Two recent developments provide encouragement in the race against H5N1, the avian influenza virus thought by many public health officials to pose the most serious threat of a new human flu pandemic.
In a paper published Monday in the early online edition of the Proceedings of the National Academy of Sciences, scientists reported that mixing gene segments from H5N1 strains with the current garden-variety flu strain resulted in viruses that were, by and large, bad at replication and worse at transmission.
The data suggested that reassortment is an unlikely way for H5N1 to become easily transmissible from human to human.
And last week, GlaxoSmithKline plc, of London, reported an interim analysis of clinical trial data that showed very low doses of its H5N1 vaccine led to a robust antibody response in 80 percent of subjects.
But public health officials warned against "complacency" in light of the good news, with the Centers for Disease Control and Prevention Director Julie Gerberding stating flatly that "we are far from out of the woods" in terms of pandemic preparedness against H5N1, or another influenza virus strain that might acquire pandemic properties.
An influenza virus consists of eight separate segments, which can recombine independently of one another in an infected animal or human host. That means that while there are influenza viruses that primarily infect humans and those that prefer birds, in practice, a virus could exist that combines human and bird segments.
Two of the three 20th-century flu pandemic strains originated by such human-bird flu segment reassortment, while the third (and most deadly) pandemic strain, the 1918 "Spanish flu" version, is thought to be a bird strain that became adapted to humans, perhaps via an intermediate host, in its entirety.
In the PNAS paper, the researchers, from the CDC in Atlanta; the National Center for Biotechnology in Madrid, Spain; the National Institute of Hygiene and Epidemiology in Hanoi, Vietnam; and the Center for Biomedical and Pharmaceutical Research and Development in Jakarta, Indonesia; tested the transmissibility of different reassortment combinations in ferrets, "which are susceptible to influenza in the same way that humans are," said senior author Jacqueline Katz, of the CDC. Speaking at a press conference, Katz cautioned that the results could not be generalized to strains beyond those that were tested directly, but called the ferret model "a useful tool to better understand the properties of transmissibility and the potential of H5N1 viruses to cause a pandemic in the future."
Using reverse genetics, Katz and her colleagues generated a variety of reassorted viruses, which combined different segments from H5N1 and H3N2 viruses. H3N2 is the most common flu strain; it also is a descendant of the flu strain that caused the 1968 pandemic.
Katz told BioWorld Today via email that H3N2 viruses are "a broad group of viruses based on the relatedness of their surface proteins," and added that "the recent H3N2 have evolved considerably from the virus that first emerged in humans in 1968. Nevertheless, they are all H3N2 viruses."
Though current H3N2 viruses cannot cause a pandemic because of pre-existing immunity in the population, and current H5N1 viruses cannot cause a pandemic because they do not transmit easily from human to human, in a worst-case scenario, reassortment could cause H5N1 to become easily transmissible from person to person and spark a pandemic - a fact that Katz and her colleagues are quite aware of: All work was carried out in a level 3 biocontainment facility to protect both the researchers and the public.
In the laboratory, however, all reassorted viruses tested by Katz and her colleagues "were not able to transmit efficiently," Katz said. "And in fact, they were also not as able to cause severe disease as the original H5N1 virus."
In an additional experiment, the researchers serially infected up to five ferrets with the same reassorted virus strain, to see whether the transmission from animal to animal would allow it to evolve in a way that made it more easily transmissible. Again, they struck out: "In this process, the virus did not acquire any additional capacity to transmit efficiently," Katz said.
CDC's Gerberding cautioned against interpreting the PNAS data as an all-clear signal. "These data do not mean that H5N1 cannot develop into a pandemic strain," she said at the press conference. But it does mean that "the genetics of that transformation are more complicated than a simple 1-to-1 exchange."
Should a pandemic arrive, vaccination of health care workers and high-risk groups will be the first line of defense. But currently, manufacturing capacity is a major obstacle to getting the necessary vaccine stockpile.
The Department of Health and Human Services has awarded a total of more than $160 million in contracts to Sanofi-Pasteur Inc., a unit of Lyon, France-based Sanofi-Aventis Group, and Emeryville, Calif.-based Chiron Corp. to produce H5N1 vaccine for a strategic national stockpile. But that stockpile is not expected to be filled until 2009 - and that's assuming no more sterility troubles for those companies. (See BioWorld Today, Oct. 6, 2004, and July 6, 2006.)
The Sanofi-Pasteur vaccine currently being stockpiled requires two shots of 90 mcg each. In GlaxoSmithKline's trial, which was conducted in Belgium, subjects received two shots of 3.8 mcg of vaccine, combined with an adjuvant, each, making for encouraging production capacity mathematics - at 90 mcg each in two shots, the Sanofi-Pasteur's vaccine requires more than 20 times the vaccine that GSK's does. Even at that much higher dose, it only induces a robust immune response in half of those vaccinated.
It is noteworthy that GlaxoSmithKline's vaccine has not been approved yet, in the U.S. or anywhere else. In a prepared statement last Wednesday, GlaxoSmithKline's CEO JP Garnier said that "there is still a lot more work to be done with this [program]," but he apparently expects that work to be done quickly. He added that "all being well, we expect to make regulatory filings for the vaccine in the coming months."