Vaccines

There is no cure to end the HIV epidemic. Although the availability of antiretroviral therapy has dramatically reduced AIDS-related deaths, these treatment regimens can be complex and costly, and some people experience side effects. In addition, HIV can become resistant to the drugs, particularly if individuals do not take them consistently over time. HIV treatment depends on long-term patient adherence; a vaccine could provide protection with minimal action on the patient's part.

A preventive HIV vaccine could help save millions of lives and billions of dollars each year in treatment costs. Safe, effective, and affordable vaccines that can prevent HIV are the best long-term hope for controlling and/or ending the HIV/AIDS epidemic.¹ ²

1 Ending AIDS — Is an HIV Vaccine Necessary? Anthony S. Fauci, M.D., and Hilary D. Marston, M.D., M.P.H. N Engl J Med 2014; 370:495-498February 6, 2014DOI: 10.1056/NEJMp1313771

2 Interview with Dr. Anthony Fauci on the need for an HIV vaccine and the advances that will help fulfill that need. Supplement to the N Engl J Med 2014; 370:495-498

Most vaccines that are in use today have taken at least 30 years to develop.3 The polio vaccine took almost 50 years to develop! On top of that, HIV presents additional scientific challenges to vaccine development:

• HIV evades neutralization and clearance by antibodies.
• There are many different strains of HIV around the world, and the virus mutates over time. The diversity of HIV within a single person living with HIV is greater than the diversity of influenza viruses worldwide.
• Animal models have not yet been shown to reliably predict vaccine efficacy, making selection of "promising" products for human trials difficult.

3 College of Physicians of Philadelphia. The History of Vaccines: A Project of the College of Physicians of Philadelphia.

Many agencies and organizations are working together to develop and test preventive HIV vaccines. These include U.S. government agencies, such as the National Institutes of Health (NIH), foreign governments, universities, charitable foundations, nonprofit organizations, and biotech and drug companies.

HIV vaccine clinical trials require large numbers of participants from all walks of life. Over 35,000 volunteers have participated in HIV vaccine research sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the NIH (NIAID, January 2017).

In 2009, a vaccine regimen tested in Thailand cut new HIV infections by about one third. This gives us hope that we can eventually find a vaccine that works well for everyone.4

Although efforts have not yet produced an HIV vaccine that is ready for licensure, each new research discovery brings scientists closer to that goal.

4 New England Journal of Medicine. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. (December 3, 2009).

B and T cells are two types of immune cells that have the ability to specifically recognize molecular targets. They identify invaders (e.g. bacteria and viruses), mark them for destruction, block them from infecting cells, or kill cells after they have been infected.

After the initial immune response to an infection, the immune system develops memory B and T cells. These memory cells remember specific molecules in the bacteria and viruses and recognize them the next time they enter the body.

Upon subsequent exposure, memory cells produce a faster and stronger immune response to the same invader, protecting the body from infection or severe disease.

Vaccines mimic infection by stimulating the production of memory B and T cells that will recognize the actual infectious agent upon exposure. It can take a few weeks after vaccination for the immune system to develop memory cells.

A preventive HIV vaccine would be effective in preventing people from contracting HIV only if given before exposure to HIV. A person can contract HIV the first time they have sexual contact with another person or engage in injecting drug use. Ideally, HIV vaccination would be recommended at an age before these behaviors typically start, such as during the pre-teen years or early adolescence. However, the vaccine could also be very useful at other ages, such as to protect adults or to protect infants born to mothers living with HIV who continue to breastfeed.

The number of vaccinations needed for HIV protection can only be determined through clinical trials and will depend on the specific vaccine regimen being tested. The ultimate goal is to develop vaccines that require the fewest possible vaccinations. It is possible that first-generation HIV vaccines will require more vaccinations, and that improvements resulting from further research will allow for fewer vaccinations.

Researchers are also looking to see whether HIV vaccines could help people who are already living with HIV. Vaccines used in this way are called therapeutic vaccines. If effective, a therapeutic vaccine would teach the body to control HIV , so the progression from HIV to AIDS would happen much more slowly or maybe even be stopped. We don't know if a vaccine that is found effective at preventing HIV would also be therapeutic. It is possible that different types of vaccines might be needed for HIV prevention and HIV therapy. Researchers are working to develop and test both kinds of vaccines.

