Influenza vaccination could boost immunity to COVID-19

A preprint study 1 published on 16 October 2020 suggests a protective effect of influenza vaccination against COVID-19 and offers. It is based on a survey carried out in a large Dutch hospital and on in-vitro work.

A preprint study1 published on 16 October 2020 suggests a protective effect of influenza vaccination against COVID-19 and offers. It is based on a survey carried out in a large Dutch hospital and on in-vitro work.

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In countries with a temperate climate, seasonal influenza epidemics usually start with the arrival of winter and continue throughout the season. In Europe, during the season the excess mortality (also known as mortality displacement) linked to influenza has been estimated at 125,000.

Several recent studies have suggested a potential beneficial effect of influenza vaccination on the susceptibility to COVID-19. Therefore, the authors of the cited study wanted to clarify this effect and understand its mechanisms. They analyzed the impact of influenza vaccination on SARS-CoV-2 infections and the severity of COVID-19 forms among employees of a university hospital in the Netherlands (located in the easter city of Nijmegen).

Caregivers vaccinated against influenza were less affected by COVID-19

Every year, all employees of the Radboud University Medical Centre (Netherlands) are offered a flu vaccination. The study authors cross-checked the hospital's database of caregivers with SARS-CoV-2 with the database showing the vaccination status of employees. They also took into consideration the vaccination coverage rate in the facility.

On 1 June 2020, at the end of the first wave of the pandemic in the Netherlands, Radboud Hospital had 10,631 employees:

 In addition, employees who tested positive were given a questionnaire to assess the duration, severity, and co-morbidities of the disease:

The authors, therefore, found that SARS-CoV-2 infection was less frequent among hospital employees who had been vaccinated against influenza during the winter 2019/2020 season. However, they point out a limitation of this study, that is, the existence of a confounding factor: employees who developed SARS-CoV-2 had more direct contact with patients. However, previous studies have shown that most of the SARS-CoV-2 infections found in hospital staff members occur outside the professional context.

Several studies and conflicting results

To the researchers, these results are in line with other studies. One of these showed a moderate to a strong negative correlation between influenza vaccination and COVID-19-related mortality in the elderly. The other study found a negative correlation between the influenza vaccine and SARS-CoV-2 seroprevalence, hospitalization rates, intensive care admissions, and COVID-19-related mortality in the elderly. A third study, even concluded, after adjusting for several variables, that a 10% increase in the influenza vaccination rate could reduce SARS-CoV-2 mortality by 28%.

Conversely, a recent report by the Evidence-Based Medicine, Public Health, and Environmental Toxicology (EBMPHET) consortium compared the vaccination coverage rate among the elderly (≥ 65 years old) and the risk of COVID-19 infection and the severity of the disease in Europe and the United States. The researchers found a statistically significant positive correlation between vaccination coverage and the incidence of COVID-19 in Europe, and with mortality in Europe and the United States. However, confounding factors were not taken into account in this report.

Overall, a majority of the biological evidence supports a possible protective effect of the influenza vaccine, but there are several limitations:


The potential interaction between vaccines and infections other than those targeted has already been noted. Some vaccines (such as BCG, measles-containing vaccines, or oral polio vaccine) have been shown to have strong protective effects because they boost innate immunity over the long term. This process is called "trained immunity".

Trained immunity is the modification of the cells of the innate immune system to create a "memory" of a pathogen. It does not create antibodies in preparation for a second contact with that agent. The most studied vaccine that induces trained immunity is BCG and is currently being examined for its presumed protective effects against the duration and severity of COVID-19 in several clinical trials.

In this study, the researchers demonstrated that in-vitro the quadrivalent inactivated influenza vaccine used in the Netherlands during the 2019-2020 season was able to induce an immune response against SARS-CoV-2. It may have improved the response of cytokines by increasing their production in peripheral blood mononuclear cells (PBMCs).

The role of BCG

The researchers used PBMCs from healthy donors (n=9) and stimulated them for 24 hours with different dilutions (10, 50, 100, or 400 times) of Vaxigrip Tetra®, combined or not with BCG. Stimulation with Vaxigrip Tetra® alone did not result in an increase in the production of IL-6, TNF-a, or IL-1β. However, its combination with BCG induced significantly higher cytokine production than BCG alone, suggesting a synergistic effect between the two vaccines. This effect was dose-dependent: a higher dilution of the influenza vaccine was associated with higher cytokine production.

Rapid induction of cytokine response at the onset of infection is crucial to lowering a viral load and preventing systemic inflammation. The amplified IL-6 response activates acute-phase proteins and stimulates T cell development and antibody production. This explains the link between innate and adaptive immunity, helping to eliminate the infection.

Anti-inflammatory cytokines such as IL-1Ra (interleukin-1 receptor antagonist) are needed to counteract excessive inflammation. In their experimental device, after stimulation with the flu vaccine and BCG, the researchers observed an increase in the production of IL-6 in parallel with that of IL-1Ra. These cytokines could therefore help maintain a balance in the individual's inflammatory status.


The results of this study suggest a protective role of the inactivated influenza vaccine on the incidence of COVID-19. They show that an inactivated quadrivalent vaccine can induce trained immunity and that BCG vaccination prior to influenza vaccination may result in improved protection.

According to the authors, in the absence of a specific SARS-CoV-2 vaccine, vaccination against influenza may reduce the impact of COVID-19. They recommend, however, that it should occur in the absence of active SARS-CoV-2 infection, because of the theoretical possibility of inducing a cytokine storm through an enhanced immune response.

1. The effect of influenza vaccination on trained immunity: impact on COVID-19. Priya A. Debisarun, Patrick Struycken, Jorge Domínguez-Andrés, Simone J.C.F.M. Moorlag, Esther Taks, Katharina L. Gössling, Philipp N. Ostermann, Lisa Müller, Heiner Schaal, Jaap ten Oever, Reinout van Crevel, Mihai G. Netea. doi:

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