 susceptible population and the vaccinated adults (Fig. 1 G and H). There was no significant difference in the antiviral neutralization titer of sera in the COVID-19 susceptible population from different genders, either in the acute phase or in the convalescent phase (Figure S1 and Fig. 1 I). Table 1 Cohort characteristics of COVID-19 patients in Guangzhou, China, from December 2022 to March 2023 in the first wave. Elderly (n = 33) Children (n = 18) Gender Gender Male 15 (45.5) Male 9 (50.0) Female 18 (54.5) Female 9 (50.0) Age-yr 72.1 ± 9.5 (60–97) Age-yr 4.2 ± 3.3 ( 1 – 11 ) Vaccination status Vaccination status Vaccinated 22 (66.7) Vaccinated 9 (50.0) Unvaccinated 11 (33.3) Unvaccinated 9 (50.0) Pregnant (n = 5) Adult (n = 30) Gender Gender Male 0 (0%) Male 16 (53.3) Female 5 (100%) Female 14 (46.7) Age-yr 27.3 ± 4.4 (19–39) Age-yr 34.4 ± 10.6 (15–59) Vaccination status Vaccination status Vaccinated 4 (80.0) Vaccinated 25 (83.3) Unvaccinated 1 (20.0) Unvaccinated 5 (16.7) Furthermore, in this study, the enrolled patients were divided into pregnant women, children, the elderly and adults groups, and the titers of anti-SARS-CoV-2 binding antibodies and neutralizing antibodies in the serum of each group were compared in detail. For SARS-CoV-2 specific binding and neutralizing antibodies, the serum antibody titers of the children group are the lowest, and the serum titers of binding antibodies against Wuhan, Delta, BA.5 and XBB strains in the children group during the convalescent period are 522, 469, 400 and 261, respectively (Fig. 2 A), and the neutralizing antibody titers are 14.1, 13.5, 18.1 and 10.0, respectively (Fig. 2 B). Compared with the children group, the binding antibody titer in the convalescent sera of pregnant women, elderly and adult groups is 17.6–63.2 times higher against Wuhan and Delta strains, 8.2–19.2 times higher against BA.5 strains and 1.4–10.3 times higher against XBB strains, and the neutralizing antibody titers in these sera showed a similar trend to that of the binding antibody (Fig. 2 A and 2 B). Considering that the vaccination rate of the COVID-19 vaccine in the children group is the lowest (Table 1 ), to exclude the influence of vaccination of the COVID-19 vaccine, this study further compared the neutralizing antibody titer of the convalescent sera of the vaccinated population in each group, and the results showed that the antiviral neutralizing antibodies of the sera in the children group were still the lowest (Fig. 2 C). We further analyzed the correlation of the binding and neutralization titers against various SARS-CoV-2 strains of the sera of BA.5 infection from the susceptible population. The binding antibody titers against the Wuhan strain, BA.5 strain, and XBB strain in the serum during the acute and recovery stages showed a positive correlation with the corresponding neutralizing antibody titers (Fig. 3 A- 3 C). For susceptible populations infected with BA.5, there is no significant correlation between the neutralizing antibody titer of acute-phase sera and that of sera in the convalescent phase against the Wuhan strain. Similarly, the neutralizing antibody titers against BA.5 and XBB in the acute phase serum were not significantly correlated with the neutralizing antibody titers against BA.5 and XBB in the convalescent phase serum, respectively (Fig. 3 D- 3 F), for the vaccinated population, the same trend was shown, with no significant difference between neutralizing antibody titers in the corresponding sera (Fig. 3 G- 3 I). During the convalescent period of BA. 5 infection, the binding antibody titers against the three different SARS-CoV-2 strains in the serum showed a positive correlation with the corresponding neutralizing antibody titers (Fig. 4 A- 4 C), the anti-Wuhan neutralizing titers of sera showed a significant positive correlation with those of anti-BA.5 and anti-XBB neutralizing titers (Fig. 4 D- 4 E), and the anti-BA.5 neutralizing antibody titers and anti-XBB neutralizing antibody titers in sera also showed a significant positive correlation (Fig. 4 F). For the vaccinated population, the titers of neutralizing antibodies against the BA.5 strain in sera showed a significant positive correlation with the titers of neutralizing antibodies against the Wuhan and XBB strains in the convalescent phase, while the titers of neutralizing antibodies against the Wuhan and XBB strains did not show a significant correlation (Fig. 4 G- 4 I). In the second wave of the COVID-19 epidemic in China, 62 SARS-CoV-2 susceptible people were enrolled in this study from the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University, including 32 elderly people, 20 children, 10 pregnant women and 39 adults who had been infected with the SARS-CoV-2 Omicron strain once or twice. In a previous study, we have reported the humoral immune characteristics of these patients against different SARS-CoV-2 strains 17 . In this study, we compared the differences in the titers of neutralizing antibodies induced in SARS-CoV-2 susceptible populations when the first infected SARS-CoV-2 strains were BA.5 and XBB, respectively. When the first infected SARS-CoV-2 strain was BA.5, the neutralizing antibody titers of the acute phase sera against Wuhan, Delta, BA.5, and XBB strains were 12.8,12.2,12.3, and 10.3, respectively, in contrast, when the first infected SARS-CoV-2 strain was XBB, the neutralizing antibody titers of the corresponding sera increased by 2.7, 2.5,1.8, and 1.5 times, respectively (Fig. 5 A). In the convalescent period of COVID-19, the titers of neutralizing antibodies against Wuhan, Delta and BA.5 strains induced in individuals with the first infection strain BA.5 and the first infection strain XBB are at a similar level, interestingly, the titer of the antibodies against XBB induced in the population with the first infection of the XBB strain was 3.5 times that of the population with the first infection of the BA.5 strain (Fig. 5 B). When analyzing the vaccinated population, the humoral immune responses against SARS-CoV-2 in the BA.5-first-infected group and XBB-first-infected group showed similar patterns (Fig. 5 C and 5 D). Discussion In this study, we systematically investigated the humoral immune responses of susceptible children, elderly and pregnant women and ordinary adults in China with BA.5 infection. We found that there were differences in antibody responses induced by SARS-CoV-2 infection in individuals of different age groups and with different SARS-CoV-2 infection and vaccine immunization backgrounds. Furthermore, XBB infection elicited a broader spectrum of antibodies than BA.5 infection. These findings have important implications for the development of novel COVID-19 vaccines tailored to different populations. Previous studies have shown that BA.5 infection does not effectively induce highly effective neutralizing antibodies against XBB