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    Topic review

    Influenza Vaccination and COVID-19

    Subjects: Others
    View times: 17
    Submitted by: Jue Liu

    Definition

    Influenza could circulate in parallel with COVID-19. In the context of COVID-19, some studies observed inverse associations between influenza vaccination and SARS-CoV-2 infection and clinical outcomes, while others did not. We conducted a meta-analysis to assess the association between influenza vaccination and SARS-CoV-2 infection and clinical outcomes, aiming to provide evidence for COVID-19 prevention and vaccination promotion. We searched four databases from inception to 10 March, 2021. Random effects and fixed effects models were used to pool odds ratios (ORs) and adjusted estimates with 95% confidence intervals (CIs).

    1. Introduction

    The coronavirus disease (COVID-19) is an acute respiratory infectious disease that was declared a global public health emergency by the World Health Organization (WHO) in January 2020 [1]. The global pandemic has hitherto caused 119 million cases of infection and 2 million cases of death [1], and imposed tremendous burden on global health and worldwide economics. Thus, effective cures and vaccines are imperatively needed to curtail the pandemic and decrease mortality. Seasonal influenza occurs from fall to spring annually, characterized by the circulation of influenza A or B virus [2]. Influenza and its complications could lead to increased worldwide mortality and morbidity, which remain a public health threat.
    Due to the seasonality of influenza outbreaks and the continuous prevalence of COVID-19, influenza could circulate in parallel with COVID-19, which largely increases the potential risk of co-infection. Though little is known about the epidemiology and clinical outcomes of co-infection, extant literature has found that the co-infection with influenza A virus enhances the infectivity of COVID-19 in a broad range of cell types [3], whereas co-infected patients seem to present similar clinical symptoms and radiological images compared with patients infected with COVID-19 alone [4][5]. In the context of the COVID-19 pandemic, the dual infection of influenza and COVID-19 could bring extra burden to health care services by utilizing limited medical resources, increasing the difficulty of treatment and the uncertainty of prognosis. Annual influenza vaccination has long been recommended by WHO to prevent influenza, especially to the high-risk populations with disproportionate infection and severe complications, such as older adults (aged > 65 years) and pregnant women [6]. To date, no highly effective pharmaceutical treatment is available against COVID-19 [7]. Though COVID-19 vaccines remain the most effective long-term solution to combat COVID-19 pandemic [8], the overall effectiveness and safety of the licensed COVID-19 vaccines remain to be fully evaluated based on real-world evidence.
    According to a previous study by Wolff [9], which investigated influenza vaccine-related virus interference by specific respiratory viruses (e.g., coronavirus, human bocavirus, and adenovirus), there was an increased odd of coronavirus in individuals receiving influenza vaccination. This finding raised much concerns of the possible relationship between influenza vaccination and coronavirus, especially in the COVID-19 pandemic. In addition, as COVID-19 and influenza are both respiratory infectious diseases caused by enveloped RNA viruses that share similarities in transmission routes and clinical characteristics [10], more and more researchers began to seek for relationships between SARS-CoV-2 infection and influenza immunity. Based on the assumptions, Del Riccio et al. [11] conducted a systematic review and found that there was overall no evidence to suggest a negative impact of influenza vaccination on SARS-CoV-2 related infections, illness, or deaths, while some of the included studies even reported significantly inverse associations. Though some of the recent studies have found that influenza vaccine uptake was negatively associated with COVID-19 incidence [12][13], severity [13][14], and mortality [13][15], others showed no evidence of such associations [16][17][18]. Therefore, a systematic review and meta-analysis of the association between influenza vaccination and SARS-CoV-2 infection and its outcomes is needed to provide conclusive evidence.
    In the dual epidemics of COVID-19 and influenza, influenza vaccination has a more significant implication than ever for preventing both influenza and COVID-19. It is especially of great necessity for vulnerable populations to receive influenza vaccination. Given the limited data of COVID-19 vaccine effectiveness among vulnerable groups, as well as the necessity of influenza vaccination in the context of COVID-19, and the lack of conclusive evidence of influenza vaccination’s effect on SARS-CoV-2 infection and its clinical outcomes, there is a need to systematically assess the potential association between influenza vaccination and COVID-19.

