Seasonal influenza and COVID-19 risk

In the Northern hemisphere, fall and winter are associated with immunization campaigns against influenza to reduce the burden of influenza disease and to decrease ambulatory and hospital services use. Either universal or targeting high-risk groups, these campaigns will distribute either inactivated influenza vaccines (IIV) containing three or four variants or live attenuated influenza vaccine (LAIV).

In a new study published on the preprint server medRxiv*, researchers from Laval University and McGill University in Canada reviewed evidence from 18 relevant studies on a possible interaction between influenza vaccines on non-influenza respiratory disease (NIRD).

Study: Could seasonal influenza vaccination influence COVID-19 risk?. Image Credit: ktsdesign / Shutterstock
Study: Could seasonal influenza vaccination influence COVID-19 risk?. Image Credit: ktsdesign / Shutterstock

Non-Specific Immunity from Live Attenuated Vaccines

Evidence is coming in that live attenuated vaccines offer non-specific immunity other than the specific protective effects against the target pathogens. These include the BCG vaccine, measles, and oral polio vaccine. On the contrary, inactivated vaccines like the diphtheria-tetanus-pertussis (DPT) vaccine are linked to a higher rate of sickness and death from other causes than the targeted diseases.

Such off-target effects, whether beneficial or pathological, are seen in children, especially for females, and might be linked to epigenetic modification of innate immunity. This is called ’trained immunity’ and results from a change in the way these cellular pathways operate as a result of the epigenetic alterations. On the other hand, some adjuvants used in vaccines also appear to increase innate immunity and provide a broader range of protection against more than just the target microbe.

With the COVID-19 pandemic still spreading, scientists fear that a second wave may occur in the fall, though seasonal flu rates are expected to diminish as already seen in Australia. In this scenario, it is vital to assess the safety of the flu shot in itself, and concerning a possible alteration in the risk of other respiratory infections because of influenza immunization.

LAIV, Not IIV, May Protect Against Other Respiratory Infections

The researchers looked for human studies that offered any evidence that influenza vaccination and disease risk due to other respiratory pathogens, including, of course, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

They found, from the data offered by four randomized controlled trials (RCTs), that LAIV immunization did not increase the risk of respiratory infection from other pathogens. In contrast, one prospective trial in the community did demonstrate that the recipients rapidly developed non-specific immunity against viral infection.

However, with IIV, six studies showed a higher risk of other respiratory infections, whether designed as RCT, cohort studies, and several observational studies/one case-control study with a test-negative design. The estimated effectiveness of the influenza vaccines was independent of the control group. This could be because the flu vaccine modifies the risk independent of the type of pathogen, though it is more probable that no specific pathogen is inhibited. Most of the studies are worthy of inclusion in the analysis, though publication bias cannot be excluded.

A protective effect of IIV against SARS-CoV-2 was apparent in one study, though significant bias was possibly present.

Influenza Results in Innate and Adaptive Immunity

Both innate and adaptive immune responses occur in response to the flu virus, and in animal models, this has been shown to extend to other viral infections, rapidly and durably. This involves the induction of type I interferons, TNF-α, neutrophils, macrophages, and monocytes, as well as dendritic cells and NK cells. When the live attenuated influenza virus is administered intranasally, it produces the immune triggering effect of wildtype influenza virus on the innate immune system.

IIV Increases Trained Immunity, LAIV Boosts Innate Immunity

Overall, past research supports the safety of LAIV in the current COVID-19 scenario. However, IIV is currently designed to stimulate adaptive immunity by increasing the production of antibodies against specific viral antigens. Animal and human studies alike show this to be less protective than LAIV-induced immunity against other influenza viruses than those included in the vaccine.

LAIV can enhance innate immunity via the upregulation of many interferon-related genes, but IIV elicits a gene signature that is linked to adaptive immunity, particularly related to plasma cells. In vitro studies show that seasonal IIV can reprogram myeloid and NK cells so that their ability to counter viral infection by cytokine secretion is enhanced. However, this has not been studied in vivo by translation product analysis.

Implications and Future Directions

The mechanistic aspect of non-specific induction of antiviral protection by IIV is unknown. An increase in trained immunity that inhibits viral replication may be responsible, since by reducing the viral load, a less intense inflammatory response occurs, limiting tissue damage.

If trained immunity does not restrict viral proliferation, on the other hand, an increase in this respect could cause viral symptoms to increase or become worse, and even trigger a cytokine storm in the more advanced phase of disease. Thus, research is required to understand if this could happen in COVID-19 following influenza immunization.

The study concludes that LAIV appears to be safe in the current COVID-19 scenario but not IIV, in all cases. However, with the small amount of data showing the possibility of harm with flu shots due to an increased risk of other respiratory viruses, it is not reasonable to stop the planned immunization campaigns this year. A more practical solution may be to use LAIV to protect high-risk children only if possible while carrying out studies to uncover more aspects of the interactions between influenza vaccines and COVID-19 risk or disease severity.

*Important Notice

medRxiv 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.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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