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R&D is surging, but new methods and data raise new manufacturing and regulatory challenges.
The vaccine business is booming, spurred by worldwide efforts to contain the global influenza pandemic and to halt the spread of AIDS and other infectious diseases. National health agencies ordered millions of H1N1 flu vaccine doses last year, prompting manufacturers to ramp up production along with R&D. Since 2000, the global vaccine market has almost tripled, reaching an estimated $20 billion. Yet delays in producing the huge quantities of requested flu vaccine has raised questions about continued reliance on decades-old production methods and delivery technologies.
The good news is that a record 120 vaccines are available to meet the health needs of people all over the world, and a significant number of vaccine candidates are moving through the R&D pipeline. Over 80 new products are in late-stage clinical testing, including some 30 that target untreated diseases, according to last fall's "State of the World's Vaccines and Immunization" report published by the World Health Organization (WHO) and UNICEF. The surge in vaccine development over the past decade has produced new vaccines for meningococcal meningitis, rotavirus diarrheal disease, pneumococcal disease and cervical cancer caused by human papillomavirus (HPV). Public–private partnerships (many funded by the Bill & Melinda Gates Foundation) are developing vaccines to counter diseases such as malaria, tuberculosis, and dengue fever, which kill millions in Third World nations.
While much of the growth in vaccine sales reflects purchases of newer, more costly products in western countries, the market expansion also supports higher immunization rates around the world. According to the WHO report, a record 106 million children were administered the traditional roster of childhood vaccines in 2008. There's also been progress on the HIV/AIDS vaccine front, despite a let-down following initial reports last year of benefits from an AIDS vaccine tested in Thailand. And the search for cancer vaccines is still going strong, supported by FDA draft guidance on how to conduct clinical trials to test new therapies designed to simulate an immune response against tumors.
Meanwhile, this burgeoning vaccine business is attracting more Big Pharma investment. Johnson & Johnson recently linked up with Crucell NV of Holland to develop vaccines, Pfizer's acquisition of Wyeth makes it a lead player in the global vaccines business, and Abbott Laboratories aims to get in the game by purchasing Solvay's drug and vaccine business. Sanofi-Aventis is looking to double its vaccine business over five years, according to CEO Chris Viehbacher; Glaxo is investing $40 million in Nabi BioPharmaceuticals' anti-smoking vaccine; and Merck recently hired Julie Gerberding, former director of the US Centers for Disease Control and Prevention (CDC), to reinvigorate its vaccines division.
Still, the vaccine business carries considerable risks. Pfizer has run into delays gaining Food and Drug Administration approval of its improved Prevnar 13 vaccine for pneumococcal disease in children, despite priority review status and a positive recommendation by an advisory committee last November. Merck has found it hard to sell its shingles vaccine Zostavax, largely due to Medicare reimbursement complications (See "Coverage Matters".)
The H1N1 vaccine shortage last fall brought home the perils involved in development and production of influenza vaccines. Last July, vaccine makers were looking to produce 80 million to 120 million doses by mid-October, and public health agencies ramped up for a major vaccination drive. Everyone lost credibility when only 40 million doses were available in September while some 20 million Americans were hit by the new flu. Health and Human Services (HHS) secretary Kathleen Sebelius said she relied on industry predictions that turned out to be wildly optimistic, while manufacturers claimed they kept health officials informed of technical problems throughout the manufacturing process.
The 2009 pandemic flu was supposed to showcase US government plans for responding to health emergencies. Speedy production of the H1N1 vaccine, however, was delayed because manufacturers first had to produce millions of doses of seasonal flu vaccine for the regular 2009 flu season. Then it took longer than expected to produce the H1N1 vaccine because the yield in each egg was much lower than with the seasonal viral strain.
Much of the blame was directed at continued use of fertile chicken eggs to produce flu vaccine, a method established in the 1930s that's still standard because the influenza virus grows well in eggs. Manufacturers are beginning to augment egg-based vaccine production with cellular methods, but vaccine experts warn that the change is no panacea for the tricky process of quickly producing a potent and pure vaccine for a viral strain that changes every year.
There have been cell-culture vaccines for mumps, measles, polio, rubella, and other diseases for decades, explained Jesse Goodman, FDA chief scientist, at a December 2009 seminar on advances in influenza vaccine technologies at the National Institutes of Health (NIH). But that approach has not been adopted for influenza because it can take a long time to get a good yield out of cell cultures. A change won't solve production problems, Goodman noted, but could lead to more reliable products and faster scale-up. Anthony Fauci, director of NIH's National Institute of Allergy and Infectious Diseases (NIAID), agreed that shifting to cell culture could establish a more flexible surge capacity. Making the transition from egg- to cell-based production "will take some time," said Fauci, "but eventually we will get there."
Another issue was vaccine strength. Although it turned out that one dose of the H1N1 vaccine provided sufficient protection for adults, low potency remained a problem for vaccine makers: AstraZeneca's MedImmune had to recall nearly 5 million doses of its nasal spray vaccine in December, while Sanofi-Aventis pulled 800,000 doses for young children. By then, the flu was ebbing, and manufacturers faced a new problem: more vaccine than anyone wanted. Last month, the French government moved to sell off millions of doses to countries in the Middle East and Latin American, and canceled sizeable orders from Sanofi, GSK, Novartis, and Baxter. Germany and other European countries made similar moves, while the US government weighed its options. The Council of Europe even considered a resolution blaming drugmakers for over-hyping the flu pandemic for economic gain.
The real "endgame" to pandemic and seasonal flu vaccine production problems, according to Fauci, is to develop a universal flu vaccine that can be administered in childhood and last a lifetime—as with most vaccines against infectious disease. Such a discovery would reduce the need to produce 120 million to 150 million doses of a new influenza vaccine each year in the US, at a cost of $2.8 billion to $4 billion. "It is doable," Fauci said, noting that researchers already are identifying possible vaccine targets that don't change with every different influenza virus.
Scientists also are looking for innovative manufacturing platforms that can accelerate vaccine production, such as DNA-based and microbial vector vaccines. A recombinant vaccine, which puts a flu virus gene into an insect virus, has been developed by Protein Sciences Corp., but safety concerns have delayed FDA market approval. Novavax has reported promising clinical results from Mexico for its virus-like particle vaccine.
Increased use of adjuvants to enhance patient response also could make influenza vaccine manufacturing more efficient, as occurred in Europe last year. FDA is looking at the potential of new adjuvants to produce a more robust immune response from a vaccine, but has concerns about inflammation and autoimmune responses.
FDA's Goodman seeks a better understanding of how adjuvants work and how they can boost the desired immune response without raising added safety issues. "We are poised for a transformation in how we produce and use influenza vaccine," Goodman commented, noting that these efforts fit the goal of FDA's leadership to strengthen the agency's scientific infrastructure to support development of novel technologies to improve public health.
Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at firstname.lastname@example.org