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.

On October 23, immunizations and enrollment in a second National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial called Phambili, or HVTN 503, were permanently stopped based on a recommendation from that trial's independent data safety monitoring board (DSMB). Phambili's DSMB also recommended at this time that study investigators unblind all participants (see Primer), telling them whether they received vaccine or placebo, and counsel them about the possibility of an increased susceptibility to HIV infection due to the vaccine (see Spotlightarticle). The vaccine candidate cannot cause HIV infection, and it is too soon to determine if there is any real link between the receipt of the vaccine candidate and an enhanced risk of HIV infection in some individuals, but investigators are proceeding cautiously.

The Phambili trial was a companion study to the STEP trial testing the same vaccine candidate, developed by Merck, at sites in South Africa (see Spotlight article). One goal of the Phambili trial was to see if the candidate vaccine, which included clade B HIV fragments to induce an immune response against the virus, would be effective in areas where the most commonly transmitted virus is clade C HIV (see VAX July 2006 Primer on Understanding HIV Clades). The Phambili trial was also conducted for the most part in heterosexual volunteers—unlike the STEP trial which enrolled primarily men who have sex with men—and was to enroll mostly women, who are at very high risk of contracting HIV in South Africa.

The Phambili DSMB had already suspended the trial a month earlier, immediately after further immunizations in the STEP trial were halted. At this time only 801 volunteers of a planned total of 3,000 were enrolled, 58 of whom had received all three vaccinations. Still, as news of the suspension reached the Phambili trial sites it felt like "stopping a steam train," says Glenda Gray of the Perinatal HIV Research Unit at the University of Witwatersrand and principal investigator of this trial. At that time, the sites throughout South Africa were enrolling as many as 50 volunteers a day.

The DSMB recommended permanently stopping immunizations and enrollment and unblinding volunteers after carefully analyzing data from the STEP trial. Following this decision, Gray and her colleagues set out to unblind and counsel all 801 volunteers. Once underway, Gray says it took only 16 days to complete the process. In what she compared to a "military operation," all volunteers were contacted by cell phone or short message service (SMS). Announcements were also made on the radio, alerting trial volunteers to come to the study sites for further information. Gray says the Phambili trial was at such an early stage it would not have yielded any substantial information, even if the participants who were already enrolled were kept blinded. All volunteers are still being encouraged to return for tests and study visits.

Merck, NIAID, and the HVTN also decided to unblind volunteers in the STEP trial shortly after this issue was discussed publicly at the annual HVTN meeting in Seattle on November 7 and the unblinding process is now underway at sites throughout North and South America, the Caribbean, and Australia. According to Susan Buchbinder of the University of California in San Francisco and principal investigator of the STEP trial, investigators had considered keeping a subset of individuals blinded, who voluntarily chose not to know if they received vaccine or placebo. But there was substantial uncertainty that investigators could learn that much more about the vaccine candidate from this type of follow up. Before the official decision was announced, some STEP volunteers had already requested to know if they received vaccine or placebo, an option available to all study volunteers at any time.

"There were many benefits to unblinding all study volunteers," Buchbinder says, "including the clarity with which we could deliver risk-reduction counseling messages and for building trust with the study volunteers and the broader community." —By Kristen Jill Kresge

The Global HIV Vaccine Enterprise announced the appointment of Alan Bernstein, founding president of the Canadian Institutes of Health Research (CIHR), as its executive director on October 11 at the Keystone Symposium on Challenges of Global Vaccine Development in Cape Town, South Africa. Bernstein will establish the permanent administrative offices of the Enterprise in New York City with US$20 million in funding from the Bill & Melinda Gates Foundation over the next four years, and an additional $7 million over the next seven years from the National Institute of Allergy and Infectious Diseases (NIAID).

The Global HIV Vaccine Enterprise is an alliance of independent organizations with a shared scientific plan that focuses on accelerating six areas of AIDS vaccine research: vaccine discovery, laboratory standardization, product development and manufacturing, clinical trials capacity, regulatory issues, and intellectual property. The idea of the Enterprise was first proposed in 2003 by a cadre of leading HIV researchers as a way to promote collaboration in the field. But the "core of the enterprise is science," said José Esparza of the Gates Foundation.

To date, the organizations of the Enterprise have raised $750 million to achieve the objectives of the scientific plan. The new executive director of this effort needs to see that this funding, and the science it supports, is deployed in innovative ways, said Esparza. "We are convinced Alan is the ideal choice," he added. "As the head of the Enterprise, Alan Bernstein will bring his passion and expertise to the challenge of developing an HIV vaccine."

Bernstein most recently presided over the $1 billion budget of CIHR, the Canadian equivalent of the US National Institutes of Health, and was a member of the scientific board of the Grand Challenges in Global Health Initiative, sponsored by the Gates Foundation. Bernstein, whose scientific experience is not within the AIDS vaccine field, views his being an "outsider" as a strength because he can bring fresh perspective.

He emphasized the need to coordinate efforts within the field and get funding agencies, industry, and regulators working together. Bernstein said he recognized that getting the scientific community to work together on an issue of global importance is a hefty task and he compared the efforts to develop an AIDS vaccine to the campaign to tackle global warming. "As a group we've received hundreds of millions of dollars," said Bernstein. "The world is watching us."

He also referred to the recently reported results from the STEP trial as a "wake-up call" for the field. "It's going to be a long journey. We need to learn from the STEP trial and all other trials before and after that. The Enterprise will accelerate the development of a vaccine, [and] make the dream of a vaccine a reality," Bernstein said. "I think it's doable and I'm looking forward to it." —By Kristen Jill Kresge

The Bill & Melinda Gates Foundation announced a new grants program called the Grand Challenges Explorations Initiative at the Keystone Symposium on the Challenges of Global Vaccine Development, held October 8-13 in Cape Town, South Africa (see Giving it their best shot). This initiative will foster innovative approaches to the greatest global health challenges by funding academic or independent research and discovery efforts in several areas of public health.

The Gates Foundation has committed US$100 million to the program over the next five years and will issue grants of $100,000 to selected applicants with the aim of encouraging the best minds to explore novel approaches to the world's greatest health challenges. "This is not about making money; this is not about publishing," said Tachi Yamada of the Gates Foundation. "It's about delivering to patients."

This initiative will also attempt to break down the interdisciplinary boundaries of research. "Innovation is a word that is misused by most," said Yamada. "They mean what I'm doing, not what you're doing."

Another guiding principle of the Explorations program is speed. Applications require no advanced data and are limited to two pages. They will be reviewed quickly and grants will be delivered within three months. The initial target areas for the grants will be announced early next year and proposals, which will be reviewed by experts in the areas of science and technology, will be accepted starting early- to mid-2008. Grantees will be expected to take on big questions and big risks and share information as soon as it's available, according to Yamada.

In September, IAVI launched a $10 million initiative focusing specifically on AIDS vaccine research and development. This program, known as the Innovation Fund, will identify and fund small- and medium-sized biotechnology companies working on innovative technologies that may have applications in AIDS vaccine research. The need for pioneering approaches to AIDS vaccine design became even more apparent after Merck's leading candidate, MRKAd5, failed to provide any degree of protection against HIV infection or to control viral load in individuals who became HIV-infected despite vaccination in a large Phase IIb test-of-concept trial called the STEP study (see Spotlightarticle).

"Let's face it, 25 years after the advent of HIV/AIDS and there's still no vaccine," said Yamada. "As a funder of this work we have to be willing to fail. But when we have success, we should be ready to invest very, very heavily in that success." —By Kristen Jill Kresge