flu season 2013 – misconceptions and facts about current flu vaccines & drugs

Extracted on 01/12/13

“Flu-pocaplyse 2013″ is upon us, as The Daily Show would likely call it. There’s even a color-coded alert level: dark red for “Intense”, as Google Trends puts it (see chart below). Pretty soon, the citizenry will be donning face masks on the streets (similar to images from Southeast China during the avian flu outbreak) as we’ve already seen reports of tremendous crowding in ped offices and emergency rooms for flu shots and medicines (NY Times report).

With as many Google searches related to the flu as suggested by Google trends, there is a ever spewing chimney “flue” of information being disseminated, and wanted to capture and compile some of those highlights here. The Huffington Post has already released a piece dispelling 7 common myths about the flu with a lot of good starters, including “The flu shot can give you the flu” and “Antibiotics can fight the flu”, both of which are critical statements to debunk. But I wanted to focus on some of the misconceptions and scientific evidence behind flu vaccines and antivirals prescribed to treat it.

- The seasonal flu vaccine is about 60-70% effective – below the standard (80-90%) of other required immunizations (@ Forbes)

You probably won’t find many health care professionals mentioning this but the season flu vaccine is not a suit of armor upon exposure to the flu virus. In fact, it has been observed that public health officials have communicated that the flu vaccine works nearly as effectively as other vaccines, which would be 70-90% efficacy. However, research studies have suggested that the benefit is overstated and that the flu vaccine is only about 60-70% effective in protecting individuals from getting the flu. The Forbes article describes two important drivers for shortfalls in efficacy (the third one–age and health status variation–being mentioned in the next section):

Dynamics associated with seasonal flu
Source: Globalsecurity.org

Vaccine strain mismatch: The current vaccine development “machine” still heavily relies on the age-old process of injecting influenza virus into chicken eggs. This limits the number of flu strains that can be included (usually three, hence the term “trivalent” vaccine) and makes for a lengthy manufacturing process that generally takes 6-8 months. As a result, the decision of likely circulating strains needs to be made far in advance, and may not completely match the actual strains during the flu season. For 2012-13, the influenza strains selected include the H1N1 strain used in last year’s vaccine and two new strains: H3N2 and B virus, and reports indicate that this season’s strain appear well-matched to the vaccine.
Susceptibility window: The protection provided by the flu shot is not directly from the injected vaccine but from the body’s immune system cranking up the production of antibodies and building a standing army in preparation for the flu season. It generally takes about 2 weeks for the vaccine to register its full protection effect leaving a window for the virus to attack. This is likely what fuels claims by individuals who say they contracted the flu as a result of the vaccine. You can infer that the susceptibility is even greater in populations with weaker immune systems such as young infants, the elderly and those with compromised immune systems (such as HIV) or lung function (such as asthma patients).

A recent report by the Center for Disease Research & Policy (CIDRAP) at the University of Minnesota was released in Oct 2012 providing an exhaustive review of 12,000 articles dating back to 1936. Their conclusions support the notion that vaccine efficacy is overstated, arguing that the claim of 70-90% efficacy that is frequently cited relies on suspect studies that stem from “suboptimal methodology, poorly defined end points, or end points not proven to be associated with influenza infection.”

The CDC website shies away from providing specific ranges for efficacy and lists the caveat mentioned in this article. They are projecting a conservative stance as the first piece of data they report is based on unpublished results from a study of the 2010-11 flu season indicating 60% efficacy across all age groups. However, they seem to suggest a norm of about 70% efficacy for the inactivated virus vaccine when they cite a study by Monte et al. (2007-08 flu season) and assure that the live-attenuated virus has comparable efficacy.

- The vaccine efficacy is less robust or unproven in the elderly but still recommended as better than nothing (@ CIDRAP)

Healthcare worker administering FluMist (AstraZeneca/MedImmune) in a young patient
Source: John Harrington/MedImmune, via PRNewsFot

Citing the same report from CIDRAP, the common references to efficacy often apply to healthy adults (years 18-65). For children aged 2 to 17 years, the evidence for the efficacy of the inactivated vaccine shot has been inconsistent, but has been remarkably strong for the live-attenuated version (about 83% efficacy based on pooled results), particularly for children ages 6 months to 7 years. The only live-attenuated vaccine available on the US market is FluMist, manufactured by AstraZeneca, but is only approved for individuals ages 2-49 (except in pregnant women). But the story is less clear for the elderly who may not have a robust enough immune system to generate enough antibodies to confer optimal protection. The review of the evidence indicate either scant evidence or inconsistent results regarding protection against the influenza virus. Dr. Osterholm, the lead author of the report, had offered the following concern regarding the cost-benefit for the elderly:

However, these vaccines do not offer consistent, high-level protection – especially in individuals at risk of medical complications or those aged older than 65 years. Unfortunately, these are the populations where we need the vaccines to work the best. We need new influenza vaccines that work for everyone, most of the time.