strain 18,19 . In this study, we further subdivided the population and found that children, elderly, pregnant women and adults infected with BA.5 can induce high levels of neutralizing antibodies against Wuhan, Delta, BA.5 during the convalescent phase of the disease, however, the neutralizing antibody titers against XBB are low which suggests that persons infected with BA.5 may still be susceptible to XBB strains, and indeed, in this study, many patients with COVID-19 XBB infection were found to have previously been infected with BA.5. In BA.5-infected patients, vaccination had little effect on SARS-CoV-2 antibody induction during the acute phase of illness, but during the convalescent phase, breakthrough vaccinated patients had higher neutralizing antibody titers against Wuhan, Delta, and BA.5 than unvaccinated patients, however, there was no significant increase in neutralizing antibodies against XBB, further indicating that XBB was evaded by antibodies induced by the COVID-19 vaccine and BA.5 infection.These results were also validated in the correlation analysis, for BA.5 infected patients, there was no strong correlation between the antibody titers of convalescent sera against the Wuhan strain and that of convalescent serum against the XBB strain, indicating that there were few broadly neutralizing antibodies in sera that could neutralize both the Wuhan strain and XBB strain. In contrast, the titers of antibodies against the Wuhan strain, BA.5 strain and XBB strain in convalescent sera of XBB-infected patients were correlated with each other, indicating that XBB infection induced a part of neutralizing antibodies that could broadly neutralize XBB, BA.5 and Wuhan strain. Most of the neutralizing monoclonal antibodies generated previously have been eluded by XBB 20–23 , the broadly neutralizing antibodies in patients with XBB infection are expected to be further screened and identified as novel antibody drugs against SARS-CoV-2. Interestingly, among the BA.5 infected patients, children group induced the lowest level of anti-SARS-CoV-2 binding and neutralizing antibody, the exact mechanism of which needs further study, and this result also indicates that after infection with BA.5, due to the low level of related neutralizing antibody, children population may be more susceptible to re-infection with SARS-CoV-2 than other populations. There was no significant difference in antibody response after infection with SARS-CoV-2 in susceptible population of different genders, and in previous studies, we also found no significant difference in antibody response induced by COVID-19 vaccination between men and women 24 . There were some limitations in this study. No studies related to T cell immunity were carried out in various populations. This study included a small number of participants, and other SARS-CoV-2 infected patients such as BF.7 were not included. Declarations Funding This work was supported by grants from the National Natural Science Foundation of China (grant number: 32170939 and 82371846). The Guangdong Basic and Applied Basic Research Foundation [grant number 2022B1515020075]. Guangdong Science and Technology Program key projects [No. 2021B1212030014]. Data availability statement The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. The source data are provided in this study. Acknowledgements This work was supported by grants from the National Natural Science Foundation of China (grant number:32170939 and 82371846). The Guangdong Basic and Applied Basic Research Foundation [grant number 2022B1515020075]. Guangdong Science and Technology Program key projects [No.2021B1212030014]. Author contributions C.S., S.O., B.L., B.Z., and W.Z. contributed to the experimental design. C.S., F.O., B.W., and Y.J., contributed to manuscript preparation. H.Z., and Z.L., performed the neutralization assays and contributed to the analysis and interpretation of data. T.P., FO., SO., X.C., and H.Z., enrolled the patients and collected the clinical data. Ethics approval and consent to participate This study was approved by the Ethics Committee in The Fifth Affiliated Hospital of Guangzhou Medical University and Baiyun branch, Nanfang Hospital, Southern Medical University. Informed consent was obtained from all participants before enrollment. Consent for publication Not applicable. Competing interests The funders had no role in the design or conduct of the study, or in the decision to submit the manuscript for publication. The authors declare no competing interests. References Zhu Y et al. International Pediatric COVID-19 Severity Over the Course of the Pandemic. JAMA Pediatr (2023). Cohen C, et al. SARS-CoV-2 incidence, transmission, and reinfection in a rural and an urban setting: results of the PHIRST-C cohort study, South Africa, 2020–21. Lancet Infect Dis. 2022;22:821–34. https://doi.org/10.1016/S1473-3099(22)00069-X . Navarrete J, Qureshi BG, Woods I, Barbre A, Meng K, Novosad L, Li S, Soe Q, Edwards MM, Wong J, Guthrie E, Keenan SH, Lamping J, Park L, Dumbuya M, Benin S, Bell LA. J. Infection and death rates among maintenance dialysis patients during delta and early Omicron waves-United States, June 30, 2021-September 27, 2022. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4185718","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":287593814,"identity":"09d76870-e98f-49cf-9c84-4642faaed129","order_by":0,"name":"Huan Zhang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences, Guangdong Provincial Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Huan","middleName":"","lastName":"Zhang","suffix":""},{"id":287593815,"identity":"74d145c3-422a-47a5-81a8-f02c9744e15b","order_by":1,"name":"Shi Ouyang","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shi","middleName":"","lastName":"Ouyang","suffix":""},{"id":287593816,"identity":"cc64744b-d9c6-4b23-a5fa-f7aae5d3fe98","order_by":2,"name":"Zhuolin Li","email":"","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhuolin","middleName":"","lastName":"Li","suffix":""},{"id":287593817,"identity":"2ac455d1-c968-491f-8418-89ac69cae690","order_by":3,"name":"Yushan Jiang","email":"","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yushan","middleName":"","lastName":"Jiang","suffix":""},{"id":287593818,"identity":"459306e6-478f-4d73-a20f-aac7024abe76","order_by":4,"name":"Tingting Peng","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Peng","suffix":""},{"id":287593819,"identity":"f70f2dc0-c697-4376-89dc-5714c583965b","order_by":5,"name":"Chang Xi","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chang","middleName":"","lastName":"Xi","suffix":""},{"id":287593820,"identity":"9c48f369-6c05-4304-8d4f-b16843bc9579","order_by":6,"name":"Bao Zhang","email":"","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bao","middleName":"","lastName":"Zhang","suffix":""},{"id":287593821,"identity":"6e79a63f-e68c-44fe-b098-06df1d7135e6","order_by":7,"name":"Bo