Introduction Some of the most important medical breakthroughs of the past century involved the development of vaccines to protect against viruses such as: smallpox

polio

hepatitis A and hepatitis B

human papillomavirus (HPV)

chickenpox But one virus still thwarts those who want to create a vaccine to guard against it: HIV. HIV was first identified in 1984. The U.S. Department of Health and Human Services announced at the time that they hoped to have a vaccine ready within two years. Despite many trials of possible vaccines, though, a truly effective vaccine is still not available. Why is it so difficult to conquer this disease? And where are we in the process?

Obstacles to an HIV vaccine It’s so hard to develop a vaccine for HIV because it’s different from other types of viruses. HIV doesn’t fit typical vaccine approaches in several ways: 1. The immune systems of almost all people are ‘blind’ to HIV The immune system, which fights disease, doesn’t respond to the HIV virus. It produces HIV antibodies, but they only slow the disease. They don’t stop it. 2. Vaccines are typically made to mimic the immune reaction of recovered people However, almost no people have recovered after contracting HIV. As a result, there’s no immune reaction that vaccines can mimic. 3. Vaccines protect against disease, not infection HIV is an infection until it progresses to stage 3, or AIDS. With most infections, vaccines buy the body more time to clear the infection on its own before disease occurs. However, HIV has a long dormant period before it progresses to AIDS. During this period, the virus hides itself in the DNA of the person with the virus. The body can’t find and destroy all of the hidden copies of the virus to cure itself. So, a vaccine to buy more time won’t work with HIV. 4. Killed or weakened HIV viruses can’t be used in a vaccine Most vaccines are made with killed or weakened viruses. Killed HIV doesn’t work well to produce an immune response in the body, though. Any live form of the virus is too dangerous to use. 5. Vaccines are typically effective against diseases that are rarely encountered These include diphtheria and hepatitis B. But people with known risk factors for HIV might be exposed to HIV daily. This means there’s more chance for infection that a vaccine can’t prevent. 6. Most vaccines protect against viruses that enter the body through the respiratory or gastrointestinal systems More viruses enter the body in these two ways, so we have more experience addressing them. But HIV enters the body most often through genital surfaces or the blood. We have less experience protecting against viruses that enter the body in those ways. 7. Most vaccines are tested thoroughly on animal models This helps ensure that they’re likely to be safe and effective before they’re tried on humans. However, no good animal model for HIV is available. Any testing that’s been done on animals hasn’t shown how humans would react to the tested vaccine. 8. The HIV virus mutates quickly A vaccine targets a virus in a particular form. If the virus changes, the vaccine may not work on it anymore. HIV mutates quickly, so it’s hard to create a vaccine to work against it.

Prophylactic vs. therapeutic vaccines Despite these obstacles, researchers continue to try to find a vaccine. There are two main types of vaccines: prophylactic and therapeutic. Researchers are pursuing both for HIV. Most vaccines are prophylactic, which means they prevent a person from getting a disease. Therapeutic vaccines, on the other hand, are used to increase the body’s immune response to fight disease that the person already has. Therapeutic vaccines are also considered treatments. Therapeutic vaccines are being investigated for several conditions, such as: cancerous tumors

hepatitis B

tuberculosis

malaria

the bacteria that cause gastric ulcers An HIV vaccine would theoretically have two goals. First, it could be given to people who don’t have HIV to prevent contracting the virus. This would make it a prophylactic vaccine. But HIV is also a good candidate for a therapeutic vaccine. Researchers hope a therapeutic HIV vaccine could reduce a person’s viral load.

Types of experimental vaccines Researchers are trying many different approaches to develop an HIV vaccine. Possible vaccines are being explored for both prophylactic and therapeutic uses. Currently, researchers are working with the following types of vaccines: Peptide vaccines use small proteins from HIV to trigger an immune response.

use small proteins from HIV to trigger an immune response. Recombinant subunit protein vaccines use larger pieces of proteins from HIV.

use larger pieces of proteins from HIV. Live vector vaccines use non-HIV viruses to carry HIV genes into the body to trigger an immune response. The smallpox vaccine uses this method.

use non-HIV viruses to carry HIV genes into the body to trigger an immune response. The smallpox vaccine uses this method. Vaccine combinations , or “prime-boost” combinations, use two vaccines one after another to create a stronger immune response.

, or “prime-boost” combinations, use two vaccines one after another to create a stronger immune response. Virus-like particle vaccines use a noninfectious HIV lookalike that has some, but not all, HIV proteins.

use a noninfectious HIV lookalike that has some, but not all, HIV proteins. DNA-based vaccines use DNA from HIV to trigger an immune response.

Clinical trial stumble An HIV vaccine study, known as the HVTN 505 study, ended in October of 2017. It studied a prophylactic approach that used a live vector vaccine. A weakened cold virus called Ad5 was used to trigger the immune system to recognize (and thus be able to fight) HIV proteins. More than 2,500 people were recruited to be part of the study. The study was stopped when researchers found that the vaccine didn’t prevent HIV transmission or reduce the viral load. In fact, 41 people on the vaccine contracted HIV, while only 30 people on a placebo contracted it. There’s no proof that the vaccine made people more likely to contract HIV. However, with the previous failure in 2007 of Ad5 in a study called STEP, researchers grew concerned that anything that caused immune cells to attack HIV might increase the risk of contracting the virus.

Hope from Thailand and South Africa One of the most successful clinical trials to date was a U.S. military HIV research trial in Thailand in 2009. The trial, known as the RV144 trial, used a prophylactic vaccine combination. It used a “prime” (the ALVAC vaccine) and a “boost” (the AIDSVAX B/E vaccine). This combination vaccine was found to be safe and somewhat effective. The combination lowered the rate of transmission by 31 percent compared to a placebo shot. A 31 percent reduction isn’t enough to prompt wide use of this vaccine combination. However, this success allows researchers to study why there was any preventive effect at all. A follow-up study called HVTN 100 tested a modified version of the RV144 regimen in South Africa. HVTN 100 used a different booster to strengthen the vaccine. Trial participants also got one more dose of the vaccine compared to people in RV144. In a group of about 200 participants, the HVTN 100 trial found that the vaccine improved people’s immune response related to HIV risk. Based on these promising results, a larger follow-up study called HVTN 702 is now underway. HVTN 702 will test whether the vaccine actually prevents HIV transmission. HVTN 702 will also take place in South Africa and involve about 5,400 people. HVTN 702 is exciting because it’s the first major HIV vaccine trial in seven years. Many people are hopeful that it will lead to our first HIV vaccine. Results are expected in 2021.

Other current trials A current vaccine trial that started in 2015 involves the International AIDS Vaccine Initiative (IAVI). This trial of a prophylactic vaccine studies people in: United States

Rwanda

Uganda

Thailand

South Africa The trial adopts a live vector vaccine strategy, using the Sendai virus to carry HIV genes. It also uses a combination strategy, with a second vaccine to boost the body’s immune response. Data collection from this study is complete. Results are expected in 2022. Another important approach currently being studied is the use of vectored immunoprophylaxis. With this approach, a non-HIV virus is sent into the body to enter cells and produce what’s called broadly neutralizing antibodies. This means the immune response would target all HIV strains. Most other vaccines only target one strain. The IAVI is currently running a study like this called IAVI A003 in the United Kingdom. The study ended in 2018, and results are expected soon.