As the influenza season approaches, health officials remain concerned about the H5N1 strain of avian flu. Humans have no immunity to this strain, which is more virulent than the 1997 version that killed six people in Hong Kong. So far, however, only one human-to-human transmission of the H5N1 virus (in Thailand) has been documented.
In the 20th century there were three major pandemics, one of which was a real whopper, said Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases (NIAID) director of the NIH, referring to the Spanish flu of 1918 which killed between 20 and 40 million people worldwide. Health experts say an avian flu outbreak would most closely resemble that pandemic.
Without vaccination or drugs, a medium-scale pandemic could affect 1535% of the U.S. population with an economic impact of $71.3$166.5 billion, according to the U.S. Centers for Disease Control and Prevention. Worldwide, the World Health Organization estimates that 2050% of the global population could be affected, and that between 2 million and 50 million persons could die.
Well likely see another pandemicprobably sooner than later, Dr. Fauci says. Its very cavalier to say it wont happen, and overly dramatic to say well die. The World Health Organization estimates that the next pandemic may result in 12.3 million hospitalizations and between 280,000 and 600,000 deaths in the industrialized nations alone.
Vaccine manufacturers are well-along in developing vaccines to combat the H5N1 strain of avian flu. Theres not a huge development difference between this and conventional flu vaccines, notes Vijay Samant, CEO, Vical (www.vical. com). They use the same methodologyjust different strains.
There are several unknowns, however, including when or whether a pandemic will occur and, if so, the level of reassortment that may take place as the virus crosses interspecies barriers.
Avian Flu Unknowns
Contrary to reports that this is a rapidly evolving virus, Dr. Fauci says, We dont know how fast it evolves but it isnt rapid. There have been only 106 cases and 54 deaths, worldwide since 1997, which indicates that it hasnt evolved to the point that it readily jumps species to infect humans.
The NIAID began a Phase I trial for vaccines combating the H5N1 strain of avian influenza, which was isolated from the virus that erupted in Southeast Asia in 2004. The vaccine induced an immune response, Dr. Fauci says. Now the question is Whats a proper dose? This is unlikely to be a one-dose vaccine. It is likely wed give a prime and a booster, he speculates.
So far, the NIH has ordered 8,000 investigational doses based on the H5N1 virus from Sanofi Pasteur (www.sanofi-pasteur.com), and the Department of Health and Human Services (HHS) has ordered two million doses of bulk vaccine. The goal is not only to learn whether the vaccine is, indeed, efficacious, but also to expand our knowledge of how to prepare a safe and effective vaccine in as short a timeframe as possible, according to David J. Williams, Sanofi Pasteur chairman and CEO.
Both the small- and large-scale work helped us evaluate the suitability of our processes to the new avian strains, elaborated James Matthews, Ph.D., director of external research and development. The results were reassuring.
Dr. Matthews says it is quite likely that adjuvants may be added to the serum to expand the supply. A further option would be to alter delivery methods, such as using intradermal, rather than subdermal, injections, to activate the dendritic cells and thus trigger a strong immune response.
The HHS also let a contract to Sanofi Pasteur to establish and maintain flocks of egg-laying hens to ensure its ability to manufacture pandemic influenza vaccine at full capacity, year-round. There is a large flock in Pennsylvania, and contingency flocks in remote areas to minimize chances that an avian flu outbreak in the flock would decimate egg production, Dr. Matthews says.
Changing the way we manage the flocks was not a trivial risk, Dr. Matthews says, but allows the company to maintain momentum and gear up quickly to produce other pandemic vaccines
In Europe, Sanofi Pasteur is producing avian influenza vaccine candidates for clinical trials in collaboration with the French health authorities, the U.K.s National Institute for Biological Standards and Control, and the European Medicines Evaluation Agency. It also is the only vaccine manufacturer participating in the EUs collaborative FLUPAN clinical trials against pandemic influenza.
Sanofi Pasteurs immediate vaccine work is based on traditional chicken egg incubation, but that may be changing. Last spring the HHS awarded the company a $97 million contract to design a U.S.-based cell culture vaccine manufacturing facility capable of producing up to 300 million monovalent influenza vaccine doses annually.
Other components of the contract focus on speeding cell culture production processes so that Phase I and II trials will be completed within three years, with Phase III trials underway, and to accelerate an existing project to produce the vaccine in large quantities so that a design is ready two years earlier than initially planned. The latter project is based on a vaccine developed from Crucells proprietary PER.C6 cell line
The NIAID also contracted with Chiron (www.chiron.com) for 40,000 doses of inactivated H9N2 vaccine and 10,000 doses to combat the highly virulent H5N1 strain. Chirons vaccine against the H9N2 influenza strain is underway, with a product manufacturer in Sienna, Italy.
The vaccine against the H5N1 strain is being developed at Chirons Liverpool, U.K., facility (where Fluvirin was made). The FDA inspected that facility in July for production of Fluvirin, but the outcome was not available at press time.
The effort Chiron has made to resolve the issues that halted its production of Fluvirin last autumn is delaying the delivery of the H5N1 investigational vaccine, according to spokesperson Alison Marquiss. Phase I trials are expected to begin later this year.
Also, Marquiss says, to help to increase output and flexibility and minimize the risks associated with traditional methods of vaccine production, We have a cell culture program in Stage III in Europe and are talking with the FDA in the U.S., about such a facility.
Vical, with initial NIH funding, is pursuing a DNA-based vaccine in which genes encoding multiple influenza proteins are put into plasmids and injected, with the goal of evoking a complete response.
The issue, explains Samant, is that the H5N1 strain has a glycoprotein on the outside that evokes a humoral response. All the H5N1 vaccines under development (by the major vaccine manufacturers) evoke only antibody-mediated responses against this glycoprotein. But you need a T-cell response against the internal proteins to evoke a more complete response.
Samant says the DNA-based vaccinestill in preclinical stageshas elicited both antibody and T-cell immune response in mice. Further development depends on the availability of additional funding, he adds.
Vicals approach is relatively independent of the particular strain of flu because it attacks the internal proteins, which are well-conserved. As such, they will mutate less often than other characteristics of the virus.
With our method, it takes about six to eight weeks to make a construct, and then additional time to move it into production, Samant says, depending on the quantities needed and the availability of fermentation and purification capacity.
Whatever vaccine emerges, Theres not enough for all who may need it, Dr. Fauci says. Two to three billion doses will be needed worldwide, yet the world makes about 300 million doses of flu vaccine annually, Samant adds. As with last seasons flu vaccine, it will be allocated to high priority individualsprobably health care workers and the ill. Discussions to broaden the recommended group are ongoing.
Iomai (www.iomai.com) seems to have a solution to that challenge, and received a $2.9 million grant from the NIH to address that problem. Its immunostimulant (IS) patch not only improves the immune response rates but also enables a fraction of the normal dosage to confer the same immune response as the full dose delivered without the immunostimulant.
Our target is to use less than 1/20th of the normal flu dose, Dr. Glenn says. Then, whatever vaccine you have can be dramatically extended.
The company is testing two variations of the product for pandemic flu. In one, the vaccine is injected normally and an IS patch is applied over the injection site. In the other, the vaccine and immunostimulant are administered together through the patch.
The skin has a high level of exposure to a hostile microbial world, and so has a very high level of competent immune system components, explains Gregory M. Glenn, M.D., senior vp and CSO.
Unlike the contents of nicotine patches, which have to penetrate the skin, vaccines or immunostimulants must only reach the epidermis. Iomais IS patch uses the adjuvant heat-labile enterotoxin from E. coli to stimulate the Langerhans cells to take up the antigen and deliver it to the draining lymph nodes, which produce an immune response in the form of white blood cells.
In Phase II tests with individuals older than 60 years, placing the IS patch over or near the vaccine injection site resulted in seroconversion rates that were between 12 and 23% higher (depending on flu strain) than for a similar patient group that did not received the IS patch, and comparable to the results for healthy adults who did not receive the patch.
Other firms are concentrating on therapies, knowing that vaccines for pandemics would probably be in short supply.
Oseltamivir, called Tamiflu by Hoffman-La Roche (www. rocheusa. com), is, at this time, the only antiviral shown to be effective against the H5N1 (and H9N1 strains of) avian influenza virus in Asia, according to Julie L. Gerberding, J.D., director, Centers for Disease Control and Prevention, in testimony May 26 before the Subcommittee on Health of the Committee on Energy and Commerce, U.S. House of Representatives.
The company had practical experience with its use during an outbreak of the H7N7 strain of avian flu in the Netherlands in 2003, and has data from animal and in vitro studies, according to George B. Abercrombie, president and CEO, in testimony June 30 before the Committee on Government Reform, U.S. House of Representatives. The Strategic National Stockpile is holding enough to treat 2.26 million adults and 100,000 children.
Abercrombie calls for stockpiling Tamiflu before a pandemic occurs, in accordance with plans being developed by the HHS and WHO. The manufacturing process, he notes, takes 8 to 12 months, making surge capacity impossible.
To help ensure adequate supplies for stockpiling, Roche is doubling production capacity for this flu season and has enhanced its supply chain to yield an almost eight-fold increase in production capacity over 2003 levels. It also developed synthetic ingredients, which relieve pressure on natural resources.
Alnylam Pharmaceuticals (www.alnylam.com) is engaged in preclinical work using short interfering RNA (siRNA) to target highly conserved sites in the flu virus, allowing the therapeutic to go after undruggable genes and those involved in replication, says John Maraganore, Ph.D., president and CEO. The benefit is that a therapy that targets highly conserved sites would remain effective against many strains of flu, including H5N1, even if the strains mutate. While RNA interference (RNAi) using siRNA compounds is an emerging technology, the siRNA pathway is part of an ancient host defense mechanism, Dr. Maraganore says, that selectively regulates or silences specific genes. Alnylam, with academic collaborators, has shown that RNAi can silence respiratory syncytial virus (RSV), which targets infants, young children, and the elderly. Expanding the research to include avian flu is a logical extension, he says. The therapeutic could be used as a prophylaxis for persons exposed to the virus and as a treatment for infected patients, according to Dr. Maraganore. When used as a therapeutic, RNAi has the potential to create highly specific drugs with higher potency and lower toxicity than existing options. Alnylam is discussing opportunities to advance its research with U.S. and global health organizations. With the availability of federal funding, we could advance to clinical trials within 12 to 18 months, Dr. Maraganore predicts.