Understanding Antibody Functions: Beyond Neutralization
What other antibody functions are being explored to explain the RV144 results?
All viruses, including HIV, must infect cells to survive. Once a virus infects a cell, it uses the cell to reproduce more virus, which is then released and goes on to infect other cells, setting off a vicious cycle of cell infection and destruction.
Most, if not all, vaccines that exist today are thought to work because they train the immune system to produce Y-shaped proteins known as antibodies. Following vaccination, some of the cells that produce these antibodies are stored away in the body. When a vaccinated individual is exposed to that same virus in the future, these cells are activated and begin rapidly producing antibodies. One job of these antibodies is to latch onto viruses and block them from ever infecting cells. This process is referred to as neutralization (see VAX February 2007 Primer onUnderstanding Neutralizing Antibodies). By neutralizing the invading virus, antibodies are able to stop an infection from occurring. Although vaccines likely induce other types of immune responses in addition to antibodies that may also play a role in protection, in most cases antibodies are required for the vaccine to be effective.
Researchers are working on developing HIV vaccine candidates that are capable of inducing neutralizing antibodies that can inactivate a large proportion of the HIV variants that are in circulation. None of the AIDS vaccine candidates that have been tested so far have been successful at inducing such a so-called broadly neutralizing antibody response against HIV. But recently, the results from a 16,000-person efficacy trial in Thailand, known as RV144, showed that two vaccine candidates administered sequentially in what is called a prime-boost regimen reduced the risk of HIV infection by about 30% as compared to an inactive placebo. This was the first evidence of efficacy for any AIDS vaccine candidate (see VAX October 2009 Spotlight article, Vaccine Research Gains Momentum).
The explanation for this protection is still unclear, but many researchers speculate that it is likely due to antibodies. However, in previous trials this combination of vaccine candidates did not generate a potent or broad neutralizing antibody response, so researchers think this is an unlikely explanation. As researchers try to understand just what immune responses may be responsible for the modest protective effect seen in RV144, they are focusing on antibody functions other than neutralization.
One of the mechanisms being investigated is known as antibody-dependent cellular cytotoxicity (ADCC). In addition to binding directly to the virus, antibodies can also bind to cells that have already been infected with HIV. The general principle of ADCC is that antibodies that bind to cells infected with HIV can facilitate the killing of these cells by other immune cells. Some researchers speculate that processes like ADCC could explain how the vaccine candidates tested in RV144 were able to protect some volunteers from HIV infection even in the absence of broadly neutralizing antibodies.
To see if ADCC is responsible for the RV144 results, researchers are planning to measure antibody responses that are involved in ADCC in samples from some RV144 participants (see VAX November 2009 Primer on Understanding the Hunt for Immune Correlates of Protection from RV144).
For ADCC to occur, an antibody acts as the bridge between an HIV-infected cell and other immune cells that can destroy it. The mechanism of ADCC requires that the tips of a Y-shaped antibody bind to an HIV-infected cell. The other end of the antibody must then bind to proteins on the surface of other immune cells, which can then kill the HIV-infected cells and stop it from pumping out more HIV.
Although it is possible that ADCC contributes to the protection afforded by some vaccines that are used today, this mechanism has not been shown to be the sole mechanism of protection for any vaccine so far. In cancer research, ADCC has been shown to play an important role in the activity of therapeutic antibodies given to treat cancer.
There is also some evidence to suggest that ADCC may play a role in the control of HIV in infected individuals. Researchers have found that the levels of ADCC activity are higher in so-called elite controllers—individuals who are infected with HIV but are able to control the virus without the use of antiretroviral therapy. Scientists are now studying the antibodies in elite controllers to see how they might differ from those in other HIV-infected people who cannot control HIV. Eventually, such studies might result in the identification of specific markers on antibodies that could help researchers identify the types of antibodies that would facilitate ADCC. This information could then be used to develop vaccine candidates capable of inducing such antibodies.
In the case of RV144, researchers think that the antibodies generated by the vaccine candidates may have facilitated ADCC without being able to directly neutralize the virus. This, however, does not mean that neutralizing antibodies cannot also facilitate ADCC. Research conducted in non-human primates suggests that blocking the ADCC function of broadly neutralizing antibodies reduces their protective effect. This suggests that a vaccine candidate that could induce broadly neutralizing antibodies may be able to attack the virus through both mechanisms.