Comparative Analysis of Adverse Event Rates and Severity Following COVID-19 mRNA Vaccinations Among SARS-CoV-2 Naïve Nursing Home Residents and Staff

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Ninety-five SARS-CoV-2 naïve participants, consisting of 26 staff (median age, 51 years) and 69 residents (median age, 88 years), were evaluated for the rate and severity of local and systemic AEs. The severity of AEs was evaluated using grading scale for each sign or symptom, and expressed as the AE score. The rates of most AEs were considerably lower in the residents after the first to the fifth dose of the mRNA vaccination, compared to the staff. The severity of AEs using AE scores were also considerably lower in the residents after the first to the fifth dose of vaccination, compared to the staff. No clear relationship was detected between receptor-binding domain IgG or neutralizing titer levels and the cumulative AE score either in staff or residents after the second, third, or fifth dose of the mRNA vaccination, although there were two exceptions. Our conclusion of lower event occurrence and milder side effects strongly corroborates the science-driven proposal of COVID-19 mRNA vaccinations for older generations in high-risk care facilities. Biological sciences/Microbiology Health sciences/Health care Health sciences/Medical research COVID-19 SARS-CoV-2 Omicron variants mRNA vaccine nursing home residents neutralizing antibodies adverse events Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Numerous clusters of coronavirus disease 2019 (COVID-19) have been documented in nursing homes during the early phase of the pandemic 1 – 3 . Given the high case fatality rates among COVID-19 patients in these facilities 3 , 4 , residents are particularly vulnerable to SARS-CoV-2. A prior report on long-term care facilities underscored the importance of preventing COVID-19 outbreaks in such settings 5 . Vaccination against SARS-CoV-2 represents a pivotal strategy in controlling the COVID-19 pandemic. COVID-19 vaccines stimulate the production of neutralizing antibodies to SARS-CoV-2 in adult individuals, albeit with a relatively high incidence of nonserious adverse events (AEs) 6 – 8 . However, the estimation of the magnitude and durability of protection through COVID-19 vaccination has become a challenge because of the emergence of the omicron variants which altered virus characteristics, such as transmissibility and antigenicity, evolving in response to herd immunity 9 . A recent study reported that frequent COVID-19 booster vaccination in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19 by analyzing COVID-19 surveillance and seroprevalence data 10 . Seven studies have investigated immune responses, including immunogenicity and reactogenicity, in healthcare workers following two doses of COVID-19 mRNA vaccination 11 – 17 . While six of these studies delineated varying degrees of correlation between humoral immune responses and AEs subsequent to COVID-19 mRNA vaccination 11 – 16 , one study did not, owing to its relatively small sample size 17 . Takano et al. identified correlations between cellular populations, such as the dynamics of NKT-like cells, CD11c − Axl + Siglec-6 + -DCs, and DC3s, and systemic adverse events post two doses of COVID-19 mRNA vaccination 11 . We and other investigators have previously observed a substantial increase in anti-RBD IgG levels and neutralizing titers (NTs) of Omicron subvariants following booster doses of monovalent (Wuhan) COVID-19 mRNA vaccination among nursing home residents 18 – 20 . Although a prior study indicated that the primary vaccination series with COVID-19 mRNA elicited robust antibody responses and mostly mild AEs in nursing home residents 21 , the relationship between AE incidence and immune responses subsequent to COVID-19 mRNA vaccination remains incompletely explored in this demographic. Here, we report a distinct difference in AEs between staff and residents, alongside a lack of correlation between immune responses and AEs after booster doses of COVID-19 mRNA vaccine in a Japanese nursing home cohort. Results Genomic Epidemiology of SARS-CoV-2 In Toyama Prefecture, the COVID-19 epidemic caused by the Omicron variant, specifically the BA.5 subvariant, surfaced between August 2022 and July 2023. Additionally, the XBB subvariant emerged during April to October 2023 (Fig. 1 ). Anti-RBD IgG and NT after Fifth Dose in SARS-CoV-2 naïve and BTI Participants The mean anti-RBD IgG titers in serum samples from 22 SARS-CoV-2 naïve participants who received the bivalent BA.1-adapted vaccine and 73 SARS-CoV-2 naïve participants who received the bivalent BA.4/BA.5-adapted vaccine were 2.7 × 10 4 U/mL and 3.3 × 10 4 U/mL, respectively, two months after the fifth dose (Fig. 2 A). Geometric mean NTs against Wuhan, BA.5, and XBB.1.5 were 48.4, 13.2, and 1.5 in 22 SARS-CoV-2 naïve participants who received the bivalent BA.1-adapted vaccine, and 62.5, 63.5, and 1.3 in 73 SARS-CoV-2 naïve participants who received the bivalent BA.4/BA.5-adapted vaccine two months after the fifth dose (Fig. 2 B). Notably, NTs against XBB were significantly lower than those against BA.4/BA.5 (p < 0.001). The mean anti-RBD IgG titers in serum samples from 8 participants with BTI during the BA.5 endemic period who received either the bivalent BA.1-adapted vaccine or the bivalent BA.4/BA.5-adapted vaccine were 3.9 × 10 4 U/mL and 4.3 × 10 4 U/mL, respectively, two months after the fifth dose (Fig. 2 C). Geometric mean NTs against Wuhan, BA.5, and XBB.1.5 in these participants were 41.5, 45.0, and 2.9, and 54.6, 214.1, and 3.7, respectively, two months after the fifth dose (Fig. 2 D). Notably, NTs against XBB.1.5 in participants with BTI during the BA.5 endemic period were significantly lower than those against BA.5 (p < 0.01). The mean of anti-RBD IgG and NTs against Wuhan and BA.5 in these SARS-CoV-2 naïve participants were at equivalent levels to those observed two months after the third dose 18 . Similarly, the mean of anti-RBD IgG and NTs against Wuhan and BA.5 in participants with BTI during the BA.5 endemic period were at equivalent levels to those observed two months after the third dose. AEs Following Vaccination The rates of most AEs were significantly lower among residents compared to staff members after the first through fifth doses (p < 0.05) (Figs. 3 A, 3 B, and 3 C). Significant differences were observed in AE rates between the two groups. Severe AEs, including local redness (4.5%), local swelling (4.8%), and fever (8.3%), occurred exclusively in staff members following the third dose (Fig. 3 A). Residents commonly experienced fever after the fourth (16.1%) and fifth doses (13.2%) of the vaccine. Rates of local redness, fever, fatigue, and headache significantly varied across different doses in staff members. Similarly, the rate of fever differed significantly among various doses in residents. Next, we compared AE scores to assess severity between staff and residents. AE scores for local pain, local swelling, fatigue, headache, muscle pain, and joint pain were significantly lower in residents compared to staff members after the first through the fifth doses (Figs. 3 D, 3 E, and 3 F). In staff members, AE scores for local redness, fever, fatigue, headache, and chills significantly differed among various doses. We also evaluated AE rates in SARS-CoV-2 naïve participants after the third to the fifth doses of the vaccines from two different manufacturers (Pfizer/BioNTech and Moderna) 22 – 24 (Supplementary Fig. 1). Except for fatigue and headache after the fourth dose of vaccination, no significant difference was found in AE rates after the third, fourth, and fifth doses of vaccination. Furthermore, we compared the cumulative AE score in SARS-CoV-2 naïve staff and residents after receiving the third, fourth, and fifth doses from two different manufacturers (Supplementary Fig. 2). No significant difference was observed in the total AE score after each dose of the vaccintion from two manufacturers in both staff and residents. Furthermore, we examined the correlations between anti-RBD IgG titers or NTs and the cumulative AE score in SARS-CoV-2 naïve participants who received five doses of vaccination (Fig. 4 ). No significant correlation was found between NTs and the cumulative AE score after the second, third, and fifth doses in both staff (N = 26) and residents (N = 69), although a weak correlation was observed between anti-RBD-IgG and the cumulative AE score two months after the third dose in residents (Fig. 4 B, p = 0.047) and between NTs against BA.5 and the total AE score two months after the fifth dose in staff (Fig. 4 I, p = 0.042). Additionally, we examined the correlations between age and the cumulative AE score after the first, second, third, fourth, and fifth doses of the vaccination (Supplementary Fig. 3). No significant correlation was observed between age and the cumulative AE score after each vaccination in both staff and residents, except for a significant correlation in staff between age and the cumulative AE score after the first dose (p < 0.001). Discussion In our study, data analysis revealed that the rate and severity of most AEs were significantly lower among residents compared to staff following the administration of the first through fifth doses of COVID-19 mRNA vaccination, with some exceptions observed across nursing homes. To our knowledge, this is the first study to demonstrate a noticeable disparity in the rate and severity of AEs post COVID-19 mRNA vaccination between nursing home residents and staff. Previously, we reported increased levels of anti-RBD IgG and NTs against the Wuhan, Alpha, Delta, and Omicron subvariants in