A race is on, in North America and abroad, to fight the fast spread of a slow killer.

Human immunodeficiency virus (HIV) continues to infect millions of people around the globe, resulting in acquired immunodeficiency syndrome (AIDS) — a disease that slowly decimates the immune system and renders the body vulnerable to infection. It also continues to engage the intense research efforts of investigators seeking what they view as the holy grail: an efficacious, preventive (or prophylactic) HIV vaccine.

The International AIDS Vaccine Initiative (IAVI) (New York, NY), an organization working to accelerate the research and development of a vaccine to prevent HIV infection and AIDS, lists more than 30 clinical trials worldwide that are investigating a preventive vaccine, either alone or in combination studies.

“Canada has built a fair bit of strength in HIV research starting in 1985 and coming up to present time,” explains Bhagirath Singh, PhD, scientific director of the Institute of Infection and Immunity (London, ON), one of the Canadian Institutes of Health Research (CIHR) (Ottawa, ON).

“Building capacity, making people aware, getting researchers on board to put their effort into this disease has taken all this time,” Singh continues. “In the meantime, there has been a major increase of the disease around the world.”

Singh says the Government of Canada’s support has been pivotal because there has been very little private sector money for HIV/AIDS research.

Aiming to strengthen Canada’s fight against HIV/AIDS, last year the federal government announced a funding increase from $42.2 million per year to $84.4 million per year by 2008-09. Through this commitment, CIHR’s share will increase to $22.6 million per year by that time, from approximately $12 million per year.

Although money is the necessary vehicle for progress, it’s not the only requirement, Singh points out.

“Even today, people deny that AIDS is caused by HIV. It’s taken us all these years of even convincing people that it has a biological cause,” Singh says. “Then there’s the other side to this, the social side — that this disease has a major social component to its spread, and we cannot just address the disease by saying that we’ll have new drugs which will get rid of (it).”

There are also scientific hurdles. For instance, HIV mutates very rapidly, Singh says.

“A single viral isolate, if it’s left unchecked in a person, within a year it will have 36 different isolates,” he says. “The only parallel to this is the flu virus, but flu virus takes a much longer time and . . . every year we need a new flu vaccine.”

The challenge, Singh says, is how to produce an immune response that will prohibit these isolates from developing, and will “more or less mop them up.”

Post-infection Panacea

An important and novel component of the HIV/AIDS arsenal is research on therapeutic vaccines.

In Canada, the first controlled trial of a therapeutic vaccine has approached the halfway mark in its 60-person target enrolment, says study leader Dr. Jonathan Angel, senior scientist at the Ottawa Hospital (Ottawa, ON) and an associate professor at the University of Ottawa (Ottawa, ON).

The trial is being conducted at three Canadian sites: the Ottawa Hospital, the Montreal Chest Institute (Montreal, QC) and the Centre hospitalier de l’Université de Montréal (CHUM) (Montreal, QC). Blood samples collected during the trial will be analysed by CANVAC, the Canadian Network for Vaccines and Immunotherapeutics (Montreal, QC).

Unlike preventive vaccines — which prime a person’s immune system before possible infection occurs — therapeutic vaccines are geared toward invigorating the immune system of those already infected with HIV.

There are currently no therapeutic vaccines for any indication, Angel says. He adds that, to date, most studies have tested single vaccines and have lacked a control. The Canadian study is assessing a combination of two vaccines: Alvac-HIV, produced by Aventis Pasteur — now called Sanofi Pasteur, the vaccine division of the Sanofi-Aventis Group (Paris, France) — and Remune® from the Immune Response Corp. (Carlsbad, CA).

The purpose of testing the vaccine combination, Angel explains, is that each one is better at stimulating a particular aspect of the immune system. Alvac-HIV is better at inducing responses from cytotoxic T-lymphocytes (CTLs) — cells that recognize and destroy virus-infected cells, and are also known as CD8+ T-cells. On the other hand, Remune excels at inducing responses from CD4+ T-cells — a type of lymphocyte that helps other cells fight infection; they are also the main target of HIV.

“In general,” Angel says, “it’s becoming kind of accepted that the best vaccines are going to stimulate many aspects of the immune system.”

