{"paper_id":"4ba34357-7b46-4588-a440-be03d375badc","body_text":"Immune Responses to SARS-CoV-2 Variants WT and XBB.1.9: Assessing Vulnerabilities and Preparedness | 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 Immune Responses to SARS-CoV-2 Variants WT and XBB.1.9: Assessing Vulnerabilities and Preparedness Limor Kliker, Michal Mandelboim, Menucha Jurkowicz, Neta S. Zuckerman, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7239482/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 The emergence of SARS-CoV-2 variants with enhanced immune evasion capabilities continues to challenge efforts to sustain population-level immunity. Among these, the XBB lineage, particularly the XBB.1.9 sub-variant, has garnered attention due to extensive spike protein mutations that reduce recognition by neutralizing antibodies. In this study, we evaluated neutralizing antibody titers against both the SARS-CoV-2 wild-type (WT) strain and the XBB.1.9 variant using serum samples collected from the Israeli population between August 2022 and January 2023, prior to widespread XBB.1.9 circulation. Our analysis revealed significantly reduced neutralizing titers against XBB.1.9 compared to WT across all demographic groups (p < 0.0001), underscoring its pronounced immune escape potential. For the WT strain, older individuals (≥ 65 years) exhibited higher titers (p < 0.0023), likely reflecting increased vaccine and booster uptake; however, this age-related difference was not observed for XBB.1.9 (p > 0.05), indicating diminished protection across age groups. Regional disparities in WT titers, higher in Northern Israel than in Jerusalem and Southern regions, suggest differential vaccine access and healthcare infrastructure, yet no such variation was seen for XBB.1.9. These findings highlight critical gaps in immunity against XBB.1.9, especially in populations historically underserved by vaccination efforts. The results underscore the urgent need for updated vaccines tailored to immune-evasive variants and for culturally sensitive outreach strategies to improve vaccine equity. Further studies should evaluate the efficacy of XBB-specific vaccines and the durability of immune protection to inform long-term strategies for SARS-CoV-2 control. Figures Figure 1 Figure 2 Figure 3 Introduction The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to substantial global morbidity, mortality, and disturbance since its initial detection in December 2019 in Wuhan, China. The virus, which is highly transmissible among humans, causes respiratory illness with symptoms ranging from mild, such as fever, cough, and headache, to severe disease requiring hospitalization and leading to long-term complications or death 1 – 3 . In Israel, the first confirmed COVID-19 case was reported in February 2020 4 . Since its emergence, SARS-CoV-2 has continuously evolved, giving rise to numerous variants with distinct genetic and phenotypic changes. The World Health Organization (WHO) classified several variants, such as Alpha, Beta, Delta, and Omicron, as Variants of Concern (VOCs), each contributing to distinct waves of infection globally and regionally. The XBB lineage, a recombinant subvariant of Omicron BA.2.75, was first identified globally in August 2022 and has since gained attention due to its increased transmissibility and potential for immune evasion 5 . In Israel, XBB variants began circulating toward the end of 2022, contributing to a surge in COVID-19 cases 6 . Among the XBB lineage, the XBB.1.9 subvariant has emerged as a recombinant variant of particular concern. First identified globally in late 2022, XBB.1.9 is characterized by extensive mutations in the spike protein, including changes in the receptor-binding domain (RBD) that enhance its ability to evade neutralizing antibodies 7 . These mutations contribute to increased transmissibility and immune escape capabilities, challenging existing immunity derived from prior infections or vaccination and raised concerns regarding the population's preparedness and highlighting the importance of updating vaccine strategies and public health measures. During December 2020, the BioNTech-Pfizer vaccine was approved by the US Food and Drug Administration (FDA). This mRNA vaccine was developed against the spike protein of the WT virus. The vaccine was previously shown to have 95% efficacy against the WT and the Alpha variants 8 and had reduced effectiveness against the Delta variant 9 . Omicron sub-lineages were even less affected by the vaccine 10 . In order to improve the protection against circulating Omicron sub-lineages, bivalent COVID-19 booster vaccines were developed 11 . In September 2022, the FDA approved the BNT162b2 bivalent vaccine (Pfizer–BioNTech) targeting both WT and Omicron (BA.4/BA.5) variants 12 . Since, two additional updated vaccines were authorized - a monovalent mRNA vaccine targeting the SARS-CoV-2 Omicron XBB.1.5 13 and the monovalent mRNA vaccine targeting KP.2 14 . Israel was among the first countries to implement a national vaccination campaign, beginning in December 2020 with the Pfizer-BioNTech BNT162b2 mRNA vaccine. The campaign quickly expanded to include booster doses as new variants emerged 15 . Emerging variants, such as those in the Omicron lineage, present new challenges due to increased transmissibility and immune evasion. Reduced neutralization has been observed in vaccinated or previously infected individuals 16 , although updated boosters, particularly bivalent formulations, provide some protection 17 . Assessing population-level immunity is critical for identifying high-risk groups, informing vaccine strategies, and optimizing public health measures. This study focuses on assessing population immunity in Israel prior to the wide circulation of the XBB.1.9 variant. By analyzing neutralizing antibody titers from serum samples collected prior to its emergence, we aim to evaluate the population’s preparedness and susceptibility to current and future variants, including XBB.1.9 and its sub-lineages. Understanding population immunity levels provides valuable insights into the likely impact of emerging variants and informs proactive public health strategies. Methods Study population and setting: This cross-sectional study analyzed 1140 serum samples collected from all ages from diverse geographical regions within Israel during 1.8.22–31.1.23. The samples were collected from laboratories included in the Israel National Sera Bank (INSB) established in 1997 in the Israel Center for Disease Control. For each sample, the data recovered were age, gender, district of residence (North, Central, Jerusalem, South and Judea and Samaria), population group (Jews and others vs. Arabs) and residential socio-economic rank, based on city of residence. Local municipalities in Israel were ranked using an index ranging between 1 (lowest) and 10 (highest) published by the Central Bureau of Statistics, based on a range of variables 18 . All samples were anonymized. Detailed sera collection and methods used for the INSB were previously described 19 . Neutralization assay: A SARS-CoV-2 lentivirus-based neutralization assay was performed to assess the WT and XBB.1.9, neutralizing antibody levels measured in 50% inhibitory dilution (ID50). The neutralizing assay was performed as previously described 6 , with minor modifications. Lentiviral particles were produced by co-transfecting HEK293T/17 cells with an expression vector encoding variant specific SARS-CoV-2 spike alongside packaging vector pCMVDR8.2, luciferase reporter vector pHR′CMV-Luc and a TMPRSS2 expression vector (as part of a partnership with Dr. Daniel Douek, Vaccine Research Institute (VRC), National Institute of Health (NIH). MD, USA). Supernatant was collected from cells 48-hour post transfection and used for subsequent neutralization. Transfection was done using Lipofectamine 3000 (Thermo Scientific, cat# L3000001) as specified by the manufacture. For neutralization, serum samples were heat inactivated in 56°C for 30 minutes. Serum samples were 2-fold diluted in a 96-well plate in dilution medium (MEM 5% FBS), overlaid with pseud-typed Lentivirus solution and incubated in 37°C for one hour. Pseudovirus-serum complexes were then overlaid with HEK293 TMPRSS2-ACE2 cells suspended in dilution medium. Cells were incubated in 37°C for 72 