The first large-scale human studies for the development of an anti-HIV vaccine using monoclonal antibodies have just begun enrollment. These are passive immunizations using a laboratory-generated antibody that proved to be highly effective in animal models. The studies are expected to run for 22 months. The studies' details were presented at AIDS 2016 by Nyaradzo Mgodi, M.B.Ch.B, M.Med., of the University of Zimbabwe.
During active immunization an antigen is injected in order to stimulate a person's own immune system to produce antibodies against a particular pathogen. By contrast, in passive immunization the antibodies themselves are injected. This form of protection from viral infections has been used for more than a century, Mgodi said.
Research in non-human primates (specifically, macaques) has shown that the monkey version of HIV, Simian Immunodeficiency Virus (SIV) and a monkey-human hybrid virus, Simian-Human Immunodeficiency Virus (SHIV), can be prevented by injecting HIV antibodies. However, to date there are no data about such prevention in humans. Two trials in the Americas and Africa, respectively, are designed to obtain such data. They are called HVTN 703 and HVTN 704, collectively dubbed AMP (antibody-mediated protocols).
Volunteers in both studies will receive infusions of a monoclonal broadly neutralizing antibody, VRC01, to determine whether this prevention strategy also works in people and what level of antibodies in the blood will be needed to protect from acquiring HIV. VRC01 was shown to be highly effective in animal studies and in the lab, disabling a variety of HIV strains across all major subtypes of the virus, including during both acute and chronic infection. It was proven safe and well tolerated in three small Phase I trials among 140 participants.
The HVTN 703 trial (also called HPTN 081) began to enroll the heterosexual women in sub-Saharan Africa in May of this year. It will eventually include 1,500 women who are 18-40 years old, not infected with HIV at the study start and generally healthy. Study sites are located in Malawi, Kenya, Botswana, South Africa, Mozambique, Tanzania and Zimbabwe.
HTVN 704 (also called HPTN 085) began enrollment of ultimately 2,700 men who have sex with men and transgender people who have sex with men or with other transgender people in three countries in the Americas in April 2016. Participating countries are the United States, Brazil and Peru. Men or transgender persons must be between the ages of 18 and 50, uninfected with HIV at the study start and otherwise healthy in order to be included in this clinical trial.
Both studies exclude volunteers who have been in a mutually monogamous relationship with an HIV-negative partner for more than a year. Everyone is counseled on standard HIV prevention methods, such as condom use. Study participants are randomized to one of three arms: infusions of 10 mg VRC01/kg of body weight, infusions of 30 mg VRC01/kg or infusion of a placebo saline solution. Trial designers opted for two different cohorts because researchers suspect that the route of HIV acquisition (anal versus vaginal intercourse), as well as the specifics of the genital tract may play a role in the efficacy of VRC01, Mgodi explained.
Study participants will attend a clinic every four weeks for a blood draw and HIV testing and to provide data for behavioral surveys. Every other visit (i.e., every eight weeks) they will receive an infusion of either VRC01 in one of the two strengths or saline solution only. The first infusion will be at the initial visit and the last one after 72 weeks, for a total of 10 infusions. Follow-up will continue through week 80 to establish HIV infection rates while receiving the vaccine.
The main goals of these clinical trials are to establish that the vaccine is safe and well tolerated among a much larger group of people, to establish that it is at least 50% effective in preventing HIV infection and to determine the plasma levels of antibodies that are necessary to confer that protection. The protocols will be monitored for harmful effects, very low/very high or no efficacy at all, and the overall safety of the antibody injections.
If the studies are successful, next steps could include development of a single dose of monoclonal antibodies to achieve the necessary plasma levels, work on the next generation of antibodies, which are more potent and have a longer half-life (their effects last longer) and development of genetic immunizations to provide even longer-term protection from HIV.
Should this antibody prove to be effective, monoclonal broadly neutralizing antibodies could also be used to prevent HIV infection of newborns around the time of birth and during breastfeeding, and to provide additional protection during the last stage of long-acting injectable pre-exposure prophylaxis agents and during a ramp-up period for a yet-to-be-developed HIV vaccine regimen, Mgodi believes. Development of a "cocktail" of multiple antibodies may also be possible in order to protect people from mutations in the virus designed to circumvent one of the antibodies in the mixture, similar to how combination antiretroviral therapy works.