What is the link between influenza vaccination and the severity of COVID-19 infection?

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Aug 25 2022

In a recent study published in Scientific Reports, researchers performed a systematic review and meta-analysis to investigate whether influenza vaccinations could reduce coronavirus disease 2019 (COVID-19) severity outcomes.

Background

Studies have reported potential mechanisms for the protective efficacy of influenza vaccinations against SARS-CoV-2 infection severity, including (i) the presence of MF59 adjuvant in influenza vaccines, which potentiates anti-SARS-CoV immune responses, and (ii) influenza vaccines could stimulate innate immunological memory cells primed for immune responses against other respiratory pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and (iii) influenza A virus and SARS-CoV-2 interact with tetraspanin antibodies and angiotensin-converting enzyme 2 (ACE2). However, results on the potential protection against COVID-19 severity by influenza vaccines have been contradictory.

About the study

In the present systematic review and meta-analysis, researchers assessed the association between influenza vaccinations and COVID-19 severity.

Databases such as PubMed, Embase, Scopus, OVID, Cochrane Central, and Web of Science were searched till August 5, 2021. Additionally, the team manually searched for relevant studies from google scholar and references to the included studies. The analysis was performed in accordance with MOOSE (meta-analysis of observational studies in epidemiology) and PRISMA-P (preferred reporting items for systematic review and meta-analysis protocols) guidelines.

Studies were included if (i) they were observational prospective or retrospective studies (cohort and case-control type), (ii) were conducted on COVID-19 patients, and (iii) compared SARS-CoV-2-positive patients who were administered influenza vaccines and SARS-CoV-2-positive patients were not administered influenza vaccines.

Studies were excluded if (i) health-related outcomes were not reported, (ii) influenza vaccinations were not the exposure, (iii) included patients without confirmed COVID-19 diagnosis, (iv) ecological type studies (v) data was untrusted or duplicated, (vi) studies published in non-English languages, (vii) conference abstracts, book chapters, editorials, letters, commentaries, and animal studies.

Studies included were reviewed independently by two reviewers, data were extracted by four reviewers, and disagreements were resolved by an additional reviewer. Data were obtained on information summary of eligible studies, study design, country, number of COVID-19 patients, influenza vaccinees, vaccination year, and SARS-CoV-2 testing reports. Patient data on demographics, comorbidities, outcomes such as mortality rates, hospitalizations, intensive care unit (ICU) admissions, duration of hospitalization, duration of ICU admission, mechanical ventilation requirements, and COVID-19-associated pneumonia and symptom incidence.

The quality of included studies was assessed using the Newcastle–Ottawa Scale (NOS), and a subgroup analysis was performed for mortality rates by geographically stratifying patients as those residing in Italy, the United States of America (USA), and other nations. Dichotomous and continuous data were obtained and pooled as risk ratio (RR) and mean difference (MD), respectively. Fixed and random effects models were used for homogeneous data and heterogeneous data, respectively.

Results

A total of 6058 records and 450 records from databases and other data sources, respectively, were identified, of which only 23 full-text articles were assessed for eligibility after the removal of duplicate records (n=4690), studies conducted on SARS-CoV-2-negative patients (n=4), duplicate studies (n=1), commentaries (n=1) or letters to the editor (n=1). As a result, 16 and 13 studies were included in the qualitative analysis (systematic review) and quantitative analysis (meta-analysis), respectively.

The review comprised cohort studies (n=14) and case-control studies (n=2) comprising 244,642 individuals, of whom 191,496 individuals were SARS-CoV-2-positive. The studies were conducted in Italy (n=6), the USA (n=5), Poland, Brazil, Iran, England, and Spain. On the basis of the NOS scale, nine studies (out of 16) were allocated full scores, whereas the remaining seven studies were scored eight (out of nine), and all the included studies had low bias risks.

Regarding mechanical ventilation requirements, the analysis results significantly favored the patients who had received influenza vaccines over those who did not receive influenza vaccines (RR= 0.7). However, no significant differences were observed between vaccinated and unvaccinated patients in mortality rates (RR= 1.2), hospitalizations (RR= 1.0), and intensive care unit (ICU) admissions (RR= 0.8). After the subgroup analysis, the results remained non-significant for individuals residing in the USA (RR=0.8), Italy (RR=1.9), and other nations (RR=1.0).

Conclusions

Overall, the study findings significantly favor mechanical ventilation for influenza-vaccinated SARS-CoV-2 patients who received influenza vaccines over the unvaccinated SARS-CoV-2-positive patients. However, no statistically significant differences between the influenza-vaccinated and unvaccinated SARS-CoV-2-positive patients in mortality rates, hospitalizations, duration of hospitalization, ICU admissions, ICU duration, and development of COVID-19 symptoms.

However, the study has a few limitations, such as (i) the inclusion of the retrospective type of studies, (ii) data heterogeneity, and (iii) viral infections apart from COVID-19 were not assessed in the majority of the included studies. The importance of vaccinations against influenza must not be overlooked in the COVID-19 pandemic. Further research must be conducted, including high-quality RCTs (randomized controlled trials), to explore further the efficacy of regularly-updated influenza vaccines against COVID-19 severity. Potential confounding factors such as socioeconomic status and health literacy must also be considered.