Vaccine protects ferrets against 3 H5N1 strains

Jun 13, 2006 (CIDRAP News) – An avian influenza vaccine made through reverse genetics produced an immune response not only to the target H5N1 virus strain but to two other H5N1 strains in a study in ferrets, according to a report published by the Journal of Infectious Diseases.

The findings, according to the study's authors and an accompanying editorial, signal that an H5N1 vaccine may be protective even when the vaccine strain does not precisely match the strain of H5N1 challenge virus. This bolsters the strategy of stockpiling such a vaccine to prepare for a pandemic.

The study was done by a team from St. Jude Children's Research Hospital in Memphis, with Elena A. Govorkova as first author. The investigators used reverse genetics to produce an inactivated, whole-virus vaccine that combined the hemagglutinin (HA) and neuraminidase genes of the H5N1 strain A/HK/203/03 with the remaining genes of a strain of H1N1 virus called A/PR/8/34.

The researchers vaccinated groups of three or four ferrets with either a single dose (7 or 15 micrograms [mcg]) of HA with aluminum hydroxide adjuvant or two doses of HA (7 mcg each, 3 weeks apart) without adjuvant.

The ferrets studied were healthy young adults that tested negative for H5N1 and H1N1 viruses, though 90% tested positive for H3N2 virus obtained through natural infection, according to the report. Four control ferrets received phosphate-buffered saline instead of vaccine.

The researchers tested serum antibody responses after vaccination. The single-dose ferrets had a mean anti-HA titer of 1:107 and 1:120 for the 7-mcg and 15-mcg doses, respectively. The mean anti-HA titer for animals receiving two doses were 1:115 after one dose and 1:982 after two.

Controls and ferrets that received the single dose of vaccine were inoculated intranasally 4 weeks later with the target subtype of H5N1 virus. Those receiving two doses were challenged 1 week after the booster dose.

After viral challenge, all control ferrets exhibited fever and weight loss, while two had respiratory signs and two showed lethargy. Six days after viral challenge, controls had lost 4% to 12% of their weight. In contrast, 1 of 3 ferrets that received a single dose of 7 mcg of HA had an elevated body temperature and weight loss, but none of the other vaccinated animals had either.

Ferrets that received a single 7-mcg dose of vaccine had significantly (P<.05) lower virus titers than did controls on day 3, and only 1 of 3 shed virus 5 days after viral challenge. Among those receiving a single 15-mcg dose, 2 of 3 animals were shedding virus on day 3, and none by day 5.

The authors state, "All vaccinated ferrets were protected against systemic spread of homologous virus [the vaccine strain]," which was not detected in the lung, brain, or olfactory bulb. In addition, they said, all vaccine regimens effectively reduced replication of the target H5N1 virus subtype in the upper respiratory tract.

When tested against different H5N1 strains, the vaccine also proved effective, according to the article. Separate groups of ferrets were tested against both the HK/156/97 and Vietnam/1203/04 strains of H5N1.

The vaccine provided protection against the HK/156/97 subtype, although those receiving a single 7-mcg dose showed minor clinical signs. Also, greater protection was noted for ferrets receiving two doses of the vaccine. All four control ferrets showed signs of disease but survived.

The vaccine similarly protected against the Vietnam/1203/04 subtype, which killed the three control animals. Again, the two-dose regimen provided the greatest benefit.

The authors report, "Our findings confirmed that a two-dose regimen is preferable for vaccination of an immunologically naïve population against a novel H5N1 strain. The second dose of vaccine significantly increased serum antibody production and conferred complete protection against challenge with a high dose of the homologous H5N1 virus."

They conclude, "The results of our study show that protection can be gained even when the vaccine strain does not match the challenge virus. . . . Therefore, the strategy of stockpiling pandemic vaccines for administration to groups at high risk offers promise. Reverse-genetics technology allows for the rapid generation of a broad spectrum of vaccine virus libraries."

In an accompanying editorial, Alan W. Hampson, Msc, deputy director of the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia, concurs. "Possibly the greatest significance of Govorkova et al's study," he writes, "is the demonstration of a significant cross-strain protective effect even in the presence of minimal antibody levels. This, together with human serological data generated with an H5N3 vaccine, strengthens the argument for stockpiling vaccine prepared from currently available H5N1 vaccine strains."

Govorkova EA, Webby RJ, Humberd J, et al. Immunization with reverse-genetics-produced H5N1 influenza vaccine protects ferrets against homologous and heterologous challenge. J Infect Dis 2006 Jul 15;194(2):159-67 [Full text]

Hampson AW. Ferrets and the challenges of H5N1 vaccine formulation (editorial). J Infect Dis 2006 Jul 15;194(2):143-5 [Full text]

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