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Pandemic preparedness

The world awaits the first swine flu vaccines to combat this newest global health threat

A hygiene facemaskA novel strain of influenza A H1N1 virus, now globally recognised as "swine flu", was identified as a significant cause of febrile respiratory illness in Mexico in April 2009. The virus rapidly spread to several countries around the world, prompting the World Health Organisation (WHO) to officially declare an influenza pandemic on June 11, 2009 – the first in over 40 years. This pandemic declaration marked the start of a frenzied race between pharmaceutical and biotechnology companies to develop the first vaccine to combat this newest global threat.

Swine flu is a respiratory disease of pigs first isolated in swine in 1930, according to the US Centers for Disease Control and Prevention (CDC). The illness is caused by four different type A influenza strains that can cause outbreaks in pigs, although subtypes H1N1 and H3N2 seem to be more common.

According to the WHO, an influenza pandemic occurs when a new virus appears against which the human population has no immunity, and it can then mutate and spread globally to cause a massive worldwide outbreak (pandemic). The WHO specifies that a pandemic must meet the following three criteria: a new virus emerges with a new haemagglutinin (HA) to which there is almost universal susceptibility; the virus is capable of causing significant disease in humans and the virus is efficiently transmitted from human to human.

During the last four centuries, an influenza pandemic has emerged about once every 30-40 years. Three distinct influenza pandemics have occurred during the 20th century: in 1918 (Spain; H1N1 subtype), 1957 (Asia; H2N2 subtype), and 1968 (Hong Kong; H3N2 subtype). The most devastating of these was the Spanish H1N1 influenza (Spanish flu) pandemic, which resulted in an estimated 50 million deaths around the world between 1918 and 1919. This was primarily due to the fact that influenza vaccines had not yet been developed.

The 2009 H1N1 virus strain is novel in its genetic makeup and is referred to as a "quadruple reassortant" virus. Although many of the genes in this new virus are very similar to influenza viruses that normally circulate in pigs in North America, further investigation has shown that the 2009 H1N1 strain consists of RNA from four different sources — two genes from influenza viruses that normally circulate in pigs in Europe and Asia, as well as avian influenza ("bird flu") genes and human influenza genes.

The WHO has recently estimated that about 30 per cent of the world's population (about two billion people) could contract the swine flu virus by the time the current pandemic ends. However, this estimate comes with a significant health warning — no one knows how many people so far have caught the new swine flu strain and the final number will never be known, as many cases are so mild they may go unnoticed.

The power of the vaccine
There is great urgency in getting a new vaccine against the 2009 H1N1 virus approved for public use, particularly before the autumn and the beginning of the 2009/2010 influenza season in the Northern Hemisphere (approximately November to April).

Vaccines are among the most important medical interventions for reducing illness and deaths during a pandemic. However, to have the greatest impact, pandemic vaccines need to be available quickly and in large quantities. The WHO has estimated that vaccine manufacturers could produce up to 4.9 billion pandemic influenza injections per year, at most.

After the pandemic H1N1 virus strain was identified at the end of April 2009, vaccine manufacturers began to develop pandemic H1N1 vaccines – some from scratch and others following alteration of an already approved "mock-up" vaccine for pandemic use (based on previous experience with the H5N1 subtype, or bird flu).

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Leading vaccine developers
The first formal clinical trials of H1N1 vaccines were initiated in Australia in July 2009 by two Australian biotechnology companies, CSL and Vaxine.

The CDC, the WHO and various regulatory authorities are working closely with various vaccine manufacturers to facilitate rapid development of an H1N1 vaccine. The CDC has generated and distributed a 2009 H1N1 seed virus to vaccine manufacturers for the development of vaccine pilot lots for testing in clinical trials.

At the time of writing this article, companies with H1N1 vaccines in clinical trials included: CSL (phase II in Australia and US); Sinovac Biotech (phase IIb in China); Sanofi Pasteur (phase II in US); Novartis (phase I in UK, Germany and US) and Vaxine (phase I in Australia).

CSL is developing a monovalent H1N1 vaccine called CSL425, which is undergoing phase II trials in Australia in healthy adults and children (≥6 months to < 9 years). US trials were initiated in early August 2009 and are being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). CSL is one of the companies that was provided with H1N1 seed virus from the CDC.

