- A preventative vaccine is a realistic prospect although it may not protect everyone or protect against HIV every time. Over decades of research, vaccine efficacy may improve.
- A successful vaccine will probably need to stimulate several branches of the immune system to respond to HIV. Learning how to stimulate long-lasting responses is the major challenge for vaccine research today.
- Several large trials are testing promising vaccines, with results expected around 2023.
A vaccine that prevents HIV infection is not available yet. But there is a real chance that a vaccine that will protect people from infection could be available within five to ten years. This page summarises the current state of research and the challenges facing scientists.
It has been difficult to develop a vaccine against HIV for several reasons. Whereas most other vaccines work by teaching the adaptive part of the immune system to produce antibodies that clear an infection, antibodies are unable to clear HIV infection. This is because HIV mutates very rapidly, evading antibodies.
Vaccine approaches that have been successful against other viruses – killed or weakened versions of a virus – have not proved suitable in the case of HIV, owing to the risk that the viral material used in the vaccine will integrate into human cells and eventually lead to new virus replication.
Another challenge is that HIV is divided into families, or sub-types, that predominate in different parts of the world. A vaccine will need to be effective against all sub-types, or different vaccines must be developed against different sub-types.
Most vaccines work by stimulating one part of the immune response to produce antibodies against an infectious agent. An HIV vaccine may need to promote effective responses to HIV by up to three parts of the immune system:
- Antibody responses, through the production of broadly neutralising antibodies that recognise parts of HIV that do not mutate.
- Cellular immune responses, consisting of CD4 T-lymphocytes that recognise HIV and stimulate other T-cells, such as CD8 cells, to destroy virus-infected cells.
- Innate immune responses, such as natural killer (NK) cells, which can be aroused by some types of antibodies stimulated by an HIV vaccine. NK cells can destroy HIV-infected cells.
Broadly neutralising antibodies have been identified in people who acquired HIV but didn’t experience immune system damage, so-called ‘elite controllers’. These antibodies can block most strains of HIV because they target regions on the surface of the virus that do not change from one generation of HIV to the next. Most people do not produce these antibodies in response to HIV infection. Vaccine developers must learn how to stimulate production of broadly neutralising antibodies using a vaccine.
A T-cell-stimulating vaccine could lead to the efficient destruction of any cells that HIV antibodies had failed to protect, or it could lead to lower levels of HIV in people who became infected despite vaccination.
But a vaccine designed to produce cellular immunity against HIV faces a challenge, as central memory T-cells are the most important reservoir of HIV-infected cells in the body. A vaccine that stimulated the production of central memory T-cells might actually increase susceptibility to infection (as appears to have happened in one trial).
The innate immune system, the most primitive but fastest-acting part, cannot actually be ‘taught’ to recognise pathogens by a vaccine in the same way. But studies of vaccines that have shown signs of efficacy indicate that one important factor was the generation of classes of antibodies that in turn stimulate the natural killer cells of the innate immune system to destroy HIV-infected cells, in a process called ADCC (antibody-directed cellular cytotoxicity).
What has been learnt so far about how to produce an effective HIV vaccine?
Vaccine researchers have learnt much from animal studies, from investigations of people who have been exposed to HIV without becoming infected, and from clinical trials of experimental HIV vaccines.
Numerous approaches to vaccine design have been tested to learn more about how to protect against HIV and how to produce strong immune responses against HIV. Vaccine trials have investigated the following questions:
- How can a vaccine introduce HIV genes or proteins into the body safely?
- How many doses of vaccine are needed to make a strong immune response?
- Might a combination of vaccines, given in a specific sequence, produce a stronger response?
- What combination of HIV proteins produces the strongest response?
- How broad is the immune response – does it work against all types of HIV?
- How long do the responses last?
The first large trial of an HIV vaccine reported results in 2003. The vaccine used in that trial, AIDSVAX, was designed to stimulate the production of antibodies against a region of an HIV surface protein, gp120. The trial found that AIDSVAX was no more effective than a placebo, or dummy vaccine, in preventing HIV infection.
Another vaccine approach was tested in a large trial called STEP. This trial tested a vaccine designed to encourage cellular immune responses. The vaccine used an adenovirus (Ad5) which causes common cold symptoms to deliver HIV proteins safely. The trial was halted in 2007 after an interim analysis showed that the vaccine had not reduced the risk of infection. Further analysis found that people with the highest levels of antibodies to the adenovirus used in the vaccine had the highest risk of becoming infected with HIV after receiving the vaccine, at least during the early phase of the trial. This study showed that care needs to be taken in the choice of virus, or vector, used to deliver HIV proteins in a vaccine.
Another study of a vaccine using the Ad5 vector but containing subtype B HIV proteins showed no effectiveness and an increase in the risk of HIV infection for vaccinated men after the study was unblinded. It is still unclear why the risk of infection increased in these participants.