hours. Following incubation, luminescence was quantified by lysing the cells with tissue culture lysis reagent (Promega, cat# E1531) and adding luciferase assay substrate (Promega, cat# E1501). Luminescence was read using a Varioskan LUX Multimode Microplate Reader (Thermo Scientific). Statistical analysis: Geometric Mean Titers (GMT) with confidence interval (CI) of 95% were calculated using GraphPad Prism 10.2.2 (GraphPad Software, Inc., San Diego, CA). Neutralization titers were assessed using the Mann-Whitney test between the following groups: participant ages 30–40 years and ≥ 65, gender, nationality, socioeconomic status and SARS-CoV-2 variant. Neutralization titers between different geographic locations were assessed using the Kruskal-Wallis test. Results To evaluate population-level immunity and preparedness for the emerging SARS-CoV-2 XBB.1.9 variant, we monitored the prevalence of SARS-CoV-2 variants in Israel and analyzed neutralizing antibody titers from 1140 serum samples collected prior to the widespread circulation of XBB.1.9. The frequency of SARS-CoV-2 variants in Israel was monitored via whole-genome sequencing of positive samples (Israel national consortium for SARS-CoV-2 sequencing, Ministry of Health). Figure 1 presents the monthly distribution of variant prevalence from March 2022 to December 2023. In early 2022, BA.1 and BA.2 were the most prevalent, followed by BA.5, which dominated from mid-2022 to November 2023. Subsequently, BQ and BA.4 gained prominence in early 2023. The XBB lineage, including XBB, XBB.1.5, and especially XBB.1.9, emerged in 2023 and gradually increased in prevalence, dominating Israel's variant endemicity with 93% between February and July of 2023. XBB.1.9 (in red) appeared between February and July 2023. Since April 2023, the detection rate of XBB.1.9 increased, rising from 24% of all sequenced samples in April to 46% in July. Towards the end of 2023, further variation of circulating variants was observed, with a decrease in the prevalence of XBB.1.9 as other lineages emerged. Next, we evaluated neutralizing antibody titers against WT and XBB.1.9. Serum samples were collected between August 1, 2022 and January 31, 2023, from a cohort of 1140 participants representing the general population. Socio-demographic characteristics of the participants is presented in Table 1 . Table 1 Demographics and characteristics of the participants. P-value was calculated between the variants WT and XBB.1.9 of each group. GMT = geometric mean titer. Group Number of participants % of total participants GMT (WT) GMT (XBB.1.9) p-value Total participants 1140 100 1057 36.97 > 0.0001 Gender Male 529 46.40 1251 42.58 > 0.0001 Female 611 53.60 1121 39.12 > 0.0001 Age group Age 30–39 385 33.77 1043 35.01 > 0.0001 Age 65+ 755 66.23 1257 43.92 > 0.0001 Socioeconomic status Low SES 782 68.60 1196 40.87 > 0.0001 High SES 189 16.58 1483 41.37 > 0.0001 Population group Jews and others 855 75.00 1245 42.09 > 0.0001 Arabs 514 45.09 1034 36.66 > 0.0001 District Jerusalem 184 16.14 1075 32.12 > 0.0001 North 372 32.63 1590 39.87 > 0.0001 Central 181 15.88 1203 53.25 > 0.0001 South 352 30.88 911.7 42.32 > 0.0001 Judea&Samaria 46 4.04 1191 35.03 > 0.0001 When comparing neutralizing antibody titers for SARS-CoV-2 WT and XBB.1.9 variants (Fig. 2 ), a statistically significant difference was observed (p < 0.0001). Antibody levels of WT (geometric mean titer (GMT) = 1180; 95% CI: 1057–1317) were markedly lower against XBB.1.9 (GMT = 40.69; 95% CI: 36.97–44.77). A significant difference in neutralizing antibody titers was observed between age groups when assessing immunity to the WT SARS-CoV-2 variant (Fig. 3 A), with older individuals (65+) showing higher mean titers compared to younger group (age 30–39), GMT 1257 (CI: 1093–1444) and 1043 (CI: 871.3–1248) respectively (p < 0.0023). However, no significant differences were detected between age groups when assessing titers against XBB.1.9 (p > 0.05). Region analysis, (Fig. 3 B), revealed further disparities in responses to the WT variant. Participants from the Northern district exhibited the highest GMT (1590, CI: 1321–1912) against the WT variant, followed by participants from the Central region (1203, CI: 922–1569) and Judea and Samaria (1191, CI: 734.4–1930). Lower GMTs were observed among participants from Jerusalem (1075, (CI: 825–1400) and the Southern district (911.7, CI: 735.4–1130), with statistically significant differences found between the North and South (p < 0.00014) and between the North and Jerusalem (p < 0.0212). No significant differences were detected between other regional pairings. In contrast, when evaluating neutralizing antibody titers against XBB.1.9, GMTs were relatively consistent across regions, ranging between 32.12 in Jerusalem and 53.25 in the Central district, with no statistically significant differences observed (p > 0.05). Across other demographic factors, including gender, socioeconomic status and nationality (Fig. 3 C, D, E), no significant differences in neutralizing antibody responses were detected for either the WT or XBB.1.9 variant (p > 0.05 for all comparisons). However, when comparing GMTs between WT and XBB.1.9 within each individual subgroup (e.g., within each age, gender, region, and socioeconomic group), a statistically significant reduction in neutralizing antibody titers was observed (p < 0.0001 for all comparisons). This consistent intra-group reduction indicates that the XBB.1.9 variant elicited markedly lower neutralization responses relative to the WT variant across all population segments. Serum samples were tested with neutralization against WT SARS-CoV-2 and XBB.1.9. Geometric mean titers (horizontal lines) with 95% confidence intervals (𝙸 bars) are presented, as well as the geometric mean titer value. Dots indicate individual serum samples. A significant reduction in immunity was observed against XBB.1.9. ****p ≥ 0.0001. Geometric mean titers (GMT) of neutralizing antibodies against SARS-CoV-2 WT and XBB.1.9 variants are shown by (A) age, (B) demographic, (C) gender, (D) socio-economic status and (E) nationality. Across all subgroups, neutralization titers were significantly lower for XBB.1.9 compared to WT (p < 0.0001). Significant differences in GMTs for the WT variant were observed between age groups (higher in adults ≥ 65 years), and across regions (notably lower in Jerusalem and Southern Israel compared to the North). No statistically significant differences in neutralization titers for the XBB.1.9 variant were observed between subgroups. Bars represent GMTs; error bars indicate 95% confidence intervals. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≥ 0.0001. Discussion The SARS-CoV-2 XBB variant was first isolated in 2022. The spike (S) protein of the XBB variant contains 14 mutations additionally to those found in the BA.2 lineage, including nine located specifically within the receptor-binding domain (RBD). The XBB.1 sub-lineage carries an extra mutation at position G252V compared to the original XBB variant 20 . XBB.1.9.1 possess amino acid substitutions in virus proteins that may affect infectivity, viral replication, transmissibility and/or pathogenicity 21 . Israel’s COVID-19 vaccination program has been recognized worldwide for its effectiveness and rapid implementation. The campaign, launched in December 2020, demonstrated the benefits of prioritizing high-risk groups such as healthcare workers and older adults, while utilizing digital infrastructure to monitor vaccine distribution and immune responses efficiently 22 . Booster doses were introduced immediately to address waning immunity and emerging variants, with high compliance significantly reducing morbidity during waves driven by Alpha, Delta, and early Omicron sub-lineages 23 , 24 . This study aimed to assess antibody responses in the Israeli population prior to the widespread circulation of XBB.1.9, providing a valuable baseline for understanding the population’s preparedness for emerging variants. We evaluated neutralization antibody titers against SARS-CoV-2 variants, WT and XBB.1.9 in the Israeli population focusing on age-related variations, regional differences and demographic disparities. According to our findings, neutralizing antibody titers against XBB.1.9 were significantly lower compared to those against the WT variant. This result is