Does the anti-influenza vaccination protect against SARS-CoV-2 infection?

In a recent study posted to the SSRN* preprint server, researchers performed a meta-analysis to evaluate the effect of influenza vaccination on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization, and associated mortality.

Study: Effect of Vaccination Against Influenza Viruses on Infection, Hospitalization, and Death from Respiratory COVID-19: A Systematic Review and Meta-Analysis. Image Credit: InsideCreativeHouse/Shutterstock.com

*Important notice: SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The coronavirus disease 2019 (COVID-19) pandemic has significantly strained health and society, notably concerning cardiovascular tissues.

Social distancing and isolation measures have been enforced to curtail SARS-CoV-2 transmission. Anti-flu vaccinations are strongly advised to prevent co-infections with SARS-CoV-2 and influenza viruses and lower the chance of increased severity.

Although influenza rates were very low after the initial COVID-19 waves, sporadic studies indicate that anti-influenza vaccination may have influenced the onset and severity of SARS-CoV-2 infections.

About the study

In the present meta-analysis, researchers investigated whether influenza vaccines protect against COVID-19 incidence and its severity outcomes, such as hospitalization and death.

The meta-analysis included retrospective and prospective, case-control and cohort studies published in English, reporting COVID-19, associated hospitalization, ICU admission, and deaths among anti-Flu vaccinated and unvaccinated individuals.

Data were searched independently by three researchers in databases such as Cochrane Library, PubMed, and Embase from inception through 31 January 2023, and discrepancies were sought by discussion.

In addition, studies were searched manually through the references cited in reviews. Sensitivity analyses were performed to assess the effects of vaccination among healthcare providers, the general public, the elderly, pregnant women, and diseased individuals; to evaluate the impact of different vaccines; and to assess the distance of vaccination against influenza to the outcome of interest.

The team excluded editorials, descriptive studies, reviews, case reports, systematic reviews, meta-analyses, and studies with missing effect sizes or risk ratios.

The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to determine the quality of evidence. Random-effects modeling was performed to calculate the odds ratios (ORs) and compare the study endpoints (COVID-19 development, hospital admission, ICU admission, and death) among vaccinated and unvaccinated participants.

Covariates for data adjustment included the number of enrolled individuals, participant age, study type, diagnostic method, vaccine type, and evidence quality.

Results and discussion

In total, 33 research papers were analyzed, including 33, 14, 11, and 19 records for COVID-19 development, hospitalization, ICU admission, and mortality, respectively. The studies included 61,029,936 individuals, among whom 15,950,169 had received influenza vaccines.

The team found significant effects of anti-Flu vaccinations on the frequency of coronavirus disease 2019 and related ICU admissions but not on SARS-CoV-2-associated hospital admissions and deaths.

The findings were significant among healthcare providers, the general public, the elderly, and sick individuals. The immune protection against SARS-CoV-3 infections among tetravalent anti-Flu vaccinees was statistically significant in all studies, among healthcare providers and the general public.

The inverse associations between the distance from influenza vaccination with the tetravalent Flu vaccines and COVID-19 showed synergistic effects.

Anti-influenza vaccines reduced COVID-19 and related ICU admission frequencies; however, the effect size of protection against COVID-19 severity was small, despite being significant for pregnant females, the general public, and hospitalized individuals aged below 50.0 years.

NOS scores were high for most studies, indicating good quality of evidence; however, the included studies had high heterogeneity.

The COVID-19-causing virus and influenza viruses are distinct pathogens but share transmission routes and pulmonary symptoms. Anti-Flu vaccines may be protective due to trained immunity, which potentiates innate immunological responses by neutrophils, dendritic cells, and macrophages through memory-like feature induction.

The memory-led response increases protection on encounters with similar or unrelated microbes. Vaccines influence adaptive immunity, affecting humoral and cell-mediated lymphocytes.

Anti-Flu vaccines potentiate the action of natural killer (NK) lymphocytes, innate immunological lymphocytes that swiftly respond to infection and shape adaptive responses regulated by T lymphocytes.

Activated NK lymphocytes are a crucial source of interferon-gamma (IFN-γ), which instructs cytotoxic cluster of differentiation 8-positive (CD8+) T lymphocyte contraction and expansion as adaptive immunological responses to various pathogens, such as viruses. IFNs may be vital in affecting the interactions between anti-influenza vaccinations and COVID-19.

Different forms of IFNs are generated in the pulmonary tissues of SARS-CoV-2-positive patients, and the transitory activation of IFNs following influenza A virus (IAV) or viral subtype contacts may impair the host’s ability to regulate SARS-CoV-2 infections.

Anti-influenza vaccines stimulate IFNs to varying degrees, implying that the wide range of IFNs generated as a response to anti-flu vaccines “interfere” with viral propagation and reproduction and may confer cross-protection to recently vaccinated individuals.

Conclusion

Overall, the study findings highlighted the protective effects of anti-influenza vaccines against COVID-19; however, the results were small in magnitude and faded over time.

*Important notice: SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.