    2. Study Selection and Study Characteristics

    A total of 2895 records were retrieved from the four databases and 1467 duplicates were excluded. After screening titles and abstracts, we excluded 1387 reviews, conference papers, animal experiments, case reports, and other studies irrelevant to the subject or published before December 2019. Among the 41 articles assessed based on full texts, 25 articles were excluded for lacking specific data or did not meet the inclusion criteria. A total of 16 studies were finally included in the review (12 studies on the association between influenza vaccination and SARS-CoV-2 infection [16][18][19][20][21][22][23][24][25][26][27][28], 6 on the association between influenza vaccination and COVID-19 clinical outcomes [10][17][20][24][29][30], 2 studies containing data on both the associations [20][24]. Nine of the 12 studies on the association between influenza vaccination and SARS-CoV-2 infection contained adjusted estimates. One [19] of the 16 studies has moderate risk of bias, while the others have low risk of bias. The primary outcome (the association between influenza vaccination and SARS-CoV-2 infection) comprised a total of 208,132 people (72,820 vaccinated and 135,112 unvaccinated). The secondary outcome (the association between influenza vaccination and clinical outcomes of SARS-CoV-2 infection) comprised a total of 82,684 COVID-19 patients and was assessed by different outcomes (mortality, intensive care, and hospitalization). The study selection procedure is shown in Figure 1. The baseline characteristics of the included studies are listed in Table 1 (primary outcome) and Table 2 (secondary outcome). The adjusted variables of the included studies were basically age, sex, comorbidities, prescribed medications and smoking status, but were not the same across studies (see Table 1 and Table 2).
    Figure 1. PRISMA flow diagram of the study selection procedure.
    Table 1. Baseline characteristics of the 12 included studies that assessed the association between influenza vaccination and SARS-CoV-2 infection.
    Study Study Design Vaccination Season Identification of COVID-19 Country Sample Size Infected (n)/Vaccinated(n) Infected (n)/Unvaccinated (n) Adjusted Estimate (95%CI) Quality Score and Risk of Bias Assessment Adjusted Factors
    Massoudi et al., (2021) [19] Case-control study 2019–2020 pulmonologist-confirmed Iran 261 3/90 77/171 - 6(moderate) -
    Kissling et al., (2021) [18] Case-control study 2019–2020 rt-PCR Europe a 1701 68/429 157/1272 0.93 (0.66–1.32) 8 (low) Study site, time, age, sex, and chronic condition
    Ragni et al., (2020) [20] Case-control study 2019–2020 rt-PCR Italy 17,608 1676/5427 3209/12,181 0.89 (0.80–0.99) 9 (low) Age, sex, Charlson index, and time of the swab test
    Belingheri et al., (2020) [21] Cross-sectional study 2019–2020 rt-PCR Italy 3520 28/817 100/2703 0.41 (0.07–2.39) 7 (low) Age, sex, and an interaction term between age and the vaccination intake in 2019/3020
    Vila-Córcoles et al., (2020) [22] Retrospective cohort study 2019–2020 rt-PCR Spain 1547 189/705 160/842 0.63 (0.43–0.92) b 8 (low) Age, sex, and comorbidities
    Pawlowski et al., (2021) [24] Retrospective cohort study 2019–2020 rt-PCR America 25,582 442/12,791 521/12,791 - 8 (low) -
    Jehi et al., (2020) [25] Prospective cohort study -c rt-PCR America 11,672 384/6324 434/5348 - 7 (low) -
    Vila-Córcoles et al., (2020) d [23] Retrospective cohort study 2019–2020 rt-PCR Spain 78,883 205/22,606 175/56,277 1.02 (0.79–1.32) b 7 (low) Age, sex, comorbidities, and medications use.
    Martínez-Baz et al., (2020) e [16] Prospective cohort study 2019–2020 rt-PCR Spain 10,714 155/3677 248/7037 1.03 (0.83–1.27) 7 (low) Age groups, sex, major chronic conditions, profession, and any ILI diagnosis in the previous five years
    Noale et al., (2020) [26] Cross-sectional study 2019–2020 rt-PCR Italy 6680 562/2246 1114/4434 0.89 (0.78–1.01) 8 (low) Age, sex, education, area of residence, self-reported comorbidities, and smoking status
    Green et al., (2020) [27] Cross-sectional study 2019–2020 rt-PCR Israel 22,563 244/4711 1580/17,852 0.79 (0.67–0.98) 9 (low) Age, ethnic, smoking status, socioeconomic status, and comorbidities
    Conlon et al., (2021) [28] Retrospective cohort study 2019–2020 rt-PCR America 27,201 525/12,997 693/14,204 0.76 (0.68–0.86) 8 (low) Ethnicity, race, sex, age, BMI, Elixhauser score, smoking status, and comorbidities
    Table 2. Baseline characteristics of the six included studies that assessed the association between influenza vaccination and SARS-CoV-2 outcomes.
    Study Study Design Vaccination Season Identification of COVID-19 Country Sample Size Events (n)/Vaccinated(n) Events (n)/Unvaccinated (n) Adjusted Estimate (95%CI) Quality Score and Risk of Bias Assessment Adjusted Factors
    Intensive Care  
    Pawlowski et al., (2020) [24] Retrospective cohort study 2019–2020 rt-PCR America 959 15/441 16/518 - 8 (low) -
    de la Cruz Conty et al., (2021) a [17] Prospective cohort study - b rt-PCR Spain 1150 7/438 15/712 - 7 (low) -
    Fink et al., (2020) [10] Retrospective cohort study - b Clinical diagnosisc Brazil 53,752 - - 0.93 (0.87–0.99) 7 (low) Age, sex, race, educational level, treatment facility, and comorbidities
    Yang et al., (2021) [30] Retrospective cohort study 2019–2020 rt-PCR America 2005 3/214 133/1791 0.30 (0.07–0.85) 8 (low) Age, sex race/ethnicity, hypertension, and comorbidities
    Hospitalization  
    Pawlowski et al., (2020) [24] Retrospective cohort study 2019–2020 rt-PCR America 959 74/441 78/518 - 8 (low) -
    Yang et al., (2021) [30] Retrospective cohort study 2019–2020 rt-PCR America 2005 43/214 747/1791 0.41 (0.28–0.60) 8 (low) Age, sex race/ethnicity, hypertension, and comorbidities
    Ragni et al., (2020) [20] retrospective cohort study 2019–2020 rt-PCR Italy 17,608 - - 0.84 (0.83–1.29) d 7 (low) Age, sex, Charlson index, and time of the swab test
    Wilcox et al., (2021) e [29] retrospective cohort study 2019–2020 rt-PCR England 6921 1166/2613 1584/4308 0.85 (0.75–0.97) 8 (low) Age, sex, BMI, socioeconomic status, smoking status, frailty score, comorbidities, and the number of prescribed medications
    Mortality  
    Fink et al., (2020) [10] Retrospective cohort study - b Clinical diagnosis c Brazil 53,752 - - 0.84 (0.77–0.91) 7 (low) Age, sex, race, educational level, treatment facility, and comorbidities
    Ragni et al., (2020) [20] retrospective cohort study 2019–2020 rt-PCR Italy 17,608 - - 1.14 (0.95–1.37) d 7 (low) Age, sex, Charlson index, and time of the swab test
    Wilcox et al., (2021) [29] retrospective cohort study 2019–2020 rt-PCR England 6921 372/2613 553/4308 0.76 (0.64–0.90) 8 (low) Age, sex, BMI, socioeconomic status, smoking status, frailty score, comorbidities, and the number of prescribed medications

