In With The New...

The AIDS vaccine field considers ways to encourage innovation and recruit new minds to 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 crystallography and the relatively new technique of structure-based drug design to define small-molecule inhibitors from the three-dimensional structure of neuraminidase, a protein found on the outer layer of the influenza virus.

Coleman’s pioneering research in structural biology 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 notion that you could use atomic-level characterization of proteins and eventually started wondering whether structural biology 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), part of the US National Institutes of Health (NIH), Kwong is using X-ray crystallography to understand one of the rare broadly neutralizing antibodies against HIV called b12. In work originally featured on the cover of the journal Nature, Kwong’s lab used X-ray crystallography to illustrate how b12 blocks HIV from entering CD4+ T cells by precise targeting of the initial contact site between virus and cell receptor (1). This work is important because the lack of immunogens capable of provoking a strong immune response against HIV remains one of the biggest barriers to the discovery of an effective AIDS vaccine.

Kwong and his collaborators Bill Schief and David Baker at the University of Washington are building epitope scaffolds—another tool of structural biology that acts as a template for monoclonal antibodies—to try and teach the immune system to create antibodies that recognize the ever-changing face of HIV. “We’re basically performing magic,” says Kwong. “But then everything in science is magic until you figure it out.”

HIV has arguably been studied more strenuously and comprehensively than any other pathogen in history. But since 1983, when French researchers and 2008 Nobel Laureates Luc Montagnier and Françoise Barré-Sinoussi discovered the retrovirus, there has not been a Eureka moment that has opened the door to an effective vaccine. Whether or not Kwong’s experiment leads to the discovery of an HIV immunogen capable of inducing antibodies against HIV, 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, notably the failure of Merck’s adenovirus serotype-5 (Ad5)-based vaccine candidate known as MRKAd5 in the STEP trial, the field is trying to invigorate research efforts by pursuing new ways to attract more young researchers like Kwong, and encourage more innovative thinking.

The search for new blood and fresh ideas face a number of practical hurdles, though, that threaten not just the pace of AIDS vaccine science but the entire research arena. The percentage of new investigators throughout academia competing for their first US government-funded general research grant, known as an R01, has 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 José Esparza, a senior advisor on HIV vaccines at the Bill & Melinda Gates Foundation.

With fewer young, less-established researchers competing for R01 grants, the pace of scientific breakthroughs, such as those that will lead to 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 innovative thinking.

The hunt for innovation

Leading the charge to spur innovation 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 a safe and effective AIDS vaccine a top priority. Last March, 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 Balancing AIDS vaccine research, IAVI Report, March-April 2008).

At the summit, which was sparked by the results of the STEP trial, some researchers urged NIAID to place a higher priority on basic discovery research because of the outstanding questions about how best to develop a vaccine. NIAID Director Anthony Fauci agreed. But with five years of flat funding to NIAID, Fauci decided to shift money allocated for clinical development to basic discovery to support two new grant programs aimed at generating new ideas that may help advance the basic understanding of how to develop a vaccine that prevents HIV infection or controls disease progression. “Money is not the answer, it is ideas we need,” says Peggy Johnston, NIAID’s director of the Vaccine & Prevention Research Program. “We need to get new blood, new people involved in AIDS vaccine research.”

The new Basic HIV Vaccine Discovery Research R01 grant program will commit $10 million to support 20-30 research projects that can engage investigators in AIDS vaccine development and related fields, individually or in a collaborative interdisciplinary manner, to substantially improve the basic understanding of the immune system’s response to natural infection and vaccination; dissect immune mechanisms of protection; identify effective immunogens and approaches toward manipulating the immune response; discover new mechanisms and pathways that could be targeted by vaccines; and conduct in vitro studies in animal models and in humans to examine how HIV pathogenic mechanisms relate to vaccine design.

