In With the New...

The AIDS vaccine field considers ways to encourage innovation and recruit new minds into the effort

By Regina McEnery

Peter Kwong clearly remembers the day a seminar helped guide his career path to AIDS vaccine research. It was 1991 and Kwong, working toward a PhD in biology at Columbia University, was among 25 students who gathered to hear pioneering Australian biologist Peter Coleman describe how he had used the relatively new technique of structural biology—a branch of molecular biology that looks at the architecture and shape of molecules—to study the influenza virus.

Coleman’s pioneering research would eventually lead to a new class of antiviral drugs against influenza, but in the early 1990s it was still conjecture whether crystallography—which primarily relies on X-rays to determine the shape and structure of proteins—was going to be useful for the pharmaceutical industry. Kwong was impressed with the approach and eventually started wondering whether structural biology and crystallography could also be useful in vaccine design, specifically for HIV.

He decided to tackle this question and now, as head of the Structural Biology Section at the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the US National Institutes of Health, he is using X-ray crystallography to decipher one of a handful of antibodies—Y-shaped proteins that bind to viruses and prevent them from infecting human cells—capable of neutralizing a broad variety of HIV variants. The antibody Kwong is studying is known as b12. “We’re basically performing magic,” he says. “But then everything in science is magic until you figure it out.”

Whether or not Kwong’s work will lead researchers to be able to design vaccine candidates that could induce this antibody in people remains unknown. But his research is one of the many innovative approaches being utilized to overcome a number of daunting biological challenges in AIDS vaccine development. Following some recent setbacks, most notably the failure of Merck’s AIDS vaccine candidate in the STEP trial, the AIDS vaccine field is trying to invigorate research efforts by pursuing new ways to attract more young researchers like Kwong, and encourage more innovative thinking.

But the search for new blood and fresh ideas faces a number of practical hurdles. The percentage of investigators, not just in AIDS vaccine research but throughout academia, competing for their first general research grant—known as an RO1—declined from 35% in 1965 to 25% in 2003. Meanwhile, the average age of principal investigators rose from 35-40 in 1983 to 50 in 2003, according to Jose Esparza, a senior advisor on HIV vaccines at the Bill & Melinda Gates Foundation.

With fewer young, less-established researchers competing for early-career grants, the pace of scientific breakthroughs, such as an AIDS vaccine, will slow considerably, Esparza and others contend. To ensure this doesn’t happen, agencies and foundations that fund AIDS vaccine research are creating new ways to encourage young scientists to enter the field and are developing new funding streams to encourage more out-of-the-box thinking.

The hunt for innovation

Leading the charge to spur innovation in the field is NIAID, which devoted US$497 million of its $1.5 billion HIV/AIDS budget to vaccine research in 2008 and has made the development of an AIDS vaccine a top priority. Last March, sparked by the results of the STEP trial, NIAID held a day-long summit attended by 200 researchers to discuss shifting priorities in AIDS vaccine research and the myriad of challenges still facing vaccine development (see VAX April 2008Spotlight on Balancing the AIDS Vaccine Budget).

Following the summit, NIAID announced two new grants to spark creative approaches to vaccine discovery and development. The Basic HIV Vaccine Discovery Research grant program will commit $10 million to fund 20-30 applications, while the Highly Innovative Tactics to Interrupt Transmission of HIV program, or HIT-IT for short, will commit $4.5 million for 5-10 applications. Both grant programs, which will be funded this year, were created to address some of the most pressing questions facing vaccine researchers today, including improving our understanding of how the immune system responds to natural infection and vaccination, new mechanisms and pathways that could be targeted by vaccines, and developing better animal models for evaluating AIDS vaccine candidates, as well as many other areas.

Last year the Gates Foundation, the largest private funder of HIV/AIDS research, awarded $100,000 grants over five years to 105 researchers through its Grand Challenges Explorations program. These grants will be awarded to individuals with novel ideas that cross a number of areas, including AIDS vaccine research and, like HIT-IT, target high-risk, outside-the-box proposals that traditionally would have a hard time attracting private and public funding.

IAVI, meanwhile, has a two-year-old Innovation Fund that provides seed money to help bring novel, early-stage technologies to the field of AIDS vaccine research. The Innovation Fund, which is partially supported by a grant from the Gates Foundation, has awarded six grants since its creation in August 2007 and nine more are expected over the next two years.