    3. The Association between Influenza Vaccination and COVID-19 and Its Outcomes

    The association between influenza vaccination and SARS-CoV-2 infection is presented in Figure 2 and Table 3. Influenza vaccination was shown to be associated with a lower risk of SARS-CoV-2 infection in both models (fixed effects model: pooled adjusted OR: 0.86, 95%CI: 0.81–0.91; random effects model: pooled adjusted OR: 0.86, 95%CI: 0.79–0.94).
    Figure 2. Forest plots for the association between influenza vaccination and SARS-CoV-2 infection: (A) adjusted OR by fixed effects model (B) adjusted OR by random effects model.
    Table 3. Summary of the overall association between influenza vaccination and SARS-CoV-2 infection and clinical outcomes.
    Outcomes Number of Studies I2 Value (%) p Value Adjusted Estimates a (95%CI)
    Fixed Effects Model Random Effects Model
    SARS-CoV-2 infection 9 41.1 0.09 0.86 (0.81–0.91) 0.86 (0.79–0.94)
    Intensive care 2 68.2 0.08 0.93 (0.87–0.99) 0.63 (0.22–1.81)
    Hospitalization 3 87.6 <0.01 0.84 (0.75–0.93) 0.74 (0.51–1.06)
    Mortality 3 82.5 <0.01 0.86 (0.81–0.93) 0.89 (0.73–1.09)
    The association between influenza vaccination and COVID-19 outcomes are presented in Table 3. The association between influenza vaccination and intensive care (adjusted OR: 0.63, 95%CI: 0.22–1.81), hospitalization (adjusted OR: 0.74, 95%CI: 0.51–1.06), or mortality (adjusted OR: 0.89, 95%CI: 0.73–1.09) among COVID-19 patients was not statistically significant by random effects model, while results by fixed effects model was somehow significant. This may be due to the substantial heterogeneity between the small number of studies (2–3 studies) and participants involved in each outcome.

