4th WHO meeting on evaluation of pandemic influenza prototype vaccines in clinical trials, 14-15 February 2008, WHO HQ, Geneva
Summary and meeting documents
Active immunization through influenza vaccination is considered to be the most important and a potentially effective intervention for mitigating the effects of an influenza pandemic. Several manufacturers have active programmes concentrating on H5N1 influenza vaccines, and on other novel subtypes, from which it is anticipated that valuable information can be obtained. On 14-15 February 2008 the Initiative for Vaccine Research (IVR) of the WHO convened the 4th meeting on “Evaluation of pandemic influenza prototype vaccines in clinical trials”. The objective of the meeting was to evaluate the immunogenicity of various candidate H5N1 vaccines as determined in recent clinical trials, studying safety data, dose response and possible antigen-sparing, as well as broadness, i.e. cross-reactivity, of the antibody response elicited by available H5N1 prototype vaccines.
As already demonstrated at previous meetings, all preparations evaluated in clinical trials were shown to be safe and well tolerated in healthy adult volunteers, and when tested, in children and in the elderly as well. Split or subunit candidate H5N1 avian influenza vaccines have demonstrated poor immunogenicity in healthy human adult volunteers, as two doses of up to 90 µg influenza H5 hemagglutinin induced seroconversion in only about 50% of recipients. Supplementation of the vaccine with aluminium salts resulted in variable but at best moderate improvement of immunogenicity. In contrast, supplementation of the split and subunit H5N1 vaccines with water-in-oil adjuvants such as MF59 (Novartis), AS03 (GlaxoSmithKline Biologicals) or AF03 (Sanofi Pasteur) resulted in remarkable improvement of immunogenicity, allowing very significant antigen-sparing and inducing broad-spectrum, cross-clade reactive anti-H5N1 antibodies that persisted for at least six months.
Three H5N1 whole inactivated virion (WIV) vaccines were tested in Phase II-III trials, the first by Omninvest (Hungary), the second by Sinovac (China) and the third, a Vero cell-derived WIV vaccine, by Baxter (Austria). The Chinese and the Hungarian vaccines are alum adjuvanted products, however the Baxter vaccine, produced directly from a wild type H5N1 isolate, is a WIV product without any adjuvant component. All of them were shown to be highly immunogenic. For instance, a single 6µg hemagglutinin (HA) dose of the Omninvest vaccine induced protective hemagglutination inhibition (HAI) and microneutralization (MN) antibody responses in >70% of volunteers, including 60-90 years-old persons.
Live attenuated influenza vaccines (LAIV) produced by MedImmune (USA) were derived by reassortment between avian influenza viruses H5N1, H9N2 or H7N3 and cold-adapted (ca) H1 virus mutants. Trials conducted at the National Institutes of Health (NIH) of the USA showed that the H5N1 ca reassortant was very little immunogenic. The conclusion was reached that avian HA and/or neuraminidase (NA) proteins probably further attenuated the infectivity and immunogenicity properties of the ca donor strains for humans. Another avian-human ca reassortant vaccine, H5N2, was described by the Institute of Experimental Medicine and the Microgen company, Russia, which, based on earlier reports, apparently did not show impaired immunogenicity in humans. Of note is the fact that the master strain carrying the ca mutations used to generate the Russian avian-human reassortants was the Leningrad 17 strain, which differs from the backbone strain (Ann Arbour) used in the US trials. Whether this explains the discrepancies between the two sets of experiments deserves additional studies in the future.
It was accepted that comparison of different vaccines or adjuvants was difficult due to lack of properly standardized Ab assays. Elaboration of standardized SOPs for HAI and neutralizing Ab assays and production of international reference reagents such as reference influenza antibodies are urgently needed.