Study shows how vaccine may have increased risk of HIV infection

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French and Swiss scientists may have uncovered the mechanism that caused participants in the STEP trial of Merck’s HIV vaccine to become infected with HIV more frequently if they received the vaccine.

The STEP trial was one the largest HIV vaccine studies to date, and there had been widespread optimism about its prospects for success, based on evidence of strong and positive immunological responses to the vaccine in earlier human studies.

However the trial was halted in September 2007 after an interim analysis showed no protective effect.

Glossary

vector

A harmless virus or bacteria used as a vaccine carrier to deliver pieces of a disease-causing organism (such as HIV) into the body’s cells to stimulate a protective immune response.

preclinical

In vitro research or research involving animals, undertaken prior to research in humans.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

culture

In a bacteria culture test, a sample of urine, blood, sputum or another substance is taken from the patient. The cells are put in a specific environment in a laboratory to encourage cell growth and to allow the specific type of bacteria to be identified. Culture can be used to identify the TB bacteria, but is a more complex, slow and expensive method than others.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

Subsequent analysis of the STEP trial, presented at several conferences in the past year, has shown that among vaccine recipients those with the highest levels of pre-existing antibodies to adenovirus-5 had a significantly higher risk of HIV infection when compared to placebo recipients.

The Merck HIV vaccine used an adenovirus-5 vector to deliver specially selected HIV genes.

Merck researchers could not explain why the vaccine had caused people with higher levels of adenovirus-5 antibodies to become infected more frequently.

Giueseppe Pantaleo of the University of Lausanne, one of the world’s leading HIV vaccine researchers, designed an experiment with collaborators at the University of Montpellier in France to determine whether adenovirus-5 antibodies had somehow made trial participants more vulnerable to HIV infection as a result of exposure to the vaccine.

They found that when both adenovirus-5 antibodies isolated from humans and the adenovirus-5 vector used in the Merck vaccine were present in a cell culture, HIV infection spread through cell cultures three times faster than without them.

They observed that adenovirus-5 antibodies tethered the Ad5-HIV vaccine to receptors on the surface of specialised immune cells, called antigen-presenting cells (APCs), thus facilitating entry of the vaccine into the cell. Once inside, components of the vaccine then activated these cells, allowing the antigen-presenting cells in turn to activate T cells. Since HIV prefers to infect active T cells, the virus was thus provided with more cells to infect.

The researchers say that future viral vector-based vaccines for HIV will need to undergo similar preclinical tests in order to determine whether similar immunological effects could occur with those vectors. Primate studies of the safety of the vaccine did not detect the problem because monkeys are not exposed to human adenoviruses.

References

Perreau M et al. Activation of a dendritic cell-T-cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells. J Experimental Medicine (early release) www.jem.org/cg/doi/10.1084/jem20081786