While the Innovation Fund does entertain and fund projects from academic researchers, the program is primarily directed at identifying novel technologies within industry, says Kalpana Gupta, IAVI’s director of new alliances and initiatives.

However, this new roadmap toward innovation is being laid out during a time of great economic uncertainty. A sharp slowdown in the global economy and prospects of what could be a deep and lengthy recession have cast a cloud over a research environment already struggling with flat budgets and increased competition for grant dollars. While NIAID’s director, Anthony Fauci, does not expect any cutbacks in AIDS spending in the near future, he also isn’t anticipating any new funding. Still, he said the $14.5 million recently pledged for the HIT-IT and Vaccine Discovery Research programs is secure. Moreover, he said the agency is “committed to not only maintaining but increasing HIV vaccine research,” particularly in basic science. Fauci says that means redirecting money from other areas of NIAID’s AIDS budget considered “less pressing.”

“There is obviously a lot of interest in HIV vaccine research,” says Fauci. “A lot of that is coming from philanthropic groups. But with the economy in free fall, the question remains whether people will be more reluctant to give money to philanthropic groups.” Also of concern is whether the economic downturn will dampen philanthropic support for high-risk projects that are likely to deliver more blanks than magic bullets.

The next generation

Another way to stimulate innovation is to encourage more early career investigators to pursue AIDS vaccine research. Because young researchers tend to have a certain naive curiosity that fosters exploration, they are often more willing to adopt novel approaches to addressing questions that have confounded their mentors.

The Global HIV Vaccine Enterprise, an international alliance of researchers and funders, is focusing on identifying potential solutions for how best to attract and retain young scientists to AIDS vaccine research through its Young and Early Career Investigators (YECI) Initiative.

“We are not a funder,” says Alan Bernstein, executive director of the Enterprise. “It is not our responsibility or mission to mandate those things directly, but I think our job in this case is to highlight a problem or opportunity and come up with possible ways of addressing it and then present that to funders.”

Dan Barouch, associate professor of medicine at Beth Israel Deaconess Medical Center in Boston, and Thumbi Ndung’u, associate professor in HIV/AIDS Research at the University of KwaZulu Natal in Durban, South Africa, were appointed to chair the YECI Committee established by the Enterprise.

The Center for HIV/AIDS Vaccine Immunology (CHAVI) and the HIV Vaccine Trials Network (HVTN), both funded by NIAID, are also reaching out to early career scientists, most notably those interested in non-human primate research. Last year CHAVI and HVTN began soliciting pilot study proposals from young researchers that “strengthen bridges between nonhuman primate studies and human research by addressing key questions in the search for a safe and effective vaccine.”

Barouch said the STEP trial findings, ironically, have given young researchers a huge opportunity. “The future has never looked more promising because the failure of the Merck [candidate] shows there is a lot more research to be done,” says Barouch, a molecular immunologist who is studying T-cell based vaccines. “The field of investigators has come to the realization that they will have to pass the torch to the next generation. The scientific problems are there, and it will need young, talented, and creative investigators to solve them.”

But to meet these challenges, particularly in countries hardest hit by the epidemic, it will require a long-term investment to prevent the kind of brain drain that has prevented many African countries from developing their own research infrastructure and holding onto their scientists, says Ndung’u, a Harvard-trained virologist whose research institute in Durban was built primarily with funds from the Doris Duke Foundation.

“It takes time to build a good research institution,” says Ndung’u. “A lot of the grants that have been given to investigators to do work in Africa, I don’t think those grantees were held to the fire in terms of making sure there is a pathway that is developed and sustained.”

In developed countries with good research infrastructure, the money is simply getting tighter. “It is getting tougher and tougher to get into the big laboratories because they don’t have the money,” acknowledges Galit Alter, who was mentored by Harvard immunologist Marcus Altfeld, director of the innate immunity program at Partners AIDS Research Center, and now has her own research laboratory there.

“The most important thing that the NIAID summit did, I think, was encourage investigators not to give up,” says Alter. “Even though funding is tight there really is a reason to stay in it. It’s survival of the fittest. Those who survive will be the creators.”

Bernstein says he hopes that the recommendations of the YECI Committee will provide traction in the AIDS vaccine arena and beyond. “These issues are not unique to HIV vaccine research,” says Bernstein. “Young people have particular challenges these days in biomedical research. If we don’t renew ourselves as a scientific community, we will be in trouble.”