Wu","email":"","orcid":"","institution":"Hoyotek Biomedical Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Wu","suffix":""},{"id":287593822,"identity":"ce09971b-51c3-439f-84ab-6df6e7f200f3","order_by":8,"name":"Fen Ouyang","email":"","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fen","middleName":"","lastName":"Ouyang","suffix":""},{"id":287593823,"identity":"d3f487c6-2467-418c-bc92-dce03c6edca7","order_by":9,"name":"Baisheng Li","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences, Guangdong Provincial Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Baisheng","middleName":"","lastName":"Li","suffix":""},{"id":287593824,"identity":"f1e70d9c-df6d-4b43-90bc-bc3e63ad8a03","order_by":10,"name":"Wei Zhao","email":"","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhao","suffix":""},{"id":287593825,"identity":"873c5756-5634-4ce8-b9ed-ffdb9443dffe","order_by":11,"name":"Chenguang Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACZuYDBh8q/jHzszcfgIgcIKSFnS2hcMaZA+ySPccSiNTCz2PwmbflAL/BjBwD4rTwNzMYbuZtuCNtwHPm86ebbQxyfDcSGD8X4NEicZgh2XDujmfG5uy926Rz2xiMJW8kMEvPwGfNYYZjBm/PMCdb9pzdxgzUkrjhRgIbMw8eHfKHGdt/8LYx12+4kfP4M1BLPUEtBoeZGQx52w4zG9zIYQA5LMGAkBbDw2wMhjPOpDEDA9lMOuechOHMMw+bpfFpkTt//gMwKm1AUfn4c06ZjTzf8eSDn/FpQQcSQMzYQIKGUTAKRsEoGAXYAAAWvlJt5QWtKgAAAABJRU5ErkJggg==","orcid":"","institution":"Zhujiang Hospital, Southern Medical University","correspondingAuthor":true,"prefix":"","firstName":"Chenguang","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2024-03-29 04:57:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4185718/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4185718/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54313217,"identity":"aee35de6-b688-401f-90ee-74afaeac30cf","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":353089,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall humoral immune response against various authentic SARS-CoV-2 subvariants by acute and convalescent sera of the elderly, children and pregnant women from BA.5 wave infection. (A).\u003c/strong\u003e ELISA endpoint titers of sera from BA.5-infected susceptible patients in the acute (0-7 days post onset) and convalescent (14-90 days post onset) stages against different SARS-CoV-2 RBD proteins (n=56). \u003cstrong\u003e(B). \u003c/strong\u003eNeutralization titers of sera from BA.5 infected susceptible patients in the acute and convalescent stages against various authentic SARS-CoV-2 strains. \u003cstrong\u003e(C-D). \u003c/strong\u003eAnalysis of serum neutralization titers in susceptible people with and without vaccination for BA.5 infection during the acute (C) and convalescent (D) phases of infection (n=21 in the unvaccinated group, and n=35 in the vaccinated group). \u003cstrong\u003e(E-F). \u003c/strong\u003eComparison of serum neutralization titers between susceptible people and adults with BA.5 infection in the acute (E) and convalescent (F) stages of infection (n=56 in the susceptible group, and n=35 in the adult group). \u003cstrong\u003e(G-H). \u003c/strong\u003eComparison of serum neutralization titers between vaccinated susceptible people and adults with BA.5 infection in the acute (G) and convalescent (H) stages of infection.\u003cstrong\u003e (I).\u003c/strong\u003e Analysis of serum neutralization titers of susceptible people with BA.5 infection in different genders during the convalescent stage (n=24 in the men group, and n=32 in the women group). The value below each column is the ratio of the GM value of each group to the GM value of the corresponding Wuhan group. * p≤0.05, ** p≤0.01，*** p≤0.001, ns (no significance).\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/1df0a8760629d7a774b62807.png"},{"id":54313216,"identity":"58434bd1-a63f-4706-860a-65e2e9d7be64","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":335836,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of the humoral immune response against various authentic SARS-CoV-2 subvariants by convalescent sera between the elderly, children, pregnant women and adults from BA.5 wave infection. (A).\u003c/strong\u003e ELISA endpoint titers of sera from BA.5 infected pregnant women, children, elderly and adult patients in the convalescent (14-90 days post onset) stage against various SARS-CoV-2 RBD proteins (n=5 in the pregnant group, n=18 in the children group, n=33 in the elderly group and n=30 in the adult group). \u003cstrong\u003e(B). \u003c/strong\u003eNeutralization titers of sera from BA.5 infected pregnant women, children, elderly and adult patients in the convalescent stage against various authentic SARS-CoV-2 strains. \u003cstrong\u003e(C). \u003c/strong\u003eComparison of serum neutralization titers between vaccinated pregnant women, children, elderly and adults with BA.5 infection in the convalescent stages of infection (n=5 in the pregnant group, n=18 in the children group, n=33 in the elderly group and n=30 in the adult group). The value below each column is the ratio of the GM value of each group to the GM value of the corresponding children group. * p≤0.05, ** p≤0.01， *** p≤0.001, **** p≤0.0001.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/d974b77703b21090b171b172.png"},{"id":54313220,"identity":"de7fb530-bb9d-418f-9db9-2e57174aab2b","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":172882,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analysis of the binding and neutralization titers against various SARS-CoV-2 strains of the sera in the acute or convalescent stage of BA.5 infection from the susceptible population. (A-C).\u003c/strong\u003e Correlation analysis between ELISA titer and neutralization titer of sera against Wuhan strain (A), BA.5 strain (B) and XBB strain (C) in the acute stage of BA.5-infected susceptible patients. \u003cstrong\u003e(D-F).\u003c/strong\u003e Correlation analysis between neutralization titer of sera from the acute stage and the convalescent stage of BA.5-infected susceptible patients against Wuhan strain (D), BA.5 strain (E), and XBB strain (F). \u003cstrong\u003e(G-I).\u003c/strong\u003eCorrelation analysis between neutralization titer of sera from the acute stage and the convalescent stage of BA.5-infected vaccinated susceptible patients against Wuhan strain (G), BA.5 strain (H), and XBB strain (I). * p≤0.05, ** p≤0.01，*** p≤0.001, **** p≤0.0001.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/c2ec40466ff65297325239f3.png"},{"id":54313222,"identity":"46a08093-4a34-44d4-8d88-5e19d3d984ee","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":219119,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analysis of the binding and neutralization titers against various SARS-CoV-2 strains of the sera in the convalescent stage of BA.5 infection from the susceptible population. (A-C).