Critics: CDC risks public trust with unsupported flu shot recommendations

But does report make ‘perfect the enemy of good’?

By Gary Evans, Executive Editor

Calling for the development of a “game-changing” universal flu vaccine, the authors of a sweeping new flu report warn that the American public may ultimately lose faith in national flu recommendations that overstate the benefit of current immunization.

In findings that have stirred some controversy, the report takes the Centers for Disease Control and Prevention to task for widely promoting vaccine uptake while downplaying the limited efficacy of the seasonal vaccine. As a result, there is little incentive to develop a much-needed new vaccine that could meet the threat of future pandemics and provide immunity to seasonal viruses for up to a decade, the Center for Infectious Disease Research & Policy (CIDRAP) at the University of Minnesota in Minneapolis reports.1

Though flu vaccine efficacy in healthy adults of 70% to 90% is frequently cited, those estimates are largely based on data “derived from studies with suboptimal methodology, poorly defined end points, or end points not proven to be associated with influenza infection,” CIDRAP found. Studies using optimal methodology have not found the level of protection often attributed to the current vaccines. For example, the current US-licensed trivalent inactivated influenza vaccine (TIV) affords only “moderate protection,” with a pooled estimate of 59% efficacy for healthy adults age 18 to 64 years. There is inconsistent evidence of protection in children age 2 to 17 years, and “a paucity of evidence” for protection in adults 65 years of age and older, the report concludes.

Michael Osterholm, PhD, MPH“[They] have overstated the benefits of this vaccine,” says Michael Osterholm, PhD, MPH, CIDRAP director and lead author of the report. “And while we strongly urge people to get vaccinated, what [public health officials] have done by suggesting that this vaccine is the answer – we just need to get more people vaccinated – is unintentionally dampen any appetite in the private sector for investing in these new vaccines. That is a very significant issue.”

Saying that new vaccine development be given a priority akin to the Manhattan Project, CIDRAP cited both the ongoing toll of seasonal toll and the recurrent threat of pandemic strains. An estimated 3,000 to 49,000 individuals in the United States die every year from seasonal influenza. The World Health Organization estimates seasonal influenza causes three to five million cases of severe illness worldwide and about 250,000 to 500,000 deaths annually, CIDRAP states. Four pandemics have occurred in the modern era: 1918, 1957, 1968, and 2009. While the death estimates are not in yet for the 2009 H1N1 influenza A pandemic, it was certainly not as severe as some of its predecessors. It is estimated that at least 50 million people died in the 1918 Spanish Flu pandemic, while the 1957 and 1968 pandemics claimed an estimated 1.5 million and 750,000 lives respectively, according to CIDRAP.

Given the inevitably of another pandemic, CIDRAP says we can ill afford to be complacent with the current state of flu vaccines. Quoting historian Daniel Boorstin, the report warns that “The greatest obstacle to discovering the shape of the earth, the continents, and the oceans was not ignorance but the illusion of knowledge.”

The CIDRAP report of more than 200 pages represents a review of some 12,000 peer-reviewed flu publications, documents, transcripts and notes dating back to 1936 as well as interviews with 88 influenza experts, the center states. In strongly questioning current policy regarding seasonal flu, the report focuses primarily on recommendations made by the CDC’s Advisory Committee on Immunization Practices (ACIP) and its Healthcare Infection Control Practices Advisory Committee (HICPAC). The latter is called to account for recommendations on health care worker flu vaccination that do not appear to be supported by the studies cited. The questionable HICPAC recommendation — given the highest possible 1A ranking — has been used to support mandatory and punitive flu immunization policies, Osterholm says.

Vaccine good, not great

William Schaffner, MDDespite its impressive breadth, the CIDRAP report inspires a counter quote of its own. The authors appear to be — to paraphrase Voltaire — “making the perfect the enemy of the good,” says William Schaffner, MD, chairman of preventive medicine at Vanderbilt University in Nashville.

