BOSTON – There is a long history of the use of antibodies for prevention and treatment of many different infectious diseases, and now it’s HIV’s turn, a vaccine investigator said.
Data from animal models and early human trials suggest that recently isolated, broadly neutralizing monoclonal antibodies (mAbs) against HIV-1 may be effective for prevention of infection and for viral suppression in infected individuals, according to Dr. John R. Mascola from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
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“Antibodies are biologically active; even a single antibody can reduce plasma virus by 1-2 logs with a single infusion. However, selection for resistant strains can occur and does occur rapidly in the setting of incomplete viral suppression. So this strongly suggests the combination of antibodies, or antibodies plus antiretroviral drugs are likely to be required for viral suppression,” he said in a plenary talk at the Conference on Retroviruses and Opportunistic Infections.
The effect of antibodies on reduction or elimination of viral reservoirs, however, is still unclear, and will require additional research, he said.
There is a long history of passive immunization with antibodies, he said, beginning with “serum therapy” for diphtheria, tetanus, and streptococcal infections, and progressing to the use of immune globulins for the prevention of common viral diseases such as measles, poliomyelitis, cytomegalovirus, hepatitis A, and respiratory syncytial virus (in high-risk infants) and for postexposure prophylaxis of hepatitis B, rabies, and varicella-zoster virus, he said.
“In the infectious disease world, the concept of using antibodies for HIV has been around for a long time, really, based on our knowledge of all these other viral diseases. But what has changed and really invigorated the field is the discovery of many potent neutralizing antibodies since 2009,” he said.
More than 20 antibodies directed against several different viral binding sites have been described in the last 6 years alone.
Two important considerations for successful prevention of binding of HIV and entry into cells is the breadth (percentage of all HIV strains that are neutralized) and potency of mAbs, Dr. Mascola said.
More recently discovered mAbs are up to 500-fold more potent than older anti-HIV antibodies, the first of which were described in the early 1990s, but the perfect antibody with the right combination of breadth and potency has not been identified to date, he said.
Prevention
Preclinical studies conducted over the last 2 decades using ape and monkey models and simian HIV (SHIV) has shown that neutralizing antibodies can prevent infection, and that more recently discovered mAbs are especially effective when given before a viral challenge. However, there are few if any data on protection against viral challenge in humans, Dr. Mascola pointed out.
“What’s encouraging is that within the next couple of years, rather than where we are now where I can tell you about antibodies to only one site, there are very likely to be antibodies to four major sites on the virus,” he added.
Several phase I trials of an antibody labeled VRC01, directed against the CD4 binding site, are currently in the recruiting or planning stages.
Questions that remain about antibodies for HIV transmission prevention in humans included what level of mAbs is required for protections, where and how mAbs work (for example, in the lumen, epithelial surface, mucosal tissue, or lymphoid tissue), and whether Fc-mediated effector functions are required for protection.
Treatment
Whereas antibodies for prevention are aimed at blocking transmission and acquisition of infection, antibodies for treatment of HIV have a different clinical use, as complements to antiretroviral therapy, with a different mechanism of action. Therapeutic antibodies have the potential to eliminate infected cells, and could help to deplete cell-associated viral reservoirs, Dr. Mascola said.
During acute infection, they could be used in tandem with antiretroviral therapy for quick reduction of viremia and to limit seeding of a viral reservoir. Some long-lasting antibodies could help with maintenance of viral suppression.
As noted before, antibodies directed against HIV-1 are biologically active and can markedly reduce plasma viremia, but are subject to rapid development of resistance in the setting of incomplete viral suppression. Thus, mAbs will likely be used in combination with other mAbs or antiretroviral drugs to achieve effective viral suppression, and antibodies with long half-lives will likely be needed to achieve depletion of viral reservoirs, Dr. Mascola said.
Dr. Mascola is an employee of the National Institutes of Health. He reported no other conflicts.