Global Health Challenges Spur Vaccine Development

It's flu season again, which always focuses public attention on the reliability and availability of the nation's vaccine supply. The Centers for Disease Control and Prevention (CDC) expect to have more vaccine available this season—166 million dosages versus 157 million in the 2010–2011 season —and have launched a major campaign to vaccinate more healthcare workers and pregnant women. Last year, about 42% of Americans were immunized, more than usual, but still far below the 80% goal set by the federal government. While the vaccine community won plaudits for responding quickly to the 2009–2010 influenza pandemic, the World Health Organization (WHO) came under fire for slow distribution of vaccines in poor countries, as well as charges that it hyped the danger of the epidemic to boost drug company sales. A blue-ribbon panel rejected those charges, but the debate reveals the highly-charged political environment surrounding immunization programs.

Jill Wechsler

Vaccines have even made it into the Republican presidential race. Texas Governor Rick Perry publicly disavowed his earlier backing of the human papillomavirus (HPV) vaccine for all young girls. Perry signed an executive order in 2007 mandating that all sixth-grade girls in Texas receive Merck's Gardasil vaccine to prevent cervical cancer. Now, candidate Perry says he made a mistake—an about-face that reflects concerns raised by social conservatives about vaccine mandates overall, and specifically about endorsing a preventive for a sexually-transmitted disease.

Other important developments this year brought good news to vaccine producers and advocates. The US Supreme Court ruled in February that manufacturers cannot be sued in state courts for injuries allegedly caused by their products. The case, Bruesewitz v. Wyeth (Feb. 22, 2011), should discourage plaintiffs from trying to circumvent the protections created by the 1986 National Childhood Vaccine Injury Act, which provides compensation from the industry-funded Vaccine Injury Compensation Program (VCIP) to patients claiming injury from vaccines. This federal pre-emption of state-based injury suits is crucial for protecting manufacturers from costly tort litigation that would drive them from the vaccine business.

The high court's decision came on the heels of reports fully discrediting earlier studies linking vaccines and autism, a claim that has plagued vaccine makers for years. The British Medical Journal published a series of articles by journalist Brian Deer documenting that data published in a 1998 paper by British physician Andrew Wakefield and colleagues was not just bad science, but deliberate fraud (1). The Lancet, which had published Wakefield's original paper, retracted it in 2010, but it was too late to repair the extensive damage to public health from antivaccine forces, which has fostered a re-emergence of measles in the United Kingdom and in parts of the United States (2, 3).

Perennial concerns about vaccine safety prompted an in-depth analysis by the Institute of Medicine (IOM), which documents in great detail that vaccines cause few adverse effects and have no links to serious health conditions. The expert committee's August 2011 report on "Adverse Effects of Vaccines" finds little scientific evidence that of health problems caused by eight widely used vaccines, and further discredits links between the measles-mumps-rubella (MMR) vaccine and autism (4). The report confirms the huge health benefits of vaccines and should encourage more parents to vaccinate their children; it also will help the US Department of Health and Human Services (HHS) decide vaccine compensation cases under the VCIP program.

Increased investment

Despite lingering safety issues, vaccine research and new product development is expanding, generating optimism for new discoveries that will guard against AIDS, cancer, and multiple infectious diseases. Led by the Bill & Melinda Gates Foundation, which has committed more than $10 billion to support vaccine innovation, donor nations are boosting support for global vaccine R&D. Researchers anticipate that a dozen new vaccines may be rolled out in the next decade against diseases such as typhoid, malaria, and dengue fever. Gates has signed up the world-famous Barcelona soccer team to promote polio eradication, despite fears of some health authorities that complete elimination of the disease is too difficult and costly.

The journal Health Affairs discussed strategies for achieving Gates' "Decade of Vaccines" in a special June 2011 issue that explores new vaccines in the pipeline along with new models for financing and paying for vaccine development and delivery. The promise is that investing more in immunization science and expanding vaccine distribution globally will reduce healthcare costs, promote economic activity, and save the lives of more than 6 million children through 2020.

Pharmaceutical manufacturers now regard vaccines as a potential source of steady revenue, if not blockbuster profits. The world market for preventive vaccines exceeded $20 billion in 2009 and grew to nearly $30 billion in 2010. Projections call for 10% annual growth during the next five years due to new product introductions and broader use. Expanded global production of seasonal flu vaccine is setting the pace: by 2015, WHO predicts that some 37 vaccine makers will be able to produce 1.7 billion doses of influenza vaccine, enough to handle any pandemic. Merck, GlaxoSmithKline (GSK), Sanofi Pasteur, Pfizer, and Novartis dominate the market and continue to invest in the field.