\u003c/strong\u003e Correlation analysis between ELISA titer and neutralization titer of sera against Wuhan strain (A), BA.5 strain (B) and XBB strain (C) in the convalescent stage of BA.5-infected susceptible patients. \u003cstrong\u003e(D-F).\u003c/strong\u003eCorrelation analysis between neutralization titer of sera against Wuhan strain and BA.5 strain (D), Wuhan strain and XBB strain (E), and BA.5 and XBB strain (E) in the convalescent stage of BA.5-infected susceptible patients. \u003cstrong\u003e(G-I).\u003c/strong\u003e Correlation analysis between neutralization titer of sera against Wuhan strain and BA.5 strain (G), Wuhan strain and XBB strain (H), and BA.5 and XBB strain (I) in the convalescent stage of vaccinated susceptible patients with BA.5 infection. * p≤0.05, ** p≤0.01，*** p≤0.001, **** p≤0.0001.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/beea1368382e4c432ba8373a.png"},{"id":54313221,"identity":"a3d233b4-8288-452f-aab1-6dcea88142d1","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":354536,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparative analysis of antiviral neutralization titers induced by the infection of different Omicron strains in susceptible people.\u003c/strong\u003e \u003cstrong\u003e(A). \u003c/strong\u003eAntiviral neutralization titers of acute phase sera from susceptible patients with primary infection with BA.5 strain and XBB strain. (\u003cstrong\u003eB\u003c/strong\u003e)\u003cstrong\u003e.\u003c/strong\u003e Antiviral neutralization titers of convalescent-phase sera from susceptible patients with primary infection with BA.5 strain and XBB strain (n=56 in the BA.5 infection group, and n=47 in the XBB infection group). \u003cstrong\u003e(C). \u003c/strong\u003eAntiviral neutralization titers of acute phase sera from vaccinated susceptible patients with primary infection with BA.5 strain and XBB strain. (\u003cstrong\u003eD\u003c/strong\u003e)\u003cstrong\u003e.\u003c/strong\u003e Antiviral neutralization titers of convalescent-phase sera from vaccinated susceptible patients with primary infection with BA.5 strain and XBB strain (n=35 in the BA.5 infection group, and n=23 in the XBB infection group). The value below each column is the ratio of the GM value of each group to the GM value of the corresponding Wuhan group. * p≤0.05, ** p≤0.01，*** p≤0.001, ns (no significance).\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/fce4a9afc1850b21d61dd56a.png"},{"id":61861715,"identity":"3b23f7ab-a665-4cfc-baa6-271d5f6caad6","added_by":"auto","created_at":"2024-08-06 11:05:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1900161,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/a36ab388-46f3-4b2f-9fdf-81501870be54.pdf"},{"id":54313219,"identity":"613cd5a7-6b45-41a5-9ae0-55142ac3ba69","added_by":"auto","created_at":"2024-04-08 17:26:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":55693,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-4185718/v1/75f9ca5b4dd32d71b981b44a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Humoral immune response characteristics of the susceptible populations after the infection of SARS-CoV-2 BA.5 strain","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEven though most of the world's population has been vaccinated against COVID-19, multiple variants of SARS-CoV-2 are still circulating the world\u003csup\u003e1\u003c/sup\u003e, and SAR-CoV-2 continues to mutate and can infect the same person multiple times over different periods\u003csup\u003e2\u003c/sup\u003e, it is worth noting that although the virulence of SARS-CoV-2 has decreased, its infection can still cause severe illness or death\u003csup\u003e3\u003c/sup\u003e. Right after lifting the dynamic zero-COVID policy in China, there have been at least two waves of SARS-CoV-2 outbreaks. The first wave was caused by Omicron BA.5 and BF.7 variants from December 2022 to February 2023\u003csup\u003e4,5\u003c/sup\u003e. The second wave occurred between April 2023 and July 2023 due to the Omicron XBB variant\u003csup\u003e6\u003c/sup\u003e. The primary vaccine used in China is the inactivated COVID-19 vaccine, which can induce high titers of SARS-CoV-2 neutralizing antibodies\u003csup\u003e7\u003c/sup\u003e. While after a certain period following vaccination, the antibody titers in the body decline\u003csup\u003e8\u003c/sup\u003e. Research has demonstrated that vaccination can mitigate the severity and reduce mortality rates during the two epidemic waves in China\u003csup\u003e9\u003c/sup\u003e. However, due to the pronounced immune escape of the Omicron variants and the decrease in anti-SARS-CoV-2 antibody titers in vaccine recipients, COVID-19 vaccination has not been very effective in preventing infections by these two waves of Omicron pandemic viruses\u003csup\u003e10,11\u003c/sup\u003e. The decision to receive the COVID-19 vaccine may potentially influence the strength and breadth of antibody responses following Omicron infection\u003csup\u003e12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVariations may occur in the specific immune responses to SARS-CoV-2 among individuals based on their vaccine type, prior SARS-CoV-2 infection history, age group, or exposure to different SARS-CoV-2 strains\u003csup\u003e13\u003c/sup\u003e. SARS-CoV-2 infection can be analogized to a robust vaccination event, triggering the host's production of SARS-CoV-2-specific neutralizing antibodies\u003csup\u003e14\u003c/sup\u003e. The strength and breadth of these neutralizing antibodies may affect an individual's susceptibility to SARS-CoV-2 in subsequent infections, thereby influencing the severity of the next wave of COVID-19 in the human population\u003csup\u003e15\u003c/sup\u003e. A systematic evaluation of neutralizing antibody patterns induced by BA.5 infections in both unvaccinated and vaccinated individuals is essential. This data will significantly contribute to COVID-19 pandemic control and the advancement of next-generation vaccines.\u003c/p\u003e \u003cp\u003eThe elderly population faces a heightened risk of severe illness and death following SARS-CoV-2 infection compared to other groups. Furthermore, special attention should be given to vulnerable populations, such as children and pregnant women, concerning their clinical characteristics and antiviral immune response patterns following SARS-CoV-2 infection\u003csup\u003e16\u003c/sup\u003e. At present, there is limited research on humoral immune responses in susceptible populations to BA.5 infections, highlighting the need for additional data in this domain. This study, initiated in December 2022 in Guangzhou, China, aims to bridge existing research gaps. It involves the recruitment of 177 individuals from three vulnerable groups: children, pregnant women, and the elderly, alongside 78 adult participants. These participants were infected with either the BA.5 variant between December 2022 and March 2023 or the XBB variant between April 2023 and June 2023, with diverse histories of inactivated vaccine administration. Serum samples were collected during both the acute and recovery phases of COVID-19 to assess the strength and spectrum of their SARS-CoV-2-specific humoral immune responses.