consistent with the enhanced immune escape properties of XBB lineages reported globally. Mutations in the spike protein of XBB.1.9 compromise antibody binding and recognition, reducing its susceptibility to immunity derived from prior infection or vaccination 25 , even among populations who received updated bivalent vaccine formulations designed to target the WT and initial Omicron sub-lineages 5 , 6 , 11 , 12 , 26 , 27 . Age-related differences in immunity were observed for the WT variant, with older adults (65+) demonstrating higher neutralizing antibody titers compared to younger individuals (30–39). No significant differences were detected for the XBB.1.9 variant. This is likely attributable to greater uptake of booster doses in the older population, as earlier vaccination campaigns in Israel prioritized older individuals early in the pandemic 28 , 29 . Booster doses have been shown to amplify antibody responses and extend the duration of protection 30 , which contributed to the stronger immunity observed against the WT variant in this age group. However, the lack of significant differences in antibody titers for XBB.1.9 suggests that immune escape mechanisms of this variant effectively reduced the benefits associated with higher vaccine uptake in older populations. Regional differences were also observed in this study, particularly in immunity to the WT variant. Individuals from Jerusalem and Southern Israel exhibited significantly lower neutralizing antibody titers against the WT compared to those from Northern Israel. These differences likely reflect disparities in vaccine acceptance rates differences in public health outreach 31 . Regions such as Jerusalem, which have higher concentrations of ultra-Orthodox Jewish and Arab populations, often face barriers to vaccination rooted in cultural beliefs, socioeconomic factors, and misinformation 32 , 33 . Similarly, Southern Israel, characterized by geographically dispersed rural communities and larger Bedouin populations, faces systemic inequities in healthcare infrastructure that hinder vaccination coverage 34 . These findings further emphasize the importance of targeted vaccination campaigns and outreach programs tailored to culturally diverse and disadvantaged populations. In contrast, no significant regional differences were observed for neutralizing antibody titers against XBB.1.9 variant, suggesting that the ability of XBB.1.9 to evade the immune system is consistent across populations, regardless of differences in vaccination rates or access to healthcare. Additionally, neutralization levels against XBB.1.9 were consistently lower in all subgroups compared to the WT variant, highlighting an underlying vulnerability across the population. Today, the COVID-19 vaccine landscape continues to evolve in response to the challenges posed by emerging variants such as XBB.1.9. Updated vaccine formulations, including bivalent vaccines targeting both the WT and Omicron sub-lineages (BA.4/BA.5), have already been deployed worldwide and in Israel. In addition, newer monovalent vaccines specifically targeting XBB.1.5 and its recombinant sub-lineages have been approved in several countries, providing a promising avenue for improving immunity in the general population. However, vaccine uptake has declined in recent months due to factors such as pandemic fatigue, misinformation, and reduced risk perception. Incorporating COVID-19 vaccines into annual vaccination campaigns, alongside influenza vaccines, represents a strategic opportunity to maintain compliance and ensure sustained immunity across populations. The findings of this study reveal critical insights into population-level immunity in Israel against SARS-CoV-2 variants, specifically the wild type (WT) and XBB.1.9. The study highlights the significant immune evasion capabilities of XBB.1.9, characterized by reduced neutralization, as well as notable disparities in immunity across age groups and geographic regions, reflecting the interplay of vaccination coverage, sociodemographic factors, and healthcare access. These results carry important public health implications. First, addressing regional disparities in vaccine uptake and immunity through customized interventions, such as culturally sensitive education campaigns and improved healthcare accessibility in underserved areas, is essential to ensure equitable protection across populations. Additionally, integrating demographic and regional factors into surveillance systems and vaccination strategies can help optimize resource allocation and strengthen overall population immunity against future waves of SARS-CoV-2. While this study provides valuable insights into immunity prior to the widespread circulation of XBB.1.9, it has several limitations. First, the cross-sectional design does not allow assessment of immune waning over time. Secondly, the study did not include cellular immunity measurements or clinical correlates of protection, such as breakthrough infection or hospitalization data. In conclusion, the findings highlight significant gaps in population-level immunity to XBB.1.9 and underscore the importance of updated vaccines and personalized interventions to reduce vulnerabilities. By improving vaccination coverage, enhancing surveillance systems, and designing proactive strategies to address gaps in access to health services, the global health community can better prepare for the health impacts of evolving SARS-CoV-2 variants and strengthen resilience against future pandemics. Declarations Ethics approval and consent to participate : The study was approved by the Sheba Medical Center's institutional review board (SMC-9353-22). Consent for publication : All authors provided intellectual contribution and reviewed and approved the final draft of the manuscript. Availability of data and materials : Data will be made available upon reasonable request. Competing interests : The authors declare that they have no competing interests. Funding : The study did not received funding. Authors' contributions : YL and VI- Conceptualization and Design LK, RB and ET- Data Acquisition MJ, NZ and LK- Data analysis MM, LK and VI- Interpretation of data MM, YL, LKB, VI and RB- Review and Editing LK- Writing Acknowledgement : Rita Lokshin for her assistance in sample collection and separation in the Israel Center for Disease Control. References Zheng YX, Wang L, Kong WS, Chen H, Wang XN, Meng Q, Zhang HN, Guo SJ, Jiang HW, Tao SC. Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins. 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Effectiveness of COVID-19 booster vaccines against COVID-19-related symptoms, hospitalization and death in England. Nat Med. 2022;28:831–7. https://doi.org/10.1038/s41591-022-01699-1 . Burki TK. Fourth dose of COVID-19 vaccines in Israel. Lancet Respir Med. 2022;10:e19. https://doi.org/10.1016/S2213-2600(22)00010-8 . Uraki R, Ito M, Kiso M, Yamayoshi S, Iwatsuki-Horimoto K, Sakai-Tagawa Y, Imai M, Koga M, Yamamoto S, Adachi E et al. (2023). Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate. iScience 26 , 108147. https://doi.org/10.1016/j.isci.2023.108147 Lin D-Y, Du Y, Xu Y, Paritala S, Donahue M, Maloney P. Durability of XBB.1.5 Vaccines against Omicron Subvariants. N Engl J Med. 2024;390:2124–7. https://doi.org/10.1056/NEJMc2402779 . Valanparambil RM, Lai L, Johns MA, Davis-Gardner M, Linderman SL, McPherson TO, Chang A, Akhtar A, Gamarra ELB, Matia H, et al. BA.5 bivalent booster vaccination enhances neutralization of XBB.1.5, XBB.1.16 and XBB.1.9 variants in patients with lung cancer. NPJ Vaccines. 2023;8:179. https://doi.org/10.1038/s41541-023-00779-8 . Rosen B, Waitzberg R, Israeli A. Israel’s rapid rollout of vaccinations for COVID-19. Isr J Health Policy Res. 2021;10:6. https://doi.org/10.1186/s13584-021-00440-6 . Ministry of Health’s World of Data https://datadashboard.health.gov.il/portal/dashboard/corona Oda Y, Kumagai Y, Kanai M, Iwama Y, Okura I, Minamida T, Yagi Y, Kurosawa T, Greener B, Zhang Y, et al. Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet Infect Dis. 2024;24:351–60. https://doi.org/10.1016/S1473-3099(23)00650-3 . Saban M, Myers V, Ben-Shetrit S, Wilf-Miron R. Socioeconomic gradient in COVID-19 vaccination: evidence from Israel. Int J Equity Health. 