The new Highly Innovative Tactics to Interrupt Transmission of HIV, or HIT-IT, R01 grant program will fund 10 proposals that target the technical and scientific hurdles facing the field by providing support for HIV pathogenesis studies on the biology of HIV transmission and human genetics. Collaborations among virologists, immunologists, molecular and cell biologists, and other relevant areas are encouraged among HIT-IT grantees and so is risk-taking. “Reviewers will be advised that unavoidable risk is acceptable as long as the probability of success is greater than zero,” the grant description reads. HIT-IT research proposals were due last November but the grant winners have not yet been announced.

These R01 grants are just one plank in a platform that reflects the shifting priorities in the AIDS vaccine field. While NIAID, the biggest public funder of AIDS research, is leading the charge, large philanthropic organizations like the Gates Foundation along with IAVI have also been trying to spark innovation with an array of projects and grants.

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, which funds novel ideas that cross a number of areas of importance to the foundation’s mission, including AIDS vaccine research.

Grand Challenges Explorations grants are small seed grants and, like HIT-IT, they target high-risk, out-of-the-box proposals that traditionally would have a hard time attracting private and public funding. The review process is less restrictive and the turnaround time for funds is quicker than traditional research streams such as the NIH’s extramural grant programs. “This program is designed to open up the gates a little, no pun intended,” says Andrew Serazin, the Gates Foundation’s program officer in Global Health Discovery. “We don’t expect full proof of concept in that first year, but you need to show us that first step in the right direction.” If a grantee manages to do just that, they could be eligible for $1 million more in funding over two years, says Serazin.

The Gates Foundation received about 4,000 applications and 31 of the 105 grants awarded fall under the category of HIV prevention and eradication. A number of other HIV-related projects fall under a more general vaccine category that involves “platforms” that could be applicable for control of a number of diseases, says Serazin.

IAVI, meanwhile, has a two-year-old Innovation Fund that provides seed capital 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 made six awards since its creation in August 2007 and nine more are expected over the next two years. Its most recent recipient, South African Elevation Biotech, is attempting to enhance the structural stability of HIV’s envelope protein in complex with a broadly neutralizing antibody and then use this to design antigens that can induce broadly neutralizing antibodies against the virus.

While the Innovation Fund does entertain and fund projects from academic researchers, the program is primarily aimed at identifying novel technologies within industry, says Kalpana Gupta, IAVI’s director of new alliances and initiatives. Gupta says antigen discovery and immunogen design are of high interest to the Innovation Fund.

Economic uncertainty

This new roadmap toward innovation is being laid out during a time of great economic uncertainty, but Fauci says the $14.5 million pledged for the HIT-IT and Vaccine Discovery Research programs, which will both kick in this summer, 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.” This may not be the case, at least for one philanthropist who recently made a $100 million commitment to AIDS vaccine development (see box below).

$100 million Gift Creates New AIDS Vaccine Research Institute 

 AIDS vaccine scientists agree a renewed emphasis on basic discovery is what is needed to solve some of the obstacles impeding AIDS vaccine development. That pursuit received an enormous boost this month after technology magnate Phillip Ragon, the founder and owner of a company that provides database software to hospitals and other industries, announced a US$100 million gift to Massachusetts General Hospital (MGH) in Boston to explore how the immune system combats disease, with an initial focus on developing an AIDS vaccine.

The gift is unprecedented for MGH, which is using the money to form the Phillip T. and Susan M. Ragon Institute, a unique collaboration of engineers, biologists, and doctors drawn from MGH as well as Harvard University and Massachusetts Institute of Technology (MIT).

The Ragon Institute—named for the donor and his wife—will be headed by Bruce Walker, an immunologist and director of the Partners AIDS Research Center, which is now part of the Ragon Institute. “It is a long-standing passion that I have, trying to help the poor and developing countries,” says Ragon.

Ragon, who has a degree in physics from MIT, became drawn to the field of AIDS vaccines after meeting Walker and hearing about his research. “He started telling me about his activities,” recalls Ragon. “I said I hear everything you say, but I still don’t understand it.”