\u003c/p\u003e \u003cp\u003eThe primary objectives of this study are to investigate and compare the humoral immune responses induced by BA.5 and XBB infections, with a particular focus on response patterns in distinct vulnerable populations. This research, in conjunction with vaccination data, will provide valuable scientific insights into the ability of susceptible individuals to effectively respond to new SARS-CoV-2 variants following various SARS-CoV-2 infections. Ultimately, it will contribute to the development of the next generation of COVID-19 vaccines, including tailored vaccines and immunization strategies for diverse populations, all grounded in robust scientific evidence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe clinical serum samples in this study were obtained from the following COVID-19 patients. The first wave of COVID-19 patients in Guangzhou after the termination of China's COVID-19 dynamic zero clearing and control policy from December 2022 to March 2023, these patients were from the Baiyun Branch of Nanfang Hospital of Southern Medical University which was the designated hospital for pregnant women, children and elderly people. The second wave of COVID-19 patients in Guangzhou after the termination of China's COVID-19 dynamic zero clearing and control policy from April 2023 to June 2023, these patients were enrolled from the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University. The COVID-19 susceptible population in this study refers to children (0\u0026ndash;11 years old), the elderly (60\u0026ndash;100 years old), and pregnant women, while adults refer to the population aged 18\u0026ndash;59. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. All the individuals had no history of earlier COVID-19 infection. Vaccinated individuals who had 2 or 3 doses of vaccination had infection with BA.5 after 6 to 15 months, while had infection with XBB after 6 to 18 months in this study. The acute phase of infection in this study is defined as the 0\u0026ndash;7 days after the onset of COVID-19, and the convalescent period is defined as the 14\u0026ndash;90 days after the onset of COVID-19. The patient's sera was collected and placed in a -20\u0026deg;C refrigerator on the same day until it was used. This study has passed relevant ethical reviews at the Baiyun Branch of Southern Medical University and the Fifth Affiliated Hospital of Guangzhou Medical University. This research protocol has passed the relevant ethical review of the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProtein expression and purification\u003c/h2\u003e \u003cp\u003eThe SARS-CoV-2 RBD recombinant protein was expressed in human HEK293F cells as a soluble protein. The RBD were purified by HisTrap HP column (GE Healthcare) and were further purified by size-exclusion chromatography with a Superdex 200 column (GE Healthcare) in 20mM Tris, pH 8.0 Enzyme-linked immunosorbent assay (ELISA), 150mM NaCl and then analyzed by reducing sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEnzyme-linked immunosorbent assays (ELISAs)\u003c/h2\u003e \u003cp\u003eMicrotiter plates (Sangon Biotech) were coated with 100 ng of each recombinant receptor binding protein of SARS-CoV-2 overnight at 4\u0026deg;C. The plates were then washed twice with 1*PBS (phosphate buffer saline) containing 0.1% v/v Tween-20 (PBST) and blocked with blocking solution (1*PBS containing 5% w/v bovine serum albumin) overnight at 4\u0026deg;C. On the day of the experiment, the plates were then washed once with PBST. The serially diluted sera were added to the wells and incubated at 37\u0026deg;C for 60 min. Then the plates were washed five times using PBST and added 100 \u0026micro;L horseradish peroxidase (HRP)-conjugated goat anti-human IgG antibody solution (Sangon Biotech) to each plate, respectively, and incubated at 37\u0026deg;C for 60 min. Wash each plate with PBST five times, and 100 \u0026micro;L of tetramethylbenzidine (TMB) substrate (Sangon Biotech) was added to each plate at room temperature in the dark and reacted for 15 min. After the reaction, the plate was stopped with a 2 M H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e solution. The absorbance was measured at 450 nm using a microplate reader. All samples were run in triplicate. The ELISA titers were determined by endpoint dilution.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSerum-neutralization assay\u003c/h2\u003e \u003cp\u003eThe day before the infection, the 6-well cell culture plates (Costar) were seeded with 10\u003csup\u003e4\u003c/sup\u003e Vero cells, and then the cells were washed twice with a cell culture medium on the day of infection. Sera from individuals thawed at room temperature and were incubated at 56\u0026deg;C for 30 min, and then diluted from 20-fold to 5120-fold. 40 \u0026micro;L aliquots of each diluted sera were added to a cell culture medium containing 100 tissue culture infective dose (TCID\u003csub\u003e50\u003c/sub\u003e) of each SARS-CoV-2 virus strain in 40 \u0026micro;L on a 96-well cell culture plate and incubated at 37\u0026deg;C for 2 h in CO\u003csub\u003e2\u003c/sub\u003e 5% v \u0026frasl; v, all the SARS-CoV-2 virus strains were isolated from Guangdong Provincial Center for Disease Control and Prevention). The mixture containing the virus and serum was then added to cells in 96-well plates and were incubated at 37\u0026deg;C for 5-day incubation. Microscopic examination for cytopathic effect (CPE) was conducted after the incubation. The highest dilution of serum that showed inhibition activity of SARS-CoV-2 was estimated as the neutralization titer. Neutralization titer assays were performed in triplicate with negative control sera. The threshold of neutralization activity is NT\u0026thinsp;\u0026ge;\u0026thinsp;4.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe two-tailed Wilcoxon signed-rank matched-pairs test was used to compare paired comparisons (α\u0026thinsp;=\u0026thinsp;0.05). In 2-tailed testing, P\u0026thinsp;\u0026lt;\u0026thinsp;0.5 was deemed statistically significant. Two-tailed Wilcoxon signed-rank matched-pairs test was used to compare paired comparisons. P\u0026thinsp;\u0026lt;\u0026thinsp;0.5 was considered to be statistically significant in 2-tailed tests. The Spearman rank correlation coefficient was used for linear correlation analysis between the expression level of plasma cytokine and Murray's score. All statistical analysis was conducted in GraphPad Prism 6.0. p values reported in the figures and figure legends indicate the following significance levels: *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, and ***p\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAt the end of 2022, after adjusting the prevention and control policy of the COVID-19 epidemic in China, the first wave of the nationwide epidemic virus was the BA.5 strain of SARS-CoV-2. Baiyun branch of Nanfang Hospital of Southern Medical University was the designated hospital for pregnant women, children and elderly people. In the first wave of the COVID-19 epidemic, 56 SARS-CoV-2 susceptible people were enrolled in this study, and their humoral immune response characteristics in the acute and convalescent phases were determined. