Pandemic panic

Stockpiling current anti-flu drugs may become futile as new strains develop resistance

The risk of a highly pathogenic avian influenza epidemic is a major public health concern worldwide. As a result of the recent outbreaks of the viruses in poultry, and their subsequent transmission to humans, the western world is gearing up for an influenza pandemic.

There are three types of influenza virus, known simply as A, B and C, and all three types can infect humans. However, only influenza A viruses cause pandemics and this article will concentrate on these and emerging vaccines and treatments.

The influenza A virus is the only type that infects birds - wild birds being the natural hosts - but can also infect pigs, horses and other animals. Influenza A can be transmitted to humans either directly from birds or virus-contaminated environments, or through an intermediate animal host, such as a pig.

A pandemic can occur when a new subtype, capable of spreading easily from person to person, is introduced into the human population, where most of the population has little or no protection against it. Of all viral subtypes, H5N1 is of significant concern because it mutates rapidly, has a propensity to acquire genes from viruses infecting other animals, and is also able to infect and cause severe disease in humans.

There are two classes of antiviral drugs available to treat influenza: adamantanes (amantadine and rimantadine) and neura-minidase inhibitors (oseltamivir and zanamivir). Amantadine, rimantadine and oseltamivir have also been approved by the US Food and Drug Administration for influenza prophylaxis, and it is expected that GlaxoSmithKline will also file for the approval of zanamivir in this indication.

All of these drugs have activity against influenza viruses, yet their lasting efficacy is not guaranteed as influenza strains can become resistant to these drugs.

Of these drugs, oseltamivir (Tamiflu) is the most recently launched. It was developed by Gilead Sciences and the University of California, Berkley, in collaboration with the Australian National University, Canberra. Oseltamivir is an ethyl ester prodrug of GS 4071, which is a potent and selective inhibitor of the influenza neuraminidase enzyme and has low oral bioavailability.

Oseltamivir has lipophilic properties and converts rapidly to the active drug. It was launched in the US in 1999 for treating influenza virus infections, and has been launched in 40 countries worldwide since that time.

The drug has also been approved in the US for the prevention of influenza in adults and adolescents. An application has also been submitted in Canada for this indication.

Panic buying

Data presented at the InterScience Conference on Antimicrobial Agents and Chemotherapy (ICAAC-2004) showed that the drug was active against human and avian H5N1 influenza viruses.

A number of countries have built stockpiles of oseltamivir in preparation for a pandemic, until a vaccine is developed.

However, as a result of the discovery, of oseltamivir-resistant influenza strains in Vietnam in late 2005, as well as the identification of amantadine and rimantadine-resistant viruses isolated from poultry and humans in Asia, it may be that zanamivir soon becomes governments' drug of choice for stockpiling.

Should an outbreak of avian influenza occur, public health officials state that the best way to control the outbreak is to combine influenza vaccination with antiviral treatments.

There is currently no vaccine available to immunise humans against the H5N1 influenza virus subtype that has been seen in Asia. However, vaccines for this and other strains are in development by a number of different organisations.

Vaccines in R&D

The two most advanced of these vaccines are being developed by DelSite Biotech-nologies and the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health. Both target the H5N1 avian influenza and are currently in phase I trials in the US.

DelSite is developing an inactivated, nasal powder vaccine against the H5N1 virus strain, based on its GelSite polymer technology - a polysaccharide that turns from a powder to a gel upon contact with nasal fluids. This results in controlled-release of the drug and increased nasal residence time of vaccine antigens.

The company has received funding from the NIAID for the development of the vaccine and a phase I trial was initiated in March 2005.

The NIAID initiated a phase I trial of a vaccine manufactured by sanofi pasteur, also in March 2005.

The vaccine was manufactured from a seed virus provided by the NIAID and is a weakened version of the wild-type virus. The trial is evaluating the safety and immunogenicity of the vaccine in 450 healthy adults.

However, vaccines take at least four months to produce, and each influenza virus subtype that emerges requires a new vaccine. While only a few of the vaccines and antiviral medications under development for avian influenza are presented here, the race is on to develop effective vaccines and treatments for this highly virulent disease.