SARS-CoV-2-naïve participants aged ≥ 80 years, two months after the third dose of COVID-19 vaccination 18 . Our findings also indicate that NTs against Omicron subvariants BA.1 and BA.5 increased two months after the third dose compared to five months after the second dose in SARS-CoV-2 naïve residents aged ≥ 80 years, given that most residents in this study were aged ≥ 80 years. Taken together with these observations, our data suggest that booster doses of the COVID-19 mRNA vaccination are beneficial not only in terms of reactogenicity but also immunogenicity for SARS-CoV-2 naïve residents. In addition to immunogenicity, a recent study reported the effectiveness of a booster dose of COVID-19 mRNA vaccination in two distinct nursing home cohorts in the United States 25 . The authors demonstrated that booster vaccination reduced SARS-CoV-2 infection by 37.7–57.7%, hospital admissions by 64.1–74.4%, and SARS-CoV-2-associated deaths by 46.6–87.9%, respectively. Following the introduction of a bivalent mRNA vaccine, a retrospective, population-based cohort study in Israel indicated that the effectiveness of a bivalent BA.4/BA.5 mRNA vaccine booster dose among adults aged ≥ 65 years was 72% (95% CI; 60–81) for hospitalizations due to COVID-19 and 68% (95% CI; 42–82%) for COVID-19-related deaths 26 . Conversely, a recent study from the National Health Care Safety Network nursing homes, where most study participants received a bivalent vaccine, reported vaccine effectiveness against infection at 31.2% 27 . Taken together, these data support the notion that booster doses of monovalent or bivalent COVID-19 mRNA vaccineation are less protective against infection but effective in preventing severe diseases and are less reactogenic among nursing home residents. Levy et al. identified a significant correlation between systemic adverse drug reaction scores and anti-RBD IgG titers, adjusted for age, gender, and days post-second vaccination, and a weaker correlation with neutralizing antibodies in 738 SARS-CoV-2 naïve HCWs with a mean age (SD) of 46.5 (11.8) years 14 . Similarly, the other five studies also reported varying degrees of correlation between the humoral immune response and AEs among HCWs following two doses of the COVID-19 vaccination 11 – 13 , 15 , 16 . In contrast, our study found no significant correlation between anti-RBD IgG or neutralizing titers and the cumulative AE score after the second, third, and fifth doses of the mRNA vaccination among nursing home residents, although there two exceptions observed in residents after the third dose and in staff after the fifth dose. The discrepancy between our findings and those of the previous six studies may be explained by the factor of aging, which attenuated the immune response after the booster dose of COVID-19 mRNA vaccination in nursing home residents 11 – 15 , 18 . The median age (range) of SARS-CoV-2 naïve residents in our study was 88 years (82–92 years), considerably higher than that of the HCW study participants in the six previous studies 11 – 15 . Other factors contributing to this discrepancy may include the relatively small sample size of our study. In this study, the mean anti-RBD IgG titers and geometric NTs against both Wuhan and BA.5, following the fifth dose of a bivalent BA.1 or BA.4/BA.5 vaccine, were comparable to those observed two months after the third dose among both SARS-CoV-2 naïve participants and those with BTI during the BA.5 period. Consistently, significantly lower NTs against XBB were noted compared to those against BA.5 in SARS-CoV-2 naïve participants and individuals with BTI during the BA.5 period, aligning with prior studies 28 , 29 . One strength of our study is the ability to compare the incidence and severity of AEs following COVID-19 mRNA vaccinations between SARS-CoV-2 naïve staff and residents within a Japanese nursing home cohort. However, several limitations exist. Firstly, the relatively small sample size of staff may have limited our ability to establish correlations between AE scores and anti-RBD IgG or NTs. Secondly, there could be a blurring of the assessment by the observer since AE information was collected by nursing home staff from nursing home residents according to the questionnaire. Lastly, we were unable to collect blood samples to determine antibody responses after the fourth dose of COVID-19 mRNA vaccination. In conclusion, we observed a notably lower rate and severity of most AEs among SARS-CoV-2 naïve residents compared to staff members following the administration of the first through fifth doses of COVID-19 mRNA vaccination in nursing homes in this study. No significant correlation was found between anti-RBD IgG or NTs and the cumulative AE score after the second, third, and fifth doses of mRNA vaccination. Although the vaccination rates of the first to the third dose of COVID-19 mRNA vaccination were higher than 90% in older adults in Japan, the vaccination rate of the Omicron XBB.1.5 mRNA vaccine 30 was reported to be relatively low (~ 53.5%) in older adults at the end of March 2024 31 . Because this vaccine was reported to be associated with 76.1% reduced risk of COVID-19 hospitalization among people older than 65 years 32 , the vaccination rates of the variant-targeted COVID-19 mRNA vaccines should be increased to lower the burden of severe COVID-19 in older adults. Our findings, highlighting the reduced incidence and severity of AEs among SARS-CoV-2 naïve nursing home residents post COVID-19 mRNA vaccination, strongly advocate for the recommendation of this vaccine for such high-risk populations. Methods Study Participants This study commenced in May 2021 across six nursing homes in Toyama Prefecture, Japan 18 . By May 2023, a total of 78 residents and 33 staff had enrolled. Among them 95 individuals were SARS-CoV-2 naïve, while 16 had experienced breakthrough infections (BTI) during the BA.5 endemic period, spanning from June 2022 to February 2023 (Table). The definition of a BTI case was as previously outlined 18 . All participants received an primary series of two doses of the COVID-19 mRNA vaccine, BNT162b2 (Pfizer/BioNTech, 30 µg per dose), targeting the Wuhan strain, administered between April and June 2021. Subsequently, for the third dose, 32 participants received the BNT162b2, while 79 received mRNA-1273 vaccine (Moderna, 50 µg per dose), between January and March 2022. For the fourth dose, 11 participants received the BNT162b2 vaccine, and 100 received mRNA-1273 vaccine between July 2022 and September 2022. Regarding the fifth dose, 30 participants received the bivalent BA.1-adapted BNT162b2 mRNA vaccine 22 , and 81 received either the bivalent BA.4/BA.5-adapted BNT162b2 mRNA vaccine 23 or the bivalent mRNA-1273.222 vaccine 24 between November 2022 and February 2023. The bivalent vaccines included an ancestral SARS-CoV-2 strain component along with a component from either BA.1 subvariant or BA.4/BA.5 subvariant. The safety profiles of these bivalent vaccines were comparable to those of monovalent vaccines (BNT162b2 or mRNA-1273) 22 – 24 . Blood samples were collected in May to June 2021 prior to the first COVID-19 vaccination, and then at two and five months following the primary series vaccination (August to September 2021 and November to December 2021, respectively). Subsequent blood sampling occurred two and five months after the third dose of booster vaccination (March to June 2022 and June to September 2022, respectively), and two months after the fifth dose of the vaccine (March to April 2023) (Fig. 1 ). Blood samples post the fourth dose could not be obtained as participants received the fifth dose before scheduled blood sampling. Genotyping of SARS-CoV-2 Clinical samples, including nasopharyngeal swabs or saliva, which tested positive via PCR or antigen tests at hospitals in Toyama Prefecture, were gathered at the Toyama Institute of Health as part of the national COVID-19 surveillance effort. In total, 2,223 samples underwent genomic analysis between March 2021 and October 2023. Whole-genome sequencing and variant classification were conducted following previously established protocols 18 , 33 . AEs after Vaccination A questionnaire was distributed to study participants to assess the presence or absence of local or systemic AEs over a 7-day period following each dose of COVID-19 mRNA vaccination. Local AEs encompassed pain, redness, and swelling at the injection site, while systemic AEs included fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, and joint pain. The severity of AEs was graded according to a previously established scale 34 , and each sign or symptom was assigned an AE score using a numerical rating scale ranging from 0 to 3. In this scale, 0, 1, 2, and 3 indicated no AE, mild AE, moderate AE, and severe AE, respectively. Nursing staff were responsible for collecting AE information from study participants and determining the AE rate for each sign or symptom following each vaccine dose. Mean AE scores were provided with standard deviations for each sign or symptom. Ninety-five SARS-CoV-2 naïve participants, comprising 26 staff and 69 residents, underwent analysis of AE rates and correlations between the cumulative AE scores and levels of anti-RBD IgG or NTs after each dose of the vaccine. The cumulative AE scores were calculated for three signs and eight symptoms in each study participant. None of the study participants required hospitalization following the vaccination. Neutralizing Activity Against SARS-CoV-2 Pseudotyped Virus Pseudotyped vesicular stomatitis virus (VSVs) bearing SARS-CoV-2 S proteins were generated following established procedures 35 . Expression plasmids for the truncated spike (S) protein of SARS-CoV-2 variants, namely