Claim that flu vaccine increases coronavirus infection is unsupported, misinterprets scientific studies

An article published on the websites DisabledVeterans.org and GreenMedInfo, as well as several Facebook posts, claimed that the flu vaccine increases the risk of coronavirus infection. This claim appeared after medical professionals announced their recommendations for people to get the flu shot during the COVID-19 pandemic, as reported by the New York Times and ABC News.

The DisabledVeterans.org article relies on a study by Gregg Wolff of the U.S. Armed Forces Health Surveillance Branch, published in early January 2020^[1], claiming that the study shows that “flu vaccine increases coronavirus risk [by] 36%”. Scientists who reviewed the claim pointed out that although the study did report a higher probability of coronavirus infection in individuals that received the flu vaccine, it examined only seasonal coronaviruses that cause the common cold, but not SARS-CoV-2, the coronavirus causing COVID-19. As such, these results cannot be extrapolated to SARS-CoV-2.

Secondly, the study did not take into account potential confounding factors such as age, which may have biased the results. Thirdly, the study by Wolff, which is based on administrative records, excluded about 20% of these records. Sheena Sullivan, associate professor at the Doherty Institute and epidemiologist for the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, explained: “There’s no analysis of how this might have impacted estimates [in the study]. Sometimes the records excluded differ from those included in meaningful ways that influence the effect estimate, so it’s important to check.”

Angeline Rouers, senior research fellow at the Singapore Immunology Network, highlighted the fact that the Wolff study itself stated that “Vaccinated personnel did not have significant odds of respiratory illnesses”.

The Wolff study includes the hypothesis that vaccine-associated virus interference may lead to increased risk for other respiratory viruses in vaccinated individuals, because the flu vaccine prevents or minimizes temporary non-specific immunity conferred by natural infection. Virus interference “occurs when a virus impacts the growth of other viruses,” said Rouers. “It may be the case with influenza virus but this phenomenon is still controversial^[2].” Indeed, the Wolff study makes it clear that this hypothesis remains unconfirmed and that studies have so far provided mixed results, but this is taken out of context in the DisabledVeterans.org article.

A study^# by Skowronski et al. published on 22 May 2020, which gathered data over seven influenza seasons from 2010 to 2017, found that the flu vaccine “significantly reduced the risk of influenza illness by >40% with no effect on coronaviruses or other [non-influenza respiratory virus (NIRV)] risk”^[5]. The study also identified a significant methodological flaw in the study by Wolff, resulting from an improper inclusion of influenza test-positive specimens in NIRV test-negative control groups. The authors explained that:

“Wolff adjusted for age and excluded specimens that tested influenza-positive. In that analysis, shown in his Table 3, the [odds ratio (OR)] approached unity indicating no vaccine effect as expected. Conversely, in unadjusted analysis of individual NIRV outcomes (e.g. coronaviruses) Wolff retained influenza test-positive specimens in NIRV test-negative control groups, thereby violating the core prerequisite for valid [test-negative design] analysis. In the context of effective influenza vaccine, influenza cases would have lower likelihood of vaccination; as such, their inclusion would systematically reduce the proportion vaccinated in the control group and thereby inflate ORs comparing vaccine exposure between NIRV cases and controls.”

The U.S. Centers for Disease Control and Prevention also addressed this concern:

“There was one study that suggested that influenza vaccination might make people more susceptible to other respiratory infections^[3]. After that study was published, many experts looked into this issue further and conducted additional studies to see if the findings could be replicated. No other studies have found this effect. For example, this article in Clinical Infectious Diseases^[4]. It’s not clear why this finding was detected in the one study, but the preponderance of evidence suggests that this is not a common or regular occurrence and that influenza vaccination does not, in fact, make people more susceptible to other respiratory infections.”

A scientific study by Cowling et al. has also been used to support the claim^[3]. This study specifically examined the risk of non-influenza respiratory infections in children who received the inactivated trivalent influenza vaccine. Sullivan pointed out that the study “did suggest increased risk of non-influenza viruses among kids who were vaccinated, but it says nothing about increased risk for seasonal coronavirus infection. Only two cases of coronavirus [out of 115 cases of respiratory infection] are mentioned in the paper.” She also cautioned that the study included only children, so it is difficult to say whether the same trend would occur in adults.