“We all know we have a good — but not great — flu vaccine,” says Schaffner, an ACIP liaison member for the National Foundation for Infectious Diseases. “We wish we had more data, but doing the studies to get those data would be enormously difficult and elaborate and there are no apparent sponsors on the horizon. So the question is do we quibble or do we act? We have a good — but not great — flu vaccine and we ought to use it. That’s where the focus ought to be rather than spending a whole lot of time worrying about the limitations. We should be vaccinating.”

To some extent, it comes down to the public health goal of annual seasonal flu immunization, Osterholm says. “Is the goal to get as many people vaccinated as possible or is the goal to get as many people protected from influenza as possible?” he says. “If you do the latter you continue to try to vaccinate people, but you point out how important it is to get new and better vaccines. You try to bring those to market.”

As a practical matter, the idea of encouraging broad vaccine uptake while discussing the limitations of the current vaccine is a difficult task in a “30-second sound bite,” Schaffner says.

“The CIDRAP authors themselves agree with the ACIP recommendation that everybody age six months and older ought to be vaccinated,” he says. “You can’t promote universal influenza immunization if you are [also telling the public], `This is not the best vaccine in the world.’ I just don’t understand that logic.”

Of course, medical discussions and public policy meetings include a full review of the flu vaccine limitations, but trying to relay such nuances to the public while urging them to be immunized is not typically done with other vaccines, Schaffner notes. “We promote — in fact there are laws — obliging kids to get varicella and mumps vaccine before they go to school,” he says. “Neither of those vaccines provides as solid and long-lasting protection as the measles vaccine, but we don’t spend a whole lot of time discussing that. We just say it’s the best thing to do.”

In addition to the TIV seasonal vaccine, CIDRAP analyzed the available data for the live-attenuated influenza vaccine (LAIV), which was licensed in the U.S. in 2003. For LAIV, they found evidence of high protection, with a pooled estimate of 83% for young children 6 months to 7 years of age. There was inconsistent evidence of protection in adults 60 years of age and older, and “a lack of evidence” for protection in individuals between 8 and 59 years of age.

Feds, pharma, investors must partner on vaccine

Key findings of an influenza report by the Center for Infectious Disease Research & Policy at the University of Minnesota include the following:

  • During some influenza seasons vaccination offers substantially more protection for most of the population than being unvaccinated; however, influenza vaccine protection is markedly lower than for most routinely recommended vaccines and is suboptimal.
  • A major barrier to the development of game-changing influenza vaccines is the perception that current vaccines are already highly effective in preventing influenza infection.
  • In an effort to reduce influenza morbidity and mortality, over the last three decades the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) has expanded the populations recommended to receive influenza vaccine. These recommendations, however, often were based on professional judgment and not on scientifically sound data.
  • Novel-antigen influenza vaccines in investigational research offer the potential of lasting, broad, and potent protection; however, substantial research support is needed to further develop and evaluate these vaccines.
  • The current US government regulatory process for approving influenza vaccines is primarily designed for incremental changes to existing vaccines and presents a barrier to the development of game-changing vaccines.
  • Substantial financial risks and inadequate incentives create significant barriers to bringing game-changing vaccines to market.
  • Coordinated partnerships involving national governments, the pharmaceutical industry, the investment community, and academia will be critical to move such vaccines through clinical trials and the licensure process.
  • Current policy goals for influenza vaccines focus on increasing production capacity and have not addressed key public health challenges related to the effectiveness of current vaccines.
  • Significant policy, investment, organizational, and leadership barriers must be overcome to achieve novel-antigen game-changing influenza vaccines.
  • Pandemic influenza remains a clear and compelling threat to our national security and requires commensurate prioritization and an unprecedented coordinated effort among government, academia, and the private sector to mitigate this threat.

Reference

  1. Osterholm MT, Kelley NS, Manske JM, et al. The Compelling Need for Game-Changing Influenza Vaccines: An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future. Center for Infectious Disease Research & Policy. Oct. 15, 2012. Available at: http://ow.ly/g0PkJ

Flu shot is among safest of all vaccines

Fears linger after 1976 swine flu

Given that concerns and myths about the safety of the seasonal flu vaccine have persisted for decades among members of the public and even health care workers, it is worth noting that an exhaustive influenza report concluded that “the currently licensed influenza vaccines in the United States are among the safest of all available vaccines.”1

The report by the Center for Infectious Disease Research & Policy (CIDRAP) at the University of Minnesota in Minneapolis states that “while unique adverse events can occur with use of these vaccines, such events are extremely rare. Given the level of safety of the current influenza vaccines, it will be challenging for new influenza vaccines to match or exceed the current safety profile.”