Sinovac Biotech also received the H1N1 seed virus from the CDC in June 2009 and subsequently initiated a phase II trial of its H1N1 vaccines in China on July 22, 2009. China's State Food and Drug Administration (SFDA) has granted fast-track approval to Sinovac's H1N1 pandemic vaccine. Sinovac is testing three vaccine candidates: a split virion vaccine (7.5 or 15μg HA per dose) to be given with an adjuvant; a split virion vaccine (15 or 30μg HA) without an adjuvant and a whole virion vaccine (5 or 10μg HA per dose) to be given with an adjuvant.

Sanofi Pasteur also received the H1N1 seed virus at the end of May 2009. In early August 2009, the company began clinical trials of its monovalent H1N1 vaccine at two dose levels (15 and 30μg of HA) in infants (aged ≥6 months), children, adolescent, adult and elderly volunteers in the US. These US trials are also being sponsored by the NIAID. The company is also investigating the effects of the H1N1 vaccine when given in combination with a seasonal influenza trivalent vaccine.

Sanofi Pasteur is also investigating the development of split virion and subvirion (ie chemically altered virions) formulations of its monovalent H1N1 vaccine. A phase II trial of the subvirion H1N1 vaccine is expected to begin in August 2009 in healthy and elderly volunteers from the US. Further phase II trials of the split virion H1N1 vaccine are expected to begin in Europe between August and September 2009 in paediatric and adolescent patients (≥6 months of age; Finland), and in healthy adult and elderly volunteers (France).

The first UK trial of a H1N1 vaccine began in July 2009. The trial is being conducted at University Hospitals in Leicester and is designed to assess the safety and immunogenicity of cell-culture non-adjuvanted and MF59-adjuvanted H1N1 vaccines developed by Novartis Vaccines.
The second H1N1 vaccine to begin clinical trials in Australia in July 2009 was developed by Vaxine and incorporates its proprietary polysaccharide Advax adjuvant. Vaxine believes its adjuvanted H1N1 vaccine may offer a more effective treatment option by allowing reduction in the required dose of influenza antigen, thereby increasing the number of available pandemic vaccine doses and reducing the overall cost of vaccine manufacture.

Data generated from trials of these vaccines will be assessed by regulatory authorities as and when they become available. The WHO has attempted to allay public fears regarding the rapid speed of development and insists that fast-track approval of the pandemic vaccines will not jeopardise safety.

Although this article focuses only on the H1N1 vaccines in clinical trials at the time of writing, there are several companies with potential prophylactic vaccine candidates and therapeutics drugs in preclinical development following closely behind. These companies include AlphaVax, Baxter International, CEL-SCI Corporation, Crucell, GlaxoSmithKline, ImmuneRegen, Inovio Biomedical, Medicago, NanoViricides, Vaxart, VaxInnate and Vical, among others.

Until a swine flu vaccine becomes available, antiviral medicines can be used for the treatment of pandemic influenza cases. The neuraminidase inhibitors, oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline) have shown effectiveness against the novel H1N1 virus.

Need for caution
The rapid speed at which vaccine development is progressing for this novel influenza A H1N1 strain, greater public awareness and extensive preventive measures that are already in place can all be regarded as positive factors to help minimise the effects of the swine flu pandemic.
There is also an inherent fear among health experts that mutations of the 2009 H1N1 virus could result in a more virulent form of the disease, which could be more devastating than its current form. There is also the possibility that any new H1N1 vaccine developed could be less effective against a more aggressive form of the virus.

One of the other concerns among health experts is that resistance to oseltamivir has already begun to develop and the WHO is now officially tracking cases of such resistance. 

The first results from clinical trials of the novel H1N1 vaccines are expected in September 2009. Shortly after, WHO officials expect that regulatory authorities will approve the world's first swine flu vaccines, allowing mass vaccination programmes to begin.
As the genetic sequence of the 2009 H1N1 virus is significantly different from the H1N1 strain contained in current seasonal influenza vaccines, it is likely that new swine flu vaccines will be given in conjunction with the seasonal trivalent influenza vaccine.
Only time and vaccine experience will determine how effective the new H1N1 virus vaccines will be in our human effort to “catch the swine”.

The Author
Pipeline was written by Asha Vaidya of Adis International (Wolters Kluwer Health), using data derived from Adis R&D Insight and Clinical Trials Insight.
For further information on Adis services, please contact Kuljeet Sohanpal on 0207 981 0714 or email:
To comment on this article, email

16th September 2009


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