Five Spanish Hospitals start international phase III clinical trial with H5N1 influenza pandemic vaccine

Both governments and the scientific community are mobilised to face the threat of a possible pandemic provoked by avian influenza. Whereas there is no need to alarm the population, we must design tools in order to fight influenza in case it develops. According to historical data and to the high genetic variability of influenza virus, the development of this pandemic is only a matter of time and that the appropriate circumstances are given.

The H5N1 virus, which affects the European fowl, has already evidenced that it could successfully break the human barrier. This is the reason why H5N1 is the best candidate to establish the bases of the development of pandemic vaccines. Five large national hospitals will participate in the first study with a H5N1 influenza pandemic vaccine held in Spain. Our specialists are working in an international study, with the participation of 7 countries, in order to assess the possible side effects and immunogenicity of this vaccine, developed by GlaxoSmithKline (GSK), in individuals over 18 years.

A total of 5,052 individuals will participate in this study, 1,500 of which will be recruited in Spain. The five Spanish centres are Hospital 12 de Octubre, Hospital Clínico San Carlos and Hospital de La Princesa in Madrid, and the centres Hospital Vall d’Hebrón and Hospital Clínic in Barcelona. People participating in the study will be randomly separated into two groups: 75% will receive two doses of influenza vaccine, and 25% will receive a dose of conventional influenza vaccine and a dose of placebo. The second dose will be administrated after 21 days after the first medical examination, and during the study, two more examinations will have place (days 43 and 180) and a telephone check (day 51). In 10% of volunteers, blood tests will be made in order to analyse the immune response triggered by the vaccine.

Furthermore, participants will fill in a monitoring card during the week after the administration of each dose, where the potential side effects that could appear, such as pain in the injection area or fever, frequent after any type of vaccination, will be noted. This study has been approved by the Ethics Committees of Clinical Research of the five hospitals and also by the Spanish Agency of Drugs and Health Products.

This vaccine is fractionated, since it only contains parts of the viral proteins which activate our immune system. Since no complete virus is administrated, it is impossible that this vaccine could cause influenza. The vaccine includes an adjuvant, similar to that used by GSK in the malaria vaccine that Hospital Clínic is testing in Mozambique, which enhances the immunogenic effects of the vaccine. The stimulation of the immune system caused by this adjuvant, has already proved successful as a part of a vaccine against conventional influenza, and permits to reduce the antigen concentration administered in each vaccination. In the hypothesis of a pandemic, we must take into account that it would be necessary to vaccinate a large amount of population, and the rhythm of production of vaccines is limited.

The efforts are focused in the development of strategies for vaccine production. Last, this vaccine has been produced following the recommendations of the WHO, so that the H5N1 virus has been recombined with the H1N1 Puerto Rico strain of 1934. This strain is highly stable and promotes the development of vaccines in chicken embryo.

The nomenclature of the several influenza virus identifies the variant they contain of the two more important genes involved in the infection. The Haemaglutinin (H) gene is related with the infectiousness and the virulence of the virus, whereas the Neuraminidase (N) gene determines the ability of progression of the infection. Genetic material of the virus is highly variable and it is found as fractionated single-strained RNA. Small changes in the H and N genes create viruses which cause the frequent annual influenza epidemic. When a large change is produced or a new version of the gene appears, an antigenic change is capable of triggering a worldwide epidemic, called pandemic.

Influenza virus with a pandemic potential could appear by direct transfer of an animal virus to humans, -as happened in the “Spanish Influenza” that in 1918 caused death to 5% of the world population- or by a genetic reassortment between human and animal viruses. Such genetic reassortment would have place in a host co-infected by two different viruses.

The probability that a pandemic human virus is generated is now low, but the risk exists, and it is increased when cases of animal flu are found in humas, such in the case of H5N1. The hundred of death cases documented until now can give an idea of the potential danger we are facing.

Furthermore, there are two circumstances that worsen this situation: this virus can mutate rapidly, and the fowl surviving the infection excrete the virus intensely through respiratory secretions and faeces during at least 10 days. Because of all this, it is important to make a both scientific and economic effort in order to obtain the best weapons to combat a possible definitive adaptation to humans of the H5N1 virus. In any case, this effort led by Spain, Germany, Holland, Sweden, Russia, France and Estonia will permit to improve the available tools in order to face this or future pandemics.