AIDS Vaccine 2012: Brave New World

New tools and strategies for HIV prevention are complicating the business of vaccine development. But, as the Boston conference revealed, HIV vaccine research continues to advance at a torrid pace.

By Regina McEnery

AIDS vaccine development has never been easy. But with the recent proliferation of new biomedical interventions to prevent HIV, it’s getting downright complicated. That much was abundantly clear from the outset at the AIDS Vaccine 2012 Conference, held Sep. 9-12 in Boston, where several satellite sessions examined how the expected rollout of some of those interventions is likely to affect the conduct of AIDS vaccine trials. 

More notably, three of the four opening plenary talks had little to do with vaccines. Instead, they covered vaginal microbicides; research into the early initiation of antiretroviral (ARV) treatment to reduce transmission risk; and an overview of what we’ve learned from trials of pre-exposure prophylaxis (PrEP), the administration of ARVs to HIV-uninfected people to prevent infection. The fourth talk, delivered by Anthony Fauci, the executive director of the US National Institute of Allergy and Infectious Diseases (NIAID)—focused on vaccines in the context of these and other preventive interventions. 

“The HIV prevention strategy will in fact,” Fauci predicted, “be a unique paradigm of non-vaccine prevention modalities together with a safe and effective vaccine.” If properly implemented, he argued, the non-vaccine modalities could by themselves probably turn the tide of the pandemic. Fauci maintained, however, that the only hope the world has of eliminating—and ultimately eradicating—HIV rests on the development of broadly effective vaccines and their deployment in addition to those other preventive interventions.

Yet making the case for vaccine development isn’t likely to get any easier, certainly not in the midst of a global economic downturn. Bill Snow, executive director of the Global HIV Vaccine Enterprise, an organizer of AIDS Vaccine 2012, argued that the AIDS vaccine field needs to redial its message. “We have gotten tired of making our own case,” said Snow. “It sounds rote, obligatory and, worst of all, next to impossible. It needn’t be that way.”  

For all the talk of other biomedical interventions, there was ample evidence of the remarkable progress of HIV vaccine design and development at the conference.

Signatures of success
Researchers have been analyzing samples collected in the RV144 trial, which demonstrated 31% efficacy against HIV and remains the only evidence available that vaccines can prevent HIV infection. At last year’s AIDS Vaccine meeting in Bangkok, investigators shared the first set of results from such analyses, identifying what they called “correlates of risk” associated with the Thai regimen—a vCP1521 canarypox viral vector prime followed by a gp120 B/E AIDSVAX boost. Subsequently published in the New England Journal of Medicine, those studies revealed, surprisingly, that one antibody response correlated with a reduced risk of HIV, while another correlated with an increased risk of infection (see VAX Sep. 2011 Spotlight article, More Surprises Stem from RV144). 

Scientists have since turned their attention to the antibody responses that correlated with a reduced risk of infection—namely, immunoglobulin G antibodies that bind to the V1/V2 region of HIV’s Envelope protein. They have examined whether those vaccine-induced antibody responses selectively blocked certain HIV variants, and what genetic changes allow the virus to elude that targeting. Scientists refer to such escape as a “sieve effect.” 

Led by researchers at the US Military HIV Research Program (MHRP), a key collaborator in the RV144 trial, the team examined nearly 1,000 HIV genetic sequences from 110 volunteers who became infected over the course of the RV144 trial—44 who received the candidate vaccine regimen and 66 who received a placebo vaccine. They then examined the viral sequences for evidence that the V2 region plays a major role in the modest protection seen in the trial. And, indeed, in a study presented in Boston, researchers detected two genetic signatures in the V2 region that closely correlated with vaccine efficacy. 

That is, viruses that bore certain sequences in two stretches of the Envelope gene appeared to be vulnerable to vaccine-induced immune responses; viruses with mutations in those regions of the gene tended to evade such responses. One of the genetic signatures appeared to be associated with an efficacy as high as 78%. “This is an independent assessment that the V2 region is important,” said Morgane Rolland, lead author of the study and a scientist at MHRP. 

The findings, published in Nature the same day they were presented at the Boston conference, buttressed the credibility of the Thai trial results—adding to the molecular evidence that the observed protection was real, and not just a statistical anomaly. 

On the other hand, they also underscored just how difficult it will be to design a broadly effective AIDS vaccine—a point raised by Jon Cohen, a reporter for the journal Science, at a press conference where Rolland presented the results of her study. “In the real world, what practical application would this have? I can see why you can use it as an argument that the efficacy [in RV144] was real, but it is far away from what people dream of—which is a vaccine [that protects] against many strains.”

