Questions linger, but so does determination, at the AIDS Vaccine 2008 conference
A new research center, dedicated to developing AIDS vaccine candidates that can elicit broadly neutralizing antibodies against HIV, was established recently by The Scripps Research Institute and IAVI. The new HIV Neutralizing Antibody Center will be housed at Scripps in California, and was established with an investment of US$30 million from IAVI, extending the existing collaboration between the two institutions. The center will bring together researchers from diverse fields to work on solving what is arguably the single biggest biological obstacle blocking the discovery of a preventive AIDS vaccine—identifying how to induce neutralizing antibodies against HIV through vaccination. These Y-shaped molecules latch on to HIV and deactivate it, thereby preventing the virus from infecting critical cells of the immune system (see VAX July 2008 Special Issue, Understanding the Immune System and AIDS Vaccine Strategies).
None of the AIDS vaccine candidates or approaches tested so far in clinical trials has induced neutralizing antibodies against HIV, yet they are thought to play a critical role in many, if not all, of the currently licensed vaccines against other viruses and bacteria, and are believed to be critical to the development of an AIDS vaccine that could effectively block transmission of the virus. “We are excited and hopeful that this collaboration will help to bring us closer to developing a vaccine that will end the AIDS pandemic,” says Seth Berkley, president and chief executive officer of IAVI.
Researchers at the new HIV Neutralizing Antibody Center will work to identify neutralizing antibodies from HIV-infected individuals and then will try to identify which immunogens—non-infectious pieces of the virus—could induce these antibodies. Scientists affiliated with the Neutralizing Antibody Consortium (NAC), an international consortium of researchers established by IAVI in 2002, will collaborate with researchers at the HIV Neutralizing Antibody Center, as well as with scientists in IAVI’s own research and development program.
Dennis Burton, an immunology professor at The Scripps Research Institute and the scientific director of the HIV Neutralizing Antibody Center, says researchers will be venturing into “uncharted waters” that hopefully will yield a greater level of understanding about the mechanisms that enable vaccines to shield people from infection.
“Having the HIV Neutralizing Antibody Center will be a terrific help to the field,” says Barton Haynes, director of the Duke Human Vaccine Institute and the Center for HIV/AIDS Vaccine Immunology at Duke University. “We shouldn’t give up on this problem and the funding of this center is a signal of renewed commitment.” —Regina McEnery
Barré-Sinoussi and Montagnier discovered the retrovirus now known as HIV in 1983, just two years after the first reports of cases described what is now known as AIDS. This critical finding paved the way for the development of methods to test for and diagnose HIV infection and eventually led to the development of antiretroviral drugs to treat HIV. —Andreas von Bubnoff
What are the limitations of the animal models used by researchers to evaluate AIDS vaccine candidates?
In the hunt for treatments and prevention tools against pathogens such as HIV, scientists often turn to animal models for insights into how the virus establishes infection and causes disease. Through the study of infection with simian immunodeficiency virus (SIV)—a monkey virus that is similar but not identical to HIV, which infects many species of nonhuman primates—researchers have uncovered several clues about how the virus is transmitted, the events following infection, and the hallmarks of disease progression or pathogenesis. There is also much to be learned from the study of SIV infection in species of nonhuman primates that can successfully control SIV infection and not develop the monkey equivalent of AIDS (see VAX September 2008 Primer on Understanding Control of Virus Replication).
Animal models are also one of the best ways to evaluate the safety and efficacy of new medicines or vaccine candidates, serving as a bridge between laboratory evaluation and clinical trials, which involve human volunteers. But finding an animal model for HIV has proven difficult. The virus exclusively infects and causes disease in humans, making it more difficult for scientists to evaluate potential AIDS vaccine candidates.
SIV vs. SHIV
However, there are many similarities between HIV and SIV and most researchers agree that studying SIV infection in nonhuman primates, particularly rhesus macaques, is so far the best model of HIV infection in humans. In rhesus macaques, SIV infection tends to follow a similar disease course as HIV. SIV-infected rhesus macaques have very high levels of virus circulating in their blood and also develop a marked decline in the number of CD4+ T cells, critical immune cells that are the primary target of both SIV and HIV. But in order to evaluate AIDS vaccine candidates in macaques, researchers must reconstruct the candidates to include non-infectious fragments of SIV, rather than HIV.
Due to this limitation, researchers have also constructed viruses that more closely mimic HIV. These hybrid viruses, known as SHIV, are a combination of SIV and HIV. SHIV was originally thought to be a better virus for evaluating the efficacy of AIDS vaccine candidates in nonhuman primates because it contained parts of HIV, but this has not been the case so far.
For instance, Merck’s Adenovirus serotype 5 (Ad5)-based vaccine candidate, known as MRKAd5, did show some degree of efficacy against SHIV in nonhuman primate studies. However similar results were not seen when this vaccine candidate was tested in the STEP trial, a Phase IIb test-of-concept study involving 3,000 volunteers. The Ad5 candidate had no effect on virus levels in vaccinated volunteers who subsequently became HIV infected through natural exposure to HIV, indicating that the SHIV model in rhesus macaques was not predictive of the response in humans. Preclinical studies with MRKAd5 in monkeys showed that it was not effective against SIV, which suggests this may be a more accurate model for evaluating vaccine efficacy.
Results from the STEP trial have sparked a debate among researchers about the role of nonhuman primate studies in AIDS vaccine research and development, with some arguing that some level of efficacy in the SIV/macaque model should be shown before an AIDS vaccine candidate is evaluated in clinical trials.
In the meantime, researchers are also focusing on other animal models that may be useful in evaluating AIDS vaccine candidates. Mice are one of the most commonly used animal models in all of medical research, but their use in HIV research is severely limited by the fact that they also cannot be infected with HIV. However, this could change. Researchers are now developing a novel type of mice that can be infected with HIV.
This new animal model involves the use of mice that are genetically altered so that they do not have an immune system and can therefore accept transplants of human cells. The human cells then develop inside the mice, creating a miniature human immune system. These so-called humanized mice have been in development for decades and during this time researchers have made substantial improvements to their immune systems. The latest batch of humanized mice in development can be infected with HIV and develop immune responses to the virus that are quite similar to those seen in HIV-infected people.
These humanized mouse models are now being used to study HIV transmission and pathogenesis and to evaluate the efficacy of new antiretrovirals for the treatment of HIV infection. But the immune responses to HIV are very complex and researchers have to do some additional fine-tuning to the humanized mouse models before it can be used as a reliable screen for AIDS vaccine candidates prior to entering Phase I clinical trials.
However, even after further optimization, the humanized mouse model will still have several limitations. A chief challenge is the small size of a mouse compared to a human. A key component of the human immune system is the movement or trafficking of different immune cells throughout the body, and this will be dramatically different in a small mouse. Researchers also have to take smaller blood samples from mice, which limits their ability to analyze immune responses in these animals.
Some researchers are also exploring using human tissues that are grown and sustained in the laboratory, rather than in a living organism, as a way to evaluate immune responses induced by different vaccine candidates. This method is known as an in vitro immune system and it too could be used in the future to preclinically evaluate AIDS vaccine candidates. Until then, the nonhuman primate/SIV model will likely remain the most trusted animal model for evaluating AIDS vaccine candidates