Three doctors from Seattle have written a review article in the 15th August edition of Clinical Infectious Diseases, summarising the state of play in HIV vaccine research. They explain that while HIV has thrown up a number of challenges to vaccine researchers, a number of studies are planned or underway that could lead the way to a vaccine in the future.
However, given the surprises and difficulties that this field has experienced over the past 20 years, the doctors stop short of estimating when a vaccine may become available.
Following the disappointment of vaccines designed to produce HIV-fighting antibodies, more recently, research has turned to attempting to stimulate cellular immunity against HIV. This type of immunity is mediated by cell-killing CD8 T-cells or ‘cytotoxic T-lymphocytes’, which can identify and destroy cells that are infected with disease-causing organisms.
The doctors write that eliciting this type of immunity is less likely to prevent HIV infection than antibody-mediated immunity. However, the development of a successful vaccine could prevent the dramatic loss of CD4 T-cells soon after HIV infection, as well as reducing the viral load of patients after infection, resulting in slower disease progression and less chance of HIV being passed on.
Difficulties in HIV vaccine research
The doctors explain that HIV has three properties that have complicated the search for an effective vaccine.
Firstly, HIV converts its genetic material from ribonucleic acid (RNA) into DNA after it infects cells, before hiding this DNA away within long-lived CD4 T-cells, ready to start producing more HIV particles at any time. This means that an effective HIV vaccine must be able to stimulate a long-lasting immune response to prevent new HIV production within the body.
Secondly, HIV damages the very immune cells that are needed for an effective vaccine; and thirdly, HIV is genetically diverse, with three main groups containing distinct clades, which are found at different proportions across the globe.
These problems have made traditional approaches to the development of a vaccine difficult. While vaccines for infections such as polio are designed to stimulate the body to produce antibodies, this approach has failed in HIV vaccine research, as the variability in the virus’s structure, both within and between patients, has resulted in responses to vaccines being too narrow and too weak.
What’s more, the doctors point out, the two vaccines that have entered large phase III trials were designed to target the envelope proteins (gp120 and gp160) on the surface of the HIV particle. It is now understood that these proteins change shape and position when they bind to the receptors on the surface of a human T-cell, rendering the antibodies ineffective.
However, recent studies have begun to show more promise. Laboratory-produced ‘monoclonal’ antibodies that target new sites on the envelope proteins can protect against a range of HIV strains in the test tube and have protected monkeys against infection with viruses related to HIV. “Understanding how to develop immunogens that can mimic the effects of these monoclonal antibodies and that can elicit the production of effective neutralising antibodies to a wide variety of circulating strains of HIV remains a challenge,” they write.
HIV vaccine research has also been dogged by problems with traditional vaccine designs. Using live ‘attenuated’ HIV-based vaccines is too dangerous due to the risk of HIV infection from the vaccine itself. Killed HIV vaccines do not produce an effective immune response.
Other approaches that have failed include using proteins isolated from HIV particles, such as the envelope protein, or short sections of HIV proteins called ‘peptides’. Neither of these have produced strong immune responses, notably in the two phase III trials that used envelope protein-based approaches.
More success has been found using DNA-based vaccines to introduce HIV genes into the body, often using vectors to carry the genes, such as other harmless viruses or bacteria. The doctors outline the current state of play in research into using these vectored vaccines, explaining that using a combination of more than one type of vaccine in a ‘prime and boost’ strategy may result in the best solution.
The most commonly-used vectors have included canarypox and two versions of the virus that causes smallpox, modified so that they do not cause disease, but these have suffered from producing only weak cell-based immunity. In contrast, the HIV vaccine vectors being developed today include the adenovirus type 5 (Ad5) vector. Two versions of this are in development, one by Merck and the other by the United States National Institutes of Health.
Although there are concerns about the effect of natural immunity to adenovirus in human populations reducing the effectiveness of these vaccines, their developers are attempting to get around these problems by using uncommon viral types, by producing hybrid virus vectors in the laboratory, or by combining the vector with another type of vaccine.
Promise for the future?
Following successful safety trials, the Merck vectors has already entered a large, long-lasting trial to determine its effectiveness in patients, while the National Institutes of Health’s vaccine is due to enter this phase next year, marking a new phase in vaccine research.
“Last year, HIV vaccine development entered the era of cytotoxic T-lymphocyte-mediated vaccine efficacy trials with the initiation of the HIV Vaccine Trials Network / Merck STEP study,” the doctors write. “Together with other ongoing and upcoming trials, this landmark study will determine whether the current viral vector vaccines are capable of eliciting the quantity and quality of T-cell responses that might alter the course of individual and global HIV infection.”
However, the disappointments and surprises of previous trials are a stark warning that optimism is rarely rewarded in the HIV vaccine field. Until the results of this, and similar trials have been collected, analysed and published, efforts to control HIV’s spread will remain focused on safer sex and injection practices, the development of microbicides and pre- and post-exposure prophylaxis, and prevention of mother-to-child transmission of the virus.
Duerr A et al. HIV vaccines: new frontiers in vaccine development. Clin Infect Dis 43: 500-511, 2006.