2021;20:242. https://doi.org/10.1186/s12939-021-01566-4 . Shkalim Zemer V, Grossman Z, Cohen HA, Hoshen M, Gerstein M, Yosef N, Cohen M, Ashkenazi S. Acceptance Rates of COVID-19 Vaccine Highlight the Need for Targeted Public Health Interventions. Vaccines (Basel). 2022;10. https://doi.org/10.3390/vaccines10081167 . Waitzberg R, Davidovitch N, Leibner G, Penn N, Brammli-Greenberg S. Israel’s response to the COVID-19 pandemic: tailoring measures for vulnerable cultural minority populations. Int J Equity Health. 2020;19:71. https://doi.org/10.1186/s12939-020-01191-7 . Muhsen K, Green MS, Soskolne V, Neumark Y. Inequalities in non-communicable diseases between the major population groups in Israel: achievements and challenges. Lancet. 2017;389:2531–41. https://doi.org/10.1016/S0140-6736(17)30574-3 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7239482\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":502993756,\"identity\":\"b90adb6a-227c-4b65-8743-2c77acf8302c\",\"order_by\":0,\"name\":\"Limor Kliker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Limor\",\"middleName\":\"\",\"lastName\":\"Kliker\",\"suffix\":\"\"},{\"id\":502993757,\"identity\":\"dde64536-f047-4155-974a-5debe232bc60\",\"order_by\":1,\"name\":\"Michal Mandelboim\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Michal\",\"middleName\":\"\",\"lastName\":\"Mandelboim\",\"suffix\":\"\"},{\"id\":502993759,\"identity\":\"5ea50557-40f5-4e66-a2b1-0cab26fcaa1b\",\"order_by\":2,\"name\":\"Menucha Jurkowicz\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Menucha\",\"middleName\":\"\",\"lastName\":\"Jurkowicz\",\"suffix\":\"\"},{\"id\":502993761,\"identity\":\"1fad85f1-103f-4420-b313-1fb243ac7cb2\",\"order_by\":3,\"name\":\"Neta S. Zuckerman\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Neta\",\"middleName\":\"S.\",\"lastName\":\"Zuckerman\",\"suffix\":\"\"},{\"id\":502993762,\"identity\":\"569fa446-7c16-4d8e-ad91-0ddb6bfa6bcb\",\"order_by\":4,\"name\":\"Enosh Tomer\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Enosh\",\"middleName\":\"\",\"lastName\":\"Tomer\",\"suffix\":\"\"},{\"id\":502993764,\"identity\":\"440c5515-48c6-4400-8653-45ea9b67c0d3\",\"order_by\":5,\"name\":\"Yaniv Lustig\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yaniv\",\"middleName\":\"\",\"lastName\":\"Lustig\",\"suffix\":\"\"},{\"id\":502993766,\"identity\":\"41191b05-b61e-4eed-9c62-2f8faf2040ee\",\"order_by\":6,\"name\":\"Lital Keinan-Boker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The Israel Center for Disease Control, Ministry of Health\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Lital\",\"middleName\":\"\",\"lastName\":\"Keinan-Boker\",\"suffix\":\"\"},{\"id\":502993767,\"identity\":\"16d03e78-75f2-4b34-8750-596d655be606\",\"order_by\":7,\"name\":\"Victoria Indenbaum\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ministry of Health, Sheba Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Victoria\",\"middleName\":\"\",\"lastName\":\"Indenbaum\",\"suffix\":\"\"},{\"id\":502993768,\"identity\":\"f9442e41-d8d2-468c-97ec-085fb6ce641d\",\"order_by\":8,\"name\":\"Ravit Bassal\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The Israel Center for Disease Control, Ministry of Health\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ravit\",\"middleName\":\"\",\"lastName\":\"Bassal\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-07-29 06:08:18\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7239482/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7239482/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":89635513,\"identity\":\"e9669b3e-c20a-41f8-a9bc-9189d0eb2cb5\",\"added_by\":\"auto\",\"created_at\":\"2025-08-22 07:10:47\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":138219,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSARS-CoV-2 variant frequencies in Israel, March 2022 – December 2023\\u003c/strong\\u003e. Frequency of SARS-CoV-2 variants as detected by whole genome sequencing of SARS-CoV-2-positive samples.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7239482/v1/09e86554d7c6bccbdd5fad47.png\"},{\"id\":89635512,\"identity\":\"49b2155e-8e50-4128-9c1c-2c289de21e8b\",\"added_by\":\"auto\",\"created_at\":\"2025-08-22 07:10:47\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":43088,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eNeutralizing antibody titers against the SARS-CoV-2 wild-type (WT) and XBB.1.9 variants in the population in Israel.\\u003c/strong\\u003e\\u003cbr\\u003e\\nSerum samples were tested with neutralization against WT SARS-CoV-2 and XBB.1.9. Geometric mean titers (horizontal lines) with 95% confidence intervals (𝙸 bars) are presented, as well as the geometric mean titer value. Dots indicate individual serum samples. A significant reduction in immunity was observed against XBB.1.9. ****p ≥0.0001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7239482/v1/43a04b95bc34d0de9e484dc9.png\"},{\"id\":89635924,\"identity\":\"08995104-452f-4a84-8b73-e3bdf441bd80\",\"added_by\":\"auto\",\"created_at\":\"2025-08-22 07:18:47\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":253781,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eNeutralizing antibody titers against the SARS-CoV-2 wild-type (WT) and XBB.1.9 variants across selected population subgroups.\\u003c/strong\\u003e\\u003cbr\\u003e\\nGeometric mean titers (GMT) of neutralizing antibodies against SARS-CoV-2 WT and XBB.1.9 variants are shown by (A) age, (B) demographic, (C) gender, (D) socio-economic status and (E) nationality. Across all subgroups, neutralization titers were significantly lower for XBB.1.9 compared to WT (p\\u0026lt;0.0001). Significant differences in GMTs for the WT variant were observed between age groups (higher in adults ≥65 years), and across regions (notably lower in Jerusalem and Southern Israel compared to the North). No statistically significant differences in neutralization titers for the XBB.1.9 variant were observed between subgroups. Bars represent GMTs; error bars indicate 95% confidence intervals. *p≤0.05, **p≤0.01, ***p≤0.001 and ****p ≥0.0001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7239482/v1/15076ad4fd4e49faeec14abc.png\"},{\"id\":90243183,\"identity\":\"29812978-5e1d-47b4-82f0-8f5d649ca4fc\",\"added_by\":\"auto\",\"created_at\":\"2025-08-31 01:31:20\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1022085,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7239482/v1/83afd72b-e3df-4657-a231-dc00daadd501.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Immune Responses to SARS-CoV-2 Variants WT and XBB.1.9: Assessing Vulnerabilities and Preparedness\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to substantial global morbidity, mortality, and disturbance since its initial detection in December 2019 in Wuhan, China. The virus, which is highly transmissible among humans, causes respiratory illness with symptoms ranging from mild, such as fever, cough, and headache, to severe disease requiring hospitalization and leading to long-term complications or death\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR2\\\" citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e. In Israel, the first confirmed COVID-19 case was reported in February 2020\\u003csup\\u003e4\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eSince its emergence, SARS-CoV-2 has continuously evolved, giving rise to numerous variants with distinct genetic and phenotypic changes. The World Health Organization (WHO) classified several variants, such as Alpha, Beta, Delta, and Omicron, as Variants of Concern (VOCs), each contributing to distinct waves of infection globally and regionally. The XBB lineage, a recombinant subvariant of Omicron BA.2.75, was first identified globally in August 2022 and has since gained attention due to its increased transmissibility and potential for immune evasion\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u003c/sup\\u003e. In Israel, XBB variants began circulating toward the end of 2022, contributing to a surge in COVID-19 cases\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e. Among the XBB lineage, the XBB.1.9 subvariant has emerged as a recombinant variant of particular concern. First identified globally in late 2022, XBB.1.9 is characterized by extensive mutations in the spike protein, including changes in the receptor-binding domain (RBD) that enhance its ability to evade neutralizing antibodies\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e. These mutations contribute to increased transmissibility and immune escape capabilities, challenging existing immunity derived from prior infections or vaccination and raised concerns regarding the population's preparedness and highlighting the importance of updating vaccine strategies and public health measures.