Results of a phase I and phase II trial on a new human vaccine against the deadly H5N1 bird flu virus that is made from cell culture instead of embryonated eggs (making it faster and cheaper to produce) show that it is safe and effective against a number of divergent strains. The experimental vaccine is made by Baxter International.

The trial is published in a paper written by the Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team that appears in the 12th June issue of the New England Journal of Medicine, NEJM. The lead authors were Dr Hartmut J. Ehrlich, vice president of global research and development for Baxter’s BioScience business, and Noel Barrett, vice president of Baxter’s vaccines research.

Many experts believe it is only a matter of time before the deadly H5N1 bird flu virus mutates into a form that passes easily from human to human, making the possibiity of an H5N1 bird flu pandemic that would kill millions of people a major global public health priority. Hence the pressing need for a cost-effective vaccine that can be produced quickly to work against a number of divergent strains.

A vaccine that takes a long time to produce is a disadvantage because by the time it is available the virus may have mutated to a strain that is so remote from that used to develop the vaccine that it loses its effectiveness.

The new cell line method developed by Baxter in Bohumil, Czech Republic, uses cell lines originally taken from African green monkey kidneys in 1962. Since then a continuous cell line has been maintained furnishing an unlimited supply of cells without having to make new ones from animals, said Baxter in a press statement.

Using the cell line method means Baxter can produce the vaccine in 12 weeks instead of the 22 weeks it would normally take using fertilized hens’ eggs, according to a report by WebMD.

The H5N1 strain that Baxter uses is the A/Vietnam/1203/2004. According to the company, the composition and structure of this strain are identical to the actual virus circulating in nature, which means the vaccine can be given without the need to boost the immune response with adjuvants, reducing the risk of side effects from these additives.

For this phase I and phase II dose-escalation study, the researchers randomized participants in Austria and Singapore to six groups to investigate the safety of an H5N1 whole-virus vaccine produced on the Baxter Vero cell cultures and find out how well it produced antibodies effective against various H5N1 strains.

There were 275 adult volunteers aged from 18 to 45 years, each given two doses 21 days apart. Each dose contained 3.75 µg, 7.5 µg, 15 µg, or 30 µg of viral hemagglutinin antigen, with or without adjuvant. The researchers analysed blood samples collected at baseline (start of study, day zero), day 21 and day 42. The volunteers recorded their daily body temperature and monitored side effects and adverse reactions for 7 days after each vaccination.

The results showed that:

  • The vaccine had stimulated a neutralizing immune response not only against the original strain (“clade” 1, A/Vietnam/1203/2004), but also against strains derived from the original (clade 2 and 3).
  • Adjuvants did not improve the antibody response.
  • 7.5 µg and 15 µg of hemagglutinin antigen without adjuvant produced the maximum responses.
  • The most common adverse events in all groups were: mild pain at the injection site (in 9 to 27 per cent of subjects) and headache (in 6 to 31 per cent of subjects).

The researchers concluded that:

“A two-dose vaccine regimen of either 7.5 µg or 15 µg of hemagglutinin antigen without adjuvant induced neutralizing antibodies against diverse H5N1 virus strains in a high percentage of subjects, suggesting that this may be a useful H5N1 vaccine.”

Dr Larry M. Baddour wrote in Journal Watch Infectious Diseases, June 11, 2008, that this study makes two major contributions:

“One is the potential availability of a safe and immunogenic vaccine against a much-feared pathogen that could produce devastating human losses either through wild-type mutational events or through bioterrorism-related molecular engineering to facilitate human-to-human viral spread.”

The other major contribution of the study, wrote Baddor, is that:

“Laboratory advances now allow the use of cell culture, which is preferable to embryonated eggs for virus production in vaccine development.”

John Oxford, professor of Virology, The Queen Mary School of Medicine, London, United Kingdom, said in a Baxter press statement that:

“Cell culture technology could represent the future of influenza vaccine production.”

“Baxter has demonstrated the ability to rapidly make large quantities of the vaccine that may protect people against divergent H5N1 viruses,” he added.

“A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture.”
Ehrlich, Hartmut J., Muller, Markus, Oh, Helen M.L., Tambyah, Paul A., Joukhadar, Christian, Montomoli, Emanuele, Fisher, Dale, Berezuk, Greg, Fritsch, Sandor, Low-Baselli, Alexandra, Vartian, Nina, Bobrovsky, Roman, Pavlova, Borislava G., Pollabauer, Eva Maria, Kistner, Otfried, Barrett, P. Noel, the Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team.
N Engl J Med 2008 358: 2573-2584.
Volume 358:2573-2584, June 12, 2008, Number 24

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Source: NEJM, Baxter, WebMD, Journal Watch Infectious Diseases.

Written by: Catharine Paddock, PhD