May 12, 2006 (CIDRAP news) – In a human trial in France, an experimental H5N1 avian influenza vaccine with an adjuvant showed modestly better performance at a lower dose compared with a similar H5N1 vaccine that was tested earlier in the United States.
The new study, published in this week’s The Lancet, showed an immune response in 67% of patients receiving two doses of 30 micrograms (mcg) of the vaccine plus an adjuvant. An accompanying commentary, however, pointed out several obstacles that need to be addressed before an effective vaccine can be mass-produced.
The vaccine is manufactured by Sanofi Pasteur, a subsidiary of France-based Sanofi Aventis. It is an inactivated, split-virion strain of H5N1 known as Vietnam/1194/2004. The company reported preliminary results of the trial in December 2005.
The study involved 300 adults (aged 18 to 40), divided into three groups receiving 7.5, 15, or 30 mcg of the vaccine, plus three groups receiving the same doses of vaccine combined with an aluminum hydroxide adjuvant. Four of the groups comprised 50 people, one 49, and one 51. Study investigators included two from Sanofi Pasteur, including the senior author.
Each patient received the vaccine on the first day of the study and 21 days later. All patients were assessed on day 21 and day 42 for immune response.
On day 42, of those receiving 30-mcg doses with adjuvant, 67% were seropositive (95% confidence interval, 52% to 79%), compared with 52% of the 30-mcg group without adjuvant. Percentages for both 15-mcg groups were 44%, and those for the 7.5-mcg groups were 43% and 28% without and with an adjuvant, respectively.
In the US study published in March, 451 adults received two doses of 7.5, 15, 45, or 90 mcg of another H5N1 vaccine made by Sanofi, all without an adjuvant. Of the 99 volunteers who received two 90-mcg doses, 54% developed H5N1 antibodies. This compared with 43% in the 45-mcg group, 22% in the 15-mcg group, and 9% in the 7.5-mcg group. The vaccine was based on a different human isolate of H5N1 than the one used in the French study. The study was published in the New England Journal of Medicine.
In the new study, some seroconversion was evident in each of the groups at day 21, after only one dose of the vaccine was administered. Seropositivity was defined as a titer of 32 or greater. The patients had no serious adverse events, few severe reactions, and no oral temperatures higher than 38°C (100.4°F).
The authors conclude, "Our two-dose 30 mcg inactivated H5N1 pandemic vaccine is safe and immunogenic. We also noted encouraging responses with lower doses of antigen."
In an accompanying commentary, however, Suryaparkash Sambhara, DVM, PhD, from the Centers for Disease Control and Prevention, and Gregory A. Poland, MD, of the Mayo Clinic in Rochester, Minn., emphasize that more hurdles need to be cleared. They write that the study results, though more promising than in the earlier US study, leave much to be desired.
"The results of these two early clinical trials,” they write, “clearly indicate that we still do not have a highly immunogenic vaccine to use against H5N1 influenza.” They cite the following factors:
It is unknown whether the antibodies induced by the vaccine would sufficiently protect people from a pandemic virus.
No published reports indicate how this "clade 1" vaccine will cross-react with other H5N1 subtypes.
The regimen of two 30-mcg doses is still high and would limit the number of doses available at current manufacturing capacity. (Seasonal flu vaccination typically consists of one 15-mcg dose.)
No data exist on the vaccine’s effect on immunocompromised people, such as the young or old.
According to the study’s authors, “In a pandemic situation, the aim will be to immunize a maximum number of people to protect them against mortality and severe disease. The level of postvaccination antibodies needed to achieve this protection is not known. Limited manufacturing capacity implies the need to adapt dose-sparing strategies. The challenge, therefore, is to find the appropriate compromise between individual protection and protection from a population perspective.”
Bresson J-L, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase 1 randomised trial. Lancet 2006 (early online publication, May 11) [Abstract]
Sambhara S, Poland GA. Avian influenza vaccines: what’s all the flap? (Commentary). Lancet 2006 (early online publication, May 11)
Dec 15, 2005, CIDRAP News story on preliminary results of French study
"Sanofi says H5N1 vaccine with adjuvant may go further"
New England Journal of Medicine report on earlier H5N1 vaccine study
March 30 CIDRAP News story "H5N1 vaccine trial shows limited benefit"