Public health officials, vaccine producers, and other experts with responsibilities for countering influenza outbreaks are scrambling to develop, evaluate, produce, and deploy vaccines to protect against both seasonal and the new H1N1 pandemic flu viruses. With so much at stake and many uncertainties, they also are reviewing a range of contingencies, even while acknowledging that circumstances will likely eliminate some of those contingencies and give rise to others. Key uncertainties as of late August included questions as to whether the H1N1 virus would better adapt to humans and become more virulent, how to overcome inefficiencies in vaccine productivity, whether to approve adjuvant use, what population groups are to be accorded priority for the H1N1 vaccine once it becomes available, and what strategy to follow in using diagnostic procedures, some of which performed poorly during earlier phases of this pandemic (Microbe, September 2009, p. 405.)

Although the novel H1N1 flu virus continued to cause outbreaks in the Northern Hemisphere throughout the summer, it appears not to be "fully adapted" to humans, according to Nancy Cox of the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga. During an advisory meeting convened in July by the Food and Drug Administration (FDA) Center for Biologics Evaluation and Research, she described efforts to analyze hundreds of flu virus isolates, including through genomic sequencing and via controlled studies with animals. One key finding, for instance, is that the H1N1 virus does not transmit between ferrets as efficiently as do seasonal flu isolates, she reports. This experimental result is consistent with epidemiologic patterns seen in human outbreaks.

Moreover, thus far, H1N1 isolates remain "very homogeneous," and there is little or no evidence that H1N1 is becoming more virulent as it continues to infect more and more people. Further, this virus tends to infect younger individuals while sparing older adults, particularly those older than 60, whose infections nonetheless can prove "dangerous," Cox says. Consistent with those findings, many older adults apparently produce antibodies that cross-react with antigens of the circulating H1N1 virus, likely accounting for some of these age differences in immunity.zzz U.S. officials are anticipating having between 50 and 100 million doses of H1N1 flu vaccines available by October, and as many as 600 million doses by March of 2010. Meanwhile, the array of vaccines to protect against seasonal flu was expected to be plentiful and available sooner.

One big problem is that yields from the initial set of H1N1 vaccine strains were only about 30% for several of the killed-virus, injectable vaccines, according to Jerry Weir of FDA. "Manufacturers are looking for strains that are higher yielding," he says. However, because the "reassortant strains" that are used for producing these vaccines uniformly "grow poorly," he adds, expectations for boosting productivity were not high as of last July.

One exception to these vaccine-productivity problems is the MedImmune H1N1 flu vaccine, which is a liveattenuated vaccine, says Raburn Mallory of the Gaithersburg, Md.-based company, which is a subsidiary of AstraZeneca in London, U.K. This vaccine, which is delivered to individuals intranasally, is being produced with "good yields" that are "much like" those for the company's live-attenuated seasonal flu vaccine, he says.

Poor productivity for several versions of the H1N1 injectable vaccine, its anticipated scarcity from September through December when the flu season gains momentum in the Northern hemisphere, and the likelihood that its poor antigenicity will force a two-dose regimen for many recipients are encouraging manufacturers and public health officials to consider the use of adjuvants to improve efficacy and to stretch limited supplies.

According to some early tests, adjuvants improve the immunogenicity of the candidate vaccines. For example, the GSK H1N1 vaccine is "poorly immunogenic" on its own but "highly immunogenic in all age groups" when used with AS03, an adjuvant that contains α-tocopherol in an oil emulsion, according to Bruce Innes of the London- based company. Even with adjuvant, however, two doses are needed to confer a full response, he adds. Although this and other adjuvants are used widely in Europe, other experts note, there is little experience with them in the United States.

Adjuvant use "is one of the hardest decisions before us," says Robin Robinson of the Biomedical Advanced Research Development Authority (BARDA) in the Department of Health and Human Services (HHS) in Rockville, Md. "Ultimately, that decision will be made by the HHS Secretary or at the White House." Experts who are members of several federal advisory committees also will have input before such decisions are made, adds Bruce Gellin, director of the HHS National Vaccine Program Office.

Amid these uncertainties, public health officials are building consensus as to what population groups will have priority for being vaccinated during the period when only limited quantities of the H1N1 vaccine will be available. Groups with high priority likely will include students and preschool children, pregnant women, health care workers, and older adults with medical impairments that would make them particularly vulnerable to flu infections. Vaccinating members belonging to some of these priority groups will amplify the impact of the vaccine, which is part of the strategy behind coping with limited supplies.

For instance, vaccinating pregnant women will help toward protecting infants who are less than 6 months old, while vaccinating school children should help in protecting their younger siblings against the virus. "For routine cases of flu-like illnesses, there is little reason to apply diagnostic tests," says John Modlin from Dartmouth-Hitchcock Medical Center in Lebanon, N.H., who chairs the FDA Vaccines and Related Biological Products Advisory Committee. However, when it comes to "assessing vaccine efficacy, there's a need for improved diagnostics." The use of diagnostic procedures to distinguish H1N1 from seasonal flu cases will be "limited," but such testing remains "important as a surveillance tool," agrees Robinson from BARDA, adding: "It's a complex issue."

Jeffrey L. Fox
Jeffrey L. Fox is the Microbe Current Topics and Features Editor.

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