key: cord-0856312-90c6u8iw authors: Tayar, E.; Abdeen, S.; Alah, M. A.; Chemaitelly, H.; Bougmiza, I.; Ayoub, H.; Kaleeckal, A. H.; Latif, A. N.; Shaik, R. M.; Al-Romaihi, H. E.; Al-Thani, M. H.; Bertollini, R.; Abu-Raddad, L. J.; Al-Khal, A. title: Effectiveness of influenza vaccination against SARS-CoV-2 infection among healthcare workers in Qatar date: 2022-05-10 journal: nan DOI: 10.1101/2022.05.09.22274802 sha: 33b3265efcd182ee467f3d38e1ea18e0673ebc89 doc_id: 856312 cord_uid: 90c6u8iw A number of studies reported that influenza vaccination is associated with lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or coronavirus disease 2019 (COVID-19) morbidity and mortality. We conducted a matched, test-negative, case-control study to estimate effectiveness of influenza vaccination, using Abbott quadrivalent Influvac Tetra vaccine, against SARS-CoV-2 infection and against severe COVID-19. The study was implemented on a population of 30,774 healthcare workers (HCWs) in Qatar during the 2020 annual influenza vaccination campaign, between September 17, 2020 and December 31, 2020, before introduction of COVID-19 vaccination. The median age in the matched samples was 36 years (interquartile range (IQR), 32-44) for cases and 35 years (IQR, 32-42) for controls. The median duration between influenza vaccination and the PCR test was 43 days (IQR, 29-62). The estimated effectiveness of influenza vaccination against SARS-CoV-2 infection >14 days after receiving the vaccine was 29.7% (95% CI: 5.5- 47.7%). The estimated effectiveness of influenza vaccination against any severe, critical, or fatal COVID-19 was 88.9% (95% CI: 4.1-98.7%). Sensitivity analyses confirmed main analysis results. Recent influenza vaccination is associated with an appreciable reduction in the risk of SARS-CoV-2 infection and COVID-19 severity. Influenza vaccination protects against influenza infection and reduces the morbidity and mortality of seasonal influenza 1 . This vaccination is strongly recommended for high-risk groups such as the elderly and healthcare workers (HCWs) 2 . A number of studies have reported that influenza vaccination is also associated with lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or coronavirus disease 2019 (COVID-19) morbidity and mortality 3-12 . However, reported apparent protection against SARS-CoV-2 infection and severe COVID-19 could have arisen due to bias and may not have reflected a genuine biological effect. In particular, this protection may have been due to the healthy user effect 13 , whereby health-aware persons are more likely to receive an influenza vaccine, and simultaneously, to practice health behaviors that reduce their risk of acquiring the infection 3,5 . Against this background, we assessed the effectiveness of influenza vaccination, using Abbott's quadrivalent Influvac Tetra vaccine, against SARS-CoV-2 infection and against any severe (acute-care hospitalization), 14 critical (intensive-care-unit hospitalization), 14 or fatal 15 among HCWs in Qatar during the 2020 annual influenza vaccination campaign, and before introduction of COVID-19 vaccination. Since variation in health behaviors among HCWs is presumably less than that among the general population, conducting this study among HCWs allowed us to minimize the influence of the healthy user effect on effectiveness estimates. This study was conducted among HCWs at Hamad Medical Corporation, the principal provider of public healthcare services in Qatar and the nationally designated entity for COVID-19-related COVID-19 vaccination campaign. During the study, SARS-CoV-2 incidence was due to the original SARS-CoV-2 virus, before introduction of SARS-CoV-2 variants of concern 29-32 . SARS-CoV-2 incidence was also relatively low during the study with no wave materializing during this time 33 . To estimate effectiveness against SARS-CoV-2 infection, we exact-matched cases (HCWs with PCR-positive tests) and controls (HCWs with PCR-negative tests) identified during the study in a 1:5 ratio by sex, 10-year age groups, 10-nationality groups, reason for PCR testing, and biweekly PCR test date, to control for known differences in SARS-CoV-2 exposure risk in Qatar 16, [33] [34] [35] [36] . Matching by these factors was shown previously in studies of different epidemiologic designs to provide adequate control of differences in the risk of exposure to SARS-CoV-2 infection in Qatar 17, 20, 22, 25, 37 . Only the first PCR-positive test for the cases and the first PCR-negative test for the controls during the study were included in the analysis. Controls included individuals with no record of a PCR-positive test during the study period. HCWs with a PCR test within 14 days after receiving the influenza vaccine and those who received COVID-19 vaccination were excluded. These inclusion and exclusion criteria were implemented to allow adequate time for build-up of immunity after vaccination 19 , and to minimize different types of potential bias, as