Another characteristic of most studies to date, he mentions, is their focus on patients with acute infection. The logic here is that if people are treated early on with antiretroviral therapy to control viral replication, there will be better protoplasm for a vaccine because their immune systems will still be fairly undamaged. “Those studies have not been particularly successful,” he adds.

For the Canadian trial, enrolled patients must have a viral load that has been suppressed for two years, which Angel says is “a fairly strict criterion.”

“You want people who are likely going to respond best to a vaccine, and those people have the best immune systems and less ongoing immune damage,” he says. “With ongoing viral replication, there is likely ongoing damage to the immune systems. That’s what we want to avoid.”

He adds, “If it doesn’t work in the best population, then it’s not going to work in anyone. So you look at what you can define as your best patients, and then you kind of broaden it to encompass more people.”

Angel says the ultimate goal of a therapeutic vaccine is to fortify the immune system, and allow patients to stay off drugs for the rest of their lives.

More realistically, he says, patients will be able cease drug intake for a matter of years, and avoid the side-effects that medications can cause.

Multifaceted Front

Just as it is important to explore different research avenues in combating HIV/AIDS, it’s also critical that a multidisciplinary approach be taken, says Rafick-Pierre Sékaly, PhD, scientific director and program leader at CANVAC.

He says it’s important to remember that trials are not only about the science itself, but that they also involve members of the community.

“We absolutely need the lobbying and the preparedness of the community people, because this is where the vaccine is going to be tested,” says Sékaly, who is also a professor at the University of Montreal (Montreal, QC).

A controversy always exists, Sékaly explains, between waiting to develop the best vaccine and testing those that are not yet optimal. But a lot can be gleaned from trials, particularly from large-scale endeavours, such as the HIV vaccine trial of 16,000 volunteers in Thailand, he says.

“The education and counselling that is being done for prevention when you undergo these large vaccine trials by itself is already decreasing the incidence of HIV,” Sékaly says. “Plus, there is going to be a lot of science done behind this. We are going to be able to get samples to look at immune responses to see first, if there’s any sign of immune response, to look at breakthroughs from vaccines; to try to associate the kind of immune responses we get with lack of protection or protection.”

Echoing Angel’s comments, Sékaly believes that an ideal vaccine would induce the broadest immune response — both functionally and in terms of specificity — and include T-cell, B-cell and innate immunity responses.

CANVAC’s major HIV/AIDS effort will look at inducing cellular and systemic immunity, Sékaly says. The organization has submitted a funding grant to the Bill & Melinda Gates Foundation (Seattle, WA) in support of this project.

“What we are going to do is to promote an approach that’s going to lead to vaccines that elicit strong mucosal immunity at the vagina interface, at the rectum interface,” he says. “We feel this is where the virus enters. So if you can bolster the immune system at these possible sites, then you might have a better sense of curtailing the entry of the virus.”

This project falls under an initiative that CANVAC and several other organizationsin Canada are putting together called CHIVE — the Canadian HIV Vaccine Enterprise, Sékaly explains.

With CHIVE, he continues, Canada plans to join the Global HIV/AIDS Vaccine Enterprise, which was spearheaded by the Gates Foundation.

“They’re trying to form an alliance of all the different research organizations and corporate sector organizations around the world to have one single strategic plan where each one does a small part of the strategic plan,” Sékaly explains of the Global Enterprise. “We need to share our expertise, our data in a much more open and transparent fashion. And that’s, I think, what’s going to really help promote the agenda to the next level.”

Immunity at Large

As evidenced by the recent funding announcement from the Grand Challenges in Global Health initiative, launched by the Gates Foundation in 2003, Canada is already strongly contributing to the worldwide research arena. Of the more than 1,500 submitted project ideas from researchers around the globe, 43 were chosen for funding, including that of Dr. Frank Plummer, scientific director of the National Microbiology Laboratory (Winnipeg, MB) of the Public Health Agency of Canada (Ottawa, ON), and professor at the University of Manitoba (Winnipeg, MB).

Since 1985, Plummer has been working with a group of female sex trade workers in Nairobi, Kenya who appear to have a natural resistance to HIV. Among the population of 2,000 women — 90 to 95 per cent of whom are infected with HIV — 120 have been classified as being resistant to the virus.