\\u003c/p\\u003e\\u003cp\\u003eDuring December 2020, the BioNTech-Pfizer vaccine was approved by the US Food and Drug Administration (FDA). This mRNA vaccine was developed against the spike protein of the WT virus. The vaccine was previously shown to have 95% efficacy against the WT and the Alpha variants\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e and had reduced effectiveness against the Delta variant\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e. Omicron sub-lineages were even less affected by the vaccine\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e. In order to improve the protection against circulating Omicron sub-lineages, bivalent COVID-19 booster vaccines were developed\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e. In September 2022, the FDA approved the BNT162b2 bivalent vaccine (Pfizer\\u0026ndash;BioNTech) targeting both WT and Omicron (BA.4/BA.5) variants\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e. Since, two additional updated vaccines were authorized - a monovalent mRNA vaccine targeting the SARS-CoV-2 Omicron XBB.1.5\\u003csup\\u003e13\\u003c/sup\\u003e and the monovalent mRNA vaccine targeting KP.2\\u003csup\\u003e14\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eIsrael was among the first countries to implement a national vaccination campaign, beginning in December 2020 with the Pfizer-BioNTech BNT162b2 mRNA vaccine. The campaign quickly expanded to include booster doses as new variants emerged\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eEmerging variants, such as those in the Omicron lineage, present new challenges due to increased transmissibility and immune evasion. Reduced neutralization has been observed in vaccinated or previously infected individuals\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e, although updated boosters, particularly bivalent formulations, provide some protection\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e. Assessing population-level immunity is critical for identifying high-risk groups, informing vaccine strategies, and optimizing public health measures.\\u003c/p\\u003e\\u003cp\\u003eThis study focuses on assessing population immunity in Israel prior to the wide circulation of the XBB.1.9 variant. By analyzing neutralizing antibody titers from serum samples collected prior to its emergence, we aim to evaluate the population\\u0026rsquo;s preparedness and susceptibility to current and future variants, including XBB.1.9 and its sub-lineages. Understanding population immunity levels provides valuable insights into the likely impact of emerging variants and informs proactive public health strategies.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStudy population and setting:\\u003c/h2\\u003e\\u003cp\\u003eThis cross-sectional study analyzed 1140 serum samples collected from all ages from diverse geographical regions within Israel during 1.8.22\\u0026ndash;31.1.23. The samples were collected from laboratories included in the Israel National Sera Bank (INSB) established in 1997 in the Israel Center for Disease Control. For each sample, the data recovered were age, gender, district of residence (North, Central, Jerusalem, South and Judea and Samaria), population group (Jews and others vs. Arabs) and residential socio-economic rank, based on city of residence. Local municipalities in Israel were ranked using an index ranging between 1 (lowest) and 10 (highest) published by the Central Bureau of Statistics, based on a range of variables\\u003csup\\u003e\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e. All samples were anonymized. Detailed sera collection and methods used for the INSB were previously described\\u003csup\\u003e\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eNeutralization assay:\\u003c/h3\\u003e\\n\\u003cp\\u003eA SARS-CoV-2 lentivirus-based neutralization assay was performed to assess the WT and XBB.1.9, neutralizing antibody levels measured in 50% inhibitory dilution (ID50). The neutralizing assay was performed as previously described\\u003csup\\u003e\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e, with minor modifications. Lentiviral particles were produced by co-transfecting HEK293T/17 cells with an expression vector encoding variant specific SARS-CoV-2 spike alongside packaging vector pCMVDR8.2, luciferase reporter vector pHR\\u0026prime;CMV-Luc and a TMPRSS2 expression vector (as part of a partnership with Dr. Daniel Douek, Vaccine Research Institute (VRC), National Institute of Health (NIH). MD, USA). Supernatant was collected from cells 48-hour post transfection and used for subsequent neutralization. Transfection was done using Lipofectamine 3000 (Thermo Scientific, cat# L3000001) as specified by the manufacture. For neutralization, serum samples were heat inactivated in 56\\u0026deg;C for 30 minutes. Serum samples were 2-fold diluted in a 96-well plate in dilution medium (MEM 5% FBS), overlaid with pseud-typed Lentivirus solution and incubated in 37\\u0026deg;C for one hour. Pseudovirus-serum complexes were then overlaid with HEK293 TMPRSS2-ACE2 cells suspended in dilution medium. Cells were incubated in 37\\u0026deg;C for 72 hours. Following incubation, luminescence was quantified by lysing the cells with tissue culture lysis reagent (Promega, cat# E1531) and adding luciferase assay substrate (Promega, cat# E1501). Luminescence was read using a Varioskan LUX Multimode Microplate Reader (Thermo Scientific).\\u003c/p\\u003e\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStatistical analysis:\\u003c/h2\\u003e\\u003cp\\u003eGeometric Mean Titers (GMT) with confidence interval (CI) of 95% were calculated using GraphPad Prism 10.2.2 (GraphPad Software, Inc., San Diego, CA). Neutralization titers were assessed using the Mann-Whitney test between the following groups: participant ages 30\\u0026ndash;40 years and \\u0026ge;\\u0026thinsp;65, gender, nationality, socioeconomic status and SARS-CoV-2 variant. Neutralization titers between different geographic locations were assessed using the Kruskal-Wallis test.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eTo evaluate population-level immunity and preparedness for the emerging SARS-CoV-2 XBB.1.9 variant, we monitored the prevalence of SARS-CoV-2 variants in Israel and analyzed neutralizing antibody titers from 1140 serum samples collected prior to the widespread circulation of XBB.1.9.\\u003c/p\\u003e\\u003cp\\u003eThe frequency of SARS-CoV-2 variants in Israel was monitored via whole-genome sequencing of positive samples (Israel national consortium for SARS-CoV-2 sequencing, Ministry of Health). Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e presents the monthly distribution of variant prevalence from March 2022 to December 2023. In early 2022, BA.1 and BA.2 were the most prevalent, followed by BA.5, which dominated from mid-2022 to November 2023. Subsequently, BQ and BA.4 gained prominence in early 2023. The XBB lineage, including XBB, XBB.1.5, and especially XBB.1.9, emerged in 2023 and gradually increased in prevalence, dominating Israel's variant endemicity with 93% between February and July of 2023. XBB.1.9 (in red) appeared between February and July 2023. Since April 2023, the detection rate of XBB.1.9 increased, rising from 24% of all sequenced samples in April to 46% in July. Towards the end of 2023, further variation of circulating variants was observed, with a decrease in the prevalence of XBB.1.9 as other lineages emerged.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eNext, we evaluated neutralizing antibody titers against WT and XBB.1.9. Serum samples were collected between August 1, 2022 and January 31, 2023, from a cohort of 1140 participants representing the general population. Socio-demographic characteristics of the participants is presented in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\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\\u003e\\u003cb\\u003eDemographics and characteristics of the participants.