Pandemic preparedness

In April 2007, the FDA announced the first approval in the US of a vaccine for humans against the H5N1 influenza virus. Its manufacturer, sanofi pasteur, does not intend to sell this vaccine to private markets but only to governments; and it is already developing newer ones. NGP spoke with Michel De Wilde, Senior Vice President R&D, sanofi pasteur, about pandemic preparedness.

Avian influenza or bird flu is caused by influenza A type viruses that occur naturally among birds. There are different subtypes of these viruses, for instance H5N1, H7N1, H7N2, H9N1, all of which can be found in birds. The main cause of concern currently is the H5N1 strain because of its potential to cause a pandemic. Not only can it infect birds and other animals but also people.

Producing vaccines is challenging enough, and when it comes to influenza, each year sanofi pasteur produces two which have to be validated by government health authorities: a northern hemisphere influenza vaccine, based on World Health Organisation (WHO) recommendations released in February each year, and a southern hemisphere influenza vaccine, based on WHO recommendations in September each year. The influenza vaccine market was sized at approximately $2.2 billion (€1.6 billion) in 2006 and is predicted to more than double in size by 2016.

The world seasonal influenza vaccine production is more or less driven by the world global demand. This is the reason why sanofi pasteur has been steadily increasing its manufacturing capacity: since 1995, sales volume of sanofi pasteur’s influenza virus vaccines has more than tripled, and since 2003, capacity has increased by more than 40 percent.

Recently, the Lyon, France, based company submitted a Biologics Licensing Application to the FDA for this first-generation candidate H5N1 vaccine in collaboration with the US Department of Health and Human Services as a first step toward enabling the US government to stockpile vaccine for use during the early stages of a pandemic. The US government has plans to stockpile enough H5N1 vaccine to protect 20 million doctors, nurses, paramedics, laboratory technicians and other emergency workers if a pandemic breaks out.

“The licensed vaccine was produced at full manufacturing scale using existing proven technology. This vaccine is an important first step, as we actively pursue further generations of candidate vaccines,” says Michel De Wilde, Senior Vice President R&D, sanofi pasteur.

Global preparedness

Committed to global pandemic preparedness, sanofi pasteur is actively involved in projects in the US, Europe and international countries with the goal of developing a vaccine to protect against a pandemic influenza virus. The company is also investing in major expansions of its influenza vaccine production capabilities globally. In July 2007, sanofi pasteur completed the construction of its new influenza vaccine manufacturing facility in the US. The new $150 million (€111 million), 140,000 square-foot (13,000 square-meter) vaccine manufacturing plant is designed to more than double the site’s capacity to over 100 million doses of influenza vaccine per year. The new manufacturing facility is currently projected to come on-line in late 2008 or early 2009 following the facility’s licensing by the FDA. Currently, sanofi pasteur is the only company manufacturing inactivated influenza vaccines in the US.

In Europe, this past May sanofi pasteur submitted a core dossier for a pandemic vaccine to European regulators. The procedure is expected to reduce the time needed for registration of a pandemic vaccine should a pandemic flu strain be identified by the WHO.

Sanofi pasteur is also a member of FLUPAN, a collaborative research project funded by the European Commission to improve the level of pandemic preparation in the EU. The six European partners in FLUPAN are the National Institute for Biological Standards and Control, UK; the University of Reading, UK; the Istituto Superiore di Sanita, Italy; the Health Protection Agency, UK; sanofi pasteur, France; and the University of Bergen, Norway. The project’s aim is to use reverse genetics to modify a highly pathogenic H7N1 avian influenza virus so that it is safe to use and will grow well on mammalian cells.

Collaborations

Sanofi pasteur has been part of the influenza vaccine industry’s heritage for half a century and is also partnering with WHO to address the critical public health threat. “Above and beyond this vital initiative with the international community and with WHO, we are actively pursuing further moves that are intended to increase influenza vaccine supply for countries in the developing world, enabling us to provide a meaningful contribution to global pandemic preparedness,” De Wilde points out.

In November 2006, The Department of Health and Human Services awarded a total of $199.45 million (€147.85 million) to three vaccine makers in order to stockpile 5.3 million additional doses of H5N1 vaccine. The bulk of the money, $117.9 million (€87.4 million), went to sanofi pasteur for 3.7 million doses of the drug. Novartis received $40.95 million (€30.36 million) for 800,000 doses and GSK also garnered $40.6 million (€30.09 million) for 800,000 doses.