“Despite many, many years of exposure to HIV, (the women) remain, as far as we can tell, uninfected,” Plummer says. “After many years of study, we’re increasingly convinced that they have some kind of immunity to HIV.”

It appears there is a genetic component to the observed immunity, he says.

“If we look at the family members of resistant women and compare them to the family members of HIV-infected women, we find much less HIV in the family members of resistant women,” Plummer explains. “Certainly, genes of the HLA system seem to be involved, but that’s once again not the total explanation. There are probably other genes, possibly immunoregulatory genes that are involved.”

Plummer’s team has assessed the immune response of the resistant group, looking at CTL responses in both peripheral blood and in vaginal and cervical secretions. They have found HIV-specific mucosal antibody in the genital tract that neutralizes HIV, whereas, detectable antibody is absent from the women’s blood.

“So we’re hypothesizing that those two factors are part of the solution, or part of the reason they’re protected,” Plummer says. To examine these factors, his group is mapping both antibody and CTL epitopes. Those epitopes will be put into vectors to deliver them mucosally.

Working in collaboration with CANVAC on the mucosal immunity project, Plummer says the ultimate goal is to test a mucosal vaccine to HIV, hopefully one that will induce both antibody and CTL responses.

While Plummer says he is excited that they’ll eventually be able to create an effective preventive HIV vaccine, the results are still far off.

“(The) time frame is years, and ultimately, even if we knew that magic answer right now, it still would be five years before there is a vaccine approved,” he says. “So I think 10 years is kind of the minimum. It’s unfortunate, a lot of people will get infected and die of HIV in that time.”

In edging toward the goal of producing a preventive vaccine, Plummer says three needs have to be balanced.

“Five million people a year get infected with this virus . . . and there are 40 million people in the world infected, and we do need better access to treatment for those people and also better treatments,” Plummer says. “Microbicides — topically acting substances that would kill HIV at the genital tract and allow women to protect themselves — is another important goal, and we need to go forward on all these fronts.”

Singh points out that prevention is key to slowing down the disease, but it may not eliminate HIV. A certain percentage of people develop drug resistance, he adds.

“So what is the future for these people — how will they be treated if we don’t have new drugs?” Singh says.

“Despite all the failures, I think the only way to move forward is through research in new candidate vaccines,” he says.

“It’s been a frustrating 20 years of work, and still very much (is) unknown (about) how long it will take to get a vaccine. In the meantime, people are living out longer thanks to the research effort. So the research has paid off in many ways to prolong life and reduce suffering,” Singh says. “But we don’t have a cure.”

NEW DEVELOPMENT

The arduous struggle against HIV/AIDS may have just intensified.

In July, the Canadian Network for Vaccines and Immunotherapeutics (CANVAC) — one of the federally funded Networks of Centres of Excellence (NCE) — learned that its proposal for NCE funding renewal was declined.

CANVAC would have obtained $34 million, says its scientific director and program leader, Rafick-Pierre Sékaly, PhD.

Because of the funding cut, clinical trials for seven vaccine candidates that were set to begin next year will be delayed, Sékaly says, including trials of three new therapeutic HIV vaccines.

Although each NCE receives confidential documentation on the funding decision, Sékaly says it is still difficult to understand the rationale for the result that has left CANVAC and its supporters “dismayed.”

“It’s the first time in my life that I contest a peer-reviewed decision,” he says. “But this one really doesn’t make sense.”

Jean-Claude Gavrel, director of the NCE program, says funding proposals are subjected to a rigorous two-stage peer review process. A selection committee reviews the reports from a first review round, as well as material prepared by the networks. “Then they determine, based on the criteria of the program and the threshold of excellence that is expected, which ones they can recommend for funding,” he says.

Regarding CANVAC’s proposal, “The expert panel recommendation is very clear, the other one is extremely general . . . sometimes it’s in direct contradiction with the expert panel committee and at the end, it says that they don’t think we can do the job,” Sékaly says.

CANVAC will survive, he says, because it has very high credibility and its partners still believe in the organization. But its work will be much more difficult.

The network will now have to secure funds from outside of Canada to support its clinical trials, he says.

“I think it’s got to change because it just doesn’t make sense,” Sékaly says. “It’s a lot of dollars and credibility that Canada is going to waste, both nationally and internationally.”