CIDRAP cites a 2011 vaccine report by the Institute of Medicine (IOM), noting that it reaffirmed the safety of influenza vaccines.2 The IOM confirmed the known threat of rare but potentially severe allergic reactions in those with egg allergies as the only significant adverse event clearly associated with flu vaccination.

Despite an excellent overall safety record, the seasonal influenza vaccine has been associated with several unique adverse events, CIDRAP reported. Foremost among these, of course, was the ‘swine flu’ incident in 1976, which began with an outbreak of a novel strain of H1N1 influenza among military recruits at Fort Dix, NJ. More than 200 cases, including 13 severe respiratory infections and one death were reported. Concerned that the novel strain could result in a pandemic, public health officals developed a strain-specific vaccine and a nationwide immunization effort began.

During the campaign, public health officials noted an unusual increase in reports of Guillain-Barré syndrome (GBS) following influenza vaccination. A relatively rare neurologic disorder, GBS was occurring in vaccine recipients about nine times higher than the expected background rate of less than one case per million vaccinated. This increased risk resulted in suspension of the immunization campaign, but “researchers still do not know why this particular vaccine caused an increased risk of GBS,” CIDRAP concluded.

Fears of a link between seasonal vaccine and GBS have persisted since the swine flu incident. However, the IOM report found that epidemiologic evidence over the last three decades does not support a causal link between flu vaccinations and GBS. However the IOM included a caveat that “an association cannot be confidently ruled out, particularly for future vaccine strains,” CIDRAP reported.

During the 2009 pandemic there was concern that the vaccine may be associated with GBS like the 1976 vaccine, the authors reminded.

“Studies have now shown, however, that with the A(H1N1) influenza vaccine there was “approximately 1 extra case of GBS per million persons vaccinated,” CIDRAP stated. “Additional work is needed to determine if the A(H1N1) influenza vaccine is causally linked to an increased risk of GBS or if this increase was associated with other factors, such as concurrent infection.”

References

  1. Osterholm MT, Kelley NS, Manske JM, et al. The Compelling Need for Game-Changing Influenza Vaccines: An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future. Center for Infectious Disease Research & Policy. Oct. 15, 2012. Available at: http://ow.ly/g0PkJ
  2. IOM Committee to Review Adverse Effects of Vaccines Board on Population Health and Public Health Practice. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: National Academy Press; 2011

“The data in our report demonstrates that the LAIV is quite effective in younger children,” Osterholm says. “We have virtually no evidence that it has any impact in older children or senior adults.”

‘Out of the hospital and the morgue’

paul Offit, MDIn sum, we have a mixed bag of data for the live attenuated vaccine and a 59% estimate of efficacy in adults age 18 to 64 years for the traditional seasonal flu shot. However, to peel the onion down another layer, the question of how you define vaccine efficacy makes a critical difference in looking at the data, says Paul Offit, MD, chief of Infectious Diseases at the Children’s Hospital of Philadelphia.

“If you define efficacy as protection against severe disease, hospitalization or death caused by influenza strains that are matched to those in the vaccine, protection is excellent — in the 90% range,” says Offit, a former member of the CDC ACIP advisory panel. “If you define efficacy as protection against influenza-like illness (ILI) — which is to say not culture confirmed, not necessarily influenza much less influenza matched to the [vaccine] strain — then it varies anywhere from 25% to 80%. “

The influenza vaccine is designed to protect against moderate to severe illness with the viral strains that are in circulation, Offit says.

“It is not going to do a good job if there is a mismatch — if the prediction as to which strains are circulating wasn’t a good one,” he says. “It is not going to do a good job with ILI — some of which is mismatched strains and some of which is not influenza. As a general rule with mucosal infections — influenza, RSV, pertussis, rotavirus — you are trying to keep people out of the hospital and out of the morgue. That’s the goal.”

