Image credit: NIH National Institute of Allergy and Infectious Diseases
Important lessons learnt from the first randomised clinical trial for a universal vaccine for HIV infections
20 Jun 2017
Scientists have reported the results of the first randomised clinical trial to test a novel strategy for curing HIV infections. Although the team found no difference between the HIV vaccine and those receiving standard treatment, the trial paves the way for testing different combinations of therapies to tackle the HIV that persists in patients who receive antiretroviral treatment (ART).
There is currently no cure for Human Immunodeficiency Virus (HIV) infections, and the HIV epidemic is one of the major health challenges worldwide, with important social and economic implications for public health. Approximately 34 million people are currently living with HIV, with a total of 24 million accumulated AIDS-related deaths, and 2.6 million new infections, as described in the UNAIDS Global Report in 2013. In 2015, an estimated 101,200 people were living with HIV in the UK.
HIV is a virus that infects and destroys immune cells, which are an essential part of the immune system. Untreated, HIV will gradually weaken the immune system, thus making HIV-infected people more susceptible to other infections which put their life at risk.
Although there is currently no cure for HIV, antiretroviral drugs target HIV and interfere with the virus’s replication process. Antiretroviral therapy (ART) is usually taken every day, and treatment is life-long. The result is that HIV-infected people can now expect to live much longer than without treatment. However, lifespan on ART drugs is still less than for the HIV-uninfected, and these treatments come with an inevitable increase in costs to the NHS. In addition, it is very difficult in practice to provide ART drugs globally, especially in developing regions. Thus it is clear that these combination antiretroviral therapies are not a long-term solution. We need more effective strategies for preventing new infections while curing existing HIV infections.
HIV is particularly difficult to tackle because it evolves very quickly; for example, during the first 10 days of infection, a single strain of HIV is estimated to mutate more times than all of the known strains of influenza virus have mutated in all of human history. Any vaccine or drug would therefore be quickly rendered ineffective as the virus rapidly evolves drug resistance, and circumvents control strategies. HIV also attacks the very immune cells that are meant to destroy it. So, each time the body launches an immune response as a result of HIV infection after vaccination, HIV quickly evolves to become invisible to this immune response, and escapes. However, not all parts of HIV can be easily disguised; to remain alive, HIV must conserve some small regions of its proteins.
Professor Tomas Hanke at the University of Oxford is taking advantage of these conserved regions of proteins and is designing a vaccine focusing the body’s defences to target these regions. Using the conserved regions of HIV for vaccine design comes with a tremendous advantage; the ability to target all HIV subtypes. The rapid evolution of HIV has resulted in many different subtypes of the virus, with varying geographical specificity; for example, an HIV infection in Africa will be very different to one in Europe. However, all these different subtypes share the same conserved regions of protein, and by designing a vaccine based on these protein regions, Professor Hanke and his team are developing a universal vaccine that can be deployed anywhere in the world. Their vaccine approach is strengthened by using a unique and potent combination of different vaccine subtypes which together induce a very strong immune response.
Professor Hanke’s universal HIV vaccine is currently being tested in several different clinical trials. Of note is the RIVER trial which is funded by the MRC in collaboration with five universities and industry partners. Led by Dr Sarah Fidler at Imperial College London, RIVER is a trial combining Professor Hanke’s vaccine efforts with two other approaches to develop a method described as ‘kick and kill’. This is necessary because HIV also has a ‘stealth mode’; the virus can inject its genes into those of long-lived immune cells, and lie dormant for years. This latent form of the infection does not immediately cause disease, but it’s invisible to the immune system and to antiretroviral drugs. Known as a viral reservoir, it makes this hidden cache of virus particles impossible to treat with antiretroviral drugs or a vaccine. Curing HIV infections will therefore require the ‘reawakening’ of these dormant viruses and then eliminating them. By using a drug called Vorinostat, the dormant HIV-containing cells are ‘woken up’ so that they can then be targeted by the vaccine. If all the hidden viruses could be activated, it should be possible to completely drain the reservoir.
Results presented at the 22nd International AIDS Conference (AIDS 2018) from the RIVER clinical trial showed that the treatment had no increased effect compared to standard antiretroviral treatment. Participants receiving the kick and kill approach were found to have similar levels of the dormant HIV-containing cells to those receiving antiretroviral drugs alone. Nevertheless, valuable lessons have been learnt from the trial. Although the component parts of the trial worked as expected, the combined effect did not appear to have the intended effect on the viral reservoir. The trial design required participants in both treatment and control groups to be on ART. A planned ART interruption – provided it can be done safely – could provide additional information about the treatment’s success or failure. Vorinostat, the drug used to ‘wake up’ dormant HIV-containing cells, is also a first generation drug and there has since been significant advances and developments in newer drugs which might be more effective. Participant feedback showed that the intervention was well tolerated by patients, which is important given that this is the first time this combination of antiretroviral drugs, vaccine and Vorinostat were used. Researchers still believe that the kick and kill approach holds promise and this result indicates that a different combination of treatments or a more effective drug to wake up the dormant cells may be needed.