Giving it their best shot

Researchers gathered recently to discuss the challenges of developing and delivering life-saving vaccines

By Kristen Jill Kresge

You've probably heard the parable about the man who was upset that he had no shoes until he met someone without feet. This came to mind during a meeting held October 8-13 in Cape Town, South Africa that brought together vaccine researchers from different disciplines to discuss developing and delivering life-saving vaccines throughout the world. Commiseration, as well as a sense of shared commitment, pervaded the meeting as researchers from various fields shared ideas and approaches to developing vaccines against three of the world's biggest killers—tuberculosis (TB), malaria, and HIV/AIDS.

This inaugural Keystone Symposium on the Challenges of Global Vaccine Development explored many of the common challenges and creative approaches, as well as some of the overlap in the strategies being investigated to combat all three diseases. The conference, which was held in conjunction with the annual meeting of the Bill & Melinda Gates Foundation's Grand Challenges in Global Health initiative, also had an added focus on efforts to successfully deliver vaccines. Tachi Yamada of the Gates Foundation says that although the foundation has always been committed to discovery, "we also have to think about how to deliver these exciting new products."

Boosting spirits

The gathering for the Keystone conference occurred just a few weeks after the initial announcement that Merck and the National Institute of Allergy and Infectious Diseases (NIAID) stopped immunizations in a large Phase IIb test-of-concept trial, known as the STEP study, because Merck's adenovirus serotype 5 (Ad5)-based AIDS vaccine candidate (MRKAd5) was not effective. At the same time, enrollment and immunizations in the Phambili or HVTN 503 trial, which was testing the same vaccine candidate in South Africa, were suspended—they have since been stopped entirely (see Removing the blindfold in Global News). These were some of the most hotly discussed issues both in and out of the meeting.

Carolyn Williamson of the University of Cape Town told the audience assembled for her plenary session that AIDS vaccine researchers, "really have to go back to the drawing board." But those from other disciplines were able to provide some fresh perspective. "I wouldn't be too downbeat," says Adrian Hill of Oxford University, who is currently developing possible vaccine candidates against malaria. "We've had candidates fail for malaria about 15 times."

Recently, there was some good news in the malaria vaccine field. The most advanced of a slew of candidates is being developed by GlaxoSmithKline Biologics in Belgium, and a recently completed Phase II safety study in Mozambique showed that it was 65% effective at protecting infants from malaria (Lancet 370, 1523, 2007). Phase III efficacy studies with the candidate, known as RTS,S or Mosquirix, will begin next year, and if similar results are observed, the first potentially licensable malaria vaccine may be available as early as 2011 (see VAX May 2005Spotlight article, Malaria vaccines: Renewed promise).

But over the last few years, researchers working on malaria vaccines have also developed a heightened interest in using viral vectors to target the disease during a different stage of the parasite's lifecycle when cellular immune responses are critical to controlling disease progression.

Researchers, including Hill, have tested various viral vectors in prime-boost combinations, including MVA and fowlpox-vector-based malaria vaccine candidates. When clinical trials were conducted in the UK and the Gambia with the fowlpox/MVA prime-boost combination, these candidates induced high levels of immune responses in human volunteers. But when this same strategy was tested in a Phase IIb clinical trial in Kilifi, Kenya, it showed no efficacy. Hill says the immunogenicity of the vaccines was markedly lower in areas where malaria transmission occurs more frequently (see VAX August 2007 Primer on Understanding Immunogenicity). He speculates that this may be a recurring problem for malaria vaccines in high-burden areas, where the vaccines could potentially have the greatest impact.

Following this failure, researchers set out to find a better prime-boost combination. This led them to explore using adenovirus as a vector. "Adenovirus vectors have in many ways been the high-flying vectors," says Myron Levine of the University of Maryland. Hill's group at Oxford compared the immunogenicity of different serotypes of human adenoviruses with simian, or monkey, versions and found that a serotype of adenovirus that infects chimpanzees (AdCh63) induced even better immune responses than human Ad5.

Hill is currently preparing to begin a Phase I safety trial to test an AdCh63/MVA prime-boost combination in humans. "There's a lot of interest in adenovirus vectors for malaria at this moment," says Hill. Chimpanzee adenoviruses have also been of keen interest to AIDS vaccine researchers, but as of yet, no candidates have been advanced into clinical trials.

Before and after

Without question, there are still substantial scientific challenges facing the development of new vaccines against the most pervasive global health threats. "Science is the critical ingredient for success," says Regina Rabinovich of the Gates Foundation, who provided the opening keynote address at the Keystone conference. "You can't get there without it."

But science is not the only barrier. There are other challenges that occur after effective vaccines are licensed for public use, including manufacturing capacity and vaccine production, as well as vaccine delivery and administration. "Finding a new way of creating a vaccine is only half the issue," says Duncan Steele of the World Health Organization (WHO). Despite high-flying success stories of late, like the licensure of effective vaccines against human papillomavirus (HPV; see VAX February 2006 Spotlight article, Cervical cancer vaccines), there are still many issues to resolve about how best to deliver these vaccines to the world's poorest people. If these aren't worked out before vaccines are licensed, it can result in a sometimes lengthy lag time between the introduction of vaccines in rich and poor countries.

Immune responses to vaccines can also vary in different populations, so even when a vaccine is delivered successfully, it still may not provide optimal protection to everyone—there is documented evidence of vaccines inducing varying levels of antibody responses in different regions of the world. For this, critical lessons can be learned from the delivery of already licensed vaccines. Overall, vaccines that are administered orally tend to induce greater immune responses in industrialized nations.

The responses induced by the live oral cholera vaccine are just one example of this phenomenon. Greatly diminished immune responses to this vaccine have been observed in Brazil, in children of low socioeconomic status in Peru, and in Indonesia, where a higher dose of the vaccine is required to achieve similar levels of immunity. For rotavirus, several of the earlier live oral candidates failed to work at all when tested in developing country populations (see VAXJuly 2006 Spotlight article, Vaccines enter battle against an intestinal virus).

But some vaccines work better in developing countries, Levine says. The vaccine against haemeophilus influenzae type b, or Hib, a bacteria that can cause a potentially fatal brain infection in children, is one example of this phenomenon. Only 10% of US infants reach the level of antibodies required for protection against Hib after a single vaccination, while 29% of infants in Chile reached this antibody level after one shot. Based on this observation, the government funded a study to evaluate fractional or partial doses of the vaccine, which at its full dosage cost more than all of the vaccines that were currently part of the country's immunization program.

This study showed that in Chile there was no difference between administering a third, a half, or a full dose of the Hib vaccine. The Chilean government never used fractional doses of Hib vaccine because its cost was eventually covered by the Global Alliance for Vaccines and Immunization (GAVI), now the GAVI Alliance. But this case suggests it may be possible to get equivalent protection in some populations with less vaccine and, as the cost of newly-licensed vaccines soars, this could translate into substantial savings. Levine suggested that studies to quantify the level of antibody required for protection for new and expensive vaccines, like those against HPV, are vital so that determinations about the dose required for protection can also be made.

One thing that is certain is the massive public health benefit that vaccines can have. Since the creation of GAVI in 2000, the WHO estimates that the introduction of vaccines in developing countries has prevented 2.6 million deaths. But these dramatic effects come with a hefty price tag. The WHO and the United Nations Children's Fund (UNICEF) estimate that GAVI will require between US$226 million and $778 million between 2011 and 2015 to continue funding vaccination programs in its target countries.