However, the CIDRAP report notes that significant increases in influenza vaccine coverage for those over 65 years of age since the late 1990s have resulted in only a minimal impact on influenza morbidity and mortality. Osterholm says “90% of the deaths today associated with influenza in seasonal flu years occur in those over 65. We have the least data that shows that the vaccine works [in that population].”

While one is tempted to conclude that this represents an insufficient immune response in the elderly, Schaffner cautions that the finding may represent in part a “historical accident” — a kind of surveillance artifact.

“If you look at population studies from 30,000 feet — where you don’t know who is vaccinated and who isn’t — it is hard to determine and demonstrate a population-based impact of influenza vaccine on hospitalizations and deaths,” he says. “It’s not like measles, which is a disease that was easy to define and diagnose. When we saw cases drop nationally, you didn’t have to know who was vaccinated or not because you saw hospitalizations, deaths and reported cases just plummet once measles vaccine was introduced. We don’t have that diagnostic specificity for influenza. Reported cases are terribly incomplete and are confused by a whole array of other viral respiratory diseases.”

Moreover, there were few studies done in the past of the elderly before ACIP recommended influenza vaccination for everyone 65 and older. “Even if there was the motivation and the funding to do those studies now, it would create a great ethical conundrum because you can’t withhold vaccine to those 65 and older,” he says. “If the CIDRAP authors have some specific ideas about how to design such studies in an ethically acceptable fashion, we would like to hear about them.”

In search of the grail

One aspect of the report that finds consensus is the need for a new novel antigen vaccine that could provide protection against all influenza subtypes to high-risk populations for long periods. Such a vaccine has been sought over the course of many a late night in influenza research labs.

“That’s the Holy Grail of influenza vaccine,” says Offit. “That’s the most important thing we could do because it’s very hard to give a yearly vaccination to our population.”

Offit is co-inventor of the RotaTeq vaccine, which has become instrumental in preventing rotavirus infections that hospitalize some 55,000 infants a year.

“Although my expertise is in rotavirus, I trained in Walter Gerhard’s flu lab at Wistar [Institute in Philadelphia],” he says. “Walter was working on the matrix protein in an attempt to try to make a universal flu vaccine.”

Indeed, Gerhard, MD, a professor emeritus of immunology at Wistar, eventually developed a prototype universal influenza vaccine that was patented in 2009. The vaccine targets a viral M2 protein that remains largely constant in seasonal flu strains. Gerhard and colleagues demonstrated the potential of targeting M2 to confer flu protection in mice, but the sticking point has been triggering an adequate human immune response.

“Remember with a disease like influenza you can get reinfected even with the same strain at a later date. It’s very hard to do something [with a vaccine] that natural infection does not,” Offit says. “You’re basically trying to make a vaccine that performs better than natural infection.”

While agreeing on the vaccine goal, both Schaffner and Offit take some exception to the CIDRAP premise that research has been stalled out by a kind of complacent acceptance of the current vaccine. On the contrary, flu vaccine research is proceeding at a level of interest and funding that hasn’t been seen in decades, Schaffner says. “I think in the last five or eight years there has been more research at every level on influenza vaccine than there has been in the previous 40,” he says. “There is actually a lot of attention being devoted to enhancing influenza vaccines, [including] nasal spray vaccines, adjuvant vaccines licensed in Europe, and a new plant has opened to develop cell-based vaccines.”

Regarding the grail — the seemingly quixotic pursuit of a universal flu vaccine — Offit says plenty of interest and effort abides.

“All I can say is that we’re trying,” he says. “I think that there is momentum to do it, but it’s just a hard thing to do. The reason it hasn’t happened is not because people don’t want it to happen. It hasn’t happened because it is hard to make it happen.”

Reference

  1. Osterholm MT, Kelley NS, Manske JM, et al. The Compelling Need for Game-Changing Influenza Vaccines: An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future. Center for Infectious Disease Research & Policy. Oct. 15, 2012. Available at: http://ow.ly/g0PkJ