At the helm of the Global HIV Vaccine Enterprise
GeoVax Launches Phase IIa Trial
A Phase IIa trial testing the safety and immunogenicity of a prime-boost regimen of two vaccine candidates developed by US-based GeoVax is now enrolling volunteers in the US and Peru. This trial, known as HVTN 205, launched on December 1, World AIDS Day, and will involve 225 volunteers.
Those randomly selected to receive the vaccine candidates will receive a prime-boost regimen of two doses of a DNA candidate carrying three HIV fragments or immunogens, followed by two doses of a modified vaccinia Ankara (MVA) virus vector carrying the same immunogens. The MVA vector cannot cause disease, and neither of the vaccine candidates can cause HIV infection.
Harriet Robinson, vice president of research and development at GeoVax, says the vaccine candidates showed "fabulous control" of infection with a hybrid virus that combines parts of HIV and simian immunodeficiency virus (SIV), the monkey equivalent of HIV, in preclinical studies in non-human primates. The candidates did not fare as well against SIV challenge but still showed a 10-fold reduction in viral load after six months compared to unvaccinated control animals, says Robinson.
Vaccinations Begin in IAVI's Phase I Trial
IAVI, in conjunction with St. Stephen's AIDS Trust and Chelsea-Westminster Hospital in the UK, has launched a Phase I clinical trial involving 32 volunteers in London to evaluate the safety and immune responses induced by two AIDS vaccine candidates administered in a prime-boost regimen.
One of these candidates, called TBC-M4, utilizes an MVA vector to deliver non-infectious HIV fragments in the hope of inducing an immune response against HIV. This candidate, developed in collaboration with the National Institute of Cholera and Enteric Diseases in India, was tested previously in a Phase I trial conducted in Chennai, India. In this new trial, administration of TBC-M4 will be preceded by a DNA-based vaccine candidate called ADVAX, which was developed at the Aaron Diamond AIDS Research Center in New York City in collaboration with Rockefeller University and IAVI. The ADVAX vaccinations will be administered with a needle-free device called Biojector 2000 to see if this delivery system induces stronger immune responses than a regular syringe injection.
This UK trial will also allow researchers to assess the merits of a new laboratory test known as a viral suppression assay to determine whether the CD8+ T cells, produced in response to the vaccine candidates, that are isolated from volunteers in the vaccine trial are capable of inhibiting HIV in the lab. "What we would like to do is see if the CD8+ T cells after vaccination stop the virus from growing," says Jill Gilmour, senior director of clinical research at IAVI.
The assay being used in this trial is an optimized version of one developed by Bruce Walker, director of the Partners AIDS Research Center at Massachusetts General Hospital, who has long advocated for researchers to use this type of assay to measure the function of immune cells produced in response to vaccination. Most often the immune responses induced by candidate vaccines in clinical trials are assessed using an ELISPOT assay. This assay detects the number of CD8+ T cells that are excreting specific proteins known as cytokines but does not measure the ability of these cells to actually inhibit HIV (see VAX August 2007 Primer on Understanding Immunogenicity). —By Regina McEnery
What role do innate immune responses play in defending against HIV infection?
Humans are repeatedly exposed to various pathogens, including viruses and bacteria. The body defends itself against these pathogens using a complex network of cells, tissues, and organs, which together form the human immune system (see VAX July 2008 Special Issue, Understanding the Immune System and AIDS Vaccine Strategies). There are two branches of the immune system, innate and adaptive, that play a critical role in eliminating invading pathogens.
The innate immune system is the first line of defense against viruses and bacteria. The cells of the innate immune system both detect the invading virus and try to control or eliminate it. Dendritic cells and macrophages are among the most important in recognizing invading viruses like HIV and are found in mucosal tissues, as well as at other sites. These cells are like the body’s 24-hour security force and are constantly patrolling for foreign invaders. Once they come in contact with viruses, they grab hold of the warring particles with the help of finger-like projections. The dendritic cells then cut the virus into small fragments called epitopes that are displayed on the cell’s surface. When these dendritic cells travel to the lymph nodes, which are the communication hubs of the immune system, the HIV fragments on their surfaces act as warning flags, alerting other immune cells of the invading virus.
Innate immune responses are activated soon after an infection occurs but they are not specific, so whether the enemy is a cold virus or HIV, the innate immune system responds in the same way. If the innate immune response is not capable of eliminating the virus or bacteria, or if these responses are evaded by the pathogen, the adaptive branch of the immune system kicks in. The adaptive immune responses, which include cellular immune responses (CD4+ and CD8+ T cells) and antibodies (Y-shaped proteins that work primarily by latching onto viruses and preventing them from infecting their target cells), are pathogen-specific and therefore take longer to become activated—typically several days.
Studying immune responses
The adaptive immune responses produced following HIV infection have been well studied and are still being fully characterized. AIDS vaccine researchers are also able to detect and measure the cellular and antibody responses induced in individuals that have received various vaccine candidates in clinical trials.
However, even though innate immunity is widely considered to be critical in shaping the body’s immune response to HIV, this type of response is much more difficult to study. Innate immune responses are only active for about six to seven days following HIV transmission, and so newly HIV-infected individuals would have to be identified very soon after they become infected for researchers to study innate responses. Also, HIV is most often a sexually transmitted infection and so the innate immune responses, which may play a key role at or very soon after transmission, may be hidden at mucosal sites that are difficult to study. Despite these complications, efforts are underway to identify infected individuals as soon as possible after HIV transmission and to better classify the very early interactions between the virus and the innate immune system.
It is also likely that the innate immune system plays an important role in the response to AIDS vaccine candidates, but this is not very well understood. Investigators involved with the Phase IIb test-of-concept trial known as STEP are currently analyzing the types of innate immune responses induced in volunteers who received Merck’s vaccine candidate. These analyses may offer new clues about the role of innate immunity following vaccination.
A wily virus
HIV has several tricks it uses to evade the immune responses mounted against it. One of the virus’s advantages is that it primarily targets and infects CD4+ T cells, a vital component of the adaptive immune response against HIV. HIV’s ability to constantly mutate also allows it to evade antibody responses.
But scientists still do not completely understand how HIV manipulates the innate immune system. It is possible that macrophages and dendritic cells may unwittingly be helping HIV by delivering virus particles directly to target CD4+ T cells, which the virus then infects. HIV is also thought to disrupt other functions of the innate immune system, including the functional capacity of a subset of cells called natural killer (NK) cells, which would otherwise recognize and destroy HIV-infected cells.
To help clarify the murky role that innate immunity plays in HIV infection, researchers are studying different groups of individuals. One group of interest is highly exposed seronegatives—individuals who remain uninfected for years despite known and often repeat exposure to the virus. Past studies have found that some women inexplicably resist HIV infection despite participating in commercial sex work and having been repeatedly exposed to the virus. Some scientists have theorized that innate immunity may explain their apparent ability to avoid HIV infection.