According to a recent article in the Boston Globe, this conclusion is not without rebuttal. Dr. Alfred DeMaria at the Massachusetts Department of Public Health argues that CIDRAP did not include an important Dutch study in 2004 which showed the elderly people that received annual flu shots were less likely to die (of any cause) during the flu season vs. those that did not receive vaccinations. Ultimately, even the CIDRAP researchers recommend that the elderly receive the flu shot since it is better than having no protection at all. Osterholm reiterates: “But some protection is better than nothing, so it’s still a good idea to get the vaccine. I just don’t think we should be overselling its benefits.” At the very least however, the CDC recommends that the elderly receive a high-dose vaccine “which may lead to greater protection against the flu.”

- This year’s flu vaccine is on the lower end of the efficacy range – about 62% – but still worth getting the flu shot (@ CDC)

If you thought the 60-70% effectiveness range was startling (and note that this is driven by healthy adults ages 18-65), the CDC (Centers for Disease Control and Prevention) just reported yesterday that the current flu vaccine has been shown to be about 62% effective. This is based on real-time analysis of early data of 1,155 children and adults with acute respiratory infection enrolled in the past month (Dec 2, 2012 to Jan 2, 2013). Adjusted based on sampling among the 5 study sites, the 95% confidence interval was 51%-71%. Across viral subtypes, this year’s vaccine was observed to be only 55% effective against Influenza A (the most commonly found strain) but 70% effective against Influenza B, as reported in the WSJ. This CDC report was accompanied with continued recommendations to obtain the flu vaccine and that (additionally) antiviral medications be used as recommended for treatment in patients, regardless of vaccination status.

- A common flu treatment drug Tamiflu seems to help shorten the disease course but may not be as effective as people think (and is the manufacturer hiding something?) (@ Forbes)

Having contracted the flu in previous seasons, I’ve been prescribed Tamiflu (oseltamivir phosphate, manufactured by Roche) before under the guise that it was a safe and effective drug in treating the flu. Tamiflu is an inhibitor of neuraminidase, a surface enzyme of the virus involved in reproduction via budding from the host cell. It is indeed approved by the FDA for the “treatment of acute, uncomplicated influenza in patients 2 weeks of age and older who have been symptomatic for no more than 2 days” and “prophylaxis of influenza in patients 1 year or older.” Anectodally, I do believe that Tamiflu may have lessened the severity and duration of my flu, which ran for ~5 days. However, questions have surfaced about the drug’s safety and efficacy based on analysis of published clinical trials and the lack of transparency in those trials that have been unpublished. There were 10 randomized trials performed on the drug, all of which were sponsored by the manufacturer; no prospective randomized trial had been conducted by an independent body. Although efficacy was based on all 10 trials, only 2 trials have been published and were peer-reviewed. In total, there have been 123 trials of Tamiflu have been conducted, but only 60% have been published, raising accusations of significant reporting/publication bias.

The Cochrane Collaboration is a group chartered in the UK but consists of scientists all over the world who work together to evaluate the effectiveness of different medical interventions. According to the Cochrane report published in Jan 2012 which reviewed the evidence for Tamiflu from both published and some unpublished data, the group found that the evidence for Tamiflu did not support that the drug was effective in reducing the risk of hospitalization nor was there sufficient evidence showing that the drug reduced complications or viral transmission. On a plus note, the group did conclude based on 5 studies that the drug likely reduced the duration of symptoms by one day, although there was significant variation in that outcomes. The Cochrane group did mention that they requested additional data from Roche but that the manufacturer did not comply to the request. The war of words between Roche and the Cochrane group continued to play out throughout the year, but the Roche offered an “olive branch” at the end of November to invite a discussion involving more data transparency. To be continued…

But the stakes are indeed substantial. Governments have been stockpiling the drug since the 2004 pandemic, and the drug is expected to draw $750 million in sales this year compared to $350 million last year.

- Relenza, a competing antiviral treatment to Tamiflu, is considered moderately effective as Tamiflu and less shady (for now)

Relenza (zanamivir, manufactured by GlaxoSmithKline) is also a neuraminidase inhibitor with a similar efficacy / safety profile to Tamiflu but an inhaled formulation rather than oral. According to an article in the Boston Globe, doctors say that both Relenza and Tamiflu reduce the course of the disease by about one day, and may be even more effective when taken within the first 24 hours upon onset of symptoms. While the FDA considers the efficacy of both drugs to be modest, it is also clear in its caveat that both drugs do not prevent flu complications such as pneumonia or prevent person-to-person transmission of the virus. The Cochrane group supports the FDA’s view and does not direct the same critique against Relenza’s manufacturer and has chosen to defer analysis of Relenza based on GlaxoSmithKline’s cooperation to provide the research group individual patient data. However, also note that the stakes are not nearly as huge for Relenza, as it has captured smaller share of the market compared to Tamiflu (as evident in 2008 market data below).