So about two years ago Walker suggested that Ragon, whose company happens to have offices in South Africa, visit AIDS clinics there. Seeing the human face of the 28-year-old epidemic affected Ragon deeply. “It was really quite shocking,” he says. “I began to talk with Bruce about what I could do to help,” and the Ragon Institute evolved from those early discussions.

“What this money means is that we can launch new collaborations in new areas with people with new perspectives, and do that immediately,” says Walker. “To me the thing that has made the most difference in my career has been flexible funding. What we are going to be able to do is track a lot of talented people and give them that license with flexible funding—the license to be innovative and creative and to take some bold chances.”

Walker’s laboratory has already done extensive research on a subgroup of HIV-infected individuals called elite

controllers, who maintain viral loads of <50 HIV RNA copies/ml plasma without antiretroviral therapy. Walker is now tracking a cohort of 1,000 elite controllers and this area of research is considered a promising avenue in AIDS vaccine research.

This new $100 million award will also elicit the expertise of scientists from fields not necessarily associated with HIV. One of these researchers is MIT scientist Darrell Irvine, a polymer scientist and immunologist who has worked on cancer vaccines. He is attempting to build the biological version of a smart car—an efficient, nimble vehicle constructed from nanoparticles that can safely deliver DNA vaccines to their intended targets.

“Many people would argue that DNA vaccines could be ideal,” says Irvine. “They are cheap to manufacture and synthetically produced so they would be well-defined. You have good quality control with them and you eliminate issues of vector-specific immunity like you have with viral vectors.”

The problem is that DNA vaccines are also the equivalent of a ‘gas guzzler.’ “DNA vaccines work in mice because you can inject a ton of DNA in a relatively large volume of solution, which promotes transfection,” says Irvine. “You cannot scale up those amounts in large animal models and humans.”

Nanoparticles can deliver molecules with a high level of precision to specific receptors inside cells, so Irvine’s laboratory is working on several different formulations that would improve immunogenicity either by directly stimulating the immune system or enhancing DNA expression. The nanoparticles are comprised of lipids and bioresorbable polymers because of their track records with other vaccines and drug delivery applications unrelated to HIV.

Christopher Love, a chemical engineering professor at MIT and another member of the Ragon Institute, is developing new assays that can monitor the immune response of single cells, allowing them to pinpoint precisely how the responses differ. His work is particularly applicable to research on elite controllers because being able to decipher what induces immunological control could help lead researchers to a vaccine that can do the same.

The Ragon Institute is also partnering with IAVI to conduct preclinical evaluation of AIDS vaccine concepts developed at the Institute. —RM


The next generation

Another way to encourage innovation is to attract young researchers to the field (see Perspective article). Because early career scientists are perceived to have a certain naive curiosity that fosters exploration, they are also considered a critical component in the pursuit of innovative approaches. Seasoned researchers generally agree that the discovery of a safe and effective vaccine will likely fall to a new generation of scientists, so they are now focusing on attracting these new minds to the cause.

The Global HIV Vaccine Enterprise—an international alliance of researchers, funders, and advocates committed to accelerating the development of an HIV vaccine—has made this issue one of its primary areas of focus and recently it established the Young and Early Career Investigators (YECI) Initiative to identify ways to attract young researchers to the vaccine field. The Enterprise has held three meetings since the NIAID summit seeking input from young/early career researchers; the most recent was at the 2008 AIDS Vaccine Conference in Cape Town.

“We are not a funder,” says Alan Bernstein, the 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.” Bernstein said the role of the YECI Initiative is two-fold—to diagnose the problem of why young investigators are not joining the AIDS vaccine effort, and to develop specific recommendations for the Enterprise’s scientific advisory board. “I would like this issue of attracting and retaining new researchers to become part of our scientific strategic plan that we hope to have ready by this fall,” says Bernstein.