pCAGG-pm3-SARS2-SHu-d19_B.1.1.529.5 (Omicron BA.5 subvariant) and pCAGG-pm3-SARS2-SHu-d19_XBB1.5 (Omicron XBB.1.5 subvariant), were generously provided by Drs. C. Ono and Y. Matsuura of the Research Institute for Microbial Diseases, Osaka University, Japan. The SARS-CoV-2 pseudotyped VSVs (SARS-CoV-2pv) were stored at -80°C until utilization. Neutralizing activity was assessed using a chemiluminescence reduction neutralizing test of SARS-CoV2pv bearing S proteins from the ancestral strain (Wuhan), Omicron BA.5 (B.1.1.529.5), and Omicron XBB.1.5, following previously established protocols 18 . SARS-CoV-2 IgG ELISA Anti- RBD IgG and anti-nucleocapsid IgG ELISA were performed as previously described 12 . Statistical Analysis Post-vaccination AEs categorized by age, sex, and anti-RBD IgG values and neutralizing activity were analyzed using IBM SPSS Statistics 27.0 (IBM, Armonk, NY). The NT value underwent log transformation. Statistical significance was defined as p < 0.05. The Mann-Whitney U test or Friedman test was employed for comparing non-parametric variables between groups. Correlations between test findings were expressed using Spearman’s correlation coefficient. The Pearson’s χ 2 test was utilized to compare the frequency of AEs per vaccination. Abbreviations COVID-19, Coronavirus Disease 2019; ELISA, Enzyme-Linked Immunosorbent Assay; AE, Adverse event; HCW, Healthcare worker; NT, Neutralizing titer; RBD, Receptor-binding domain; S, Spike; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SARS-CoV-2pv, Severe acute respiratory syndrome coronavirus 2 pseudotyped virus; VSVs, Vesicular stomatitis viruses. Declarations Acknowledgments We extend our gratitude to the residents and staff of the nursing homes and the nurses from the Toyama City Medical Association. Special thanks to Izumi Kawaguchi for their outstanding technical and secretarial support. We also appreciate the cooperation of Yukari Murotani (Alpen Rehabilitation Hospital, Toyama), Yoichi Sugimori and Mayumi Ishikuro (Nursing Home Asitanenomori, Toyama), Yosuke Hirata (Nursing Home Miyabi, Toyama), Miwa Ise (Nursing Home Harukaze, Toyama), Maki Sakai (Nursing Home Kagayaki, Toyama), Eijiro Minami, and Kazuyoshi Haba (Nursing Home Kurehaen, Toyama) in facilitating this study. Additionally, we thank Makoto Kuroda and Tsuyoshi Sekizuka at the Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, for their technical assistance in sequence analysis. We would like to thank Editage (www.editage.com) for English language editing. Author Contributions Conceptualization and methodology: M.I., H.T., and K.O.; investigation: M.I., S.Y., Y.S., T.S., K.T., E.M., J.I., C.K.; original draft preparation: M.I., S.Y., H.T., and K.O.; review and editing: M.I., H.T., and K.O.; supervision: H.T., H.S., and K.O.; funding acquisition: M.I. and H.T. All authors have read and approved the final version of the manuscript. Data availability Data are available within the manuscript or supplementary information. Competing Interest The authors declare no conflicts of interest. Funding This work was supported in part by the [Japan Society of Public Health] under Grant [2021] (H.T.); [Daido Life Insurance Company] under Grant [2021-14] (H.T.) [2023] (M.I); and [Kurozumi Medical Foundation] under Grant [2021] (M.I.). Ethics declarations This study received approval from the Ethical Review Committee of the Toyama Institute of Health (approval number #R4-14) and adhered to the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants or their surrogates. References White, E.M., et al . Variation in SARS-CoV-2 prevalence in U.S. skilled nursing facilities. Am. J. Geriatric Society 68 , 2167–2173 (2020). Shimizu, K., et al . 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The cabinet of Japan. https://www.kantei.go.jp/jp/headline/kansensho/vaccine.html (2024) Hansen, C.H., et al . Short-term effectiveness of the XBB.1.5 updated COVID-19 vaccine against hospitalisation in Denmark: a national cohort study. Lancet Infect. Dis. 24 , e73-e74. 10.1016/S1473-3099(23)00746-6 (2024). Itokawa, K., Sekizuka, T., Hashino, M., Tanaka, R., & Kuroda, M. Disentangling primer interactions improves SARS-CoV-2 genome sequencing by multiplex tiling PCR. PLoS One 15, e0239403; 10.1371/journal.pone.0239403 (2020). Food and Drug Administration in US. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. https://www.fda.gov/media/73679/download (2005). Tani, H., et al . Evaluation of SARS-CoV-2 neutralizing antibodies using a vesicular stomatitis virus possessing SARS-CoV-2 spike protein. Virol. J . 18 , 16: 10.1186/s12985-021-01490-7 (2021). Table Table. Sex, age, and vaccination status of study participants SARS-CoV-2 naïve SARS-CoV-2 BTI during BA.5 endemic period Total Staff Residents Subtotal p-value a Staff Residents Subtotal p-value a Participants (n) 26 69 95 7 9 16 111 Female (%) 14 (54) 57 (83) 71 (75) p<0.01 5 (71) 8 (89) 13 (81) p=0.375 84(76) Age, years, median (IQR) 51 (43-59) 88 (82–92) 77 (66-91) p<0.05 46 (41–53) 84 (82-86) 68 (51-85) p<0.001 83(62-90) Vaccination history First dose Wuhan (BNT162b2) 26 69 95 7 9 16 111 Second dose Wuhan (BNT162b2) 26 69 95 7 9 16 111 Third dose Wuhan (BNT162b2) 8 16 24 0 8 8 32 Wuhan (mRNA-1273) 18 53 71 7 1 8 79 Fourth dose Wuhan (BNT162b2) 5 3 8 1 2 3 11 Wuhan (mRNA-1273) 21 66 87 6 7 13 100 Fifth dose bivalent BA.1 (BNT162b2) 1 21 22 0 8 8 30 bivalent BA.4/BA.5 (BNT162b2) 24 33 57 6 1 7 64 bivalent BA.4/BA.5 (mRNA-1273) 1 15 16 1 0 1 17 a The Mann-Whitney U test or The Chi-square test was used to analyze the differences between staff and residents. Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformation.docx Cite Share Download PDF Status: Published Journal Publication published 07 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 10 May, 2024 Reviews received at journal 30 Apr, 2024 Reviews received at journal 29 Apr, 2024 Reviewers agreed at journal 24 Apr, 2024 Reviewers agreed at journal 22 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 Editor assigned by journal 22 Apr, 2024 Editor invited by journal 18 Apr, 2024 Submission checks completed at journal 15 Apr, 2024 First submitted to journal 09 Apr, 2024 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. 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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-4239620","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":291270208,"identity":"ff5d1f96-7baf-4cc7-8e4b-3c62fffa7f72","order_by":0,"name":"Masae Itamochi","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Masae","middleName":"","lastName":"Itamochi","suffix":""},{"id":291270209,"identity":"02ee81ef-0402-453d-a9bc-3e6834af381e","order_by":1,"name":"Shunsuke Yazawa","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Yazawa","suffix":""},{"id":291270210,"identity":"e4d58a9e-46e9-4727-9040-b651a193b22a","order_by":2,"name":"Yumiko Saga","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Yumiko","middleName":"","lastName":"Saga","suffix":""},{"id":291270212,"identity":"703e8b98-eb2c-4dec-a978-20cd85c3dea6","order_by":3,"name":"Takahisa Shimada","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Takahisa","middleName":"","lastName":"Shimada","suffix":""},{"id":291270213,"identity":"e37ff542-9118-4211-a37b-f013efd2a493","order_by":4,"name":"Kosuke Tamura","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Tamura","suffix":""},{"id":291270215,"identity":"ca0b1283-e6db-414b-a681-3dfd82e77a30","order_by":5,"name":"Emi Maenishi","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Emi","middleName":"","lastName":"Maenishi","suffix":""},{"id":291270216,"identity":"06f5ad13-ac21-47f6-8043-8eba7e782fa8","order_by":6,"name":"Junko Isobe","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Junko","middleName":"","lastName":"Isobe","suffix":""},{"id":291270220,"identity":"5c897db7-48d8-47eb-9d78-7828d9d5083a","order_by":7,"name":"Hitoshi Sasajima","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Sasajima","suffix":""},{"id":291270221,"identity":"3413c3ea-946a-4f4a-9913-4e0300bf5e8f","order_by":8,"name":"Chikako Kawashiri","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Chikako","middleName":"","lastName":"Kawashiri","suffix":""},{"id":291270222,"identity":"a0fe024a-3d1b-4e2d-a818-f42d44799a37","order_by":9,"name":"Hideki Tani","email":"","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Tani","suffix":""},{"id":291270223,"identity":"212ce976-21ec-448a-ac6d-6dcf62dfd96a","order_by":10,"name":"Kazunori Oishi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIie2QMUvDQBSAXwgkDg+yXrmS/oUrgYJYzF+pFJwu4CQOAQOFZonO/R/+gQsP4hI7C3Zw6uRQLIggVM8tLXeCm+B9w+N4733v7h2Aw/GHQaaD2oDCTlKZWzuKVy9+o4BWfEJL1x5pWA1fH/Nxv1feKBrnq35U+PX2AlYxeA/GAYhtwmVzjhyXE5LNGpkKpnwB6wRgOTEqTAouA8JYHygrCAXgyEegswJaYVGSD7n7xHjwIui4o1z/oIx4NlfIGQryOop+lEVpm8uT7HaKvUqKumoIGeldtD6cW3YJy9ndk3w7Tdl9m2zec0qjclZv8YoGETP/GMDR4e3+d9DJgLVmA8JnSwGiylZxOByO/8UXyDtavmKoHZIAAAAASUVORK5CYII=","orcid":"","institution":"Toyama Institute of Health","correspondingAuthor":true,"prefix":"","firstName":"Kazunori","middleName":"","lastName":"Oishi","suffix":""}],"badges":[],"createdAt":"2024-04-09 04:30:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4239620/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4239620/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-73004-8","type":"published","date":"2024-10-07T15:57:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55061340,"identity":"0e001634-f33f-4b92-b18a-fa2019e1dd2f","added_by":"auto","created_at":"2024-04-22 02:47:24","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":235956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGenomic Epidemiology and Study Design.