\\u003c/b\\u003e P-value was calculated between the variants WT and XBB.1.9 of each group. GMT\\u0026thinsp;=\\u0026thinsp;geometric mean titer.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"7\\\"\\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=\\\"char\\\" char=\\\".\\\" 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\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eGroup\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eNumber of participants\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e% of total participants\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eGMT (WT)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eGMT (XBB.1.9)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eTotal participants\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1140\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e100\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1057\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e36.97\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003eGender\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eMale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e529\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e46.40\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1251\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e42.58\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eFemale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e611\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e53.60\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1121\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e39.12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003eAge group\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eAge 30\\u0026ndash;39\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e385\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e33.77\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1043\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e35.01\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eAge 65+\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e755\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e66.23\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1257\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e43.92\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003eSocioeconomic status\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eLow SES\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e782\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e68.60\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1196\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e40.87\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eHigh SES\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e189\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e16.58\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1483\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e41.37\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003ePopulation group\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eJews and others\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e855\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e75.00\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1245\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e42.09\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eArabs\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e514\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e45.09\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1034\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e36.66\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"4\\\" rowspan=\\\"5\\\"\\u003e\\u003cp\\u003eDistrict\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eJerusalem\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e184\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e16.14\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1075\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e32.12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eNorth\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e372\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e32.63\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1590\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e39.87\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eCentral\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e181\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e15.88\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1203\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e53.25\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSouth\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e352\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e30.88\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e911.7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e42.32\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eJudea\\u0026amp;Samaria\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e46\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e4.04\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1191\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e35.03\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u0026gt;\\u0026thinsp;0.0001\\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\\u003eWhen comparing neutralizing antibody titers for SARS-CoV-2 WT and XBB.1.9 variants (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e), a statistically significant difference was observed (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001). Antibody levels of WT (geometric mean titer (GMT)\\u0026thinsp;=\\u0026thinsp;1180; 95% CI: 1057\\u0026ndash;1317) were markedly lower against XBB.1.9 (GMT\\u0026thinsp;=\\u0026thinsp;40.69; 95% CI: 36.97\\u0026ndash;44.77).\\u003c/p\\u003e\\u003cp\\u003eA significant difference in neutralizing antibody titers was observed between age groups when assessing immunity to the WT SARS-CoV-2 variant (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eA), with older individuals (65+) showing higher mean titers compared to younger group (age 30\\u0026ndash;39), GMT 1257 (CI: 1093\\u0026ndash;1444) and 1043 (CI: 871.3\\u0026ndash;1248) respectively (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0023). However, no significant differences were detected between age groups when assessing titers against XBB.1.9 (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05).\\u003c/p\\u003e\\u003cp\\u003eRegion analysis, (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eB), revealed further disparities in responses to the WT variant. Participants from the Northern district exhibited the highest GMT (1590, CI: 1321\\u0026ndash;1912) against the WT variant, followed by participants from the Central region (1203, CI: 922\\u0026ndash;1569) and Judea and Samaria (1191, CI: 734.4\\u0026ndash;1930). Lower GMTs were observed among participants from Jerusalem (1075, (CI: 825\\u0026ndash;1400) and the Southern district (911.7, CI: 735.4\\u0026ndash;1130), with statistically significant differences found between the North and South (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.00014) and between the North and Jerusalem (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0212). No significant differences were detected between other regional pairings. In contrast, when evaluating neutralizing antibody titers against XBB.1.9, GMTs were relatively consistent across regions, ranging between 32.12 in Jerusalem and 53.25 in the Central district, with no statistically significant differences observed (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05).\\u003c/p\\u003e\\u003cp\\u003eAcross other demographic factors, including gender, socioeconomic status and nationality (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eC, D, E), no significant differences in neutralizing antibody responses were detected for either the WT or XBB.1.9 variant (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05 for all comparisons).