Understanding Immune Correlates of Protection, Part II
How can animal models be used to identify the correlates of protection for an AIDS vaccine?
Using animal models to study HIV infection and the progressive development of AIDS is an important way for researchers to analyze how the virus behaves in humans (see VAX October 2006 Primer on Understanding AIDS Vaccine Pre-clinical Development). Despite its limitations, the non-human primate model is immensely useful to researchers. Studying the related simian immunodeficiency virus (SIV) in non-human primates, typically rhesus macaques, provides important information about HIV, even though these studies involve a different virus. Many discoveries about how SIV interacts with the immune system and causes disease, a principle known as pathogenesis, in macaques have later been shown to also be true for HIV in humans. For example, the finding that HIV preferentially kills CD4+ T cells, a critical subset of immune cells, at the mucosal surfaces of the intestine or gut early in the course of infection was first observed with SIV infection in rhesus macaques (see VAX April 2006 Primer on Understanding the Early Stages of HIV Infection).
Non-human primate studies are also an important tool for researchers who are studying the immune correlates of protection so that they can design improved AIDS vaccine candidates (see VAX November 2006 Primer onUnderstanding Immune Correlates of Protection). If they can successfully identify the specific types of immune responses (antibodies, CD4+ or CD8+ T-cell responses, other natural immune responses, or some combination of these) that protect rhesus macaques from SIV infection, it will most likely provide vital clues about the types of responses that would be protective against HIV infection in humans.
Working with non-human primates also allows researchers to conduct studies that would be impossible to do in humans. Due to safety concerns, researchers have not tested any AIDS vaccine candidates in humans that contain either a killed version of HIV or a live but weakened version of the virus. However, researchers are able to test live-attenuated SIV vaccine candidates in rhesus macaques and then try to infect or challenge them with SIV and see if they are protected. These challenge studies would never be conducted with human volunteers, but the results of these animal studies may be important in the identification of the correlates of protection.
When rhesus macaques are given a live-attenuated SIV vaccine and then challenged with exactly the same viral strain, the majority of animals are protected from SIV infection. So far this is the only model where researchers have been able to induce sterilizing immunity against the virus.
This indicates that there is an immune response, or a combination of responses, which are capable of protecting macaques. Now researchers have to identify the exact immune responses that are responsible for this protection. Work in this area is ongoing and researchers, many of whom are working as part of larger scientific consortia, are now studying this question. Researchers have already identified an antibody that is directed to the envelope protein on the surface of the specific SIV strain used in these experiments. This antibody is capable of neutralizing the virus and therefore is correlated with protection, but it is still unknown if this response is actually responsible for the protection.
Researchers are also studying other immune responses induced at specific sites, like the intestine, and the genetic makeup of the macaques to see if these factors are also contributing to protection. Defining the precise correlates of protection is an incredibly difficult and time-consuming task. Since many different laboratories are working in this area, it is also important that researchers use the same tests or assays to evaluate the immune responses so that their data can be compared.
Mechanism of protection
Even after researchers identify the antibodies or cellular immune responses that correlate with protection there are still many other questions. These responses are still just correlated or associated with protection and often researchers don't know specifically how these immune responses interact with HIV. Pinpointing the precise method by which these immune molecules and cells kill the virus and block HIV infection is also an important area of research. This mechanism of protection can be particularly instructive when researchers are considering how to induce these responses with vaccination.
There are several complications with determining the mechanism of action between these immune responses and the virus. In some cases the immune responses that researchers identify as the correlate of protection may only be masking another antibody or cellular immune response that is actually the one responsible for protection. It is also possible that another genetic factor not related to the immune system provides protection.
If researchers are able to define the correlates of protection in non-human primate models, developing an AIDS vaccine candidate that can provide sterilizing immunity in humans will still be a complex process. It may be difficult to stimulate similar immune responses without using a live-attenuated AIDS vaccine candidate, and it is unlikely that this approach will ever be tested in humans.
Most of the vaccine candidates that are currently in clinical trials trigger primarily cellular immune responses and specifying the correlates of protection with these types of vaccines will be even more difficult, in both animals and humans. Some researchers think it is possible that different vaccine candidates may even stimulate different CD4+ or CD8+ T cell responses, and therefore have different correlates of protection.
Despite these challenges, working with non-human primates is still the best model available to AIDS vaccine researchers and it is likely to provide them with critical clues that will help improve the design of novel candidates.