\u003c/strong\u003e Genomic epidemiology of SARS-CoV-2 variants or Omicron subvariants in Toyama Prefecture. Abbreviations: V2+2M, V2+5M; two months, five months after the second dose of the vaccination (monovalent Wuhan), respectively, V3+2M, V3+5M; two months, five months after the third dose of the vaccination (monovalent Wuhan), V5+2M; two months after the fifth doses of the vaccination (bivalent BA.1- or BA.4/BA.5 adapted vaccine). Alpha; Alpha variant of SARS-CoV-2, Delta; Delta variant of SARS-CoV-2, BA1; Omicron BA.1 subvariant, BA.5; Omicron BA.5, XBB; Omicron XBB subvariant.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/e669aed91a92f31a95327869.jpeg"},{"id":55061337,"identity":"a6393974-c984-44f4-abbc-b758a873384b","added_by":"auto","created_at":"2024-04-22 02:47:24","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":372939,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnti-RBD IgG Titers and NTs against Wuhan Strain, BA.1 or BA.4/BA.5 Subvariant at Two Months after Fifth Dose of Omicron BA.1 Bivalent COVID-19 mRNA Vaccine or Omicron BA.4/BA.5 Bivalent COVID-19 mRNA Vaccine.\u003c/strong\u003e Anti-RBD IgG titers (A) and NTs against SARS-CoV-2pv (B) in SARS-CoV-2 naïve participants, Anti-RBD IgG titers (C) and NTs against SARS-CoV-2pv (D) in the study participants with BTI during BA.5 epidemic period (June 2022 to Mar 2023) following fifth dose. The SARS-CoV-2 naïve participants received fifth dose of Omicron BA.1 bivalent vaccine (n=22) or Omicron BA.4/BA.5 bivalent vaccine (n=73). The study participants with SARS-CoV-2 BTI during BA.5 period (n=8) received fifth dose of Omicron BA.1 bivalent vaccine (n=8) or fifth dose of Omicron BA.4/BA.5 bivalent vaccine (n=8). Friedman test and Bonferroni correction, ***, p \u0026lt; 0.001; **, p \u0026lt; 0.01. Abbreviations: RBD, receptor-binding domain; NT, neutralizing titer, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; BTI, breakthrough infection.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/2c909a4215c6c3201e20488f.jpeg"},{"id":55061342,"identity":"f31ccdbd-41a7-4f75-bdc9-693e8d408e1e","added_by":"auto","created_at":"2024-04-22 02:47:24","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1015120,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of the Rate of Adverse Events (AEs) and the AE Scores in Between SARS-CoV-2 Naïve Staff and Residents After the First to the Fifth Dose of COVID-19 mRNA Vaccinations.\u003c/strong\u003e The light gray, the medium gray, or the closed bracket denotes the case with mild, moderate, or severe AE (Fig. 3A, 3B). The mean AE scores (SD) in the staff and the residents are shown (Fig. 3D, 3E). Results of statistical analyses are shown for the comparison of the rate of AE in between the staff and the residents (Fig. 3C, 3F). The rate of AEs were compared between staff and residents by the χ\u003csup\u003e2\u003c/sup\u003e test. The AE scores were compared between staff and residents by Mann-Whitney's U test. The AE scores were compared by Friedman's test. ***, p \u0026lt; 0.001; **, p \u0026lt; 0.01; *, p \u0026lt; 0.05. Abbreviations: AE, adverse event, NS, not significant, SD, standard deviation.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/6ff6412545172b0a39159d90.jpeg"},{"id":55062240,"identity":"d1640436-bc05-4593-ac9a-06a790036d4b","added_by":"auto","created_at":"2024-04-22 02:55:25","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":808367,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between RBD IgG or NT Titers and the Cumulative Adverse Event (AE) Scores after the Second, the Third, and the Fifth Dose of COVID-19 Vaccination in SARS-CoV-2 Naïve Staff and Residents.\u003c/strong\u003eThe NTs were measured against Wuhan, Omicron BA.5, and XBB.1.5 subvariants. The cumulative AE scores of all study participants were calculated for each finding or symptom as described in the Materials and Methods.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/9680c66596eaa71f93d0d910.jpeg"},{"id":66597225,"identity":"47d2baff-6a8b-41e9-9c2e-9cc9943b5d8e","added_by":"auto","created_at":"2024-10-14 16:08:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3169247,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/c0f727b2-4860-4fc8-b8d0-d849be473b44.pdf"},{"id":55061338,"identity":"48a93f71-60d4-456c-a770-d3e66607ba4b","added_by":"auto","created_at":"2024-04-22 02:47:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1200964,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4239620/v1/8f34382f821d344625c8edc3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Analysis of Adverse Event Rates and Severity Following COVID-19 mRNA Vaccinations Among SARS-CoV-2 Naïve Nursing Home Residents and Staff","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNumerous clusters of coronavirus disease 2019 (COVID-19) have been documented in nursing homes during the early phase of the pandemic\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. Given the high case fatality rates among COVID-19 patients in these facilities \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003c/sup\u003e residents are particularly vulnerable to SARS-CoV-2. A prior report on long-term care facilities underscored the importance of preventing COVID-19 outbreaks in such settings \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVaccination against SARS-CoV-2 represents a pivotal strategy in controlling the COVID-19 pandemic. COVID-19 vaccines stimulate the production of neutralizing antibodies to SARS-CoV-2 in adult individuals, albeit with a relatively high incidence of nonserious adverse events (AEs) \u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, the estimation of the magnitude and durability of protection through COVID-19 vaccination has become a challenge because of the emergence of the omicron variants which altered virus characteristics, such as transmissibility and antigenicity, evolving in response to herd immunity \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. A recent study reported that frequent COVID-19 booster vaccination in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19 by analyzing COVID-19 surveillance and seroprevalence data \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeven studies have investigated immune responses, including immunogenicity and reactogenicity, in healthcare workers following two doses of COVID-19 mRNA vaccination \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. While six of these studies delineated varying degrees of correlation between humoral immune responses and AEs subsequent to COVID-19 mRNA vaccination \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, one study did not, owing to its relatively small sample size \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Takano et al. identified correlations between cellular populations, such as the dynamics of NKT-like cells, CD11c\u003csup\u003e\u0026minus;\u003c/sup\u003e Axl\u003csup\u003e+\u003c/sup\u003eSiglec-6\u003csup\u003e+\u003c/sup\u003e-DCs, and DC3s, and systemic adverse events post two doses of COVID-19 mRNA vaccination \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe and other investigators have previously observed a substantial increase in anti-RBD IgG levels and neutralizing titers (NTs) of Omicron subvariants following booster doses of monovalent (Wuhan) COVID-19 mRNA vaccination among nursing home residents \u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Although a prior study indicated that the primary vaccination series with COVID-19 mRNA elicited robust antibody responses and mostly mild AEs in nursing home residents \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, the relationship between AE incidence and immune responses subsequent to COVID-19 mRNA vaccination remains incompletely explored in this demographic. Here, we report a distinct difference in AEs between staff and residents, alongside a lack of correlation between immune responses and AEs after booster doses of COVID-19 mRNA vaccine in a Japanese nursing home cohort.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGenomic Epidemiology of SARS-CoV-2\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn Toyama Prefecture, the COVID-19 epidemic caused by the Omicron variant, specifically the BA.5 subvariant, surfaced between August 2022 and July 2023. Additionally, the XBB subvariant emerged during April to October 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnti-RBD IgG and NT after Fifth Dose in SARS-CoV-2 na\u0026iuml;ve and BTI Participants\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe mean anti-RBD IgG titers in serum samples from 22 SARS-CoV-2 na\u0026iuml;ve participants who received the bivalent BA.1-adapted vaccine and 73 SARS-CoV-2 na\u0026iuml;ve participants who received the bivalent BA.4/BA.5-adapted vaccine were 2.7 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e U/mL and 3.3 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e U/mL, respectively, two months after the fifth dose (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Geometric mean NTs against Wuhan, BA.5, and XBB.1.5 were 48.4, 13.2, and 1.5 in 22 SARS-CoV-2 na\u0026iuml;ve participants who received the bivalent BA.1-adapted vaccine, and 62.5, 63.5, and 1.3 in 73 SARS-CoV-2 na\u0026iuml;ve participants who received the bivalent BA.4/BA.5-adapted vaccine two months after the fifth dose (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Notably, NTs against XBB were significantly lower than those against BA.4/BA.5 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe mean anti-RBD IgG titers in serum samples from 8 participants with BTI during the BA.5 endemic period who received either the bivalent BA.1-adapted vaccine or the bivalent BA.4/BA.5-adapted vaccine were 3.9 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e U/mL and 4.3 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e U/mL, respectively, two months after the fifth dose (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Geometric mean NTs against Wuhan, BA.5, and XBB.1.5 in these participants were 41.5, 45.0, and 2.9, and 54.6, 214.1, and 3.7, respectively, two months after the fifth dose (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Notably, NTs against XBB.1.5 in participants with BTI during the BA.5 endemic period were significantly lower than those against BA.5 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eThe mean of anti-RBD IgG and NTs against Wuhan and BA.5 in these SARS-CoV-2 na\u0026iuml;ve participants were at equivalent levels to those observed two months after the third dose \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Similarly, the mean of anti-RBD IgG and NTs against Wuhan and BA.5 in participants with BTI during the BA.5 endemic period were at equivalent levels to those observed two months after the third dose.