Two early career scientists, Dan Barouch, associate professor of medicine at Beth Israel Deaconess Medical Center in Boston, and Thumbi Ndung’u, associate professor at the University of KwaZulu Natal in Durban, South Africa, are chairing a YECI committee that has been charged with figuring out how to bring new researchers on board.

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 (NHP) research. “The ultimate goal is to build a team of new and established scientists committed to advance our understanding of NHPs to predict immunogenicity and efficacy of candidate vaccines in humans, to develop novel models of pre-clinical evaluation of candidate vaccines, and to define new concepts in correlates of protection from infection or immune control after acquisition,” according to the grant summary.

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. “There are a lot of problems to be solved and it’s clear that the development of an HIV vaccine is not going to occur in the next few years. 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.”

Survey Says...

 As the AIDS vaccine field focuses increasingly on basic discovery research, innovation and engaging a new generation of researchers is becoming a high priority. In response to this, IAVI, the AIDS Vaccine Advocacy Coalition, and The Global Vaccine Enterprise surveyed a group of 75 young investigators who attended the AIDS Vaccine 2008 conference in Cape Town, South Africa, and conducted interviews with more veteran researchers to assess the obstacles to engaging young investigators and retaining promising researchers already involved in AIDS vaccine work.

The primary obstacles identified by respondents were limited access to funding, particularly for those young investigators who lack a significant publication record, and negative perceptions of the field due to recent trial outcomes. Young investigators also expressed concern about not receiving proper credit for their work in large consortia, due to their junior status and the hierarchical nature of such settings.

Some recommendations suggested by respondents for improving the environment for young researchers included: continuing and improving mentorship programs; fostering opportunities for young investigators to publish their findings; continuing evaluation and improvement of peer review processes; and developing funding mechanisms to strengthen research capacity in low- and middle-income countries to engage new and young researchers as well as retain and support those already involved.

The majority of those interviewed saw the need to engage young investigators, especially from fields other than vaccine research, as necessary to sustain the vitality of the field. Additionally, bringing these eager young minds into the field may prove critical to spurring the innovative ideas and approaches necessary to advance AIDS vaccine research and development. —Genevieve Lynch, contributing writer

Bernstein says he hopes that the recommendations of the YECI committee will provide traction in the AIDS vaccine field, but also well beyond that. “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.”

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.

He said salaries in Africa are low and with a few notable exceptions, such as South Africa, most countries lack infrastructure and trained personnel to support basic AIDS vaccine science. “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.”

And 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 worked with Marcus Altfeld at Partners AIDS Research Center and now has her own research laboratory there.

Alter said a professor at McGill University, where she completed her undergraduate and graduate training, literally ordered her, at the age of 19, to join his HIV lab. She was skeptical about her abilities but agreed. “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.”

Several new grant programs, including many at the US National Institutes of Health (NIH), are designed to encourage innovation in AIDS vaccine research and attract new investigators to the field. Listed below are some additional NIH grant/award programs that apply to innovation but are not specific to the AIDS vaccine field.

PIONEER AWARD PROGRAM: Supports individual scientists of exceptional creativity who propose pioneering or transformative approaches to major challenges in biomedical and behavioral research. Initiated in 2003, each award provides US$2.5 million over five years. Sixteen awards were granted in 2008.

NEW INNOVATOR AWARD: Seeks to stimulate highly innovative research and support promising new

investigators. Targeted for young researchers who have not received a traditional NIH research grant. Established in 2007, it provides $1.5 million over five years per recipient.

TRANSFORMATIVE R01 PROGRAM (T-R01): In response to concerns that traditional R01 grants may discourage submission of risky research proposals, NIH created T-R01 grants to support exceptionally innovative, unconventional, and high-risk projects with a potential for high impact. Launched in 2008, the NIH expects to invest $250 million over the next five years on this program, beginning with 60 awards in 2009.

More information about these programs is available from the NIH 

1. Nature 445, 732, 2007