At the 14th annual Conference on Retroviruses and Opportunistic Infections, Brigitte Autran of the Hospital Pitié-Salpétrière in Paris presented results showing that therapeutic vaccination with the recombinant canarypox vaccine candidate vCP1452, developed by Sanofi Pasteur, offered no benefit to individuals interrupting their current antiretroviral (ARV) treatment (CROI). Volunteers in this trial received either three or four injections (three primes and one boost) of the vaccine candidate or placebo and were given the option to suspend ARV therapy after receiving the first dose of vaccine. Researchers then monitored these individuals closely and placed them back on therapy if their CD4+ T cells declined below 250 cells per ml of blood-a sign that the immune system is starting to fail.
In previous studies the vaccine candidate showed significant immunogenicity in HIV-infected volunteers and provided modest benefit, according to Autran. But at CROI she reported that in this latest study all volunteers who received the vaccine candidate actually had to resume HAART sooner than those who received placebo. Half of the 20 volunteers who received three immunizations and 14 of 19 who received four injections of vCP1452 had to resume therapy. Meanwhile, only 3 of the 15 volunteers who received placebo had a decline in CD4+ T-cell count that warranted resuming ARV treatment.
Autran called these results "very disappointing" but said that she didn't think this trial should stop further study of this therapeutic vaccination approach. This Sanofi-Pasteur vaccine candidate, vCP1452, is also currently being tested in a preventive AIDS vaccine clinical trial alone or in combination with another vaccine, known as LIPO-5, at HIV Vaccine Trials Network (HVTN) sites in the US. For more information about this or other preventive AIDS vaccine trials, visit the IAVI Report clinical trials database.
The Canadian government, with additional funding from the Bill & Melinda Gates Foundation, is establishing a research institute dedicated to the development of an effective AIDS vaccine. In February Prime Minister Stephen Harper announced his government's pledge of just over US$95 million to fund the new program, which is called the Canadian HIV Vaccine Initiative, and the Gates Foundation also announced it is committing up to $24 million to the project. The Foundation's contribution is another component of the Global HIV Vaccine Enterprise, which was established in 2003 as a way to further accelerate AIDS vaccine research and development.
The primary goals of the Canadian HIV Vaccine Initiative are to support Canadian scientists who are working on the scientific challenges to developing promising AIDS vaccine candidates, construct a new facility capable of manufacturing vaccine candidates for testing in clinical trials, and foster collaboration between researchers, both in Canada and internationally. Canada was one of the first countries to create a national AIDS vaccine plan and the government recently awarded IAVI CAD$20 million to continue its work on the development of a safe and effective AIDS vaccine.
All articles written by Kristen Jill Kresge
What evidence exists for immune control of HIV/SIV?
Developing a safe and effective AIDS vaccine is both an urgent public health issue and a huge scientific challenge. The genetic variation of HIV, which is due to the virus's very rapid mutation rate, far exceeds that of many other viruses. To illustrate, the global variation of influenza virus each year is less than the variation of HIV in a single infected individual. This genetic variation means that HIV can escape the immune responses mounted against it by the human immune system during the course of natural infection.
Many successful vaccines have used a killed or weakened version of the virus to induce strong pathogen-specific immune responses. But these classical approaches are not being considered for HIV because of safety concerns. Researchers worry that a killed or weakened virus could mutate once inside the body and regain its ability to cause disease (pathogenicity). Despite these obstacles, many researchers still think it is possible to develop a vaccine that will protect against HIV/AIDS.
There is evidence from several different categories of individuals, including exposed seronegatives and long-term nonprogressors, which suggests the human immune system is capable of controlling or even preventing HIV infection, as well as evidence from non-human primate studies to support the notion that vaccine-induced protection is possible. Analyzing the immune responses to HIV or SIV in certain individuals and non-human primates will provide valuable information to researchers who are designing AIDS vaccine candidates.
One group of individuals that seems to be protected from HIV infection is known as exposed (or highly-exposed) seronegatives (ESNs). These individuals remain free of HIV infection despite frequent exposure to the virus through sexual contact with HIV-infected partner(s). The most well-studied cohort of ESNs is a group of commercial sex workers in Nairobi, Kenya, but several other cohorts are also currently being followed by researchers, including serodiscordant couples where one partner is HIV infected and the other remains uninfected. Researchers are analyzing the immune responses—both cellular and antibody—to HIV in these individuals, as well as any genetic characteristics that they have in common, to try to find out what enables their immune systems to fend off HIV infection. Information collected from ESNs may provide important clues for the design of a preventive AIDS vaccine.
HIV begins replicating very rapidly immediately after an individual is infected and the viral load—the amount of virus in the blood—skyrockets. But after the first few weeks and months of infection, the immune system responds to the virus through the adaptive immune system (see VAX February and March 2004 Primers on Understanding the Immune System, Parts I and II) and makes both cellular and antibody responses specific to HIV. In almost all individuals the immune system is able to effectively control HIV replication. This control lasts, on average, 10 years. During this time there are often no symptoms associated with infection, which is why many people may not know they are actually infected. Eventually HIV overtakes the immune system and an infected person should begin antiretroviral (ARV) therapy. This temporary, but prolonged, control of HIV infection shows that the immune system can mount an effective response against the virus, although it is insufficient to prevent infection or eventual disease progression.
There are also some individuals, known as long-term nonprogressors (LNTPs), who are able to control viral replication for much longer than 10 years without ever taking ARVs (see VAX September 2006 Primer onUnderstanding Long-term Nonprogressors). There are several different categories of LTNPs and probably many different explanations for why these individuals can effectively control HIV. Studying these individuals can provide information about the type of immune responses or the genetic characteristics that are capable of keeping HIV infection in check.
Studies of simian immunodeficiency virus (SIV) infection in non-human primates (see VAX October 2006 Primer onUnderstanding AIDS Vaccine Preclinical Development) show that a live but weakened, or live-attenuated, version of SIV can protect against subsequent SIV infection. So far this is the only type of vaccine candidate in human or non-human primate studies that provides complete protection against infection. Again, such studies suggest that protection against HIV is possible and researchers are now trying to learn precisely what immune responses are responsible for protection in non-human primates (see VAX December 2006 Primer on Understanding Immune Correlates of Protection, Part II).
Broadly neutralizing antibodies
Currently none of the vaccine candidates being developed or tested are capable of inducing broadly neutralizing antibodies against HIV (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). However several antibodies that occur in natural infection have been isolated from HIV-infected individuals that, in laboratory experiments, can neutralize many strains of HIV. Also, giving high doses of neutralizing antibodies to non-human primates can protect them from subsequent SIV infection. These studies suggest that the immune system is able to make neutralizing antibodies against HIV and that these antibodies are able to prevent infection. Now researchers need to design the right immunogen, or piece of HIV protein that can be used in a vaccine to cause such an immune response. Unfortunately, designing such an immunogen has proven extremely difficult.
Long road ahead
Information collected from studying ESNs, LTNPs, and the protection of non-human primates from SIV infection will help in the design of better AIDS vaccine candidates. There are still many scientific obstacles to the development of an effective AIDS vaccine but progress in understanding how certain individuals and animals control the virus will help researchers overcome these challenges.