Developing an HIV vaccine
HIV impairs the immune system over time, and ending its spread requires several preventive strategies, best used in combination, of which only a vaccine would not rely on sustained behaviour. More than 30 years after the virus was discovered, no HIV vaccine had been approved: the virus mutates quickly and attacks the immune system a vaccine would try to trigger, and no reliable correlate of protection was known. In 2018, three groups of vaccine concepts were being studied for efficacy in humans.
HIV and its prevention
HIV, the pathogen that causes AIDS, can be transmitted when a person's body fluids, such as blood and genital secretions, come into contact with those of an infected person. It spreads mainly through sexual contact, and also through needle-sharing among intravenous drug users. HIV has two types: HIV-1, the more common and more infectious, and HIV-2, which is relatively uncommon, is less infectious and has a lower mortality rate. HIV impairs the immune system over time, leading to AIDS. When the body's white blood cells are destroyed, its ability to fight off other diseases is compromised. Active treatment with antiretroviral drugs, which help to maintain or restore immune function, can keep people healthy for years.
Managing and ending the spread of HIV requires a variety of highly effective preventive strategies, best used in combination. A comprehensive toolkit to prevent HIV transmission would include antiretroviral therapy as prevention, which minimises the infectiousness of people with HIV; pre-exposure prophylaxis; post-exposure prophylaxis; behavioural changes; male circumcision; microbicides; needle and syringe exchange programmes; and a vaccine, among other strategies. Vaccines are the only means of prevention that do not rely on sustained behaviour.
Like other vaccines, an HIV vaccine would have an impact in the fight against the HIV pandemic. A therapeutic HIV vaccine would also have an impact, by reducing the infectiousness, or viral load, of those already infected. If an HIV vaccine reduces the number of people who become infected, the number of people who can pass the virus on to others will fall significantly. By preventing future infections, a vaccine can halt the spread of the disease and save millions of lives. Even a vaccine of low efficacy and limited coverage would still have a significant effect on public health. To be considered successful, a preventive HIV vaccine would have to substantially affect acquisition of infection, and a therapeutic one would have to substantially affect progression of disease among the already infected or their infectiousness.
Why an HIV vaccine is hard to develop
More than 30 years after HIV was discovered as the agent that causes AIDS, no effective vaccine against it had been developed. The path to one had been riddled with challenges, many of them unique to HIV. As a result, advocates, scientists and funders had to move away from a "home run" philosophy that had anticipated early success. Much had been learned along the way about the genetic diversity of the virus, the limitations of animal studies, and the cultural infrastructure and regulatory challenges involved in testing HIV vaccines. Coordinated approaches to the difficulties of developing an HIV vaccine are a logical way forward, and with them more progress can be made toward a successful vaccine, in spite of all the uncertainties.
Although researchers had worked for many years to develop a vaccine that would treat or prevent HIV infection, little headway had been made. Many potential vaccines had been developed, but none had been good enough for approval. This was because of numerous challenges in creating a successful HIV vaccine. One is that HIV, a lentivirus, mutates much faster than other viruses, which makes it difficult to target. Another is that HIV targets the immune system, the very thing a vaccine would try to trigger to elicit protection, so developing a vaccine that activates the immune system without harming it, as the virus does, is not an easy task. Immunity that wanes over time after vaccination is a further challenge.
The genetic diversity of HIV
Classifying HIV isolates from different geographical areas into genetic subtypes, or clades, has made it possible to map the epidemiological spread of infection. This mapping has given the rationale for basing the immunogens used in vaccine trials on local isolates from the trial sites, for example subtype B in the Americas, subtype C in Africa and subtype E in Thailand. The heterogeneity of HIV lies particularly in the genes that encode the gp120 and gp41 proteins. Unique circulating forms can also result from recombination among the different HIV subtypes. In 2018, how this genetic variability relates to any vaccine-induced protection observed remained unclear. Trials of experimental mosaic vaccines may shed some light on this. A mosaic vaccine uses as its immunogens proteins assembled from natural sequences of different prevalent HIV subtypes, which together are known as a mosaic antigen.
The unknown correlate of protection
For most other diseases that vaccines can prevent, the natural or vaccine-induced immune response correlates with protection against infection or disease. With HIV, a wide range of immune responses is seen when a person becomes infected, and these responses neither eradicate all of the infection in the body nor prevent progression to AIDS. So in 2018 there was no known reliable correlate of protection, and even the immunological mechanism by which a vaccine might protect, whether by preventing the acquisition of disease or by modulating it, was still unknown. Immunogenicity data or a probable mode of action should be provided to justify conducting an HIV vaccine trial, but not enough was known about the candidate vaccines, the regimens or the amount of immunogenic response to make rational go/no-go decisions in HIV vaccine development. The lack of clear scientific criteria for advancing a vaccine into efficacy studies was a challenge. One option would be to submit a trial application without these correlates and use the proposed study to identify them.
HIV vaccine concepts under study
In 2018, HIV vaccine development strategies aimed to induce both humoral and cell-mediated immunity. The HIV vaccine concepts then under study for efficacy in humans fell into three groups.
Broadly neutralising monoclonal antibodies were discovered in people who had controlled the virus naturally, without antiretrovirals, for over 15 years. These antibodies bind to the CD4 cell site that HIV targets. In vitro studies gave hope that broadly neutralising monoclonal antibodies such as VRC01 could be used to design reasonably efficacious preventive vaccines that give passive immunity in humans against different HIV strains.
Vaccines targeting specific HIV-1 strains built on progress made in the Thai prime-boost trial RV144. Different HIV-1 subtypes, or clades, are found in different regions of the world. Subtype C, found in the population of southern Africa, is the target of the vCP2438 and bivalent subtype C gp120/MF59 prime-boost regimen.
A global vaccine targeting multiple HIV-1 strains uses a mosaic antigen to increase the range of immune responses for improved worldwide coverage. The Ad26.Mos4.HIV and clade C gp140 prime-boost regimen was first being tested in young women at high risk of HIV infection, in a proof-of-concept study.