A main target of vaccine research is the development of new treatments for third-world diseases. A new meningitis A vaccine has been distributed to more than 19 million people in West Africa, providing a model for collaboration to produce and distribute a vaccine that costs less than 50 cents. Sanofi Pasteur is testing the first vaccine for dengue fever, which sickens some 2 million children a year, primarily in Latin America and Asia. Researchers have begun early clinical trials for a new vaccine for tuberculosis, with initial results expected next year. Colorado-based Inviragen is collaborating with the University of Texas and federal agencies to develop a novel recombinant chikungunya virus vaccine. Vaccines are under development for schistosomiasis, hookworm, rabies, and Ebola virus. Earlier this year, Merck and Britain's Wellcome Trust announced a joint project to design an oral rotavirus vaccine that will be cheaper and easier to use than current shots.

Several groups are working on new malaria vaccine projects. The most advanced describes dozens of vaccine candidates in development to prevent this disease. The most advanced is GSK's RTS,S vaccine candidate, now in Phase III studies in Africa under the auspices of the PATH Malaria Vaccine Initiative. In addition, the Infectious Diseases Research Institute (IDRI) is collaborating with the US Agency for International Development and the Walter Reed Army Institute of Research to develop an antimalarial vaccine that combines new antigens.

Despite numerous failures in developing an AIDS vaccine, scientists remain optimistic that success is possible. Researchers point to advances in understanding the complexities of an AIDS vaccine and are developing new vectors, delivery technologies, adjuvants, and immune assays to address these challenges. For example, the International AIDS Vaccine Initiative (IAVI), Scripps Research Institute, and several biotech companies recently reported the isolation of novel antibodies capable of neutralizing a broad spectrum of variants of HIV. Researchers were encouraged that this could provide new targets for the design of vaccine candidates that can elicit similar antibodies to protect against the virus.

New cancer vaccines are on everyone's wish list, encouraged by success in developing HPV vaccines for cervical cancer and the prostate cancer treatment, Dendreon's Provenge. A recent announcement from the Mayo Clinic in Rochester, Minnesota, cites plans for Phase I clinical trials for new vaccines to prevent the recurrence of ovarian and breast cancer.

Bioterrorism threats also are spurring vaccine development. Last year, the HHS Biomedical Advanced Research and Development Authority (BARDA) awarded approximately $50 million to organizations seeking to reduce the time and cost of testing new medical countermeasures. Projects aim to increase the shelf life of influenza vaccine stockpiles for future use in a pandemic and to develop adjuvant formulations to enhance influenza vaccine immunogenicity and cross-protection to new viral strains. BARDA is providing Emergent BioSolutions with $100 million over several years to develop a state-of-the-art production facility for its anthrax vaccine. More than $1 billion in contracts during the past six years have gone to manufacturers developing cell-based technology for seasonal influenza production, plus recombinant technology and adjuvented influenza vaccines. The expectation is that these innovations will foster development of other commercial products and medical countermeasures, such as next-generation smallpox vaccine.

Price and access

Vaccine development generates tension among companies regarding how to make R&D profitable enough to encourage private-sector investment while also being able to offer sufficiently low prices to make products available to poor nations. While public health officials admit that the most cost-effective vaccine is one that's free, the stated goal is to provide emerging markets with vaccines that cost less than $5 per dose. UNICEF is supporting this effort by publishing the prices it pays individual manufacturers for immunizations as a way to encourage competition in vaccine pricing for developing nations. In response, manufacturers are cutting prices significantly on vaccines for developing nations. At a June 2011 meeting in London to secure donor funding for the Global Alliance for Vaccines and Immunization (GAVI), India-based manufacturers promised a record low $1.75 per dose price for pentavalent vaccines that protect against five diseases: diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b (HIB). GSK and Merck reduced rates on rotavirus and HPV vaccines, and other leading manufacturers announced similar moves.

