Understanding if Broadly Neutralizing Antibodies are the Answer

Researchers are pursuing multiple paths to determine if antibodies can block HIV infection

Antibodies are Y-shaped proteins that work primarily by latching onto viruses and preventing them from infecting target cells. Antibodies are induced by most, if not all, existing vaccines and are thought to play a crucial role in the protection these vaccines afford.

While it is still unclear precisely what types of immune responses will need to be triggered by a vaccine to protect against HIV infection, many scientists believe that an AIDS vaccine will need to induce antibodies (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). And because HIV is an incredibly diverse virus, with multiple clades or serotypes in circulation around the world, researchers are focusing on developing vaccine candidates that can induce antibodies that are capable of blocking or neutralizing many circulating HIV strains, so-called broadly neutralizing antibodies (bNAbs).

Such bNAbs against HIV exist. The immune systems of individuals who are naturally infected with HIV generate antibodies against the virus, some of which are broadly neutralizing. By screening blood samples from HIV-infected individuals, researchers have been able to isolate several bNAbs. Just recently, eight new bNAbs were discovered, some of which are more potent than those previously identified (see VAX March 2010 Primer on Understanding Advances in the Search for Antibodies Against HIV).

Researchers are now studying these bNAbs and using them to design vaccine candidates that would ideally be able to induce these antibodies in people before they are exposed to HIV, thereby protecting them against infection. However, this is a difficult task and it may take some time before vaccine candidates based on these bNAbs are ready for clinical testing. Until then, researchers are also conducting other studies in animals and humans to try to determine whether these bNAbs will be capable of blocking HIV infection.

Protection in animals

There is evidence from studies in animals to suggest that if scientists could learn how to induce bNAbs against HIV through a vaccine, they might be able to block infection. To evaluate this, researchers conduct what are referred to as passive immunization studies. In these studies, researchers inject bNAbs directly into animals and then purposely expose them to either HIV, or a hybrid virus known as SHIV that is a combination of HIV and simian immunodeficiency virus, the monkey form of HIV.

In studies with one of the bNAbs known as b12, scientists found that this antibody was able to block HIV infection in mice that were genetically altered to have human immune cells. In some studies, non-human primates passively immunized with b12 were completely protected against infection when they were purposely exposed to SHIV. While in other studies, infection of b12-immunized monkeys was delayed compared to those that were not immunized with b12.

Researchers are now planning to do similar studies in non-human primates with some of the newly discovered, more potent bNAbs to see how well they can protect against infection in animal models.

Evidence for protection in humans

Although these passive immunization studies in mice and non-human primates provide some evidence that bNAbs can block HIV infection from occurring, there is little evidence that this is also true in humans.

For many years, researchers have been studying individuals who although repeatedly exposed to HIV, seem to be able to ward off infection. Although it has been suggested that antibodies may be what protects these individuals from infection, in these cases, it is difficult to draw firm conclusions.

Another way researchers are attempting to learn if bNAbs can protect against HIV is by studying the passive transfer of maternal antibodies. Pregnant women pass antibodies to their fetuses through the placenta. If the mother is HIV infected, she may also pass HIV-specific antibodies to her fetus.

In a study of 100 infants born to HIV-infected mothers, researchers found that although the mothers had indeed transferred HIV-specific neutralizing antibodies to the infants, there was no evidence that these antibodies actually protected the infants against HIV infection during the breast-feeding period. While this suggests that these antibodies were not effective at blocking HIV, it does not mean that some of the newer, more potent bNAbs would not be effective.

To determine this, researchers are considering conducting a clinical trial of passive immunization in HIV-uninfected people. This type of study would show whether directly administering one or more of the more potent, recently discovered bNAbs into HIV-uninfected individuals through injection would protect them against HIV if they were naturally exposed to the virus.

Scientists are also hoping to conduct a clinical trial soon to evaluate another antibody strategy, known as gene transfer, to see if it can protect against HIV infection (see VAX November 2008 Primer on Understanding Approaches to Inducing Neutralizing Antibodies). Rather than directly injecting bNAbs, the gene transfer approach involves introducing the genes that could make the bNAbs into HIV-uninfected people.