What role does competition play in pandemic preparedness? De Wilde shrugs his shoulders. “Competition in any field or industry, and especially combating and preventing disease, can only benefit the public. Moreover, pandemic is a global Public Health concern, not a competitive one, and certainly not ‘business as usual’. Health authorities, international organizations and industry should collaborate in order to optimize the response to a pandemic crisis.”

Cell culture technology

Traditionally, influenza vaccines have been produced in fertilized chicken eggs. The egg-based production of influenza vaccines is safe, robust, consistent, has an excellent track record and knowledge base. 1.5 billion doses of seasonal influenza vaccine from sanofi pasteur have been administered worldwide over the past 50 years. However, egg-based production does have disadvantages. Extensive planning, including the procurement of many million eggs, is necessary. This limits the flexibility in case of exponentially increasing demand. It is questionable whether or not a flu pandemic could be contained and defeated on egg-based production, because it takes a long time and eggs don’t grow on demand.

An alternative way of producing flu vaccines is based on cell or tissue cultures – a technology that De Wilde believes will eventually become an alternative to egg based production. “To be economically competitive and to become a meaningful alternative, cell based production will need to be carried out at very large scale using an extremely robust process. With this in mind, we partnered with Crucell and Lonza, combining our own know-how with best in class partners in terms of cell line and large scale experiences. Our efforts supported by a US Government contract are progressing very well. We have established a very robust scalable process and are moving in phase II clinical study,” says De Wilde

Cell culture based systems hold great promise. They could be rapidly expanded and scaled up in times of emergency. De Wilde, however, shakes his head: “Currently, no alternative technology has reached a stage where it can competitively replace mass production of influenza vaccines. Cell-based technology has to be fully developed and needs to go through comprehensive clinical development before obtaining market authorization from health authorities. This process is expected to take several years.”

In the coming years, De Wilde has no doubts that influenza vaccine production will rely on egg-based technology. It requires the absolute necessity to secure and anticipate embryonated eggs production and availability all year long. This is the reason why one of the first sanofi pasteur priorities was to secure the yearly egg availability in guarantying the security and safety of its fully-dedicated and totally isolated poultry farms including a wide geographical distribution of these farms. The challenge in case of a pandemic, De Wilde believes, is to produce as many doses as possible in the shortest possible term to protect millions of humans, virtually the whole planet.

R&D portfolio

Committed to continuing its robust research and development program for pandemic preparedness, sanofi pasteur is currently not only exploring the use of cell culture production processes but also dose-sparing strategies, evaluating the use of a new proprietary, non-aluminium based adjuvant and assessing the ability of vaccine formulations to generate immune responses against other strains of the H5N1 virus.

De Wilde: “One of today’s most promising solutions to produce billions of pandemic influenza doses in a pandemic situation is the dose-sparing strategy with new adjuvant families which are added to the egg-based avian influenza vaccines and which may allow us to achieve high seroprotective immune response with very low dosage of hemagglutine antigen.”

Sanofi pasteur’s wide R&D portfolio contains 24 vaccines that are currently in development at different stages: 12 in preclinical or clinical phase I, and 12 in clinical phase II or III. De Wilde: “Our pipeline balance covers several aspects: line extension, new formulation, new delivery systems, new production processes and new targets: flu pandemic, dengue, chlamydia, HIV, malaria as well as the new avenue of therapeutic vaccines against cancer. All of these projects are very motivating and tremendously exciting ones, mainly because of their crucial, worldwide importance to public health.”

De Wilde believes that addressing the current and future public health needs and trying to do all that can be done to combat the many diseases that threaten human health is one of the biggest challenges in the vaccine industry. The vaccine world market is expected to double by 2012. Sanofi pasteur is intending to grow accordingly. With many major vaccine launches scheduled in the near and medium term, the chances are that the company will. Amongst the launches are the pediatric combination vaccine Pentacel in the US, the expansion of the Menactra vaccine indication for two to 10-year-olds in the US, Pentaxim in Mexico, as well as microinjection influenza vaccines.

“As the world leader in influenza vaccine production, addressing the threat of a pandemic influenza outbreak and exploring new paths to define the best formulation of a pandemic vaccine in order to offer optimal protection to the greatest number of people will remain our highest priority,” says De Wilde.

BIO
Michel De Wilde

As Senior Vice President, Research and Development for sanofi pasteur, the vaccines division of the sanofi-aventis Group, Michel De Wilde is responsible for R&D at the company’s three sites: in France, Canada and the USA. He oversees a global professional staff of 1500. Prior to joining sanofi pasteur in 1999, he had a long career with GSK Biologicals in Rixensart, Belgium.