GAVI will have the funds to purchase these more affordable products because the Gates Foundation and major donor nations pledged $4.3 billion in June to support its international immunization program. The UK led the list with a $1.3 billion pledge, followed by Gates, Norway, the US, and several other countries. Japan and Brazil gave for the first time this year. This support helped GAVI fend off criticism from international relief organizations that it does not do enough to negotiate lower prices for vaccines, allegedly because of too-close ties to big vaccine makers. GAVI also responded by appointing Seth Berkley to head the organization, a prominent AIDS vaccine researcher who has campaigned for years to make all vaccines equally available to children throughout the world.

Even in the US, high prices appear to limit vaccine utilization. Sales have been sluggish for Dendreon's Provenge despite a positive national coverage decision from Medicare that has prompted insurer coverage. Full treatment still costs more than $100,000 due to a complex regimen that involves manipulation of a patient's own immune cells. Physicians appear reluctant to prescribe Provenge because of tight insurer utilization requirements, high copays, and limited evidence of effectiveness.

Price may be a factor in slow vaccination rates for the HPV vaccine as well. A 2010 CDC analysis found that more teens received vaccines to protect against meningitis (63%) and tetanus-diphtheria-pertussis (69%), but only 49% of young girls received one dose of the HPV vaccine, and only 32% received the full three-dose regimen. "Our progress is stagnating," complained Anne Schuchat, director of CDC's National Center for Immunization and Respiratory Diseases. "Now that we have the tools to prevent most cervical cancers, it is critical that we use them." The CDC report noted lower HPV immunization rates among poor and minority teens, a sign that the $400-price tag for the full course of treatment probably is a problem. Moreover, some parents have raised concerns about side effects linked to Merck's Gardasil, and that some teenagers may regard vaccination as a green light for premarital sex.

Merck's efforts to expand Gardasil's label to include male protection from anal cancer also has run into opposition due to cost and effectiveness issues. An analysis for CDC's Advisory Committee for Immunization Practices (ACIP) indicates a much higher cost for vaccinating boys and men to prevent cancer and death, due to much lower incidence of the male disease.

Although cost issues may limit utilization of some vaccines, adult immunization has gained support from health reform legislation. President Obama's Affordable Care Act requires insurers to cover all recommended vaccines for adults, with no copays or deductibles, as part of efforts to expand preventive care. The policy applies now to new group and individual health plans, but is expected to affect all coverage over time.

Manufacturing challenges

While policymakers wrestle with cost and access issues, manufacturers still face difficulties ensuring the quality of vaccine production. One reason for low utilization of Merck's Zostavax vaccine for shingles has been supply shortages due to manufacturing problems at Merck's West Point, Pennsylvania, vaccines plant; reports of charred particles in vials have further complicated remedial efforts. Merck's adult vaccines for hepatitis A and hepatitis B also are in short supply, and the company has stopped producing its ProQuad varicella-MMR vaccine.

Indian manufacturers seeking to ramp up production of low-cost vaccines also have run into production problems. WHO recently removed combination vaccines produced by Panacea Biotech from its pre-qualification list due to inspections that found quality management deficiencies at the firm's plant near Punjab, India.

Meanwhile, FDA has concerns about manufacturing deficiencies and particulate contamination at several vaccine companies. FDA sent a Warning Letter to Australia-based influenza `dicated that the company had not addressed manufacturing problems identified at a site visit in April 2010. The initial FDA investigation stemmed from adverse-event reports citing reports of fever and convulsions in children taking its influenza vaccine in during the 2009–2010 pandemic, but uncovered a number of deficiencies in recordkeeping and quality control.

The challenges of ensuring vaccine safety and quality were illustrated in 2010 when FDA suspended the marketing of GSK's rotavirus vaccine, Rotarix, for several months to assess the effect of adventitious porcine virus found in this product. After evaluation, FDA recommended that physicians continue to use Rotarix, as well as Merck's Rota Teq vaccine, which has a similar problem. The agency cited strong safety records for the products and no evidence that the viruses pose a safety risk to humans. The case points to difficulties in adopting advanced analytic technologies that can uncover previously undetectable contaminants. The challenge for regulators is to weigh the risk of halting vaccination for a dangerous health condition against uncertain effects of apparently benign extraneous viral material.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com.

References

1. B. Deer, British Medical Jrnl., Jan. 5, 2011 and Jan. 19, 2011.

2. A. Wakefield, The Lancet, 35, 637–641 (1998).

3. Editorial Retraction, The Lancet, Feb. 2, 2010.

4. IOM,Adverse Effects of Vaccines (Washington, DC, 2011), www.iom.edu/vaccineadverseeffects.