25 Sept 2019

An overview: HIV vaccine approaches at IGH

There are two major types of the human immunodeficiency virus or HIV, HIV-1 and HIV-2, and current treatment for HIV-1 is with life-long antiretroviral therapy. In this blog, IGH researchers Professor Bill Paxton and Dr Georgios Pollakis updates us on recent developments in HIV-1 vaccine approaches.

HIV-1 is the most common form of the HIV virus, and research to produce a vaccine is still ongoing. There is still considerable debate as to what is going to result in a successful HIV-1 vaccine, either preventative or therapeutic, and which strategies should be best employed to do so. It is still relatively unknown which combination of cellular or antibody immune responses are going to provide the optimal immunity required. The group of Bill Paxton and Georgios Pollakis are involved in two EU funded programmes analysing two different approaches, one is a T cell approach (a type of cell that forms the immune system) and the other is antibody (a protein produced by the immune system to neutralise pathogens).  

The ongoing H2020 funded European HIV-1 Vaccine Alliance programme includes HIV-1 infected individuals boosted with a substance designed to stimulate the immune system (an immunogen) aimed at heightening the response of T-cells to HIV-1. Participants receiving successful antiretroviral therapy will be vaccinated with a regime of a T-cell boosting immunogen after which they will be taken off therapy (treatment interruption) and time to viral rebound and to what extent measured. This will include a control arm to which time to viral rebound can be compared. During the vaccination protocol cellular immune responses will be measured by looking at HIV-1 viral loads. Furthermore, this study incorporates an arm receiving immunogen/placebo along with a special antibody (Vedolizumab) that has been linked with heightened immune response in the body’s mucosal linings. This study will identify whether therapeutic vaccination can provide benefit through increased elimination of HIV-1 infected cells and control of virus spreading through the blood. 

An EDCTP EU (bnAb-baby) funded proposal (started May 2019) is a vaccine proof of concept study looking to address whether neutralising antibodies have the potential to prevent HIV-1 infection in infants. A highly potent human neutralising antibody (VRC-007LS) will be administered to HIV-1 negative infants being breastfed by HIV-1 positive mothers. It is known that HIV-1 transmission can occur via this route even though mothers receive antiretroviral therapy. Breakthrough cases will be identified where virus being transmitted will be studied. These results will indicate whether high levels of circulatory antibodies have the potential to block HIV-1 transmission via this route of exposure and identify how potent they can be, whilst at the same time providing an indication of potential viral escape. How to induce such antibody responses would be the obvious aim stemming from these results.  

For vaccines to be successful they will likely have to induce immune responses that can clear HIV-1  ‘hiding’ in a resting or latent state in our own immune cells, or prevent the early establishment of such cells in newly infected individuals. Therefore, better understanding the cellular molecular environments that induce latency or support active viral replication is relevant to not only therapy but also vaccine success. Conversely, using therapeutic vaccines to activate T-cells may well enhance the possibility of HIV-1 transmission as well as virus replication in the case of therapeutic vaccines. Indeed, there are indications that the failure of the STEP vaccine trial, where more infections were reported among vaccine recipients than placebos, was due to cell activation and recruitment of cells to sites of exposure and thereby increased transmission. We are therefore actively involved in better understanding the molecular events that lead to increased infection and replication and are currently studying such mechanisms using cellular materials from the participants within our vaccine trials.

Certain types of parasite are known to change the immune response of their host through dampening or skewing T cell activation, to avoid the host immune system. Our most recent work (Mouser et.al. PLoS Pathogens e1007924, 5th Sep 2019) demonstrates that two different antigens (kappa-5 and omega-1) from parasitic blood flukes can differentially effect HIV-1 interactions with the immune system. Kappa-5 has been shown to bind dendritic cells (part of the immune system) and can prevent viral capture and transfer, whilst omega-1 matures dendritic cells towards skewing T cells with a reduced capacity to support HIV-1 replication. These results indicate that co-pathogen interactions can alter HIV-1 transmission as well as subsequent viral replication. Vaccines that induce a similar immune response would therefore be advantageous as they would reduce the detrimental effects mentioned earlier, such as increased virus replication and transmission.
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