\\u003c/p\\u003e\\u003cp\\u003eHowever, when comparing GMTs between WT and XBB.1.9 within each individual subgroup (e.g., within each age, gender, region, and socioeconomic group), a statistically significant reduction in neutralizing antibody titers was observed (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001 for all comparisons). This consistent intra-group reduction indicates that the XBB.1.9 variant elicited markedly lower neutralization responses relative to the WT variant across all population segments.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eSerum samples were tested with neutralization against WT SARS-CoV-2 and XBB.1.9. Geometric mean titers (horizontal lines) with 95% confidence intervals (\\u0026#120440; bars) are presented, as well as the geometric mean titer value. Dots indicate individual serum samples. A significant reduction in immunity was observed against XBB.1.9. ****p\\u0026thinsp;\\u0026ge;\\u0026thinsp;0.0001.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eGeometric mean titers (GMT) of neutralizing antibodies against SARS-CoV-2 WT and XBB.1.9 variants are shown by (A) age, (B) demographic, (C) gender, (D) socio-economic status and (E) nationality. Across all subgroups, neutralization titers were significantly lower for XBB.1.9 compared to WT (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001). Significant differences in GMTs for the WT variant were observed between age groups (higher in adults\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years), and across regions (notably lower in Jerusalem and Southern Israel compared to the North). No statistically significant differences in neutralization titers for the XBB.1.9 variant were observed between subgroups. Bars represent GMTs; error bars indicate 95% confidence intervals. *p\\u0026thinsp;\\u0026le;\\u0026thinsp;0.05, **p\\u0026thinsp;\\u0026le;\\u0026thinsp;0.01, ***p\\u0026thinsp;\\u0026le;\\u0026thinsp;0.001 and ****p\\u0026thinsp;\\u0026ge;\\u0026thinsp;0.0001.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThe SARS-CoV-2 XBB variant was first isolated in 2022. The spike (S) protein of the XBB variant contains 14 mutations additionally to those found in the BA.2 lineage, including nine located specifically within the receptor-binding domain (RBD). The XBB.1 sub-lineage carries an extra mutation at position G252V compared to the original XBB variant\\u003csup\\u003e\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e. XBB.1.9.1 possess amino acid substitutions in virus proteins that may affect infectivity, viral replication, transmissibility and/or pathogenicity\\u003csup\\u003e\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eIsrael\\u0026rsquo;s COVID-19 vaccination program has been recognized worldwide for its effectiveness and rapid implementation. The campaign, launched in December 2020, demonstrated the benefits of prioritizing high-risk groups such as healthcare workers and older adults, while utilizing digital infrastructure to monitor vaccine distribution and immune responses efficiently\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e. Booster doses were introduced immediately to address waning immunity and emerging variants, with high compliance significantly reducing morbidity during waves driven by Alpha, Delta, and early Omicron sub-lineages\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eThis study aimed to assess antibody responses in the Israeli population prior to the widespread circulation of XBB.1.9, providing a valuable baseline for understanding the population\\u0026rsquo;s preparedness for emerging variants. We evaluated neutralization antibody titers against SARS-CoV-2 variants, WT and XBB.1.9 in the Israeli population focusing on age-related variations, regional differences and demographic disparities. According to our findings, neutralizing antibody titers against XBB.1.9 were significantly lower compared to those against the WT variant. This result is consistent with the enhanced immune escape properties of XBB lineages reported globally. Mutations in the spike protein of XBB.1.9 compromise antibody binding and recognition, reducing its susceptibility to immunity derived from prior infection or vaccination\\u003csup\\u003e\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e, even among populations who received updated bivalent vaccine formulations designed to target the WT and initial Omicron sub-lineages\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eAge-related differences in immunity were observed for the WT variant, with older adults (65+) demonstrating higher neutralizing antibody titers compared to younger individuals (30\\u0026ndash;39). No significant differences were detected for the XBB.1.9 variant. This is likely attributable to greater uptake of booster doses in the older population, as earlier vaccination campaigns in Israel prioritized older individuals early in the pandemic\\u003csup\\u003e\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u003c/sup\\u003e. Booster doses have been shown to amplify antibody responses and extend the duration of protection\\u003csup\\u003e\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e, which contributed to the stronger immunity observed against the WT variant in this age group. However, the lack of significant differences in antibody titers for XBB.1.9 suggests that immune escape mechanisms of this variant effectively reduced the benefits associated with higher vaccine uptake in older populations.\\u003c/p\\u003e\\u003cp\\u003eRegional differences were also observed in this study, particularly in immunity to the WT variant. Individuals from Jerusalem and Southern Israel exhibited significantly lower neutralizing antibody titers against the WT compared to those from Northern Israel. These differences likely reflect disparities in vaccine acceptance rates differences in public health outreach\\u003csup\\u003e\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e\\u003c/sup\\u003e. Regions such as Jerusalem, which have higher concentrations of ultra-Orthodox Jewish and Arab populations, often face barriers to vaccination rooted in cultural beliefs, socioeconomic factors, and misinformation\\u003csup\\u003e\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e,\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e\\u003c/sup\\u003e. Similarly, Southern Israel, characterized by geographically dispersed rural communities and larger Bedouin populations, faces systemic inequities in healthcare infrastructure that hinder vaccination coverage\\u003csup\\u003e\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e. These findings further emphasize the importance of targeted vaccination campaigns and outreach programs tailored to culturally diverse and disadvantaged populations.\\u003c/p\\u003e\\u003cp\\u003eIn contrast, no significant regional differences were observed for neutralizing antibody titers against XBB.1.9 variant, suggesting that the ability of XBB.1.9 to evade the immune system is consistent across populations, regardless of differences in vaccination rates or access to healthcare. Additionally, neutralization levels against XBB.1.9 were consistently lower in all subgroups compared to the WT variant, highlighting an underlying vulnerability across the population.\\u003c/p\\u003e\\u003cp\\u003eToday, the COVID-19 vaccine landscape continues to evolve in response to the challenges posed by emerging variants such as XBB.1.9. Updated vaccine formulations, including bivalent vaccines targeting both the WT and Omicron sub-lineages (BA.4/BA.5), have already been deployed worldwide and in Israel. In addition, newer monovalent vaccines specifically targeting XBB.1.5 and its recombinant sub-lineages have been approved in several countries, providing a promising avenue for improving immunity in the general population. However, vaccine uptake has declined in recent months due to factors such as pandemic fatigue, misinformation, and reduced risk perception. Incorporating COVID-19 vaccines into annual vaccination campaigns, alongside influenza vaccines, represents a strategic opportunity to maintain compliance and ensure sustained immunity across populations.