Avian Flu Diary: Clin. Infect. Diseases: Revisiting the 2009 pH1N1 `Canadian Problem'

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Fair warning: You may want to pour a cup of coffee, we've some ground to cover before we get to today's study.

In the summer of 2009 news leaked of several unpublished Canadian studies suggesting prior seasonal flu vaccination made one more at risk of contracting the recently emerged 2009 H1N1 Pandemic virus.

At the time, delivery of the pandemic monovalent vaccine was still several months away - but there were plans to roll out the regular seasonal vaccine first – to protect against non-pandemic strains.

Helen Branswell, science and medical reporter - writing at the time for the Canadian Press - was among the first to report (see Branswell On The Canadian Flu Shot Controversy) on what was quickly dubbed `The Canadian Problem'.

Suddenly, there were genuine concerns that with a pandemic virus on the way, that rolling out the seasonal vaccine might be the wrong thing to do.

The CDC, the World Health Organization, and other public health organizations scrambled to look at the limited data they had, and stated that they could find no correlation between the seasonal vaccine and susceptibility to the pandemic flu . . . but that they would continue to look.

Meanwhile, with concerns rising, a number of Canadian Provinces halted or announced delays in their seasonal flu shot campaign, even though the studies had yet to be published (see Ontario Adjusts Vaccination Plan).

October saw a number of new reports and studies that failed to corroborate the (still unpublished) findings, including a study published in the BMJ (British Medical Journal) that suggested exactly the opposite - that getting the seasonal flu vaccination may be slightly protective against the swine flu (see When Studies Collide).

By November, with no compelling corroboration of the `Canadian Problem’, Canada’s National Advisory Committee on Immunization (NACI) came out in favor of resuming seasonal flu jabs (see NACI: Canada Should Resume Seasonal Flu Vaccinations).

But the controversy was far from over.

In April of 2010 the original Canadian studies were finally published by PLoS Medicine. Writing for CIDRAP, Maryn McKenna detailed their findings.

New Canadian studies suggest seasonal flu shot increased H1N1 risk

Maryn McKenna Contributing Writer

Apr 6, 2010 (CIDRAP News) – Despite a rapidly launched range of studies, investigators in Canada are still unable to say—or to rule out—whether receiving a seasonal flu vaccination in the 2008-09 season made it more likely that Canadians would become ill from 2009 pandemic H1N1 flu.

Other studies, however (see 2010 Eurosurveillance On `The Canadian Problem’ and 2012’s EID Journal: Revisiting The `Canadian Problem’), failed to find a correlation.

We would revisit this controversy repeatedly over the next few years, including in 2013's Branswell: Universal Flu Vaccines & The `Canadian Problem’, which looked at a study in Journal Science Translational Medicine that raised concerns over the prospects of creating the Holy Grail of immunology; the Universal Flu Vaccine, as described by Helen Branswell:

Study raises red flag for universal flu vaccine

By: Helen Branswell The Canadian Press, Published on Wed Aug 28 2013

Phenomenon, known as the “Canadian problem,” sees vaccination against one strain of flu actually seems to raise the risk of severe infection after exposure to a related but different strain

The scientists say it’s not currently known why the effect happens. Nor is it clear that it would be seen in other species — this research was done in piglets — or with the kinds of flu vaccines used to protect people. But they suggest the findings should be considered during the development and assessment of experimental universal flu vaccines.

(Continue . . . )

The phenomenon was dubbed VAERD or vaccine-associated enhanced respiratory disease by the authors. Somewhat related issues of OAS (Original Antigenic Sin) and ADE (Antigenic Dependent Enhancement), have come up often in this blog, including most recently in:

Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression

WHO: Audio Of SAGE Press Conference On Vaccines (including Dengvaxia (tm))

Philippines: FDA Withdraws Dengvaxia® Vaccine - Sanofi Quantifies Risk

The evidence for a problem in 2009 - while far from conclusive - remains worrisome and in theory, could have ramifications with other vaccines.

There is, however, another theory on the table on what may have happened; the Temporary Immunity Hypothesis.

In November of 2010, an article appeared in the Eurosurveillance Journal (see Eurosurveillance: The Temporary Immunity Hypothesis) that suggested that contracting seasonal flu temporarily ramped up the body’s immune system against other respiratory viruses – and that this protective effect could last for months.