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAEs Following Vaccination\u003c/h2\u003e \u003cp\u003eThe rates of most AEs were significantly lower among residents compared to staff members after the first through fifth doses (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Significant differences were observed in AE rates between the two groups. Severe AEs, including local redness (4.5%), local swelling (4.8%), and fever (8.3%), occurred exclusively in staff members following the third dose (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Residents commonly experienced fever after the fourth (16.1%) and fifth doses (13.2%) of the vaccine. Rates of local redness, fever, fatigue, and headache significantly varied across different doses in staff members. Similarly, the rate of fever differed significantly among various doses in residents. Next, we compared AE scores to assess severity between staff and residents. AE scores for local pain, local swelling, fatigue, headache, muscle pain, and joint pain were significantly lower in residents compared to staff members after the first through the fifth doses (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE, and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). In staff members, AE scores for local redness, fever, fatigue, headache, and chills significantly differed among various doses.\u003c/p\u003e \u003cp\u003eWe also evaluated AE rates in SARS-CoV-2 na\u0026iuml;ve participants after the third to the fifth doses of the vaccines from two different manufacturers (Pfizer/BioNTech and Moderna) \u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e (Supplementary Fig.\u0026nbsp;1). Except for fatigue and headache after the fourth dose of vaccination, no significant difference was found in AE rates after the third, fourth, and fifth doses of vaccination. Furthermore, we compared the cumulative AE score in SARS-CoV-2 na\u0026iuml;ve staff and residents after receiving the third, fourth, and fifth doses from two different manufacturers (Supplementary Fig.\u0026nbsp;2). No significant difference was observed in the total AE score after each dose of the vaccintion from two manufacturers in both staff and residents.\u003c/p\u003e \u003cp\u003eFurthermore, we examined the correlations between anti-RBD IgG titers or NTs and the cumulative AE score in SARS-CoV-2 na\u0026iuml;ve participants who received five doses of vaccination (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). No significant correlation was found between NTs and the cumulative AE score after the second, third, and fifth doses in both staff (N\u0026thinsp;=\u0026thinsp;26) and residents (N\u0026thinsp;=\u0026thinsp;69), although a weak correlation was observed between anti-RBD-IgG and the cumulative AE score two months after the third dose in residents (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, p\u0026thinsp;=\u0026thinsp;0.047) and between NTs against BA.5 and the total AE score two months after the fifth dose in staff (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eI, p\u0026thinsp;=\u0026thinsp;0.042). Additionally, we examined the correlations between age and the cumulative AE score after the first, second, third, fourth, and fifth doses of the vaccination (Supplementary Fig.\u0026nbsp;3). No significant correlation was observed between age and the cumulative AE score after each vaccination in both staff and residents, except for a significant correlation in staff between age and the cumulative AE score after the first dose (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, data analysis revealed that the rate and severity of most AEs were significantly lower among residents compared to staff following the administration of the first through fifth doses of COVID-19 mRNA vaccination, with some exceptions observed across nursing homes. To our knowledge, this is the first study to demonstrate a noticeable disparity in the rate and severity of AEs post COVID-19 mRNA vaccination between nursing home residents and staff. Previously, we reported increased levels of anti-RBD IgG and NTs against the Wuhan, Alpha, Delta, and Omicron subvariants in SARS-CoV-2-na\u0026iuml;ve participants aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years, two months after the third dose of COVID-19 vaccination \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Our findings also indicate that NTs against Omicron subvariants BA.1 and BA.5 increased two months after the third dose compared to five months after the second dose in SARS-CoV-2 na\u0026iuml;ve residents aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years, given that most residents in this study were aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years. Taken together with these observations, our data suggest that booster doses of the COVID-19 mRNA vaccination are beneficial not only in terms of reactogenicity but also immunogenicity for SARS-CoV-2 na\u0026iuml;ve residents.\u003c/p\u003e \u003cp\u003eIn addition to immunogenicity, a recent study reported the effectiveness of a booster dose of COVID-19 mRNA vaccination in two distinct nursing home cohorts in the United States \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The authors demonstrated that booster vaccination reduced SARS-CoV-2 infection by 37.7\u0026ndash;57.7%, hospital admissions by 64.1\u0026ndash;74.4%, and SARS-CoV-2-associated deaths by 46.6\u0026ndash;87.9%, respectively. Following the introduction of a bivalent mRNA vaccine, a retrospective, population-based cohort study in Israel indicated that the effectiveness of a bivalent BA.4/BA.5 mRNA vaccine booster dose among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years was 72% (95% CI; 60\u0026ndash;81) for hospitalizations due to COVID-19 and 68% (95% CI; 42\u0026ndash;82%) for COVID-19-related deaths \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Conversely, a recent study from the National Health Care Safety Network nursing homes, where most study participants received a bivalent vaccine, reported vaccine effectiveness against infection at 31.2% \u003csup\u003e27\u003c/sup\u003e. Taken together, these data support the notion that booster doses of monovalent or bivalent COVID-19 mRNA vaccineation are less protective against infection but effective in preventing severe diseases and are less reactogenic among nursing home residents.\u003c/p\u003e \u003cp\u003eLevy et al. identified a significant correlation between systemic adverse drug reaction scores and anti-RBD IgG titers, adjusted for age, gender, and days post-second vaccination, and a weaker correlation with neutralizing antibodies in 738 SARS-CoV-2 na\u0026iuml;ve HCWs with a mean age (SD) of 46.5 (11.8) years \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Similarly, the other five studies also reported varying degrees of correlation between the humoral immune response and AEs among HCWs following two doses of the COVID-19 vaccination \u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In contrast, our study found no significant correlation between anti-RBD IgG or neutralizing titers and the cumulative AE score after the second, third, and fifth doses of the mRNA vaccination among nursing home residents, although there two exceptions observed in residents after the third dose and in staff after the fifth dose. The discrepancy between our findings and those of the previous six studies may be explained by the factor of aging, which attenuated the immune response after the booster dose of COVID-19 mRNA vaccination in nursing home residents \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The median age (range) of SARS-CoV-2 na\u0026iuml;ve residents in our study was 88 years (82\u0026ndash;92 years), considerably higher than that of the HCW study participants in the six previous studies \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Other factors contributing to this discrepancy may include the relatively small sample size of our study.