informed by earlier analyses in the same population 17, 25 . Every control that met the inclusion criteria and that could be matched to a case was included in the analysis. Classification of COVID-19 case severity 14 , criticality 14 , and fatality 15 followed World Health Organization guidelines, and assessments were made by trained medical personnel using individual chart reviews, as part of a national protocol applied to every hospitalized COVID-19 patient. Details of COVID-19 severity, criticality, and fatality classifications are found in Supplementary Section S1. Every hospitalized COVID-19 patient underwent infection severity assessment every three days until discharge or death. We classified individuals who progressed to severe, critical, or fatal COVID-19 between the time of the PCR-positive test and the end of the study based on their worst disease outcome, starting with death 15 , followed by critical disease 14 , and then severe disease 14 . Details of laboratory methods for real-time reverse-transcription PCR (RT-qPCR) testing are found in Supplementary Section S2. All PCR testing was conducted at the Hamad Medical Corporation Central Laboratory or at Sidra Medicine Laboratory, following standardized protocols. Baseline characteristics of cases and controls were reported using descriptive statistics. Groups were compared using standardized mean differences (SMDs), with SMD close to 0.1 indicating adequate matching 38 . Conditional logistic regression factoring the matched design was performed to compare the odds of influenza vaccination in cases versus controls. This analytical approach, including matching by bi-weekly PCR test date, minimizes potential bias due to variation in epidemic phase 23, 39 and roll-out of vaccination during the study 23, 39 . Interactions were not considered. The resulting estimates for the adjusted odds ratio and 95% confidence interval (CI) were then used to estimate influenza vaccination effectiveness and corresponding 95% CI using the equation 23, 24 : All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Effectiveness was estimated against SARS-CoV-2 infection, whether symptomatic or asymptomatic, and against any severe, critical, or fatal COVID-19. Sensitivity analyses were conducted to investigate the impact of adjusting for prior infection in the conditional logistic regression, and of modifying the study inclusion and exlusion criteria on the estimate of influenza vaccination effectiveness. The latter was informed by an established analysis plan to invistigate sources of potential bias 17, 25 , guidelines. The STROBE checklist can be found in Table S1 . Figure 1 shows the process of selecting the study population. Of 30,774 HCWs at Hamad Medical Corporation, 12,015 had one or more SARS-CoV-2 PCR tests between September 17, 2020 and December 31, 2020. Of these, 576 HCWs with a PCR-positive test and 10,033 with exlusively PCR-negative tests were egligible for inclusion in the study. Exact-matching on a 1:5 ratio yielded 518 cases matched to 2,058 controls. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 10, 2022. ; Table 1 describes the demographic characteristics of cases and controls. The median age was 36 years (interquartile range (IQR), 32-44) for cases and 35 years (IQR, [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] for controls in the matched samples. Slightly less than half (~ 46%) of cases and controls were males. Participants were of diverse nationalities, and nearly two-thirds were tested because of COVID-like symptoms. Matched study groups were well balanced across the matching factors. The median duration between influenza vaccination and the PCR test was 43 days (IQR, 29-62). The estimated effectiveness of influenza vaccination against SARS-CoV-2 infection >14 days after receiving the vaccine was 29.7% (95% CI: 5.5-47.7%). All sensitivity analyses yielded consistent results confirming main analysis results (Table 2) . Of the 127 PCR-positive cases who received influenza vaccination in the matched samples, only 1 progressed to severe, but none to critical or fatal COVID-19 ( Figure 1 ). Meanwhile, of the 391 PCR-positive cases who did not receive influenza vaccination, 17 progressed to severe, 2 to critical, but none to fatal COVID-19. The estimated effectiveness of influenza vaccination against any severe, critical, or fatal COVID-19 was 88.9% (95% CI: 4.1-98.7%; Table 2 ). Recent influenza vaccination was associated with a 30% reduction in the risk of SARS-CoV-2 infection by the original virus, before introduction of variants of concern. Recent influenza vaccination was also associated with a 90% reduction in the risk of severe COVID-19, but the 95% confidence interval of the effectiveness estimate was wide. Incidence of severe COVID-19 was rare among those vaccinated, with only one case of severe COVID-19 documented among them. