Understanding Immune Correlates of Protection, Part I

How can researchers identify the correlates of protection for an AIDS vaccine?

An effective, preventive vaccine works by training the immune system to recognize and then eliminate a specific pathogen (either a virus or a bacterium) that a person may be exposed to in the future. So for a vaccine to work it must induce pathogen-specific immune responses—either antibodies, cellular (CD4+ or CD8+ T cell) responses, or other natural immune responses—that are capable of blocking a pathogen. Typically a subset of the immune responses induced by vaccination is what is actually required for a person to be protected against an infection. Researchers refer to these specific immune responses as the immune correlates of protection since without these particular responses a person is still susceptible to infection.

Determining the precise correlates of protection for a certain pathogen is difficult. For some viruses a single type of antibody is enough to protect someone against future infection, but often it is a combination of immune responses. Identifying this exact combination of antibody and/or quality of cellular response that confers protection can be like finding a needle in a haystack.

This is especially true for HIV. Since the virus actually attacks the immune system itself, it is more complicated for researchers to tease out the HIV-specific immune responses in infected individuals. It is still unclear what immune responses are necessary to protect against infection with HIV, but researchers are using several different human and animal models to try to determine the correlates of protection and to use this information to design a preventive AIDS vaccine.

Problematic for HIV

For most infectious diseases the simplest way to identify the immune correlates of protection is to study someone who has recovered from a natural infection because their immune system was able to defeat the pathogen. Although this is an imperfect model—it is likely that the immune responses necessary to prevent infection will not be exactly the same as those present after a person has cleared an infection—it can still provide researchers with invaluable guidance on the types of immune responses that a vaccine should induce. This information could help them design a vaccine to mimic these responses. Unfortunately this is not possible for an AIDS vaccine because there is not a single documented case of a person who was able to clear an established HIV infection.

Another way to identify the immune correlates of protection is to already have an effective vaccine. Historically when researchers set out to develop vaccines against pathogens, they haven't known exactly what types of immune responses would be protective and so have experimented by trial and error, sometimes called the empirical approach. Researchers typically constructed vaccines using either a killed version of the specific virus or bacteria or a live, but attenuated, version that would cause at most a mild infection in humans. Often this approach induced robust immune responses specific to the pathogen that could protect against infection for many years after immunization. Researchers could then closely study these immune responses to identify exactly which ones were necessary for protection. However using a live-attenuated or whole-killed vaccine for HIV is not possible because of safety concerns. Researchers fear that the virus could mutate and become virulent.

Sometimes the correlates of protection are difficult to identify even with an effective vaccine. Two recently developed vaccines for rotavirus and human papillomavirus are highly effective but the precise immune responses that confer protection are still unknown (see VAX July and February 2006 Spotlight articles, Vaccines enter battle against intestinal virus and Cervical cancer vaccines). But in the absence of an effective AIDS vaccine, researchers often talk about the correlates of protection as an important way to guide them in the design of improved candidates.

Models to study correlates of protection

Researchers have identified individuals who remain uninfected by HIV despite repeat exposure to the virus. These individuals, known as exposed seronegatives (ESNs), may hold important clues. For several years researchers have been studying groups of sex workers in Kenya and the Gambia who are considered ESNs to try to identify just what makes them able to fend off HIV infection. There are several possible reasons for their apparent resistance to HIV infection, including the properties of the virus they are exposed to, their own genetic makeup, or that they are generating immune responses that are able to keep HIV at bay. If researchers can identify the HIV-specific immune responses in these individuals they can then use this information to design AIDS vaccine candidates.

Another group of individuals that could provide important clues are long-term nonprogressors (see VAX September 2006 Primer on Understanding Long-term Nonprogressors). These are HIV-infected individuals who are successfully controlling their infection without antiretrovirals, and the types of immune responses that they generate may also be informative to researchers developing preventive vaccines.

Also, if a vaccine candidate shows any efficacy in a Phase III trial it will likely give researchers an idea about the immune responses necessary for protection against HIV infection and could help them develop improved candidates that will be even more effective. Designing a Phase III vaccine trial to try to determine both the vaccine's efficacy and the correlates of immunity, however, may require an even larger number of volunteers as well as more sophisticated laboratory tests. This will make these already expensive and time-consuming trials even more complex.

AIDS vaccine researchers are also using animal models to try to identify the correlates of protection (see next month's VAX Primer). Researchers are hopeful that studying the correlates of protection in non-human primates, as well as in humans, will provide even more information that can aid the development of an effective vaccine.