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displayed the demographic characteristics of the participants in the first COVID-19 wave, including 33 elderly people, 18 children, 5 pregnant women and 30 adults who had not received any vaccines or had received two or three doses of inactivated SARS-CoV-2 vaccines. First, the ELISA binding reactivity of the sera from susceptible patients against the receptor binding domain (RBD) proteins of different SARS-CoV-2 strains (Wuhan, Delta, BA.5 and XBB) was evaluated. In the acute phase of COVID-19 (0\u0026ndash;7 days post onset), the IgG titers against all SARS-CoV-2 RBDs in the sera were at low levels. In contrast, in the convalescent phase of COVID-19 (14\u0026ndash;90 days post onset), the SARS-CoV-2-specific IgG titers were significantly increased, when compared to the sera in the acute stage, the IgG titer against Delta, BA.5 and XBB increased by 22.2, 20.3, 11.6 and 6.4 times, respectively; The IgG antibody titer against the Wuhan strain was the highest, for the convalescent sera, the IgG titers against Delta, BA.5, and XBB decreased by 1.2, 2.3, and 5.6 times compared with those against the Wuhan strain, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The neutralization titer of COVID-19 susceptible people's sera against the SARS-CoV-2 virus showed the same trend as the titer of the IgG antibody, only a few sera samples in the acute phase showed a low level of neutralization titer against the SARS-CoV-2 virus. Compared with the sera in the acute phase, the neutralization titer of convalescent sera against Wuhan, Delta, BA.5 and XBB increased by 6.5, 6.3, 3.8 and 1.5 times, respectively. The geometric mean (GM) values of neutralization titers of sera against Wuhan, Delta, BA.5 and XBB during the convalescent stage were 82.6, 76.3, 46.8 and 15.1, respectively, of concern, all sera had low neutralization titers against XBB (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). In this COVID-19 wave, before infection with BA.5, most people had been vaccinated with two or three doses of the COVID-19 vaccine, and the difference in humoral immune response between vaccinated and unvaccinated people after infection with BA.5 was compared further. In the acute phase of BA.5 infection, the neutralizing antibody levels against SARS-CoV-2 in the sera of vaccinated and unvaccinated patients were comparable (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC), while in the convalescent phase of BA.5 infection, the neutralizing antibody titer against various SARS-CoV-2 strains in the sera of vaccinated patients was significantly higher than that of unvaccinated patients, and the neutralizing antibody titers in the sera of vaccinated population against Wuhan, Delta, BA.5 and XBB were 6.9, 6.7, 2.5 and 1.3 times higher than those of the unvaccinated population, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Next, this study compared the differences in neutralizing antibody titers against SARS-CoV-2 in the sera of the SARS-CoV-2 susceptible population (elderly, children and pregnant women) and adults (18\u0026ndash;60 years-old population), the results showed that there was no significant difference in the titers of neutralizing antibodies between SARS-CoV-2 susceptible population and adults in the acute phase and convalescent phase of COVID-19 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF), although, in the convalescent phase, the neutralizing antibody titer of sera in the adult's group is higher than that of the susceptible population (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). Excluding the unvaccinated population, there was also no significant difference in the titers of neutralizing antibodies against different SARS-CoV-2 between the vaccinated SARS-CoV-2 susceptible population and the vaccinated adults (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG and H). There was no significant difference in the antiviral neutralization titer of sera in the COVID-19 susceptible population from different genders, either in the acute phase or in the convalescent phase (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCohort characteristics of COVID-19 patients in Guangzhou, China, from December 2022 to March 2023 in the first wave.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eElderly (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eChildren (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge-yr\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5 (60\u0026ndash;97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eAge-yr\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVaccination status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVaccination status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnvaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnvaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePregnant (n\u0026thinsp;=\u0026thinsp;5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003eAdult (n\u0026thinsp;=\u0026thinsp;30)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (53.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (46.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge-yr\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 (19\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eAge-yr\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34.4\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6 (15\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVaccination status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVaccination status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (83.