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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. 

Vape Factory:

FDA regulation on vape manufacturers and retailers

For Manufacturer of E-Cigarettes, Vapes

As a manufacturer of electronic cigarettes (e-cigarettes), vapes, or other Electronic Nicotine Delivery Systems (ENDS), it is crucial to be aware of the regulatory framework imposed by the U.S. Food and Drug Administration (FDA). The FDA oversees various aspects of ENDS, including manufacturing, importation, packaging, labeling, advertising, promotion, sale, and distribution. However, it's important to note that FDA regulations apply to ENDS components and parts, excluding accessories.

Regulated Components and Parts of ENDS

The following are examples of components and parts of ENDS that fall under FDA regulations:

  • E-liquids: These are the fluids used in ENDS devices, typically containing nicotine and other ingredients.

  • Glass or plastic vial containers: Used to store and dispense e-liquids.

  • Cartridges: These are pre-filled containers that hold e-liquids and are attached to ENDS devices.

  • Atomizers: The atomizer is the part of an ENDS device responsible for heating the e-liquid and converting it into vapor for inhalation.

  • Cartomizers and clearomizers: Similar to atomizers, these components deliver e-liquid in vapor form.

  • Certain batteries: FDA regulations cover specific types of batteries used in ENDS devices.

  • Digital display or lights: Components that enable users to adjust settings and view information on the device.

  • Tank systems: Reservoirs that hold e-liquids.

  • Drip tips or mouthpieces: The part of an ENDS device that users inhale vapor from.

  • Flavorings: Various flavors added to e-liquids.

  • Programmable software: ENDS devices that contain programmable software are subject to FDA regulations.

  • Products marketed for therapeutic purposes: ENDS products advertised as aids for smoking cessation fall under the regulation of FDA's Center for Drug Evaluation and Research (CDER). The FDA has clarified the criteria for determining when tobacco-derived products are classified as tobacco products, drugs, and/or devices.

Compliance Requirements for ENDS Manufacturers

If you engage in any of the following activities related to ENDS, you must comply with the FDA's requirements for manufacturers:

  • Making or modifying ENDS products

  • Mixing or preparing e-liquids containing nicotine

  • Manufacturing, fabricating, or assembling ENDS devices

  • Processing, labeling, repacking, or relabeling ENDS products

  • Importing ENDS products

To ensure compliance, it is essential to familiarize yourself with the specific regulations governing ENDS manufacturing. For guidance and assistance with understanding FDA requirements, you can reach out to the Office of Small Business Assistance within the FDA's Center for Tobacco Products (CTP). This office provides valuable resources, including online educational materials, to help regulated industries navigate FDA regulations and policies effectively.

Are You a Retailer of ENDS Products?

If you operate as a retailer of ENDS products, it is crucial to understand your role in safeguarding the well-being of consumers, particularly youth, and adhering to FDA regulations. The following resources can assist you in complying with FDA tobacco regulations:

"This is Our Watch" Program

"This is Our Watch" is a voluntary education program designed to provide resources to tobacco retailers, enabling them to better understand and comply with FDA regulations. By actively participating in this program, retailers play a direct role in protecting young individuals from nicotine addiction and the harmful effects of tobacco use. To safeguard the future generation from tobacco-related diseases, it is essential for tobacco retailers to be well-informed about the rules and regulations.

Retail Sales of Tobacco Products

For comprehensive information regarding federal rules that retailers must follow, the Retail Sales of Tobacco Products offers valuable insights. This resource provides guidance, regulations, and access to webinars specifically curated for retailers in the tobacco industry. By staying updated with these resources, retailers can ensure compliance and contribute to the health and well-being of their communities.

Vape Shops with Mixing or Modification Services

If you operate a vape shop that offers services such as mixing or preparing e-liquids containing nicotine or modifying ENDS products, it is important to note that you may be classified as both a manufacturer and a retailer of tobacco products. Consequently, you are required to comply with the regulations outlined for both roles, as mentioned above.


In conclusion, understanding and complying with FDA regulations is crucial for vape manufacturers and retailers involved in the production, distribution, and sale of E-Cigarettes, Vapes, or other ENDS. By adhering to these regulations, you contribute to the safety and well-being of consumers, particularly young individuals. Stay informed, seek guidance when needed, and ensure compliance to navigate the regulatory landscape effectively.


1. Are accessories for ENDS devices regulated by the FDA?
No, FDA regulations for ENDS cover components and parts but exclude accessories.

2. What are some examples of regulated components of ENDS?
Regulated components include e-liquids, cartridges, atomizers, batteries, tank systems, flavorings, and more.

3. What should I do if I have specific questions about FDA requirements for small businesses?
You can contact the Office of Small Business Assistance within the FDA's Center for Tobacco Products (CTP) for guidance and answers to your queries.

4. How can vape shops comply with FDA regulations?
Vape shops must adhere to the requirements for both manufacturers and retailers, as they may have legal responsibilities in both capacities.

5. What resources are available for tobacco retailers to understand and comply with FDA regulations?
The "This is Our Watch" program and the Retail Sales of Tobacco Products provide valuable resources, guidance, and webinars for tobacco retailers to ensure compliance with FDA regulations.

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ENDS Manufacturers: Understanding FDA Regulations and Compliance Requirements



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Learn about FDA regulations and compliance requirements for ENDS manufacturers. Understand the guidelines for retailers of ENDS products and vape shops. Discover how to comply and ensure consumer safety.