Eurosurveillance, Volume 15, Issue 47, 25 November 2010

Perspectives

Seasonal influenza vaccination and the risk of infection with pandemic influenza: a possible illustration of non-specific temporary immunity following infection

H Kelly , S Barry, K Laurie, G Mercer

Unlike the Canadian researchers, these scientists could find no increased susceptibility to the pandemic H1N1 virus among Australians who had been vaccinated the previous year against seasonal flu. The difference between the two findings, they posited, came from three separate factors:

A theory regarding temporary immunity following any influenza infection
The timing of the arrival of the pandemic virus in Canada
And the protective effects of seasonal flu vaccination against seasonal - but not pandemic - flu.

Simply put, Canadians who were vaccinated in the fall of 2008 were better protected against seasonal influenza infection during the winter, but their collective immunity was running low by the time pdmH1N1 appeared.

Those who had skipped the fall 2008 vaccine were more likely to have caught seasonal flu over the winter, and therefore acquired some `non-specific temporary immunity' - which carried into the spring - making them less likely to be infected with the pandemic strain.

While only a hypothesis, it could explain why different countries reported different outcomes.

All of this, believe it or not, is only a fraction of the story. But it suffices as a broad introduction to the following study of more than 600,000 U.S. military personnel who received the H1N1 pandemic vaccine in the fall of 2009 either with, or without prior, seasonal flu vaccination.

In this case, the authors found `. . . no clinically significant difference in ILI, influenza, or pneumonia attack rates among those receiving the pH1N1 vaccine with or without presence of the seasonal vaccine.'

I've only included an excerpt from the abstract. The full study is available at the link below:

Seasonal Influenza Vaccine Impact on Pandemic H1N1 Vaccine Efficacy

Rachel U Lee Christopher J Phillips Dennis J Faix
Clinical Infectious Diseases, ciy812, https://doi.org/10.1093/cid/ciy812
Published: 20 September 2018

Background

In 2009, a novel influenza A (pH1N1) was identified, resulting in a pandemic with significant morbidity and mortality. A monovalent pH1N1 vaccine was separately produced in addition to the seasonal trivalent influenza vaccine. Formulation of the seasonal influenza vaccine (injectable trivalent inactivated influenza vaccine [TIV] vs. intranasal live, attenuated influenza vaccine [LAIV]) was postulated to have impacted the efficacy of the pH1N1 vaccination.

Methods

We reviewed electronic health and manpower databases, which included vaccination records, along with healthcare encounters for influenza-like illness (ILI), influenza, and pneumonia among US military members (aged 18–49 years) in the contiguous United States. We examined rates by vaccination type to identify potential factors associated with the risk for study outcomes.

Results

Compared with those receiving the seasonal influenza vaccine alone, subjects receiving the pH1N1 vaccine, either alone (RR, 0.49) or in addition to the seasonal vaccine (RR, 0.51), had an approximately 50% reduction in ILI, 88% reduction in influenza (RR, 0.11 and 0.12, respectively), and 63% reduction in pneumonia (RR, 0.37 and 0.35, respectively). There was no clinically significant difference in ILI, influenza, or pneumonia attack rates among those receiving the pH1N1 vaccine with or without presence of the seasonal vaccine. Similarly, there was no clinically relevant difference in pH1N1 effectiveness between seasonal TIV and LAIV recipients.

Conclusions

During the 2009–2010 pandemic, the pH1N1 vaccination was effective in reducing rates of ILI, influenza, and pneumonia in young healthy adults. Administration of the seasonal vaccine should continue without concern of potential interference with a novel pandemic vaccine, though more studies are needed to determine if this is applicable to other influenza seasons.

There are, of course, some potentially significant differences between the demographics - and general health - of active duty military personnel vs. the general public. But this is the largest, and most detailed, population study we've seen on this topic, which adds to its weight.

Even if the `Canadian Problem' can be adequately explained by the Temporary Immunity Hypothesis (which is mentioned in the full study), the role and potential impact of OAS and ADE remain poorly understood.

For more on these thorny issues, you may wish to revisit: