Getting a shot to prevent or treat a disease is arguably the most cost-effective form of medicine in healthcare. So why are there so few vaccine manufacturers, and why is the technology used to make some vaccines, notably flu vaccine, woefully out of date?
Vaccine research and development is costly and time-consuming, while the profit potential can be marginal. Bringing a new vaccine from the research and development stage through clinical trials can typically cost $500 million, says Andrew Pasternak, a director at Mercer Management Consulting who specializes in the vaccine industry. Federal regulatory burdens are understandably high, while demand for the product is low--unlike pills, which a patient takes throughout the course of a disease, vaccines are often needed only once or several times in a lifetime.
Perhaps most significant is the liability manufacturers can face. Injecting potentially infectious agents into live, healthy human beings can be a dangerous game, and companies that produce the vaccines are on the hook if something goes wrong.
These conditions have led to consolidation in the vaccine industry, to the point that there are only a handful of major vaccine producers worldwide. But that trend may soon turn around, thanks to promising technological advances, the specter of a flu pandemic that may funnel federal dollars to vaccine manufacturers and recent financial successes that demonstrate vaccines can have a rapid and profitable public health impact. All of these factors combined may give the industry a needed shot in the arm.
"I think the exciting thing is we're in a period of time right now as it relates to vaccines and immunization that is more dynamic than at any point in the recent past, and perhaps ever," says Stephen Cochi, acting director of the national immunization program at the Centers for Disease Control and Prevention. In 1985, there were seven vaccines--diphtheria, measles, mumps, pertussis, polio, rubella and tetanus--in the routine childhood immunization schedule, according to the CDC. Now, 26 years later, with the recent addition of a hepatitis A vaccine, the list totals 14. "That represents the ability of the U.S. immunization system to be on the forefront of introducing new technologies and new vaccines for the benefit of children and adults," Cochi says.
He points to several new vaccines in development--among them one to prevent cervical cancer and one to prevent rotavirus, a common childhood gastrointestinal ailment that causes 50,000 hospitalizations in the U.S. annually and nearly half a million deaths worldwide. And President Bush's recent call to arms to try to avert a flu pandemic has the potential to jump-start the manufacturing of new and improved flu vaccines with increased federal financing.
In the longer term, vaccines are also being developed to fight HIV infections and autoimmune diseases, and to treat cancers that are not responsive to chemotherapy and radiation. And that may be only the beginning. As Michael Ramsay, president of the Baylor Research Institute at Baylor Health Care System in Dallas, says: "We think the immune system is the Holy Grail to any disease process."
There are numerous types of vaccine approaches. Inactivated vaccines are made by killing the microbe that causes the disease and using the dead virus or bacteria as the basis for the vaccine. Live vaccines are created when the living microbe has been attenuated, or weakened, so it stimulates an immune system response without causing the disease. Live vaccines stimulate a stronger response than killed vaccines, but they can be dangerous for people with compromised immune systems and have the potential to mutate into forms that can cause disease.
Engineering new vaccines
More recent technology has led to another class of vaccines called "subunit" vaccines, which use only the antigens, or the parts of the microbe that stimulate the immune response. These have fewer side effects than live vaccines, and can provoke a stronger immune response than a killed vaccine. One of the ways antigen molecules can be created is through recombinant DNA technology. The hepatitis B vaccine, which became a routine infant vaccination in the U.S. in 1991, was one of the first vaccines to use this technology, now also being explored for flu vaccines.
Such a technology was also used in the vaccine currently being developed by Merck & Co. to prevent cervical cancer. The genetically engineered vaccine, called Gardasil, was shown to be 100% effective at preventing infection by two types of the human papilloma virus, HPV 16 and 18, which together cause about 70% of cervical cancers. The vaccine is in Phase III trials--the last stage before Food and Drug Administration approval--and Merck anticipates applying for a license from the FDA by the end of the year. If the FDA approves it, the vaccine could be added to the schedule of childhood vaccinations as early as next year.
"What is unique is that this recombinant protein that we generate genetically self-assembles itself into virus-like particles, empty shells consisting of viral protein but no viral DNA," says Deb Wambold, a Merck spokeswoman. "These (particles) closely simulate HPV without causing disease and are capable of generating an immune response in the body." Cervical cancer is one of the leading cancers among women and results in about 290,000 deaths worldwide every year, according to Merck. GlaxoSmithKline is also testing an HPV vaccine.
Several vaccine experts say the HPV vaccine represents an important step forward. "This technology is great because the human immune system--the white blood cells and the antibodies--see a particle that looks just like the naturally occurring virus, but it doesn't have the genetic material so it can't infect and replicate itself," says the CDC's Cochi.
Conjugate vaccines offer another promising technology. These are vaccines in which proteins that are recognized by the immune system are linked to the molecules that coat disease-causing bacteria to initiate an immune response. They are often used for very young children, whose immature immune systems cannot recognize the outer coating of the bacteria and thus are especially susceptible to disease. Significant conjugate vaccines include pneumococcal conjugate vaccine, meningococcal conjugate vaccine, and Haemophilus influenzae type b, or Hib, vaccine. These three vaccines have taken on the three leading causes of bacterial meningitis in children. "This new technology was a huge step forward," Cochi says.
Cochi says another genetically based vaccine against rotavirus, the leading cause of diarrhea in children and a cause of hundreds of thousands of deaths each year in developing countries, might be added to the growing list of recommended vaccines for children in the near future. Merck earlier this year submitted a license application to the FDA for its rotavirus vaccine, called Rotateq.
Preventing rotavirus infections could save lives and healthcare dollars. Worldwide, there are nearly half a million deaths annually from rotavirus in children under 5. But rotavirus also shows one of the risks to vaccine manufacturers. In July 1999, Wyeth-Ayerst Laboratories had to withdraw supplies of its rotavirus vaccine, called RotaShield, after reports of a possible association between the vaccine and intussusception, a type of bowel obstruction.
Influenza represents possibly one of the most dynamic areas of vaccination research and the area most in need of modernization. Earlier this month, President Bush outlined a $7.1 billion emergency funding proposal to avert a potential flu pandemic. Pandemic flu differs from seasonal flu in that humans would not likely have any immunity to it and it could spread rapidly throughout the world.
Researchers at the National Institutes of Health have developed a vaccine based on the current strain of the avian flu virus, known as H5N1, the strain that has sparked fears of a worldwide pandemic. Bush called on Congress to provide HHS with $1.2 billion to stockpile enough doses of this flu vaccine to inoculate 20 million people. The so-called seed stock for this vaccine came from St. Jude Children's Research Hospital in Memphis, Tenn. St. Jude conducts research at its own vaccine manufacturing site to help treat its patients, primarily children with cancer.
"One of the major things that was discovered here, and why we were able to help with the emerging influenza vaccine ... is that you can make an entirely artificial vaccine," says Elaine Tuomanen, chair of the infectious disease department at St. Jude. "The ability to produce live vaccines that are specifically synthesized to be the perfect vaccine for that agent, and the ability to make that very quickly, are key to controlling this emerging infection." Tuomanen says St. Jude was able to make the influenza seed stock in four weeks. "That type of technology, where you can turn it around fast ... is going to be critical," she says.
Sometimes it can be the process of making the vaccine, rather than the actual product, that presents the technological challenge. The common seasonal flu vaccines that people receive each fall are made by infecting chicken eggs with influenza virus and then using them to develop and produce vaccines, a '50s-era process that can take more than six months to complete. By that time, a pandemic flu could easily spread around the world. As part of his flu plan, Bush requested $2.8 billion to speed development of cell culture technology, which would involve growing the flu virus in vats of cells instead of chicken eggs and would be much faster.
Many companies are racing to come up with pandemic flu vaccines based on many different models. In September, HHS Secretary Mike Leavitt announced that the NIH's National Institute of Allergy and Infectious Diseases and biotech company MedImmune were teaming up to research and develop vaccines against avian influenza viruses. MedImmune created the first seasonal flu vaccine that delivers a live, attenuated form of the virus through a nasal spray. Jamie Lacey, a MedImmune spokeswoman, says the nasal spray might be an advantageous delivery mechanism for a pandemic vaccine, since it would be convenient and easily disposed of. In addition, administering the weakened virus through the nose may provide additional protection in the area of the respiratory tract where the flu first affects people, she says. Mass production of such a vaccine would take about four months after the seed stock became available, she estimates.
Others see growth opportunities in flu vaccines, too. Swiss pharmaceutical company Novartis announced last month that it was acquiring the publicly held shares it did not already own of Chiron for about $5.1 billion. Chiron is the world's fifth-largest vaccinemaker with vaccine revenue of $510 million in 2004. Novartis officials described the flu vaccine industry as a "dynamic growth market." The global vaccine market is expected to double its 2004 sales in the next five years to more than $20 billion, according to Novartis.
"This is a major acknowledgement of the relative commercial promise of the vaccine arena, as it is the first time in recent history where a major pharma company has made a major move to enter this market," says Mercer's Pasternak. "In the past, all the moves were in the other direction."
Hospitals are also getting in on vaccine action. About a year ago, Baylor Health Care formed its own biotech company to develop and produce patient-specific cancer vaccines, beginning with one to treat mela-noma patients. The company, ODC Therapy, was created to try to get therapies to patients as quickly as possible, Baylor officials say.
"The goal of these therapies is to stimulate the immune system to destroy tumor cells wherever they have spread in the body," Baylor's Ramsay said in a November 2004 news release. "This vaccination approach is being developed to provide a therapy where conventional treatments, such as surgery, radiation and chemotherapy, have limited or no effect and is designed to extend and maintain the patient's quality of life."
Scientists at Baylor are focusing on dendritic cells, which are critical in identifying and capturing antigens, to create their cancer vaccines. The vaccines are produced by removing dendritic cell precursors from a patient, loading them with a tumor antigen, and then reintroducing them into the same patient. Jacques Banchereau, director of the Baylor Institute for Immunology Research, is a pioneer in the use of dendritic cells to develop some of the therapies being tested there.
Ramsay says Baylor stepped into the business to maintain some control over the end product. "The question always is `What do you do with a successful research project?' " he says. "If you license it to a biopharma company, what happens to it after that is almost a crap shoot. They may develop it slowly; they may not develop it the way you want to go. By and large you've lost total control." Baylor has so far invested $7 million in the company, which has 13 employees.
Ramsay estimates that a successful mela-noma vaccine, which ODC is testing in Phase II clinical trials, could produce annual revenue of $500 million in the U.S. A vaccine for another cancer that ODC is targeting--prostate cancer--could yield more than $1 billion in annual sales, he says.
"In the next five years, you're going to see a major difference in how we diagnose and treat disease," Ramsay says. "And it's all going to be in the way we identify genes that are expressed. That will help diagnose disease before you get it."
Although it may be further away, vaccines to prevent HIV infection are also being researched. Gary Nabel, director of the NIH's Vaccine Research Center, says one of the challenges of HIV is that like the flu, it constantly mutates.
That said, Nabel's center recently began Phase II testing for safety and efficacy for an HIV vaccine using a viral vector approach. As Nabel explains it, an adenovirus-such as those that lead to the onset of the common cold--is utilized by taking out the genes that allow it to replicate and inserting parts of other viruses to generate an immune response. "It has a very good safety profile," Nabel says. "The challenge will be to prove the efficacy."
Barbara Kirchheimer is a freelance writer based in Highland Park, Ill. She can be reached at [email protected]