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'Home-Grown' H5N1 Vaccine Trials in UK
UK biotechnology company PowderMed has asked for approval to start clinical trials of a 'rapid response' vaccine for the H5N1 strain of avian influenza.
Although other vaccines against H5N1 are further forward in development, PowderMed believes that its candidate, which is based on viral DNA, could have an advantage in terms of speed of production over vaccines made in either eggs or cell culture-based systems.
The plasmid DNA for PowderMed's vaccine is produced using a bacterial fermentation process that could carve the production time down from nine months with egg-based systems to a matter of weeks, which could make for rapid production of vaccine in response to a rapidly-emerging pandemic strain.
If the strain of virus causing an influenza pandemic mutated, it would be relatively simple to isolate the new strain, get hold of its key DNA sequences and produce new vaccine. Moreover, the use of DNA means that limited supplies of vaccine antigen can be stretched further: PowderMed estimates that 1 kg of H5N1 DNA could be manufactured in just three months and provide enough antigen to vaccinate the UK population of 60 million people twice over.
PowderMed aims to carry out the trial at a clinical research centre in London, which is already involved in recruiting patients for flu vaccine trials. It hopes the findings will back up results from a US study of a seasonal flu vaccine, reported in the journal Vaccine, which showed that the vaccine achieved 100% efficacy in stimulating antibodies against the virus.
Information on the trial published on the website indicates that it will enroll a target group of 75 adult volunteers and is scheduled to get underway this month, with completion in May 2007. It will look at four different doses of the vaccine, given as a prime-boost regimen on days 0 and 28.
The vaccine takes the form of microscopic gold particles, coated with DNA, that are shot through the skin and penetrate local immune cells in order to stimulate a response.

Safety and Immunogenicity of an Inactivated Subvirion Influenza A (H5N1) Vaccine
John J. Treanor, M.D., James D. Campbell, M.D., Kenneth M. Zangwill, M.D., Thomas Rowe, M.S., and Mark Wolff, Ph.D. From the Department of Medicine, University of Rochester, Rochester, N.Y.(J.J.T.); the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore (J.D.C.); the Los Angeles Biomedical Research Institute and UCLA Center for Vaccine Research, Harbor-UCLA Medical Center, Los Angeles (K.M.Z.); Southern Research Institute, Birmingham, Ala. (T.R.); and EMMES, Rockville, Md. (M.W.).
NEJM March 2006
Background Influenza A (H5N1) viruses could cause a severe worldwide epidemic, with high attack rates, large numbers of deaths and hospitalizations, and wide disruption. Effective vaccines against these viruses in humans are urgently needed.
Methods We conducted a multicenter, double-blind two-stage study involving 451 healthy adults 18 to 64 years of age who were randomly assigned in a 2:2:2:2:1 ratio to receive two intramuscular doses of a subvirion influenza A (H5N1) vaccine of 90, 45, 15, or 7.5 mg of hemagglutinin antigen or placebo. The subjects were followed for the safety analysis for 56 days. Serum samples obtained before each vaccination and again 28 days after the second vaccination were tested for H5 antibody by microneutralization and hemagglutination inhibition.
Results Mild pain at the injection site was the most common adverse event for all doses of vaccine. The frequency of a serum antibody response was highest among subjects receiving doses of 45 mg or 90 mg. Among those who received two doses of 90 mg, neutralization antibody titers reached 1:40 or greater in 54 percent, and hemagglutination-inhibition titers reached 1:40 or greater in 58 percent. Neutralization titers of 1:40 or greater were seen in 43 percent, 22 percent, and 9 percent of the subjects receiving two doses of 45, 15, and 7.5 mg, respectively. No responses were seen in placebo recipients.
Conclusions A two-dose regimen of 90 mg of subvirion influenza A (H5N1) vaccine does not cause severe side effects and, in the majority of recipients, generates neutralizing antibody responses typically associated with protection against influenza. A conventional subvirion H5 influenza vaccine may be effective in preventing influenza A (H5N1) disease in humans. ( number, NCT00115986 [] .)
This study demonstrates that is it possible to generate immunity against H5 influenza with the use of a purified, subvirion vaccine administered in two relatively high doses. Our results are similar to those observed in a study conducted with the use of a purified, recombinant H5 hemagglutinin in humans,14 in which intramuscular administration of two doses of approximately 90 mg each of a baculovirus-expressed recombinant H5 hemagglutinin resulted in neutralizing antibody titers of 1:80 or greater in 56 percent of healthy adult recipients, whereas lower doses were considerably less immunogenic. Although that study used a different vaccine and slightly different assays to measure immune responses, both those results and ours show that high doses of relatively purified protein vaccines were required to induce immunity in most recipients.
The interpretation of the significance of these findings should be done in the context of our current understanding of immunity to H5 viruses. Our decision to use a neutralizing antibody titer of 1:40 as the primary immunogenicity end point was not based on observations of antibody-mediated protection in the field but, rather, on the development of criteria that appeared to distinguish between infected and uninfected persons during serologic surveys performed during the previous outbreak of H5 virus infection in 1997.15 It is possible that lower titers of neutralizing antibody could be associated with protection, as has been observed in studies of conventional human influenza viruses.16,17,18,19 The development of a sensitive hemagglutination-inhibition assay for H5 viruses12 should facilitate further studies, but the level of antibody associated with protection in this assay has yet to be determined.
On the basis of these preliminary data, a two-dose schedule of 90 mg of subvirion H5 vaccine would probably have an acceptable tolerability profile and could be effective in preventing H5 influenza in healthy adult recipients. Elderly persons, persons with impaired immunity, or children may have a different response, and trials of the vaccine in these populations are in progress. Production of the vaccine and this clinical trial are important steps toward control of a pandemic, and the current vaccine would probably be acceptable for licensure, if needed. However, the need for a vaccine with a total dose of 180 mg would pose a considerable barrier to rapid production of a supply that would be adequate to meet the world's requirements should a pandemic occur. Therefore, dose-sparing approaches should be pursued aggressively. These approaches could include the use of adjuvants such as aluminum20 or MF5921 and the use of intradermal administration of vaccine,22,23 both of which have been reported to be potentially dose sparing for influenza vaccines in small studies. In addition, the recent demonstration of a substantial increase in the immune response when a third dose of H5 vaccine was administered to subjects 16 months after a primary series24 suggests that another strategy for improving the immune response would be prepriming, perhaps by including an H5 component in the annual vaccine. Combinations of these approaches may be needed. Finally, live attenuated vaccines are being developed. As the results of studies to evaluate each of these options become available, our results may be useful for comparison.
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