MHRP Director Nelson Michael acknowledged the challenges that HIV’s genetic diversity and mutability present to vaccine designers, but was optimistic those challenges can be resolved. “We are making substantive progress in understanding what it will take to develop a more effective HIV vaccine, which will ultimately help us end this pandemic,” he said.

In a separate talk, Rolland reported results from a monkey study that found additional evidence supporting the importance of vaccine-induced responses against the V2 region.

Stalled trials
Researchers hope to improve upon the results of RV144. But at a separate satellite session, Jerome Kim, deputy director of science at MHRP, discussed issues impeding two such planned studies—one involving men who have sex with men (MSM) in Thailand and a second among heterosexual men and women in South Africa. 

The Pox Protein Public-Private Partnership, or P5, launched a year ago to boost the vaccine efficacy seen in the RV144 trial to at least 50%, had hoped to start both studies by late 2012. But a number of setbacks ranging from money to laboratory infrastructure to manufacturing have scuttled P5’s plans, said Kim. The earliest start date for the Africa trial, now expanded to include southern Africa, is now pegged at late 2014, and it is unclear when the MSM trial in Thailand will get off the ground. 

The vaccine regimen slated to be tested in a Phase IIb licensure trial in southern Africa includes an ALVAC viral vector vaccine candidate as the prime, followed by a gp120 protein boost containing a well characterized adjuvant known as MF59. The efficacy trial among MSM in Thailand, meanwhile, is to test an ALVAC prime coupled with a gp120 boost that is also formulated with MF59. 

Kim said a major challenge in the MSM trial in Thailand has been finding a manufacturer for the proposed gp120 boost. The company that owns the intellectual property rights for the protein boost in the RV144 trial is unable to produce enough for another trial, which means a new manufacturer must be found. Novartis Vaccines and Biologics, located in Massachusetts, has the contract to make the protein boost for the southern Africa trial. Kim said discussions with Novartis are ongoing to see if they will make protein for a Phase IIb trial in Thailand as well.

Broadly speaking
The expanding arsenal of bNAbs isolated from chronically HIV-infected individuals dominated the conference, reflecting growing optimism that their analysis will yield clues to the design of a broadly effective HIV vaccine. Several talks dealt with novel approaches to visualizing the interactions of these antibodies with their targets on the HIV Envelope trimer, a three-legged spike-like protein complex that has long proved resistant to structural analysis (seePrimer, this issue). 

Researchers described how they are applying computer modeling to reverse engineer immunogens based on the molecular structures—or epitopes—targeted by bNAbs on the Env protein. One approach involves scanning a vast database of known protein structures to identify those that might hold such epitopes in an orientation and context optimal for bNAb binding. When used as immunogens, such structural mimics of bNAb targets ought to elicit similar antibodies against HIV and so confer broad immunity to circulating virus strains. That, at least, is the theory.

And it would appear to be on sound footing: Bill Schief, an associate professor of immunology at The Scripps Research Institute in La Jolla, CA, and a member of IAVI’s Neutralizing Antibody Center, presented a proof of concept for the strategy. He and his colleagues devised a candidate immunogen for a vaccine against the respiratory syncytial virus (RSV)—a major cause of respiratory tract infections in infants. Using computational modeling and scaffolding, they created a molecular mimic of the epitope targeted by a known neutralizing antibody against the virus. When monkeys were immunized with this candidate immunogen, they produced antibodies that neutralized laboratory strains of RSV. Schief and other researchers, most notably at NIAID’s Vaccine Research Center and IAVI’s Neutralizing Antibody Consortium, are using this approach to devise novel immunogens for HIV vaccine candidates.

Mosaic antigens
Researchers in Boston also presented new animal data on mosaic antigens, which are immunogens that have been computationally designed to address the overwhelming diversity of HIV. Most vaccine inserts contain HIV gene sequences from a single virus found in a certain region of the world, or a single sequence shared by a variety of circulating viruses. Mosaic antigens, however, are cocktails of several intact, full-length or near full-length proteins that are created by tiling together genetic sequences that not only represent several HIV variants but have also been optimized for their potential to induce vigorous and effective immune responses against the diverse viruses in the HIV pandemic. 

Researchers have found that some prime-boost regimens containing mosaic antigens reduced the risk of infection by 90% per exposure in monkeys. Bette Korber, who oversees the HIV Database and Analysis Project at the Los Alamos National Laboratory in New Mexico, said mosaic inserts are now being made for inclusion in Phase 1 clinical trials.