key: cord-0776809-jxugukdi
authors: Bruxvoort, Katia J; Ackerson, Bradley; Sy, Lina S; Bhavsar, Amit; Tseng, Hung Fu; Florea, Ana; Luo, Yi; Tian, Yun; Solano, Zendi; Widenmaier, Robyn; Shi, Meng; Van Der Most, Robbert; Schmidt, Johannes Eberhard; Danier, Jasur; Breuer, Thomas; Qian, Lei
title: Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in older adults
date: 2021-12-28
journal: J Infect Dis
DOI: 10.1093/infdis/jiab633
sha: 08afcde1cd28ecad3d22790c1018411583381513
doc_id: 776809
cord_uid: jxugukdi

BACKGROUND: Some vaccines elicit non-specific immune responses that may protect against heterologous infections. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and COVID-19 outcomes at Kaiser Permanente Southern California. METHODS: In a cohort design, adults aged ≥50 years who received ≥1 RZV dose before 3/1/2020 were matched 1:2 to unvaccinated individuals and followed until 12/31/2020. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive SARS-CoV-2 test and controls had only negative tests, during 3/1/2020-12/31/2020. Adjusted odds ratios (aOR) and 95% CIs for RZV receipt were estimated using logistic regression. RESULTS: In the cohort design, 149,244 RZV recipients were matched to 298,488 unvaccinated individuals. The aHRs (95% CI) for COVID-19 diagnosis and hospitalization were 0.84 (0.81-0.87) and 0.68 (0.64-0.74), respectively. In the test-negative design, 8.4% of 75,726 test-positive cases and 13.1% of 340,898 test-negative controls had received ≥1 RZV dose. The aOR (95% CI) was 0.84 (0.81-0.86). CONCLUSION: RZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization. Further study of vaccine-induced non-specific immunity for potential attenuation of future pandemics is warranted.

A c c e p t e d M a n u s c r i p t 4 Background 24 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes 25 coronavirus disease 2019 (COVID-19) triggered a global pandemic with >270 million 26 infections and >5 million deaths. [1] Despite extraordinarily rapid development of highly 27 efficacious COVID-19 vaccines, nearly 12 months elapsed before vaccine 28 implementation, [2] and only 47% of the global population was fully vaccinated as of 29 December 2021. [1] 30 Traditionally, immune memory consisting of pathogen-specific cellular and humoral 31 responses is the hallmark of the adaptive response. However, a growing body of 32 evidence suggests that the innate immune system can develop trained immunity which 33 can ameliorate a broad array of infectious diseases, sometimes for prolonged 34 periods. [3] [4] [5] Several studies of Bacillus Calmette-Guérin (BCG), measles, oral polio, 35 and influenza vaccines demonstrate the ability of the innate immune system to provide 36 non-specific protection against heterologous infections. [4] [5] [6] 37 Recombinant adjuvanted zoster vaccine (RZV) contains AS01 adjuvant, which elicits an 38 innate immune response and robust cellular and humoral responses. [7] We 39 hypothesized that RZV could induce trained immunity that might reduce SARS-CoV-2 40 infections in older adults. Therefore, we evaluated the association of RZV receipt with 41 COVID-19 diagnosis and hospitalization.

Study setting 44 We employed matched cohort and test-negative designs in an observational study 45 conducted at Kaiser Permanente Southern California (KPSC), an integrated health care A c c e p t e d M a n u s c r i p t 5 system with 15 M a n u s c r i p t 6 We identified clinical characteristics in the year before 3/1/2020 including: body mass Test-negative design 90 The test-negative design included individuals tested for SARS-CoV-2 during 3/1/2020-91 12/31/2020, who had ≥1-year prior membership and were aged ≥50 years. Test-positive M a n u s c r i p t 7 cases were defined as the first positive test for individuals with any positive tests, and 93 test-negative controls were defined as the first negative test for individuals with only 94 negative tests. Separate analyses were conducted defining the exposure as receipt ≥14 95 days before the SARS-CoV-2 test of ≥1 RZV dose or of 2 RZV doses ≥4 weeks apart. 96 We described characteristics of test-positive cases and test-negative controls in the 97 year before their SARS-CoV-2 test date, using similar methods as for the cohort design. 98 We used logistic regression to estimate adjusted odds ratios (aOR) and 95% CI 99 comparing odds of RZV vaccination among test-positive cases and test-negative 100 controls. We also conducted analyses stratifying the RZV exposure by time from most 101 recent RZV dose to SARS-CoV-2 test (15 days to <1 month, 1 to <6 months, 6 months 102 to <1 year, and ≥1 year).

The KPSC Institutional Review Board approved the study, waiving the requirement of 104 informed consent.

Cohort design 107 The cohort design with ≥1 RZV dose as the exposure included 149,244 RZV vaccinated 108 and 298,488 matched unvaccinated individuals (Table 1) . Overall, 16.2% were aged 50-109 59 years and 12.8% were ≥80 years, 57.8% were female, and 54.1% were non- Table 2) . 127 In sensitivity analyses among individuals who had received influenza vaccine but no 128 other vaccines, we observed similar results ( observed in children. [15] 185 Our study found a durable reduction in the risk of COVID-19 diagnosis following receipt 186 of RZV vaccine, consistent with the durable protection against heterologous infections 187 provided by trained immunity. [6] It is possible that the AS01 adjuvant in RZV, which 188 activates innate immune responses, may be associated with the reduced risk of COVID- 189 19 diagnosis and hospitalization observed in this study. [7, 16, 17] Our findings support A c c e p t e d M a n u s c r i p t 18 

WHO Coronavirus (COVID-19) Dashboard. Available at

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Commentary: Test-negative design reduces confounding by healthcareseeking attitude in case-control studies

≥1 RZV dose N=149244 N=298488

Abbreviations: COVID-19, coronavirus disease

RZV, recombinant zoster vaccine a Adjusted for covariates: body mass index, smoking, number of outpatient visits, hypertension (model for ≥1 RZV dose and 1 RZV dose only), and other vaccinations

A c c e p t e d M a n u s c r i p t 14 A c c e p t e d M a n u s c r i p t 20