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. These results for a HCW population where the influence of the healthy user effect is perhaps minimized, support the conclusion that recent influenza vaccination has a genuine biological effect in protecting against SARS-CoV-2 infection and COVID-19 severity. The findings also corroborate findings of studies that found similar protective effects for influenza vaccination 3-12 , though other studies did not 40, 41 . These findings may be explained by influenza vaccination triggering a nonspecific immune activation, or trained or bystander immunity that is protective against SARS-CoV-2 infection 3-5,7,42-47 . This study has limitations. Effectiveness of only recent influenza vaccination was investigated. The analysis did not factor influenza vaccination from prior seasons. However, given that nonspecific immune activation may not last beyond few weeks, and in context of the relatively rapid waning of COVID-19 vaccine immunity 17, 25, [48] [49] [50] , the observed effectiveness of influenza vaccination is likely short lived. Matching was done for sex, age, nationality, reason for PCR testing, and bi-weekly PCR test date, but it was not possible for other factors, such as comorbidities. However, matching by these factors successfully controlled bias in our earlier studies 17, 20, 22, 25, 37 . The majority of HCWs in our sample were also young and less likely to be affected by comorbidities. Nonetheless, one cannot exclude the possibility that in real-world data, bias could arise in unexpected ways, or from unknown sources, such as subtle differences or changes in test-seeking behavior. With the young and occupational nature of our population, these findings may not generalize to the elderly population or to the wider general population. Notwithstanding these limitations, extensive sensitivity and additional analyses were conducted to investigate effects of potential bias in this study and in our earlier studies that used the same methodology. These included different adjustments and controls in the analysis and different All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.09.22274802 doi: medRxiv preprint study inclusion and exclusion criteria, to investigate whether effectiveness estimates could have been biased 17, 25 . These analyses showed consistent findings 17, 25, 28, 51, 52 . In conclusion, recent influenza vaccination is associated with an appreciable reduction in the risk of SARS-CoV-2 infection and COVID-19 severity. The findings support benefits for influenza vaccination that extend beyond protection against influenza infection and severe disease. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Abbreviations: IQR, interquartile range; PCR, polymerase chain reaction; SMD, standardized mean difference. * Cases and controls were exact-matched on a 1:5 ratio by sex, 10-year age group, 10 nationality groups, reason for PCR testing, and bi-weekly PCR test date. † SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. ‡ SMD reported here is for the mean difference between groups divided by the pooled standard deviation. § Nationalities were chosen to represent the most numerous groups in the population of Qatar. ¶ There were 22 other nationalities in the total case population, 74 other nationalities in the total control population, 22 other nationalities among matched cases, and 38 other nationalities among matched controls. Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; PCR, polymerase chain reaction. * Cases and controls were exact-matched on a 1:5 ratio by sex, 10-year age group, 10 nationality groups, reason for PCR testing, and bi-weekly PCR test date. † Vaccine effectiveness was estimated using the test-negative, case-control study design 23, 24 . ‡ Severity 14 , criticality 14 , and fatality 15 were defined as per World Health Organization guidelines. Nasopharyngeal and/or oropharyngeal swabs were collected for PCR testing and placed in Universal Transport Medium (UTM). Aliquots of UTM were: extracted on a QIAsymphony platform (QIAGEN, USA) and tested with real-time reverse-transcription PCR (RT-qPCR) using TaqPath™ COVID-19 Combo Kits (Thermo Fisher Scientific, USA) on an ABI 7500 FAST (Thermo Fisher, USA); tested directly on the Cepheid GeneXpert system using the Xpert Xpress SARS-CoV-2 (Cepheid, USA); or loaded directly into a Roche cobas® 6800 system and assayed with a cobas® SARS-CoV-2 Test (Roche, Switzerland). The first assay targets the viral S, N, and ORF1ab gene regions. The second targets the viral N and E-gene regions, and the third targets the ORF1ab and E-gene regions. Medicine Laboratory, following standardized protocols. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses Results, paragraph 3 & Table 2 Discussion All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based Sources of support and acknowledgements All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.09.22274802 doi: medRxiv preprint 20200420-EN.pdf?ua=1. Document Number: WHO/HQ/DDI/DNA/CAT. 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