\u003c/p\u003e \u003cp\u003eIn this study, the mean anti-RBD IgG titers and geometric NTs against both Wuhan and BA.5, following the fifth dose of a bivalent BA.1 or BA.4/BA.5 vaccine, were comparable to those observed two months after the third dose among both SARS-CoV-2 na\u0026iuml;ve participants and those with BTI during the BA.5 period. Consistently, significantly lower NTs against XBB were noted compared to those against BA.5 in SARS-CoV-2 na\u0026iuml;ve participants and individuals with BTI during the BA.5 period, aligning with prior studies \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOne strength of our study is the ability to compare the incidence and severity of AEs following COVID-19 mRNA vaccinations between SARS-CoV-2 na\u0026iuml;ve staff and residents within a Japanese nursing home cohort. However, several limitations exist. Firstly, the relatively small sample size of staff may have limited our ability to establish correlations between AE scores and anti-RBD IgG or NTs. Secondly, there could be a blurring of the assessment by the observer since AE information was collected by nursing home staff from nursing home residents according to the questionnaire. Lastly, we were unable to collect blood samples to determine antibody responses after the fourth dose of COVID-19 mRNA vaccination.\u003c/p\u003e \u003cp\u003eIn conclusion, we observed a notably lower rate and severity of most AEs among SARS-CoV-2 na\u0026iuml;ve residents compared to staff members following the administration of the first through fifth doses of COVID-19 mRNA vaccination in nursing homes in this study. No significant correlation was found between anti-RBD IgG or NTs and the cumulative AE score after the second, third, and fifth doses of mRNA vaccination.\u003c/p\u003e \u003cp\u003eAlthough the vaccination rates of the first to the third dose of COVID-19 mRNA vaccination were higher than 90% in older adults in Japan, the vaccination rate of the Omicron XBB.1.5 mRNA vaccine \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e was reported to be relatively low (~\u0026thinsp;53.5%) in older adults at the end of March 2024 \u003csup\u003e31\u003c/sup\u003e. Because this vaccine was reported to be associated with 76.1% reduced risk of COVID-19 hospitalization among people older than 65 years \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, the vaccination rates of the variant-targeted COVID-19 mRNA vaccines should be increased to lower the burden of severe COVID-19 in older adults. Our findings, highlighting the reduced incidence and severity of AEs among SARS-CoV-2 na\u0026iuml;ve nursing home residents post COVID-19 mRNA vaccination, strongly advocate for the recommendation of this vaccine for such high-risk populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Participants\u003c/h2\u003e \u003cp\u003eThis study commenced in May 2021 across six nursing homes in Toyama Prefecture, Japan \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. By May 2023, a total of 78 residents and 33 staff had enrolled. Among them 95 individuals were SARS-CoV-2 na\u0026iuml;ve, while 16 had experienced breakthrough infections (BTI) during the BA.5 endemic period, spanning from June 2022 to February 2023 (Table). The definition of a BTI case was as previously outlined \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAll participants received an primary series of two doses of the COVID-19 mRNA vaccine, BNT162b2 (Pfizer/BioNTech, 30 \u0026micro;g per dose), targeting the Wuhan strain, administered between April and June 2021. Subsequently, for the third dose, 32 participants received the BNT162b2, while 79 received mRNA-1273 vaccine (Moderna, 50 \u0026micro;g per dose), between January and March 2022. For the fourth dose, 11 participants received the BNT162b2 vaccine, and 100 received mRNA-1273 vaccine between July 2022 and September 2022. Regarding the fifth dose, 30 participants received the bivalent BA.1-adapted BNT162b2 mRNA vaccine \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, and 81 received either the bivalent BA.4/BA.5-adapted BNT162b2 mRNA vaccine \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e or the bivalent mRNA-1273.222 vaccine \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e between November 2022 and February 2023. The bivalent vaccines included an ancestral SARS-CoV-2 strain component along with a component from either BA.1 subvariant or BA.4/BA.5 subvariant. The safety profiles of these bivalent vaccines were comparable to those of monovalent vaccines (BNT162b2 or mRNA-1273) \u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBlood samples were collected in May to June 2021 prior to the first COVID-19 vaccination, and then at two and five months following the primary series vaccination (August to September 2021 and November to December 2021, respectively). Subsequent blood sampling occurred two and five months after the third dose of booster vaccination (March to June 2022 and June to September 2022, respectively), and two months after the fifth dose of the vaccine (March to April 2023) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Blood samples post the fourth dose could not be obtained as participants received the fifth dose before scheduled blood sampling.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGenotyping of SARS-CoV-2\u003c/h2\u003e \u003cp\u003eClinical samples, including nasopharyngeal swabs or saliva, which tested positive via PCR or antigen tests at hospitals in Toyama Prefecture, were gathered at the Toyama Institute of Health as part of the national COVID-19 surveillance effort. In total, 2,223 samples underwent genomic analysis between March 2021 and October 2023. Whole-genome sequencing and variant classification were conducted following previously established protocols \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAEs after Vaccination\u003c/h2\u003e \u003cp\u003eA questionnaire was distributed to study participants to assess the presence or absence of local or systemic AEs over a 7-day period following each dose of COVID-19 mRNA vaccination. Local AEs encompassed pain, redness, and swelling at the injection site, while systemic AEs included fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, and joint pain. The severity of AEs was graded according to a previously established scale \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, and each sign or symptom was assigned an AE score using a numerical rating scale ranging from 0 to 3. In this scale, 0, 1, 2, and 3 indicated no AE, mild AE, moderate AE, and severe AE, respectively. Nursing staff were responsible for collecting AE information from study participants and determining the AE rate for each sign or symptom following each vaccine dose. Mean AE scores were provided with standard deviations for each sign or symptom.\u003c/p\u003e \u003cp\u003eNinety-five SARS-CoV-2 na\u0026iuml;ve participants, comprising 26 staff and 69 residents, underwent analysis of AE rates and correlations between the cumulative AE scores and levels of anti-RBD IgG or NTs after each dose of the vaccine. The cumulative AE scores were calculated for three signs and eight symptoms in each study participant. None of the study participants required hospitalization following the vaccination.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eNeutralizing Activity Against SARS-CoV-2 Pseudotyped Virus\u003c/h2\u003e \u003cp\u003ePseudotyped vesicular stomatitis virus (VSVs) bearing SARS-CoV-2 S proteins were generated following established procedures \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Expression plasmids for the truncated spike (S) protein of SARS-CoV-2 variants, namely pCAGG-pm3-SARS2-SHu-d19_B.1.1.529.5 (Omicron BA.5 subvariant) and pCAGG-pm3-SARS2-SHu-d19_XBB1.5 (Omicron XBB.1.5 subvariant), were generously provided by Drs. C. Ono and Y. Matsuura of the Research Institute for Microbial Diseases, Osaka University, Japan. The SARS-CoV-2 pseudotyped VSVs (SARS-CoV-2pv) were stored at -80\u0026deg;C until utilization. Neutralizing activity was assessed using a chemiluminescence reduction neutralizing test of SARS-CoV2pv bearing S proteins from the ancestral strain (Wuhan), Omicron BA.5 (B.1.1.529.5), and Omicron XBB.1.5, following previously established protocols \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSARS-CoV-2 IgG ELISA\u003c/h2\u003e \u003cp\u003eAnti- RBD IgG and anti-nucleocapsid IgG ELISA were performed as previously described \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePost-vaccination AEs categorized by age, sex, and anti-RBD IgG values and neutralizing activity were analyzed using IBM SPSS Statistics 27.0 (IBM, Armonk, NY). The NT value underwent log transformation. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The Mann-Whitney U test or Friedman test was employed for comparing non-parametric variables between groups. Correlations between test findings were expressed using Spearman\u0026rsquo;s correlation coefficient. The Pearson\u0026rsquo;s χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e test was utilized to compare the frequency of AEs per vaccination.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOVID-19, Coronavirus Disease 2019; ELISA, Enzyme-Linked Immunosorbent Assay; AE, Adverse event; HCW, Healthcare worker; NT, Neutralizing titer; RBD, Receptor-binding domain; S, Spike; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SARS-CoV-2pv, Severe acute respiratory syndrome coronavirus 2 pseudotyped virus; VSVs, Vesicular stomatitis viruses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extend our gratitude to the residents and staff of the nursing homes and the nurses from the Toyama City Medical Association. Special thanks to Izumi Kawaguchi\u0026nbsp;for their outstanding technical and secretarial support. We also appreciate the cooperation of Yukari Murotani (Alpen Rehabilitation Hospital, Toyama), Yoichi Sugimori and Mayumi Ishikuro (Nursing Home Asitanenomori, Toyama), Yosuke Hirata (Nursing Home Miyabi, Toyama), Miwa Ise (Nursing Home Harukaze, Toyama), Maki Sakai (Nursing Home Kagayaki, Toyama), Eijiro Minami, and Kazuyoshi Haba (Nursing Home Kurehaen, Toyama) in facilitating this study. Additionally, we thank Makoto Kuroda and Tsuyoshi Sekizuka at the Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, for their technical assistance in sequence analysis. We would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and methodology: M.I., H.T., and K.O.; investigation: M.I., S.Y., Y.S., T.S., K.T., E.M., J.I., C.K.; original draft preparation: M.I., S.Y., H.T., and K.O.; review and editing: M.I., H.T., and K.O.; supervision: H.T., H.S., and K.O.; funding acquisition: M.I. and H.T. