In December researchers at the Karolinska Institute in Stockholm, Sweden and colleagues at the US Military HIV Research Program (USMHRP) and the Muhimbili University College of Health Sciences in Tanzania began a second vaccine trial to evaluate the safety and immunogenicity of administering immunizations of two vaccine candidates sequentially. This Phase I/II trial will enroll 60 volunteers in Dar es Salaam, Tanzania.
The first vaccine candidate is a DNA plasmid comprised of several HIV genes. This candidate is given as a prime immunization and then is followed by a booster immunization with a modified vaccinia Ankara (MVA) vaccine candidate also containing HIV genes. Neither candidate can cause HIV infection. The DNA vaccine candidate was developed at the Swedish Institute for Infectious Disease Control and is based on HIV strains circulating in Tanzania. The MVA candidate, known as MVA-CMDR, was developed by the US National Institute of Allergies and Infectious Diseases (NIAID) and is manufactured by the Walter Reed Army Institute of Research (WRAIR). The Karolinska Institute is also conducting another Phase I trial in Sweden evaluating the safety and immunogenicity of the MVA candidate alone in 38 volunteers.
Last year at the 2006 AIDS Vaccine Conference in Amsterdam, Eric Sandström of the Karolinska Institute presented preliminary results of another placebo-controlled, Phase I trial in Sweden where volunteers received the DNA and MVA candidates in a prime-boost manner. This combination induced promising immune responses in the volunteers without causing serious safety issues.
More recently the South African AIDS Initiative (SAAVI) and the HIV Vaccine Trials Network (HVTN), which is part of NIAID, initiated a second Phase IIb test-of-concept trial in collaboration with Merck to evaluate the company's adenovirus-based vaccine candidate (MRKAd5). The trial is being called Phambili, which means 'going forward' in Xhosa, and will recruit 3000 volunteers in four South African provinces, including trial sites in Soweto, Cape Town, Klerksdorp, Medunsa, and Durban.
Another test-of-concept trial, known as the Step study, with the MRKAd5 candidate is currently ongoing at HVTN sites in the US, Canada, Peru, Dominican Republic, Haiti, Puerto Rico, Australia, Brazil, and Jamaica. South Africa is currently hosting other AIDS vaccine trials as well as other HIV prevention trials; however, the Phambili trial is the country's largest AIDS vaccine trial to date. It also marks the first time Merck's leading vaccine candidate is being evaluated in a population where the predominately circulating strain of HIV is not genetically matched with the antigens in the vaccine candidate (see VAX July 2006 Primer on Understanding HIV Clades). The epidemic in South Africa is primarily clade C HIV and the candidate is based on clade B. For more information about these or other ongoing preventive AIDS vaccine trials, visit the IAVI Report clinical trials database and the January 2007 Special Issue of VAX.
All articles written by Kristen Jill Kresge
Why are HIV-specific neutralizing antibodies so difficult to induce with vaccination?
The human immune system uses many different types of defenses to combat pathogens such as viruses and bacteria, and these can be divided into two broad categories known as innate and adaptive immunity (see VAX February and March 2004 Primers on Understanding the Immune System, Part I and II). The innate immune responses are the first responders on the scene when the body encounters a new pathogen. They can either prevent an infection or limit it until additional help from the immune system can be rallied. Often this additional help is necessary and this is where adaptive immunity kicks in. Adaptive immune responses are customized to act upon a particular pathogen, such as HIV. These adaptive immune responses are further divided into two main branches—cellular and humoral immunity. Cellular immune responses are carried out by cells known as CD4+ T helper cells that orchestrate the activities of another group of cells known as cytotoxic T lymphocytes (CTLs) that can kill cells infected with a particular virus. Humoral immunity consists of cells called B cells that generate antibodies, which are Y-shaped protein molecules that can latch onto specific viruses and thereby block them from infecting cells.
Why are antibodies important?
Many types of human cells need to replicate or make copies of themselves. When a virus first enters the body it infects human cells and hijacks the machinery the cell normally uses to replicate and instead creates more copies of the virus. These viruses can then infect even more cells, setting off a vicious cycle of infection. With HIV, this has an especially disastrous effect because the primary cells infected by the virus are those of the human immune system and as they are infected and destroyed the immune system begins to break down.
Both cellular and humoral immune responses can stop this cycle by preventing HIV from infecting more cells, but they act at different stages. CTLs target cells that are already infected with the virus, while antibodies act on the virus before it enters the cell. A virus and a cell are like two puzzle pieces that fit together, but when an antibody attaches to the virus it comes between the two, blocking them from connecting. The HIV puzzle piece is the virus's envelope protein, also known as gp120. The cellular piece of the puzzle is the CD4 receptor protein on the surface of the CD4+ T helper cells, the primary target of HIV. The receptor protein is what HIV attaches to and uses to gain entry into the cell.
Since antibodies could stop a virus like HIV in its tracks, or neutralize it, they will be a particularly important component of a future AIDS vaccine candidate that could prevent people who are exposed to HIV from becoming infected. Many existing vaccines—including those against measles, hepatitis A and B, and polio—work because they induce virus-specific antibodies that are capable of protecting against infection.
Not all antibodies are created equal
To learn more about the types of antibodies that are produced in response to HIV, researchers have closely analyzed the immune responses in HIV-infected individuals at various times during the course of their infection. They have found that many types of HIV-specific antibodies are produced by the humoral immune system, but very few of them are capable of actually binding to the virus and neutralizing it. Those select few antibodies that can successfully stop the virus from infecting cells are known as neutralizing antibodies. Antibodies that can effectively neutralize many different strains of HIV are called broadly neutralizing antibodies. These are very rare and so far only a handful have been identified.
HIV has several tricks it uses to avoid being neutralized by antibodies. One is that the virus can change itself, or mutate, very rapidly. This mutation can be a slight change in the virus's shape or structure. Most HIV-infected individuals produce HIV-specific antibodies soon after becoming infected. But even in the short amount of time it takes for the adaptive immune system to gear up and start producing HIV-specific antibodies, the virus can alter itself so dramatically that the antibody no longer recognizes the majority of the virus in the body and is therefore ineffective.
Another reason why there are so few broadly neutralizing antibodies against HIV is that the virus itself is coated in bulky sugar molecules that act as a shield, effectively blocking the antibodies from reaching their target. In fact the region of the HIV envelope protein—gp120—that antibodies would latch on to is the most heavily protected viral protein scientists have ever studied.
There has been little success to date in inducing broadly neutralizing antibodies through vaccination. Recently however a team of researchers in the US has discovered a possible chink in HIV's protective armor. When studying the exact site where one of the already-identified broadly neutralizing antibodies binds to the virus, researchers found it was the precise place where the virus would connect to the CD4 receptor protein on cells, blocking the two from fitting together. Another promising finding is that this CD4-binding region on gp120 is highly conserved—meaning it doesn't mutate as much—since this region of the virus is needed to attach to human cells. This means that this site should be similar in most strains of HIV. This exciting news provides a new window of opportunity for AIDS vaccine researchers to design vaccine candidates that can induce antibodies to target this vulnerable point on the virus.