In summary, the question of whether the flu vaccine causes an increased risk of coronavirus infection requires more scientific studies to answer. While the studies by Wolff and Cowling et al. suggest a potential increase in the risk of viral respiratory infections after receipt of the flu vaccine, another much larger study found no significant difference in risk between vaccinated and unvaccinated groups^[4]. This study monitored individuals over six influenza seasons, whereas the two studies cited in the claim covered only one influenza season.

To be clear, despite suggestions even from top politicians that the flu vaccine protects against COVID-19, this has not been substantiated. However, the vaccine can provide several indirect benefits during this pandemic, such as reducing the risk of flu infections, thereby reducing cases of flu complications like pneumonia that require hospitalization. This “will reduce the burden on hospitals and ensure that facilities are available for patients in need,” said Rouers. This is the same goal driving the popular “flatten the curve” catchphrase: preventing the healthcare system capacity from being overloaded.

In addition, it is also possible to be infected with both influenza and SARS-CoV-2 at the same time, as this case report from China shows, although how common this is and whether co-infection would affect a patient’s clinical outcome is still unclear.

“We definitely want to avoid people having a flu at the same time as potentially having coronavirus—so having two infections and the body becoming overwhelmed,” said Holly Seale, a senior lecturer in the School of Public Health and Community Medicine at the University of New South Wales, in this ABC News report. She added that “health authorities wanted to avoid people presenting to their local hospital or GP with seasonal flu, which could put them at increased risk of catching another virus, including coronavirus.”

The article and the Facebook posts claim that the flu vaccine increases the risk of infection by other respiratory viruses, such as coronavirus. This is based on a recent scientific article published in the journal Vaccine in January 2020^[1]. However the scientific publication itself is not so definitive in its conclusions. We just have to read the Highlights at the top of the article: “Vaccinated personnel did not have significant odds of respiratory illnesses” and “Odds of virus interference by vaccination varied for individual respiratory viruses”.

The associated risk of infection by other respiratory viruses in the vaccinated group does exist, but it remains low and limited to human metapneumovirus and coronavirus according to this study. Coronavirus is a family of viruses but this study did not look at COVID-19 specifically, so it can be misleading for readers in the current context. Also good to highlight that it’s difficult to establish a direct link between this observation and the vaccine.

As suggested, this potential increased risk of infection by other respiratory viruses might come from a phenomenon known as viral interference. It occurs when a virus impacts the growth of other viruses. It may be the case with influenza virus but this phenomenon is still controversial[2]. The hypothesis is that the flu vaccine (by protecting against influenza virus) could give the opportunity to other viruses to infect the host. Since this hypothesis is not clearly demonstrated and due to the mortality rate from influenza every year, it is probably better to continue to get vaccinated.

These viral posts followed recommendations in mainstream news to get a flu vaccine to be protected during the COVID-19 pandemic. However, the posts take these mainstream news articles out of context, which is misleading for the general public: the news articles did not mean that the flu vaccine can protect against coronavirus, but that being protected against flu and its complications will reduce the burden on hospitals and ensure that facilities are available for patients in need.

Some comments on the Wolff article^[1]:

1. The paper suggests there may be increased odds of infection with seasonal coronaviruses of 1.36 (95% CI: 1.14, 1.63). However, this odds ratio appears to be a crude estimate and has not been adjusted for any confounders. At a minimum, age may be an important confounder here.
2. There are some limitations to using administrative data to identify cases and to determine the vaccination status. These records may be misclassified, which can bias the observed odds ratio. They did check the influence of potentially misclassified vaccination status and it seemed to have minimal impact, so maybe they’re OK.
3. They excluded a lot of records (~20%), and there’s no analysis of how this might impact estimates. Sometimes the records excluded differ from those included in meaningful ways that influence the effect estimate, so it’s important to check.
4. Data were not disaggregated by the type of seasonal coronavirus (NL63, HKU1, 229E, or OC43), so it is unclear whether the apparent association is consistent across strains.

