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Review 1: "The effect of influenza vaccination on trained immunity: impact on COVID-19"

This study explores whether the influenza vaccine elicits protection against SARS-CoV-2 via trained immunity. While some of the study's findings are compelling, the work's major claims are generally unsubstantiated by the data offered.

Published onNov 25, 2020
Review 1: "The effect of influenza vaccination on trained immunity: impact on COVID-19"
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key-enterThis Pub is a Review of
The effect of influenza vaccination on trained immunity: impact on COVID-19

Every year, influenza causes 290.000 to 650.000 deaths worldwide and vaccination is encouraged to prevent infection in high-risk individuals. Interestingly, cross-protective effects of vaccination against heterologous infections have been reported, and long-term boosting of innate immunity (also termed trained immunity) has been proposed as the underlying mechanism. Several epidemiological studies also suggested cross-protection between influenza vaccination and COVID-19 during the current pandemic. However, the mechanism behind such an effect is unknown. Using an established in-vitro model of trained immunity, we demonstrate that the quadrivalent inactivated influenza vaccine used in the Netherlands in the 2019-2020 influenza season can induce a trained immunity response, including an improvement of cytokine responses after stimulation of human immune cells with SARS-CoV-2. In addition, we found that SARS-CoV-2 infection was less common among Dutch hospital employees who had received influenza vaccination during the 2019/2020 winter season (RR = 0,61 (95% CI, 0.4585 - 0.8195, P = 0.001). In conclusion, a quadrivalent inactivated influenza vaccine can induce trained immunity responses against SARS-CoV-2, which may result in relative protection against COVID-19. These data, coupled with similar recent independent reports, argue for a beneficial effect of influenza vaccination against influenza as well as COVID-19, and suggests its effective deployment in the 2020-2021 influenza season to protect against both infections.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



I read this manuscript with significant interest.  The group poses the hypothesis that the flu vaccination may train the innate immune system and thus prevent future SARS-COV-2 infection and subsequent COVID-19 disease.  As we are all aware, this is a very relevant topic at this time given the new increase in cases around the world and the upcoming influenza season.  Their findings consist mostly of cellular work with some extrapolation into clinical findings.  While their benchwork has merit and puts forward new ideas that may help in the fight to control this current pandemic, their clinical findings are weak at best.  They, unfortunately, do not present any direct evidence that supports their hypothesis that trained immunity, either with the influenza vaccination or the BCG vaccination, can prevent SARS-CoV-2 infection.  Their manuscript, as it stands, seems like 2 separate papers—a basic science paper and a clinical paper.  The basic science paper seems to revolve more around how trained immunity with BCG can potentially protect against SARS-CoV-2 infection.  Their clinical work is related to the influence of the influenza vaccination on SARS-CoV-2 infection.  Issues that I believe will need to be addressed:

1)     In order to appropriately conclude that healthcare workers who were vaccinated were protected against COVID-19, the difference in the two groups must be controlled for patient-contact and other risk factors for contracting COVID-19.  As the authors state in their manuscript that they are unable to gather some of this data, what data can they get?  At the very least, the analysis to control for direct patient contact should be done though.

2)     Do we know the vaccination status of the healthy blood donors?  Given that we are concerned with previous exposures to viral antigens affecting PBMC’s, I think knowing the healthy subjects’ prior vaccination status will play a role.  It may also explain the lack of any sort of significant release when initially exposed to the flu vaccine in Fig 2.

3)     The negative control or “0” dilution in Fig 2 and Fig 3 are unclear.  I think it is better just to designate the negative control as it can be confusing for readers when they see a ‘0” dilution.

4)     At this point, their argument that trained immunity can prevent a SARS-COV-2 infection is weak.  Do they know of any data that shows that trained immunity can prevent other viral infections that we can draw parallels with?  Have the authors measured the trained response to other viruses such as influenza and how do the responses compare?  If the cytokine release after training by the influenza vaccine is similar to SARS-CoV-2, then I think that would help support their argument that this particular response to SARS-CoV-2 actually has a clinical significance. 


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