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available within the manuscript or supplementary information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eInterest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by the [Japan Society of Public Health] under Grant [2021] (H.T.); [Daido Life Insurance Company] under Grant [2021-14] (H.T.) [2023] (M.I); and [Kurozumi Medical Foundation] under Grant [2021] (M.I.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received approval from the Ethical Review Committee of the Toyama Institute of Health (approval number #R4-14) and adhered to the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants or their surrogates.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWhite, E.M., \u003cem\u003eet al\u003c/em\u003e. Variation in SARS-CoV-2 prevalence in U.S. skilled nursing facilities.\u003cem\u003e\u0026nbsp;Am. J. Geriatric Society\u003c/em\u003e \u003cstrong\u003e68\u003c/strong\u003e, 2167\u0026ndash;2173 (2020).\u003c/li\u003e\n \u003cli\u003eShimizu, K., \u003cem\u003eet al\u003c/em\u003e. Epidemiology of SARS-CoV-2 infection in nursing facilities and the impact of their clusters in a Japanese core city. \u003cem\u003eJ. Infect. Chemother\u003c/em\u003e. \u003cstrong\u003e28\u003c/strong\u003e, 955-961 (2022).\u003c/li\u003e\n \u003cli\u003eTamura, K., \u003cem\u003eet al\u003c/em\u003e. Impact of COVID-19 and closed transmission of SARS-CoV-2 during the first wave in Toyama Prefecture, Japan, March 30 to May 18, 2020.\u003cem\u003e\u0026nbsp;Jpn. J. Infect. Dis\u003c/em\u003e. \u003cstrong\u003e77\u003c/strong\u003e, 75-82 (2023).\u003c/li\u003e\n \u003cli\u003eComas-Herrera, A., \u003cem\u003eet al\u003c/em\u003e. LT Covid International living report on COVID-19 and Long-Term Care. https://ltccovid.org/international-living-report-covid-ltc/ (2022).\u003c/li\u003e\n \u003cli\u003eIritani, O., \u003cem\u003eet al\u003c/em\u003e. Clusters of COVID-19 in long-term care hospitals and facilities in Japan from 16 January to 9 May 2020. \u003cem\u003eGeriatr. Gerontol. Int.\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, 715-719 (2020).\u003c/li\u003e\n \u003cli\u003eMatsumura, T., Takano, T., \u0026amp; Takahashi, Y. Immune responses related to immunogenicity and reactogenicity of COVID-19 mRNA vaccine. \u003cem\u003eInt. Immunol\u003c/em\u003e. \u003cstrong\u003e35\u003c/strong\u003e, 213\u0026ndash;220 (2022).\u003c/li\u003e\n \u003cli\u003ePolack, F.P., \u003cem\u003eet al\u003c/em\u003e. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. \u003cem\u003eN Engl. J. Med\u003c/em\u003e. \u003cstrong\u003e383\u003c/strong\u003e, 2603-2615 (2020).\u003c/li\u003e\n \u003cli\u003eWalsh, E.E., \u003cem\u003eet al\u003c/em\u003e. Safety and immunogenicity of two RNA-based COVID-19 vaccine. \u003cem\u003eN. Engl. J. Med\u003c/em\u003e. \u003cstrong\u003e383\u003c/strong\u003e, 2439-2450 (2020).\u003c/li\u003e\n \u003cli\u003eIketani, S., \u003cem\u003eet al\u003c/em\u003e. Antibody evasion properties of SARS-CoV-2 Omicron sublineages. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e604\u003c/strong\u003e, 553-556 (2022).\u003c/li\u003e\n \u003cli\u003ePark, H.J., \u003cem\u003eet al\u003c/em\u003e. Comparing frequency of booster vaccination to prevent severe COVID-19 by risk group in the United States. \u003cem\u003eNat\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e\u003cem\u003e\u0026nbsp;commun\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 1883; 10.1038/s41467-024-45549-9 (2024).\u003c/li\u003e\n \u003cli\u003eTakano, T., \u003cem\u003eet al\u003c/em\u003e. Distinct immune cell dynamics corelate with the immunogenicity and reactogenicity of SARS-CoV-2 mRNA Vaccine. \u003cem\u003eCell Rep. Med\u003c/em\u003e. \u003cstrong\u003e3\u003c/strong\u003e, 100631; 10.1016/j.xcrm.2022.100631 (2022).\u003c/li\u003e\n \u003cli\u003eKoike, R., \u003cem\u003eet al\u003c/em\u003e. Systemic adverse effects induced by the BNT162b2 vaccine are associated with higher antibody titers from 3 to 6 months after vaccination. \u003cem\u003eVaccines (Basel)\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;10,\u0026nbsp;\u003c/strong\u003e451; 10.3390/vaccines10030451 (2022).\u003c/li\u003e\n \u003cli\u003eKobashi, Y., \u003cem\u003eet al\u003c/em\u003e. Factors associated with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibody titer and neutralizing activity among healthcare workers following vaccination with the BNT162b2 vaccine. \u003cem\u003ePLoS One\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e17,\u0026nbsp;\u003c/strong\u003ee0269917; 10.1371/journal.pone.0269917 (2022).\u003c/li\u003e\n \u003cli\u003eLevy, I., \u003cem\u003eet al\u003c/em\u003e. Correlation between adverse events and antibody titers among healthcare workers vaccinated with BNT161b mRNA COVID-19 vaccine. \u003cem\u003eVaccines (Basel)\u003c/em\u003e \u003cstrong\u003e10,\u0026nbsp;\u003c/strong\u003e1220; 10.3390/vaccines10081220 (2022).\u003c/li\u003e\n \u003cli\u003eHeld, J., \u003cem\u003eet al\u003c/em\u003e. Reactogenicity correlates only weakly with humoral immunogenicity after COVID-19 vaccination with BNT162b2 mRNA (Comirnaty\u003csup\u003eR\u003c/sup\u003e). \u003cem\u003eVaccines (Basel)\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;9\u003c/strong\u003e, 1063; 10.3390/vaccines9101063 (2021).\u003c/li\u003e\n \u003cli\u003eTani, N., \u003cem\u003eet al\u003c/em\u003e. Relation of fever intensity and pntipyretic use woth specific antibody response after two doses of the BNT612b2 mRNA. \u003cem\u003eVaccine\u003c/em\u003e \u003cstrong\u003e40,\u0026nbsp;\u003c/strong\u003e2062-2067 (2022).\u003c/li\u003e\n \u003cli\u003eTakeuchi, M., Higa, Y., Esaki, A., Nabeshima, Y., \u0026amp; Nakazato, A. Does reactogenicity after a second injection of the BNT162b2 vaccine predict spike IgG antibody levels in healthy Japanese subjects ? \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e16,\u0026nbsp;\u003c/strong\u003ee0257668; 10.1371/journal.pone.0257668 (2021).\u003c/li\u003e\n \u003cli\u003eItamochi, M., \u003cem\u003eet al\u003c/em\u003e. Neutralization of Omicron subvariants BA.1 and BA.5 by a booster dose of COVID-19 mRNA vaccine in a Japanese nursing home cohort. \u003cem\u003eVaccine\u003c/em\u003e \u003cstrong\u003e41,\u003c/strong\u003e 2234-2242 (2023).\u003c/li\u003e\n \u003cli\u003eCanaday, D.H., \u003cem\u003eet al\u003c/em\u003e. COVID-19 vaccine booster dose needed to achieve Omicron-specific neutralisation in nursing home residents. \u003cem\u003eEBioMedicine\u003c/em\u003e \u003cstrong\u003e80,\u003c/strong\u003e 104066; 10.1016/j.ebiom.2022.104066. (2022).\u003c/li\u003e\n \u003cli\u003eChong, Y., \u003cem\u003eet al\u003c/em\u003e. Pronounced antibody elevation after SARS-CoV-2 BNT162b2 mRNA booster vaccination in nursing home residents.\u003cem\u003e\u0026nbsp;Influenza Other Respir. Viruses\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 1066-1071 (2022).\u003c/li\u003e\n \u003cli\u003eOyebanji, O.A., \u003cem\u003eet al\u003c/em\u003e. Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents? \u003cem\u003eAging Clin. Exp. Res.\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e33\u003c/strong\u003e, 3151\u0026ndash;3160 (2021).\u003c/li\u003e\n \u003cli\u003eWinokur, P., \u003cem\u003eet al\u003c/em\u003e. Bivalent Omicron BA.1-adapted BNT162b2 booster in adults older than 55 years. \u003cem\u003eN. Engl. J. Med.\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e388\u003c/strong\u003e, 214-227 (2023).\u003c/li\u003e\n \u003cli\u003eUsdan, L., \u003cem\u003eet al\u003c/em\u003e. A bivalent Omicron\u0026ndash;BA.4/BA.5\u0026ndash;adapted BNT162b2 booster in \u0026sup3;12\u0026ndash;year\u0026ndash;olds. Clin. Infect. Dis. ciad718; 10.1093/cid/ciad718 (2023).\u003c/li\u003e\n \u003cli\u003eChalkias, S., \u003cem\u003eet al\u003c/em\u003e. Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim result. \u003cem\u003eNat. Med.\u003c/em\u003e \u003cstrong\u003e29,\u0026nbsp;\u003c/strong\u003e2325-2333 (2023).\u003c/li\u003e\n \u003cli\u003eMcConeghy, K.W., \u003cem\u003eet al\u003c/em\u003e. Infections, hospitalizations, and deaths among US nursing home residents with vs without a SARS-CoV-2 vaccine booster. \u003cem\u003eJAMA Network Open\u003c/em\u003e \u003cstrong\u003e5,\u0026nbsp;\u003c/strong\u003ee2245417; 10.1001/jamanetworkopen.2022.45417 (2022).\u003c/li\u003e\n \u003cli\u003eArbel, R., \u003cem\u003eet al\u003c/em\u003e. Effectiveness of a bivalent mRNA vaccine booster dose to prevent sever COVID-19 outcomes: a retrospective cohort study. \u003cem\u003eLancet Infect. Dis.\u003c/em\u003e \u003cstrong\u003e23,\u0026nbsp;\u003c/strong\u003e914\u0026ndash;921 (2023).\u003c/li\u003e\n \u003cli\u003eWong, E., \u003cem\u003eet al\u003c/em\u003e. Effectiveness of up to date COVID-19 vaccination in preventing SARS-CoV-2 infection among nursing home residents\u0026ndash;United States, November 29, 2022\u0026ndash;January 8, 2023. \u003cem\u003eMMWR Morbid. Mortal. Wkly. Rep.\u003c/em\u003e \u003cstrong\u003e72,\u003c/strong\u003e 690\u0026ndash;693 (2023).\u003c/li\u003e\n \u003cli\u003eKurhade, C., \u003cem\u003eet al\u003c/em\u003e. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. \u003cem\u003eNat. Med.\u003c/em\u003e \u003cstrong\u003e29,\u003c/strong\u003e 344-347 (2023).