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Understanding Approaches to Inducing Neutralizing Antibodies

What are some of the novel approaches researchers are exploring to induce broadly neutralizing antibodies against HIV?

When viruses and bacteria invade the body, the human immune system fights back in two ways (see VAX July 2008Special IssueUnderstanding the Immune System and AIDS Vaccine Strategies). Initially, the innate immune responses are activated. These responses are always on standby and can act quickly against any pathogen to either eradicate or help limit an infection. The adaptive immune responses, which include both antibody and cellular immune responses, are the second line of defense.

Antibodies are Y-shaped proteins that work primarily by latching onto viruses, like HIV, and preventing them from infecting their target cells (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Antibodies that can effectively neutralize many different forms of HIV are referred to as broadly neutralizing antibodies. Cellular immune responses act against cells once they have already been infected by HIV (see VAX April 2008 Primer onUnderstanding Cellular Immune Responses).

Unfortunately, while several AIDS vaccine candidates are able to induce cellular immune responses against HIV, none of the candidates tested so far have been successful at inducing neutralizing antibody responses. This is one of the major scientific obstacles to the development of a preventive AIDS vaccine (see Global News, this issue).

Identifying neutralizing antibodies

To find broadly neutralizing antibodies against HIV, researchers closely study the immune responses in HIV-infected individuals. Although most HIV-infected people do develop antibody responses against HIV, very few of them are actually capable of neutralizing or inactivating the virus. So far only about five broadly neutralizing antibodies against HIV have been identified. And even though these antibodies have been well studied and characterized, researchers still do not know how to induce them through vaccination. Solving this problem requires figuring out which non-infectious fragment of HIV, known as an immunogen, will stimulate the immune system in such a way that it produces one of these broadly neutralizing antibodies. But this has proven difficult. Designing immunogens that can induce neutralizing antibodies against HIV is a major area of focus in AIDS vaccine research.

A novel approach

Meanwhile, a subset of investigators are taking a different approach. Studies have shown that injecting large quantities of one of the already identified broadly neutralizing antibodies against HIV directly into nonhuman primates can protect them from infection with a virus that is a cross between HIV and simian immunodeficiency virus (SIV)—the monkey equivalent of HIV—known as SHIV. If the antibodies are present in a sufficient quantity when the animal is exposed to SHIV, they are capable of blocking an infection. Scientists have also observed that infusing antibodies into people infected with HIV temporarily suppresses their viral loads—the amount of HIV in the blood—when antiretroviral therapy is interrupted. This suggests that if broadly neutralizing antibodies were induced in humans at sufficient levels, they might be able to fend off an infection.

However, regularly administering enough of the broadly neutralizing antibody into humans to protect them against HIV would be impractical, both logistically and economically, over the long term. So rather than introducing the antibody itself, some researchers are instead trying to administer the gene that could direct the body to make the broadly neutralizing antibody. Within a cell, genes are responsible for overseeing the production of proteins, including antibodies. So by introducing the gene for a broadly neutralizing antibody into a cell, researchers are hopeful that the body’s own cells would do the work, producing a continuous supply of antibody.

Like other vaccine strategies that use non-infectious viruses to deliver fragments of HIV to the immune system, researchers are using a crippled virus as a vector to chauffeur the antibody genes into human cells (see VAX September 2004 Primer on Understanding Viral Vectors).

So far this strategy has provided encouraging preclinical results. In studies with nonhuman primates, vaccination resulted in production of neutralizing antibodies that researchers could detect a year later. Even more encouraging, the antibody did appear to be effective at blocking infection against SIV in some of the vaccinated monkeys. Researchers are now conducting additional preclinical studies to try to determine what quantity of antibody needs to be produced to provide protection and whether the antibodies will be present in mucosal tissues, which are the primary entry point for HIV during sexual transmission.

After researchers adequately address any possible safety concerns with this approach, the goal is to conduct a clinical trial to see if this type of strategy could stimulate production of broadly neutralizing antibodies against HIV in humans. If so, it could potentially open the door to new strategies in both preventive and therapeutic AIDS vaccine research.