\\u003c/p\\u003e\\u003cp\\u003eThe findings of this study reveal critical insights into population-level immunity in Israel against SARS-CoV-2 variants, specifically the wild type (WT) and XBB.1.9. The study highlights the significant immune evasion capabilities of XBB.1.9, characterized by reduced neutralization, as well as notable disparities in immunity across age groups and geographic regions, reflecting the interplay of vaccination coverage, sociodemographic factors, and healthcare access. These results carry important public health implications. First, addressing regional disparities in vaccine uptake and immunity through customized interventions, such as culturally sensitive education campaigns and improved healthcare accessibility in underserved areas, is essential to ensure equitable protection across populations. Additionally, integrating demographic and regional factors into surveillance systems and vaccination strategies can help optimize resource allocation and strengthen overall population immunity against future waves of SARS-CoV-2.\\u003c/p\\u003e\\u003cp\\u003eWhile this study provides valuable insights into immunity prior to the widespread circulation of XBB.1.9, it has several limitations. First, the cross-sectional design does not allow assessment of immune waning over time. Secondly, the study did not include cellular immunity measurements or clinical correlates of protection, such as breakthrough infection or hospitalization data.\\u003c/p\\u003e\\u003cp\\u003eIn conclusion, the findings highlight significant gaps in population-level immunity to XBB.1.9 and underscore the importance of updated vaccines and personalized interventions to reduce vulnerabilities. By improving vaccination coverage, enhancing surveillance systems, and designing proactive strategies to address gaps in access to health services, the global health community can better prepare for the health impacts of evolving SARS-CoV-2 variants and strengthen resilience against future pandemics.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cu\\u003eEthics approval and consent to participate\\u003c/u\\u003e: The study was approved by the Sheba Medical Center's institutional review board (SMC-9353-22).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eConsent for publication\\u003c/u\\u003e: All authors provided intellectual contribution and reviewed and approved the final draft of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAvailability of data and materials\\u003c/u\\u003e: Data will be made available upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eCompeting interests\\u003c/u\\u003e: The authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eFunding\\u003c/u\\u003e: The study did not received funding.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAuthors' contributions\\u003c/u\\u003e:\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eYL and VI- Conceptualization and Design\\u003c/p\\u003e\\n\\u003cp\\u003eLK, RB and ET- Data Acquisition\\u003c/p\\u003e\\n\\u003cp\\u003eMJ, NZ and LK- Data analysis\\u003c/p\\u003e\\n\\u003cp\\u003eMM, LK and VI- Interpretation of data\\u003c/p\\u003e\\n\\u003cp\\u003eMM, YL, LKB, VI and RB- Review and Editing\\u003c/p\\u003e\\n\\u003cp\\u003eLK- Writing\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cu\\u003eAcknowledgement\\u003c/u\\u003e: Rita Lokshin for her assistance in sample collection and separation in the Israel Center for Disease Control.\\u003cbr\\u003e\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eZheng YX, Wang L, Kong WS, Chen H, Wang XN, Meng Q, Zhang HN, Guo SJ, Jiang HW, Tao SC. 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Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate. iScience \\u003cem\\u003e26\\u003c/em\\u003e, 108147. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/j.isci.2023.108147\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.isci.2023.108147\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLin D-Y, Du Y, Xu Y, Paritala S, Donahue M, Maloney P. Durability of XBB.1.5 Vaccines against Omicron Subvariants. N Engl J Med. 2024;390:2124\\u0026ndash;7. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1056/NEJMc2402779\\u003c/span\\u003e\\u003cspan address=\\\"10.1056/NEJMc2402779\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eValanparambil RM, Lai L, Johns MA, Davis-Gardner M, Linderman SL, McPherson TO, Chang A, Akhtar A, Gamarra ELB, Matia H, et al. BA.5 bivalent booster vaccination enhances neutralization of XBB.1.5, XBB.1.16 and XBB.1.9 variants in patients with lung cancer. 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Int J Equity Health. 2021;20:242. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1186/s12939-021-01566-4\\u003c/span\\u003e\\u003cspan address=\\\"10.1186/s12939-021-01566-4\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eShkalim Zemer V, Grossman Z, Cohen HA, Hoshen M, Gerstein M, Yosef N, Cohen M, Ashkenazi S. Acceptance Rates of COVID-19 Vaccine Highlight the Need for Targeted Public Health Interventions. 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Int J Equity Health. 2020;19:71. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1186/s12939-020-01191-7\\u003c/span\\u003e\\u003cspan address=\\\"10.1186/s12939-020-01191-7\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMuhsen K, Green MS, Soskolne V, Neumark Y. Inequalities in non-communicable diseases between the major population groups in Israel: achievements and challenges. Lancet. 2017;389:2531\\u0026ndash;41. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/S0140-6736(17)30574-3\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/S0140-6736(17)30574-3\\\" 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\":\"info@researchsquare.com\",\"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\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7239482/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7239482/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eThe emergence of SARS-CoV-2 variants with enhanced immune evasion capabilities continues to challenge efforts to sustain population-level immunity. Among these, the XBB lineage, particularly the XBB.1.9 sub-variant, has garnered attention due to extensive spike protein mutations that reduce recognition by neutralizing antibodies. In this study, we evaluated neutralizing antibody titers against both the SARS-CoV-2 wild-type (WT) strain and the XBB.1.9 variant using serum samples collected from the Israeli population between August 2022 and January 2023, prior to widespread XBB.1.9 circulation.\\u003c/p\\u003e\\u003cp\\u003eOur analysis revealed significantly reduced neutralizing titers against XBB.1.9 compared to WT across all demographic groups (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001), underscoring its pronounced immune escape potential. For the WT strain, older individuals (\\u0026ge;\\u0026thinsp;65 years) exhibited higher titers (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0023), likely reflecting increased vaccine and booster uptake; however, this age-related difference was not observed for XBB.1.9 (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05), indicating diminished protection across age groups. Regional disparities in WT titers, higher in Northern Israel than in Jerusalem and Southern regions, suggest differential vaccine access and healthcare infrastructure, yet no such variation was seen for XBB.1.9.\\u003c/p\\u003e\\u003cp\\u003eThese findings highlight critical gaps in immunity against XBB.1.9, especially in populations historically underserved by vaccination efforts. The results underscore the urgent need for updated vaccines tailored to immune-evasive variants and for culturally sensitive outreach strategies to improve vaccine equity. Further studies should evaluate the efficacy of XBB-specific vaccines and the durability of immune protection to inform long-term strategies for SARS-CoV-2 control.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Immune Responses to SARS-CoV-2 Variants WT and XBB.1.9: Assessing Vulnerabilities and Preparedness\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-08-22 07:10:43\",\"doi\":\"10.21203/rs.3.rs-7239482/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"522cb3f0-9899-43c7-a0d2-80cbd23adfbb\",\"owner\":[],\"postedDate\":\"August 22nd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-08-31T01:23:10+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-08-22 07:10:43\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7239482\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7239482\",\"identity\":\"rs-7239482\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}