\u003c/li\u003e\n \u003cli\u003eAmano, M., \u003cem\u003eet al\u003c/em\u003e. Neutralization against Omicron sublineages (BA.2/BA.5/ BQ1.1/ XBB/XBB.1.5) in bivalent BNT161b2-vaccinated HCWs with or without risk actors or following BT infection with Omicron. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e: 17404; 10.1038/s41598-023-44484-x (2023).\u003c/li\u003e\n \u003cli\u003eGayed, J., \u003cem\u003eet al\u003c/em\u003e. Safety and immunogenicity of the monovalent Omicron XBB.1.5-adapted BNT162b2 COVID-19 vaccine in individuals \u0026sup3;12 years old: a phase 2/3 trial. \u003cem\u003eVaccines\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 118. 10.3390/vaccines12020118 (2024).\u003c/li\u003e\n \u003cli\u003eThe vaccination rates of COVID-19 vaccine. The cabinet of Japan. https://www.kantei.go.jp/jp/headline/kansensho/vaccine.html (2024)\u003c/li\u003e\n \u003cli\u003eHansen, C.H., \u003cem\u003eet al\u003c/em\u003e. Short-term effectiveness of the XBB.1.5 updated COVID-19 vaccine against hospitalisation in Denmark: a national cohort study. \u003cem\u003eLancet Infect. Dis.\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, e73-e74. 10.1016/S1473-3099(23)00746-6 (2024).\u003c/li\u003e\n \u003cli\u003eItokawa, K., Sekizuka, T., Hashino, M., Tanaka, R., \u0026amp; Kuroda, M. Disentangling primer interactions improves SARS-CoV-2 genome sequencing by multiplex tiling PCR. \u003cem\u003ePLoS One\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e15,\u003c/strong\u003e e0239403; 10.1371/journal.pone.0239403 (2020).\u003c/li\u003e\n \u003cli\u003eFood and Drug Administration in US. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. https://www.fda.gov/media/73679/download (2005).\u003c/li\u003e\n \u003cli\u003eTani, H., \u003cem\u003eet al\u003c/em\u003e. Evaluation of SARS-CoV-2 neutralizing antibodies using a vesicular stomatitis virus possessing SARS-CoV-2 spike protein. \u003cem\u003eVirol. J\u003c/em\u003e. \u003cstrong\u003e18\u003c/strong\u003e, 16: 10.1186/s12985-021-01490-7 (2021).\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable. Sex, age, and vaccination status of study participants\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"992\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.620967741935484%\" valign=\"top\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.443548387096776%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eSARS-CoV-2 na\u0026iuml;ve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9153225806451613%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"30.443548387096776%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eSARS-CoV-2 BTI during BA.5 endemic period\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9153225806451613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.661290322580645%\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.847494553376908%\" valign=\"top\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.278867102396514%\" valign=\"top\"\u003e\n \u003cp\u003eStaff\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.25925925925926%\" valign=\"top\"\u003e\n \u003cp\u003eResidents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.278867102396514%\" valign=\"top\"\u003e\n \u003cp\u003eSubtotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.189542483660131%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.0697167755991286%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.25925925925926%\" valign=\"top\"\u003e\n \u003cp\u003eStaff\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.278867102396514%\" valign=\"top\"\u003e\n \u003cp\u003eResidents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.278867102396514%\" valign=\"top\"\u003e\n \u003cp\u003eSubtotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.189542483660131%\" valign=\"top\"\u003e\n \u003cp\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.0697167755991286%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eParticipants (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e14 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e57 (83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e71 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003ep\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e5 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e13 (81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003ep=0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e84(76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e51 (43-59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e88 (82\u0026ndash;92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e77 (66-91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003ep\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e46 (41\u0026ndash;53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e84 (82-86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e68 (51-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e83(62-90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eVaccination history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eFirst dose \u0026nbsp; Wuhan (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eSecond dose Wuhan (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eThird dose \u0026nbsp;Wuhan (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Wuhan (mRNA-1273)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eFourth dose Wuhan (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Wuhan (mRNA-1273)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003eFifth dose bivalent BA.1 (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003ebivalent BA.4/BA.5 (BNT162b2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56539235412475%\" valign=\"top\"\u003e\n \u003cp\u003ebivalent BA.4/BA.5 (mRNA-1273)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.551307847082494%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.639839034205232%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9114688128772637%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.645875251509055%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eThe Mann-Whitney U test or The Chi-square test was used to analyze the differences between staff and residents.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, SARS-CoV-2, Omicron variants, mRNA vaccine, nursing home residents, neutralizing antibodies, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-4239620/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4239620/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe aimed to assess the rate and severity of adverse events (AEs), and the relationship between antibody responses and AEs after COVID-19 mRNA vaccination in a nursing home cohort. Ninety-five SARS-CoV-2 na\u0026iuml;ve participants, consisting of 26 staff (median age, 51 years) and 69 residents (median age, 88 years), were evaluated for the rate and severity of local and systemic AEs. The severity of AEs was evaluated using grading scale for each sign or symptom, and expressed as the AE score. The rates of most AEs were considerably lower in the residents after the first to the fifth dose of the mRNA vaccination, compared to the staff. The severity of AEs using AE scores were also considerably lower in the residents after the first to the fifth dose of vaccination, compared to the staff. No clear relationship was detected between receptor-binding domain IgG or neutralizing titer levels and the cumulative AE score either in staff or residents after the second, third, or fifth dose of the mRNA vaccination, although there were two exceptions. Our conclusion of lower event occurrence and milder side effects strongly corroborates the science-driven proposal of COVID-19 mRNA vaccinations for older generations in high-risk care facilities.\u003c/p\u003e","manuscriptTitle":"Comparative Analysis of Adverse Event Rates and Severity Following COVID-19 mRNA Vaccinations Among SARS-CoV-2 Naïve Nursing Home Residents and Staff","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-22 02:47:19","doi":"10.21203/rs.3.rs-4239620/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-10T09:07:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-30T10:25:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-29T17:43:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"483dbf95-2fdb-4755-8ed7-40ccd593911e_SNPRID","date":"2024-04-24T12:06:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"e2473864-731f-4972-8065-4e298563e453","date":"2024-04-22T15:24:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-22T15:18:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-22T15:13:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-04-18T12:09:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-15T08:46:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-04-09T04:29:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8ae2eb1e-c534-4cc1-b07d-34f5cdc3db2a","owner":[],"postedDate":"April 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30678085,"name":"Biological sciences/Microbiology"},{"id":30678086,"name":"Health sciences/Health care"},{"id":30678087,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2024-10-14T16:03:09+00:00","versionOfRecord":{"articleIdentity":"rs-4239620","link":"https://doi.org/10.1038/s41598-024-73004-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-07 15:57:05","publishedOnDateReadable":"October 7th, 2024"},"versionCreatedAt":"2024-04-22 02:47:19","video":"","vorDoi":"10.1038/s41598-024-73004-8","vorDoiUrl":"https://doi.org/10.1038/s41598-024-73004-8","workflowStages":[]},"version":"v1","identity":"rs-4239620","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4239620","identity":"rs-4239620","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}