The HIV vaccine field is just now beginning to recover from the disappointments of prior large-scale vaccine studies and is beginning to show momentum, but where is that momentum headed? While much has been learned from those prior studies and vaccinology in general, one could well argue that HIV vaccine efforts are not as robust as they could be, likewise they do not take into consideration the overall picture of the requirements for an HIV vaccine. In particular, AIDS is a pandemic requiring cost-effective treatment. Even a partially active vaccine would have great benefit if they were cost-effective, easy to use and safe.
At one end of the spectrum we have seen truly heroic efforts to generate an immune response to HIV. Argos Therapeutics is conducting trials of a personalized therapeutic HIV vaccine based on advances made in the field of cancer immunotherapy. This uses the patient’s own immune cells (dendritic cells) that are modified in the laboratory and re-infused back into the patient.
While the results have been encouraging and trials are ongoing, it’s clear that this type of treatment will never be available to more than a small fraction of HIV patients due to the costs. One might say this is a matter of looking for lost keys where the light is rather than where they were dropped, but frequently this is how science moves forward; extending the utility of prior discoveries into new areas. Indeed much has been learned from the truly astonishing advances that have been made in the field of cancer immunotherapy, and some of those advances may well have more practical applicability to HIV vaccines than the approach taken by Argos.
A new HIV vaccine trial is expected to launch in November of this year in South Africa. It is being conducted by the NIH-supported HIV Vaccine Trials Network (HVTN) and is co-funded by The Bill and Melinda Gates Foundation along with the South African Medical Research Council. Sanofi Pasteur and Novartis Vaccines will manufacture the vaccine for the study. As impressive as all this sounds, the vaccine itself is basically a re-hash of vaccines used previously that entail the use of viral vectors for delivering components of HIV to elicit an immune response.
Previously, trials with these types of vaccines have given a protection level of about 30%. A particular problem with viral vectors is that it’s not uncommon for individuals to have a pre-existing immune response to the vector itself, which can blind the immune system to the HIV components the vector is delivering. Similarly, Janssen is conducting another viral-vector based vaccine study using an adenoviral vector. As adenoviruses cause the common cold it’s clear that significant immunity to these viruses is present in the population. While the particular vector that Janssen is using is derived from a rare strain of adenovirus, pre-existing immunity may still be a problem.
A somewhat overlooked modality for vaccine development is the use of peptides; small fragments of proteins that make up the various components of HIV. The advantage here is that there are virtually no extraneous components to generate or trigger an immune response other than what one wants. Additionally, there is also the advantage that they are easily manufactured by entirely synthetic means. This is also different from viral vectors, which rely on some type of culture system for their manufacture, adding a layer to both regulatory requirements and cost.
While some HIV vaccine peptides are being tested in the clinic, they are considered first-generation peptide vaccines. One such vaccine being tested is LIPO-5, which was designed to stimulate a response in CD8+ cytotoxic T lymphocytes (CTLs). The reason for this is that CTLs have the ability to destroy infected cells, which is important in clearing the overall load of virus. However, what’s become clear from other peptide vaccines studies, similarly designed to increase CTL activity, is that CTLs are only partially activated in the absence of CD4+ T cell activation. There is now a plethora of data showing the importance of having good CD4+ T cell activation to generate a robust immune response both for cancer immunotherapy as well as for control of HIV.
There are vaccine peptides being developed that are particularly designed to activate CD4+ T cells. One such company doing so is Antigen Express. In fact, they have developed a technology platform to make a peptide vaccine specific to essentially any pathogen or protein. Late phase II studies of a peptide designed to generate a CD4+ T cell response to a protein specific for a variety of cancers has shown promise in reducing relapse in triple negative breast cancer patients.
Reduced capital in part caused by prior disappointments in the field of HIV vaccine research have forced those efforts onto the back burner. We can only hope that the situation will turn around.
By David Miller