The Cowling paper describes potential temporary non-specific immunity^[3]:

1. This paper did suggest increased risk of non-influenza viruses among kids who were vaccinated, but it says nothing of increased risk for seasonal coronavirus infection. Only two cases of coronavirus are mentioned in the paper.
2. Only children were included in the study, which makes it difficult to know whether these results are generalizable to adults.

Another paper by Sundaram et al. reported no association between influenza vaccination and coronavirus[4]. I couldn’t find any other studies reporting on that specific relationship.

In general there is very weak evidence supporting concerns that influenza viruses may lead to increased risk of seasonal coronavirus infection. More evidence is needed.

The paper published on the study conducted by the U.S. Department of Defense indicates that the incidence of some viral infections in individuals who received the flu vaccine is higher in the study group versus non-vaccinated individuals^[1]. While this study deserves the attention of epidemiologists as well as virologists and immunologists in the field for further investigation, it has some shortcomings in design and implementation, hence the results has to be interpreted very carefully:

1. Almost 20% of the subjects have been excluded prior to the analysis based on the exclusion criteria defined by the study. For example, people with bacterial infections, and also people with flu and non-flu co-infections have been excluded. These subjects are an important group in which the immune system encounters multiple threats, therefore the findings in this group might not be necessarily the same as in the study group. It indeed could change the final picture accordingly.
2. The number of vaccinated subjects included in the study is more than twice the number of unvaccinated persons. In order to be able to draw a sound and fair conclusion in this case, it’s better to have nearly the same number of subjects in both groups, as sample size could have possibly affected the findings. In many studies the number of control subjects are even twice the number in the study group for the sake of fair and robust comparison.
3. Overall, the number of no-pathogen detected subjects was higher in the vaccinated group compared to the non-vaccinated group (37.3% versus 27.3%). This finding suggests a relatively more favorable status in flu-vaccinated individuals, although it has to be interpreted with caution due to above-mentioned reasons.
4. Most importantly, the percentage of people with corona-virus infection in vaccinated group is 7.8% versus 5.8% in the non-vaccinated group. These figures are relatively small and have been evaluated within a one-year period only, so the conclusion based on these figures cannot be very robust.
5. One of the very important points here is that the people who keep sharing these data on social media claiming that the flu vaccine increases the risk of coronavirus infections, fail to clarify that the coronavirus strains evaluated in this study were not inclusive of SARS-CoV-2. The novel coronavirus is certainly different from the previously known members of the coronavirus family and it’s not very well characterized by far in terms of epidemiological data, viral interference and pathogenesis. Therefore, there is no way, based on the Vaccine study published in January 2020^[1], to link COVID-19 incidence and vaccination for seasonal influenza and draw conclusions on viral interference!
6. Last but not least, it is very crucial to remember: At this time during the COVID-19 pandemic, the hospitals and healthcare systems across the world are overwhelmed with coronavirus patients. The least the flu vaccination can do (as it’s shown in the DoD study as well) is to lower the total number of flu infections significantly! This means the number of people coming down with flu symptoms and rushing to hospitals would be much less, so the health professionals can focus on COVID-19 cases and avoid the further collapse of healthcare infrastructure. Considering that currently there is no vaccine available/approved for the novel coronavirus, it is wise to limit the number of other viral infections that are highly preventable via vaccination such as the seasonal flu.

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A fact-check by Lead Stories reported this claim to be “not true”.

REFERENCES

• 1 – Wolff GG. (2020) Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017–2018 influenza season. Vaccine.
• 2 – Feng et al. (2018) Assessment of virus interference in a test-negative study of influenza vaccine effectiveness. Epidemiology.
• 3 – Cowling et al. (2012) Increased Risk of Noninfluenza Respiratory Virus Infections Associated With Receipt of Inactivated Influenza Vaccine. Clinical Infectious Diseases.
• 4 – Sundaram et al. (2013) Influenza Vaccination Is Not Associated With Detection of Noninfluenza Respiratory Viruses in Seasonal Studies of Influenza Vaccine Effectiveness. Clinical Infectious Diseases.
• 5 – Skowronski et al. (2020) Influenza vaccine does not increase the risk of coronavirus or other non-influenza respiratory viruses: retrospective analysis from Canada, 2010-11 to 2016-17. Clinical Infectious Diseases.