The focus of HIV vaccine research has shifted over time as one aspect or another has offered more of a glimmer of hope for success. Lack of progress in creating a vaccine that prevents infection led to a focus on T cells in the hope that if one could not prevent infection, then perhaps one could modify the course of that infection and live with it not progressing to disease, as is the case with most monkeys that become infected with the simian version of HIV.
But that approach was dealt a massive blow when a Merck HIV vaccine trial was halted in the autumn of 2007 because more people who received the vaccine were becoming infected than those who received placebo. After months of meetings and analysis, a follow up study was cancelled, and only now is getting underway in a much revised format.
Antibodies have been the big story lately. Over the last two years researchers have identified dozens of antibodies that can either neutralise the virus or bind to it and disrupt its transmission through the mucosa, which is the principle route of sexual transmission.
They have always known that the body could produce antibodies to HIV but the virus is so unstable, creating myriad variations in each cycle of replication, that some of those variants were impervious to neutralisation. Often accumulated sugars on the outside envelop of the virus blocked access to the binding site used by early rising antibodies. It can take months, sometimes years for an antibody to the proper structure to be able to avoid the sugar overlay and bind at a conserved site on the virus.
The big news from the AIDS Vaccine Conference was release of correlates of protection in the Thai RV144 study, which used a modified poxvirus as one of the vaccines. It had taken two years of intense preparation, tests, and analysis to uncover those associations.
“We found IgG antibodies that matched the scaffolded-V1V2 of the recombinant protein [of the study vaccine], that correlated inversely with the infection rate. That means, the higher the IgG antibody, the lower the infection rate,” said Duke University researcher Barton Haynes who led that effort.
Second, we found that envelop binding to the plasma IgA correlated directly with infection rates. The higher the IgA to envelop, the higher the infection rate.”
This and additional analysis led Haynes to hypothesise, “Vaccines with high V1V2 antibodies received protection from vaccination, whereas those with low responses received less or no protection.” Haynes believes that monomeric plasma IgA antibodies may bind to HIV envelop on infected cells and block IgG from binding and carrying out its effector function.
NYVAC-KC is a second generation poxvirus in a preclinical study that is likely to be used in a follow up clinical study to the Thai RV144 study. It has a number of advantages including greater safety and the generation of a stronger neutralising antibody response.
Sex workers in Mombasa
Some members of an ongoing cohort study of female sex workers in Mombasa, Kenya have either not become infected with HIV despite what is likely to have been numerous exposures to the virus, or are controlling their infection extraordinarily well. Reports some years ago suggested that they remained protected so long as they were sufficiently exposed to the virus but became vulnerable to it after returning from an extended holiday from the sex business.
University of Washington researcher Valerie Cortez looked at the antibodies of these women over time in stored samples of blood. She found that “superinfection” with a second version of HIV produced an enhanced neutralising antibody response that provided both broader coverage and cross reactivity to the virus.
Only those who were “superinfected” developed those responses, suggesting that mere exposure to another strain of the virus was not sufficient to develop antibodies – which often take months if not years to add residues and mature – only a durable infection provided sufficient exposure to generate such a response.
Geographic location also might be important. Mombassa is where clades A and C of the virus overlap and where many mosaic recombinations of the virus clades occur. Cortez agreed with a suggestion from the audience that perhaps exposure to a sufficiently different virus is necessary to trigger a “superinfection” that generates the type of neutralising antibodies she observed. It might not occur if a person were to become “superinfected” with different variants of the clade B virus that is prevalent in the US and Europe.
Bob Roehr is a biomedical journalist based in Washington, DC, and a regular contributor to the BMJ.