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnvaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnvaccinated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurthermore, in this study, the enrolled patients were divided into pregnant women, children, the elderly and adults groups, and the titers of anti-SARS-CoV-2 binding antibodies and neutralizing antibodies in the serum of each group were compared in detail. For SARS-CoV-2 specific binding and neutralizing antibodies, the serum antibody titers of the children group are the lowest, and the serum titers of binding antibodies against Wuhan, Delta, BA.5 and XBB strains in the children group during the convalescent period are 522, 469, 400 and 261, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), and the neutralizing antibody titers are 14.1, 13.5, 18.1 and 10.0, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Compared with the children group, the binding antibody titer in the convalescent sera of pregnant women, elderly and adult groups is 17.6\u0026ndash;63.2 times higher against Wuhan and Delta strains, 8.2\u0026ndash;19.2 times higher against BA.5 strains and 1.4\u0026ndash;10.3 times higher against XBB strains, and the neutralizing antibody titers in these sera showed a similar trend to that of the binding antibody (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Considering that the vaccination rate of the COVID-19 vaccine in the children group is the lowest (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), to exclude the influence of vaccination of the COVID-19 vaccine, this study further compared the neutralizing antibody titer of the convalescent sera of the vaccinated population in each group, and the results showed that the antiviral neutralizing antibodies of the sera in the children group were still the lowest (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). We further analyzed the correlation of the binding and neutralization titers against various SARS-CoV-2 strains of the sera of BA.5 infection from the susceptible population. The binding antibody titers against the Wuhan strain, BA.5 strain, and XBB strain in the serum during the acute and recovery stages showed a positive correlation with the corresponding neutralizing antibody titers (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). For susceptible populations infected with BA.5, there is no significant correlation between the neutralizing antibody titer of acute-phase sera and that of sera in the convalescent phase against the Wuhan strain. Similarly, the neutralizing antibody titers against BA.5 and XBB in the acute phase serum were not significantly correlated with the neutralizing antibody titers against BA.5 and XBB in the convalescent phase serum, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD-\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF), for the vaccinated population, the same trend was shown, with no significant difference between neutralizing antibody titers in the corresponding sera (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eG-\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eI). During the convalescent period of BA. 5 infection, the binding antibody titers against the three different SARS-CoV-2 strains in the serum showed a positive correlation with the corresponding neutralizing antibody titers (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC), the anti-Wuhan neutralizing titers of sera showed a significant positive correlation with those of anti-BA.5 and anti-XBB neutralizing titers (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD-\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE), and the anti-BA.5 neutralizing antibody titers and anti-XBB neutralizing antibody titers in sera also showed a significant positive correlation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF). For the vaccinated population, the titers of neutralizing antibodies against the BA.5 strain in sera showed a significant positive correlation with the titers of neutralizing antibodies against the Wuhan and XBB strains in the convalescent phase, while the titers of neutralizing antibodies against the Wuhan and XBB strains did not show a significant correlation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eG-\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eI).\u003c/p\u003e \u003cp\u003eIn the second wave of the COVID-19 epidemic in China, 62 SARS-CoV-2 susceptible people were enrolled in this study from the Fifth Affiliated Hospital of Guangzhou Medical University and Nanfang Hospital of Southern Medical University, including 32 elderly people, 20 children, 10 pregnant women and 39 adults who had been infected with the SARS-CoV-2 Omicron strain once or twice. In a previous study, we have reported the humoral immune characteristics of these patients against different SARS-CoV-2 strains\u003csup\u003e17\u003c/sup\u003e. In this study, we compared the differences in the titers of neutralizing antibodies induced in SARS-CoV-2 susceptible populations when the first infected SARS-CoV-2 strains were BA.5 and XBB, respectively. When the first infected SARS-CoV-2 strain was BA.5, the neutralizing antibody titers of the acute phase sera against Wuhan, Delta, BA.5, and XBB strains were 12.8,12.2,12.3, and 10.3, respectively, in contrast, when the first infected SARS-CoV-2 strain was XBB, the neutralizing antibody titers of the corresponding sera increased by 2.7, 2.5,1.8, and 1.5 times, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). In the convalescent period of COVID-19, the titers of neutralizing antibodies against Wuhan, Delta and BA.5 strains induced in individuals with the first infection strain BA.5 and the first infection strain XBB are at a similar level, interestingly, the titer of the antibodies against XBB induced in the population with the first infection of the XBB strain was 3.5 times that of the population with the first infection of the BA.5 strain (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB). When analyzing the vaccinated population, the humoral immune responses against SARS-CoV-2 in the BA.5-first-infected group and XBB-first-infected group showed similar patterns (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we systematically investigated the humoral immune responses of susceptible children, elderly and pregnant women and ordinary adults in China with BA.5 infection. We found that there were differences in antibody responses induced by SARS-CoV-2 infection in individuals of different age groups and with different SARS-CoV-2 infection and vaccine immunization backgrounds. Furthermore, XBB infection elicited a broader spectrum of antibodies than BA.5 infection. These findings have important implications for the development of novel COVID-19 vaccines tailored to different populations.\u003c/p\u003e \u003cp\u003ePrevious studies have shown that BA.5 infection does not effectively induce highly effective neutralizing antibodies against XBB strain\u003csup\u003e18,19\u003c/sup\u003e. In this study, we further subdivided the population and found that children, elderly, pregnant women and adults infected with BA.5 can induce high levels of neutralizing antibodies against Wuhan, Delta, BA.5 during the convalescent phase of the disease, however, the neutralizing antibody titers against XBB are low which suggests that persons infected with BA.5 may still be susceptible to XBB strains, and indeed, in this study, many patients with COVID-19 XBB infection were found to have previously been infected with BA.5.