    The entry is from 10.3390/vaccines9050529

    References

    1. World Health Organization. Weekly Epidemiological Update on COVID-19. Available online: (accessed on 10 April 2021).
    2. Nelson, M.I.; Tan, Y.; Ghedin, E.; Wentworth, D.E.; St George, K.; Edelman, L.; Beck, E.T.; Fan, J.; Lam, T.T.-Y.; Kumar, S.; et al. Phylogeography of the spring and fall waves of the H1N1/09 pandemic influenza virus in the United States. J. Virol. 2011, 85, 828–834.
    3. Bai, L.; Zhao, Y.; Dong, J.; Liang, S.; Guo, M.; Liu, X.; Wang, X.; Huang, Z.; Sun, X.; Zhang, Z.; et al. Coinfection with influenza A virus enhances SARS-CoV-2 infectivity. Cell. Res. 2021, 31, 395–403.
    4. Xiang, X.; Wang, Z.H.; Ye, L.L.; He, X.L.; Wei, X.S.; Ma, Y.L.; Li, H.; Chen, L.; Wang, X.R.; Zhou, Q. Co-infection of SARS-COV-2 and Influenza A Virus: A Case Series and Fast Review. Curr. Med. Sci. 2021, 41, 51–57.
    5. Konala, V.M.; Adapa, S.; Gayam, V.; Naramala, S.; Daggubati, S.R.; Kammari, C.B.; Chenna, A. Co-infection with Influenza A and COVID-19. Eur. J. Case. Rep. Intern. Med. 2020, 7, 001656.
    6. Buchy, P.; Badur, S. Who and when to vaccinate against influenza. Int. J. Infect. Dis. 2020, 93, 375–387.
    7. Liu, Y.; Morgenstern, C.; Kelly, J.; Lowe, R.; Jit, M. The impact of non-pharmaceutical interventions on SARS-CoV-2 transmission across 130 countries and territories. BMC Med. 2021, 19, 40.
    8. Moore, J.P.; Klasse, P.J. COVID-19 Vaccines: “Warp Speed” Needs Mind Melds, Not Warped Minds. J. Virol. 2020, 94, e01083-20.
    9. Wolff, G.G. Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017–2018 influenza season. Vaccine 2020, 38, 350–354.
    10. Fink, G.; Orlova-Fink, N.; Schindler, T.; Grisi, S.; Ferrer, A.P.S.; Daubenberger, C.; Brentani, A. Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil. BMJ Evid. Based Med. 2020, in press.
    11. Del Riccio, M.; Lorini, C.; Bonaccorsi, G.; Paget, J.; Caini, S. The Association between Influenza Vaccination and the Risk of SARS-CoV-2 Infection, Severe Illness, and Death: A Systematic Review of the Literature. Int. J. Environ. Res. Public Health 2020, 17, 7870.
    12. Cocco, P.; Meloni, F.; Coratza, A.; Schirru, D.; Campagna, M.; De Matteis, S. Vaccination against seasonal influenza and socio-economic and environmental factors as determinants of the geographic variation of COVID-19 incidence and mortality in the Italian elderly. Prev. Med. 2021, 143, 106351.
    13. Amato, M.; Werba, J.P.; Frigerio, B.; Coggi, D.; Sansaro, D.; Ravani, A.; Ferrante, P.; Veglia, F.; Tremoli, E.; Baldassarre, D. Relationship between Influenza Vaccination Coverage Rate and COVID-19 Outbreak: An Italian Ecological Study. Vaccines 2020, 8, 535.
    14. Arokiaraj, M.C. Considering Interim Interventions to Control COVID-19 Associated Morbidity and Mortality-Perspectives. Front. Public Health 2020, 8, 444.
    15. Marín-Hernández, D.; Schwartz, R.E.; Nixon, D.F. Epidemiological evidence for association between higher influenza vaccine uptake in the elderly and lower COVID-19 deaths in Italy. J. Med. Virol. 2021, 93, 64–65.
    16. Martínez-Baz, I.; Trobajo-Sanmartín, C.; Arregui, I.; Navascués, A.; Adelantado, M.; Indurain, J.; Fresán, U.; Ezpeleta, C.; Castilla, J. Influenza Vaccination and Risk of SARS-CoV-2 Infection in a Cohort of Health Workers. Vaccines 2020, 8, 611.
    17. De la Cruz Conty, M.L.; Encinas Pardilla, M.B.; Garcia Sanchez, M.; Gonzalez Rodriguez, L.; Muner-Hernando, M.L.; Royuela Vicente, A.; Pintado Recarte, P.; Martinez Varea, A.; Martinez Diago, C.; Cruz Melguizo, S.; et al. Impact of Recommended Maternal Vaccination Programs on the Clinical Presentation of SARS-CoV-2 Infection: A Prospective Observational Study. Vaccines 2021, 9, 31.
