Market need for influenza and other viral vaccines

Influenza, in humans, causes up to 500,000 deaths and 3 – 5 million cases of severe illness worldwide. Severe illness is caused by either seasonal or pandemic strains of influenza viruses. Seasonal influenza is the annual epidemic of influenza that is passed from human to human and is highly variable from year to year. Pandemic influenza arises from a new influenza strain, often from swine or birds, which enters the human population. Pandemic influenza occurs periodically and mortality is generally much higher than for seasonal influenza, with high-fatality H5N1 bird flu and (to date) lower-fatality H1N1 swine flu being recent examples.

Gamma Vaccines is targeting both the seasonal and pandemic flu markets, currently estimated to be over US$2.8 billion and growing by at least 12.6% p.a. Gamma Vaccines’ initial product, Gamma-Flu^™, is being developed to be effective against both seasonal and pandemic influenza. Gamma-Flu™ aims to address most of the major unmet needs in the treatment of influenza:

• Current vaccines are less effective in the elderly, who are generally more susceptible to seasonal flu. GammaFlu ^™ is expected to have higher efficacy in the elderly due to its mode of administration and the way in which it induces immunity
• The current egg-based manufacturing method is no longer sufficient to meet demand, despite being well established and cost effective. The yield of vaccine from egg-based manufacture varies from strain to strain (of flu virus) and on average between one and two eggs are required to prepare each dose of vaccine. The improved immunogenicity of Gamma-Flu^™ ought to result in production of a larger number of doses per egg – an important advance in the face of the threat of a global pandemic
• Injections are painful, - injection site pain is the most widespread side effect reported in clinical trials since 1998. GammaFlu^® will be administered intranasally
• Vaccines don’t last more than one season, mainly due to the extreme annual variability of the influenza virus. GammaFlu^® is intended to be a long-lasting vaccine with efficacy against both seasonal and pandemic strains.

In addition to humans, animals and especially water birds and poultry, are particularly susceptible to “avian” strains of influenza viruses. Globally, there are over 30 billion broilers, almost 5 billion egg layers and unknown (but large) numbers of breeder chickens.
The emergence of a highly pathogenic avian influenza virus (HPAIV) of the H5N1 subtype causes high mortality in domestic poultry. Asian governments took firm action in 2004 to stamp out an H5N1 outbreak by mass culling of poultry and restricting poultry movement. However, this approach has been superseded by the use of avian influenza (AI) vaccines in poultry in many South East Asian countries. Despite this, HPAIV infection continues to occur, in part because existing vaccines cannot keep pace with the emergence of genetic variants of AI strains.
Gamma Vaccines avian influenza product is expected to be effective against H5N1 strains as well as other subtypes of avian influenza.

Why is influenza so hard to treat?

Influenza viruses contain two proteins called haemagglutinin and neuraminidase that sit in the membrane surrounding the influenza virus. The influenza strains are named according to the type of haemagglutinin and neuraminidase they contain. Hence, an H3N2 influenza virus produces a type 3 haemagglutinin and a type 2 neuraminidase. The recent H1N1 swine flu pandemic strain has a type 1 haemagglutinin and type 1 neuraminidase and H5N1 bird flu has a type 5 haemagglutinin and type 1 neuraminidase. Strains of influenza that have different H and N types are known as heterotypic strains. The emergence of a new heterotypic strain by a process known as “antigenic shift”, with a different combination of H and N types, is the cause of new pandemics of influenza. These antigenic shifts are rare events occurring on average every 20 years or so, and can lead to strains that are highly infectious with high morbidity and mortality. Examples include the H1N1 pandemic of 1918 that resulted in at least 50 million deaths worldwide. The Hong Kong flu of 1968 was the last major pandemic shift before H5N1 bird flu emerged in 2003. The recent H1N1 (swine flu) outbreak of 2009 illustrated just how rapidly new strains can spread around the globe. Fortunately, the swine flu strain, whilst highly transmissible did not (at least at this stage) cause high mortality.
By contrast to “antigenic shifts’ responsible for new pandemics, currently circulating seasonal flu strains can also mutate by what is known as “antigenic drift”. This leads to changes in their respective H and N proteins making them less capable of binding antibodies produced by immunization with the previous year’s seasonal flu vaccine.

Gamma-Flu^™, unlike existing seasonal flu vaccines or WIV vaccines killed by alternative methods, has been found to stimulate highly effective cytotoxic T-cell immunity that protect against different influenza A virus strains. The striking difference in protective effect is shown below in an experiment in mice, in which WIV vaccines, killed by either formaldehyde treatment or exposure to ultraviolet light or gamma irradiation, were tested for their ability to protect against a live challenge with a fully heterotypic influenza strain.
Only the gamma-irradiated WIV vaccine afforded protection in these studies.
The figure below shows the results of an experiment in which groups of 9-10 BALB/c mice were intranasally vaccinated by mock vaccination (as a control) (A), immunised with formalin-treated influenza virus A/PC (H3N2) (B), immunised with UV-treated influenza virus A/PC (H3N2) (C) or immunised with gamma-irradiated influenza virus A/PC (H3N2) (GammaFlu^®) (D) and then challenged three weeks after the immunisation with a lethal dose of live influenza virus A/PR8 (H1N1). All mice were then monitored daily for weight loss.
As can be seen, over the next ten days the GammaFlu^® (A/PC; H3N2) vaccinated mice were fully protected against heterotypic challenge with A/PR8 (H1N1). By contract, mice vaccinated using formalin- or UV-treated A/PC (H3N2) vaccines were not protected from challenge with A/PR8 (H1N1) virus.

Comparison of trials of gamma-irradiated vaccine and controls in mice

Intranasal vaccination in mice with gamma-irradiated influenza virus protects against heterotypic challenge with bird flu