\u003c/p\u003e \u003cp\u003eIn BA.5-infected patients, vaccination had little effect on SARS-CoV-2 antibody induction during the acute phase of illness, but during the convalescent phase, breakthrough vaccinated patients had higher neutralizing antibody titers against Wuhan, Delta, and BA.5 than unvaccinated patients, however, there was no significant increase in neutralizing antibodies against XBB, further indicating that XBB was evaded by antibodies induced by the COVID-19 vaccine and BA.5 infection.These results were also validated in the correlation analysis, for BA.5 infected patients, there was no strong correlation between the antibody titers of convalescent sera against the Wuhan strain and that of convalescent serum against the XBB strain, indicating that there were few broadly neutralizing antibodies in sera that could neutralize both the Wuhan strain and XBB strain. In contrast, the titers of antibodies against the Wuhan strain, BA.5 strain and XBB strain in convalescent sera of XBB-infected patients were correlated with each other, indicating that XBB infection induced a part of neutralizing antibodies that could broadly neutralize XBB, BA.5 and Wuhan strain. Most of the neutralizing monoclonal antibodies generated previously have been eluded by XBB\u003csup\u003e20\u0026ndash;23\u003c/sup\u003e, the broadly neutralizing antibodies in patients with XBB infection are expected to be further screened and identified as novel antibody drugs against SARS-CoV-2.\u003c/p\u003e \u003cp\u003eInterestingly, among the BA.5 infected patients, children group induced the lowest level of anti-SARS-CoV-2 binding and neutralizing antibody, the exact mechanism of which needs further study, and this result also indicates that after infection with BA.5, due to the low level of related neutralizing antibody, children population may be more susceptible to re-infection with SARS-CoV-2 than other populations. There was no significant difference in antibody response after infection with SARS-CoV-2 in susceptible population of different genders, and in previous studies, we also found no significant difference in antibody response induced by COVID-19 vaccination between men and women\u003csup\u003e24\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eThere were some limitations in this study. No studies related to T cell immunity were carried out in various populations. This study included a small number of participants, and other SARS-CoV-2 infected patients such as BF.7 were not included.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (grant number: 32170939 and 82371846). The Guangdong Basic and Applied Basic Research Foundation [grant number 2022B1515020075]. Guangdong Science and Technology Program key projects [No. 2021B1212030014].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. The source data are provided in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (grant number:32170939 and 82371846). The Guangdong Basic and Applied Basic Research Foundation [grant number 2022B1515020075]. Guangdong Science and Technology Program key projects [No.2021B1212030014].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.S., S.O., B.L., B.Z., and W.Z. contributed to the experimental design. C.S., F.O., B.W., and Y.J., contributed to manuscript preparation. H.Z., and Z.L., performed the neutralization assays and contributed to the analysis and interpretation of data. T.P., FO., SO., X.C., and H.Z., enrolled the patients and collected the clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee in The Fifth Affiliated Hospital of Guangzhou Medical University and Baiyun branch, Nanfang Hospital, Southern Medical University. Informed consent was obtained from all participants before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funders had no role in the design or conduct of the study, or in the decision to submit the manuscript for publication. The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhu Y et al. International Pediatric COVID-19 Severity Over the Course of the Pandemic. JAMA Pediatr (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen C, et al. SARS-CoV-2 incidence, transmission, and reinfection in a rural and an urban setting: results of the PHIRST-C cohort study, South Africa, 2020\u0026ndash;21. 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J Med Virol. 2022;94:6065\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/jmv.28049\u003c/span\u003e\u003cspan address=\"10.1002/jmv.28049\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Humoral immune characteristics, COVID-19, Susceptible populations, BA.5, Neutralizing antibody","lastPublishedDoi":"10.21203/rs.3.rs-4185718/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4185718/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study compared the humoral immune characteristics of children, elderly people, pregnant women, and adults infected with BA.5 and XBB strains in Guangzhou, China. It was found that binding and neutralizing antibodies the titers against distinct SARS-CoV-2 strains were low in the acute-phase sera of BA.5 infected patients, while the corresponding titers were significantly increased in the convalescent phase, the antibody titers against the Wuhan strain were the highest. Regardless of whether they were vaccinated, BA.5 infection did not induce high neutralizing antibodies against XBB. During the recovery phase, the titers of antiviral antibodies in the vaccinated population are more robust than those in the unvaccinated population. For BA.5 infections, the specific binding and neutralizing antibody titers in the children group were lower compared to other population groups. In the convalescence period of the disease, the titers of neutralizing antibodies against Wuhan, BA.5 and XBB strains induced by BA.5 infections are significantly correlated in pairs. XBB can induce a broader and balanced antiviral humoral immune response than BA.5 as a first-time infected strain. This finding can provide a reference for the judgment of the future epidemic law of SARS-CoV-2, and provide a scientific basis for developing novel COVID-19 vaccines, especially for discovering customized vaccines and immune strategies for different populations.\u003c/p\u003e","manuscriptTitle":"Humoral immune response characteristics of the susceptible populations after the infection of SARS-CoV-2 BA.5 strain","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-08 17:26:44","doi":"10.21203/rs.3.rs-4185718/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c76953b4-011f-4b5f-a0c2-416d716f3b82","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-06T10:56:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-08 17:26:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4185718","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4185718","identity":"rs-4185718","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}