    18. Kissling, E.; Hooiveld, M.; Brytting, M.; Vilcu, A.M.; de Lange, M.; Martínez-Baz, I.; Sigerson, D.; Enkirch, T.; Belhillil, S.; Meijer, A.; et al. Absence of association between 2019-20 influenza vaccination and COVID-19: Results of the European I-MOVE-COVID-19 primary care project, March-August 2020. Influenza Other Respir. Viruses. in press.
    19. Massoudi, N.; Mohit, B. A Case–Control Study of the 2019 Influenza Vaccine and Incidence of COVID-19 among Healthcare Workers. J. Clin. Immunol. 2021, 41, 324–334.
    20. Ragni, P.; Marino, M.; Formisano, D.; Bisaccia, E.; Scaltriti, S.; Bedeschi, E.; Grilli, R. Association between Exposure to Influenza Vaccination and COVID-19 Diagnosis and Outcomes. Vaccines 2020, 8, 675.
    21. Belingheri, M.; Paladino, M.E.; Latocca, R.; De Vito, G.; Riva, M.A. Association between seasonal flu vaccination and COVID-19 among healthcare workers. Occup. Med. 2020, 70, 665–671.
    22. Vila-Córcoles, Á.; Ochoa-Gondar, O.; Torrente-Fraga, C.; Vila-Rovira, Á.; Satué-Gracia, E.; Hospital-Guardiola, I.; de Diego-Cabanes, C.; Gómez-Bertomeu, F.; Basora-Gallisà, J. Evaluation of incidence and risk profile for suffering Covid-19 infection by underlying conditions among middle-aged and older adults in Tarragona. Rev. Esp. Salud. Publica 2020, 94, e202006065.
    23. Vila-Córcoles, A.; Ochoa-Gondar, O.; Satué-Gracia, E.M.; Torrente-Fraga, C.; Gomez-Bertomeu, F.; Vila-Rovira, A.; Hospital-Guardiola, I.; de Diego-Cabanes, C.; Bejarano-Romero, F.; Basora-Gallisà, J. Influence of prior comorbidities and chronic medications use on the risk of COVID-19 in adults: A population-based cohort study in Tarragona, Spain. BMJ Open 2020, 10, e041577.
    24. Pawlowski, C.; Puranik, A.; Bandi, H.; Venkatakrishnan, A.J.; Agarwal, V.; Kennedy, R.; O’Horo, J.C.; Gores, G.J.; Williams, A.W.; Halamka, J.; et al. Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations. Sci. Rep. 2021, 11, 4741.
    25. Jehi, L.; Ji, X.; Milinovich, A.; Erzurum, S.; Rubin, B.P.; Gordon, S.; Young, J.B.; Kattan, M.W. Individualizing Risk Prediction for Positive Coronavirus Disease 2019 Testing: Results From 11,672 Patients. Chest 2020, 158, 1364–1375.
    26. Noale, M.; Trevisan, C.; Maggi, S.; Antonelli Incalzi, R.; Pedone, C.; Di Bari, M.; Adorni, F.; Jesuthasan, N.; Sojic, A.; Galli, M.; et al. The Association between Influenza and Pneumococcal Vaccinations and SARS-Cov-2 Infection: Data from the EPICOVID19 Web-Based Survey. Vaccines 2020, 8, 471.
    27. Green, I.; Ashkenazi, S.; Merzon, E.; Vinker, S.; Golan-Cohen, A. The association of previous influenza vaccination and coronavirus disease-2019. Hum. Vaccines Immunother. in press.
    28. Conlon, A.; Ashur, C.; Washer, L.; Eagle, K.A.; Hofmann Bowman, M.A. Impact of the influenza vaccine on COVID-19 infection rates and severity. Am. J. Infect. Control 2021, in press.
    29. Wilcox, C.R.; Islam, N.; Dambha-Miller, H. Association between influenza vaccination and hospitalisation or all-cause mortality in people with COVID-19: A retrospective cohort study. BMJ Open. Respir. Res. 2021, 8, e000857.
    30. Yang, M.J.; Rooks, B.J.; Le, T.T.; Santiago, I.O., 3rd; Diamond, J.; Dorsey, N.L.; Mainous, A.G., 3rd. Influenza Vaccination and Hospitalizations among COVID-19 Infected Adults. J. Am. Board Fam. Med. 2021, 34, S179–S182.
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