Even with the influenza season winding down in the Northern Hemisphere, talk about vaccines continues.  Some of that conversation focuses on alternative flu vaccines, while another focus is on where vaccines in general fit into the U.S. health care system, and what can be done to improve their production and use. These two conversations converged in Washington, D.C., albeit in separate venues, last December.

Addressing national vaccine needs in broad terms, a committee of the Institute of Medicine (IOM) in Washington, D.C., issued a report last December advising the federal government where to focus when it comes to updating the National Vaccine Plan. That plan provides a broad outline for coordinating disparate efforts throughout the federal government but also involving the private sector, when it comes to developing, producing, distributing, and using vaccines to protect the public from a growing list of illnesses as well as from vaccinerelated adverse reactions.

The IOM report, "Priorities for the National Vaccine Plan," includes 20 recommendations and 18 priority actions, according to Claire Broome of the Rollins School of Public Health at Emory University in Atlanta, Ga., who chaired the IOM committee responsible for the report. Amid that list of recommendations, she says, "Coordination is at the heart of the National Vaccine Plan, and it needs to be strengthened."

Another key recommendation is for the federal government to do more about studying and improving vaccine safety, with a key goal being to regain public confidence in vaccines, according to committee member Edgar Marcuse of the University of Washington and Seattle Children's Hospital. "We have to broaden the safety research agenda . . . to guarantee public confidence," he says. One recommendation is to establish a safety subcommittee as part of the National Vaccine Advisory Committee. Another effort would be to strengthen electronic medical record keeping for tracking vaccine use and conducting surveillance for adverse effects.

Recent experiences with the H1N1 influenza vaccine provide a prism through which to view the recommendations in the IOM report. In keeping with much of what the report says on safety, use of the H1N1 flu vaccine led to few if any adverse effects. Nonetheless, a wide sector of the public expressed distrust about its safety, and many parents were reluctant to let their children be vaccinated. This skepticism about the safety of this vaccine took place amid a barrage of information attesting to the safety and value of the H1N1 and other flu vaccines.

During the second week of January, for example, the federal government sponsored a series of events as part of National Influenza Vaccination Week to emphasize the value of being vaccinated against flu and to reassert its safety. "The H1N1 vaccine is safe, effective, and the best way to prevent the flu," said Health and Human Services (HHS) Secretary Kathleen Sebelius in announcing those programs. "We urge all Americans to protect themselves and their families by getting the H1N1 flu vaccine."

A few weeks earlier, several vaccine authorities within HHS agencies summarized the status of current flu vaccines and what could change during the next few years. The widely used killed-virus vaccine, typically formulated with three viral strains and administered by injection, is "tried and true, has been used for decades, works, and is quite safe," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "But it has downsides." For example, formulating and producing it each season takes several months; the procedures are inflexible, and the vaccine supply is directly dependent on having a plenitude of chickens to produce the eggs in which it is made.

Several "new platforms" for flu vaccines are under active study, Fauci continues. They include candidate vaccines consisting of DNA encoding flu virus proteins, recombinant subunits, viable microbial vectors such as adenovirus carrying flu antigens, virus- like particles that contain antigens but no genetic material, and synthetic peptides that are condensed version of flu antigens. Recently, for example, Gary Nabel and his collaborators at the NIAID Vaccine Research Center launched a clinical trial testing a candidate DNA vaccine, which encodes the hemagglutinin (HA) that is found in the 2009 H1N1 flu virus. That trial, which involves 20 volunteers, is assessing the safety of the vaccine and its ability to elicit appropriate immune responses.

Another approach is to develop a "universal" flu vaccine, one that will not need adjusting for its HA and neuraminidase components every season, Nabel says. In addition to one candidate that targets the stem of HA, other experimental vaccines of this type target the highly conserved M2 and NP proteins of the influenza virus. Because they elicit immune responses that are not so robust as are those for conventional flu vaccines, investigators assume these newer vaccines will need to be administered in a "primeboost" series, he says. Moreover, because of the evolutionary "dance" between host and virus, even these seemingly universal vaccines might need to be formulated in "cocktails" containing enough antigenic variants to cover the range of viable and infectious flu viruses that circulate.

Even if the universal flu vaccine proves successful, its adoption "won't happen overnight," Nabel points out. First would come a thorough evaluation for safety and effectiveness, along with a "period of adjustment" to phase out the seasonal vaccine. Jesse Goodman, Chief Scientist at the Food and Drug Administration, reinforces this point, noting that "new types of vaccine will require clinical trials to prove that they protect people." Once efficacy is established, he adds, it becomes feasible to develop "correlates" of protection to use for future "accelerated" regulatory reviews of updated versions of those newer flu vaccines.

Jeffrey L. Fox

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