An alternative approach designed to stimulate both cellular immunity and antibody production was tested in the RV144 trial. This study used two vaccines in what is called a ‘prime-boost’ approach. A vaccine called ALVAC-HIV was used to ‘prime’ the cellular immune system, using three sequences of HIV proteins. The AIDSVAX vaccine was used to boost the immune response later. ‘Prime-boost’ vaccines are designed to produce strong and long-lasting immune responses.
The RV144 trial showed that the prime-boost combination reduced the risk of infection by 31%. Many researchers were surprised by this result as AIDSVAX had not protected against infection when used alone. Another surprising result was that the vaccine did not produce strong CD8 T-cell responses in a majority of participants and did not result in reduced viral load in people who became infected despite vaccination. The vaccine did produce strong antibody responses to a region of the HIV surface protein.
Further analysis showed that specific antibody responses which also encouraged innate-cell immune responses (antibody-dependent cell-mediated cytotoxicity, ADCC) were strongly associated with a reduced risk of infection in vaccine recipients. This finding encouraged researchers to test further prime-boost vaccine strategies.
A version of the vaccine combination used in the RV144 trial adapted for the type of HIV common in southern and eastern Africa (subtype C) was tested in the HVTN 100 study. That study found the vaccine produced very strong antibody responses of the type associated with protection against infection in the RV144 trial. The vaccine was then tested in a much larger trial in southern Africa. The HVTN 702 study (also known as Uhambo) recruited 5407 people and aimed to test whether the vaccine could reduce the risk of HIV infection by at least 50%. The trial was also set up to find out whether strong immune responses to HIV last longer when using this vaccine compared to the RV144 trial, where the protective effect of the vaccine began to wane after one year. However, it was announced in February 2020 that this trial had been stopped early, because an interim review found that the vaccine was ineffective. This is a major setback, but the results have not yet been analysed in detail.
Ongoing major vaccine studies
A different prime-boost vaccine approach is being tested in another large study in southern Africa. This vaccine approach has produced strong immune responses in animal studies and in preliminary human studies. The HVTN 705 study (also known as Imbokodo) uses a ‘prime’ vaccine consisting of an adenovirus vector that delivers a ‘mosaic’ of HIV envelope and internal proteins from four HIV subtypes designed to produce responses against a wide range of HIV subtypes. The adenovirus used in this vaccine (Ad26) is much less common than the adenovirus used in the STEP study (Ad5) in the hope that pre-existing antibodies will be less common and will not interfere with the activity of the vaccine.
The booster vaccine used in this study has been shown to stimulate the production of antibodies against the HIV envelope protein gp140.
The Imbokodo study has recruited 2637 women aged 18 to 35, the population at highest risk of acquiring HIV infection in southern Africa. Results from this study are expected in 2023.
Another study (the HVTN 706 trial) of the same mosaic vaccine approach is expected to begin recruiting participants in North America, Latin America and Europe in 2019. This trial will use a prime and booster designed to produce responses to subtype B HIV which predominates in Europe and the Americas. This trial will not produce results before 2023.
A very different approach is being tested in the AMP studies. Rather than using a vaccine to produce broadly neutralising antibodies, these studies are testing the concept of giving an infusion of broadly neutralising antibodies – Antibody-Mediated Prevention (AMP). The studies will test how well these antibodies protect against HIV infection. If the method is successful, antibody-mediated prevention may provide an additional prevention method until vaccines can be developed to stimulate broadly neutralising antibody responses.
One study (HVTN 704) is testing an infusion of the broadly neutralising antibody VRC01 in 2700 men who have sex with men and transgender women in the US, Peru, Brazil and Switzerland. Another study, HVTN 703, is testing the same antibody in 1900 women in southern Africa. Results are expected in 2022.
Will a vaccine protect everyone?
It is widely expected that the first generation of HIV vaccines will only be partially effective. Some people will have weaker immune responses after vaccination or will miss doses of the vaccine and fail to achieve protection. The RV144 vaccine reduced the risk of infection by only 31% but trials of newer vaccines are looking for reductions in the risk of infection of at least 50%, and preferably 65% or more, to move forward. A vaccine which only halved the risk of infection may nevertheless be highly cost-effective in regions of the world where rates of infection are high and the cost of providing treatment will continue to grow if the rate of infection cannot be reduced.
When will an HIV vaccine be available?
Scientists have swung from optimism to pessimism about the chances of developing an effective vaccine over the past thirty years. Scientists are becoming optimistic again after the results of recent studies.
Even if the large trials underway produce positive results after 2023, it will take several years for the results to be fully analysed and submitted for regulatory approval. Vaccine manufacturing will need to be scaled up and money will need to be pledged by donors to pay for HIV vaccination campaigns in lower-income countries. Also, further studies may be needed to check that vaccines effective in one clinical trial show similar efficacy in other populations.
Even if vaccine studies produce positive results in the next few years, this will not mean that the need for HIV vaccine research will stop. Further research will be needed to improve the efficacy of vaccines, to make vaccines easier and cheaper to manufacture, and to find out how to deliver them to the largest number of people in different regions of the world. Having an effective vaccine is one challenge, but another major challenge will be to make sure that everyone who is at risk of HIV can be vaccinated.