All clinical trial participation has both known and unknown risks. Like most licensed and approved vaccines, the HIV vaccines used in clinical trials may cause side effects such as soreness and redness at the injection site, low-grade fever, and body aches. These side effects tend to go away quickly. Other potential risks will vary according to the specific vaccine product. Before volunteering for a trial, potential participants should be sure they understand the risks, which are described in the informed consent process. Any questions can be directed to the study site staff.

No. There is NO risk of getting HIV from the preventive vaccines being tested because they do not contain HIV. They contain only lab-made, synthetic copies that look like pieces of HIV. These synthetic copies are not able to cause infection.5 We do not know if study vaccines will decrease, increase, or not change a participant's chance of contracting HIV if they are exposed to the virus.

Several studies have tested whether HIV vaccines can reduce the risk of getting HIV from another person. In some studies, people who got the vaccine seemed to have the same risk of contracting HIV as people who did not get the vaccine. In one study, people who got the vaccine were at lower risk of contracting HIV than people who did not get the vaccine. In another study, some men who got the vaccine had a higher risk of contracting HIV than men who did not get the vaccine. As soon as researchers noticed this trend, they stopped giving the vaccine. The vaccine in that trial, however, did not cause people to contract HIV; participants in the study who contracted HIV got the virus from another person who had HIV.

5 Cooper, C. J., Metch, B., Dragavon, J., Coombs, R.W., Baden, L. R. (2010). Vaccine-induced HIV seropositivity/reactivity in noninfected HIV vaccine recipients. JAMA, 304.

Studies that test whether an experimental vaccine works are called efficacy studies. Not all vaccine studies are efficacy studies. Early vaccine studies test if the study vaccine is safe to give to people, and whether people are able to take the study vaccine without becoming too uncomfortable. Another important goal of early studies is to test if people’s immune systems respond to the study vaccines. Efficacy studies are done after these smaller, early studies show the vaccine is safe and the immune system reacts to it in the desired ways.

When you go through the informed consent process, you will find out if the study you want to join is an early study or an efficacy study. With all studies, it may take several years before the results are known. Efficacy studies can last as long as 5 years.

Regardless of what the study is looking for (whether it is safety or efficacy), all HIV vaccine studies teach us something important and bring us closer to finding a vaccine that works.

Until vaccine candidates are more advanced in their development, pregnant people will not be accepted as volunteers in HIV vaccine clinical trials. People who plan to become pregnant should postpone becoming pregnant until after the trial. Pregnancy tests are done as part of the screening process and before each immunization. People of childbearing potential must agree to use adequate methods of birth control before and during the immunization period. People who become pregnant during a trial continue to be monitored for safety.

Participants who receive an HIV vaccine in a preventive clinical trial may test positive for HIV antibodies on standard HIV tests, such as ELISA, Western blot, and "rapid tests," even if they do not have HIV.5 This is because the vaccine elicited measurable antibodies to HIV proteins, resulting in a study participant having a vaccine-induced seropositive (VISP) test result. This may also be referred to as vaccine-induced seroreactive test result. The HIV Vaccine Trials Network uses a multi-step algorithm of HIV testing to measure HIV presence directly to determine whether or not someone with VISP truly has HIV. Therefore, testing is provided free of charge for study volunteers, and can be provided even after the study has ended, or if the patient no longer lives near the study site.

An antibody response may be needed for a vaccine to be effective. However, for a participant with VISP, an incorrect HIV diagnosis resulting from standard HIV antibody testing could have significant undesired impacts, including:

• Unnecessary distress
• Unwarranted HIV reporting to public health authorities.
• Compromise of the participant's "blind" HIV vaccine study participation, which is needed for accurate analysis of the vaccine's effect on safety, immunogenicity, and efficacy.
• Inability to donate blood, organs, or tissue.

Because of the possibility of VISP, patients who are current or former HIV vaccine trial participants are counseled not to submit to an HIV test outside of the clinical trial site (unless the trial is finished and the participant received the placebo). The clinical trial sites can test current and former trial participants for HIV using methods that distinguish true HIV from VISP. With the patient's permission, results on the individual's HIV status can be shared with health care providers.

5 Cooper, C. J., Metch, B., Dragavon, J., Coombs, R.W., Baden, L. R. (2010). Vaccine-induced HIV seropositivity/reactivity in noninfected HIV vaccine recipients. JAMA, 304.

HIV vaccine-induced seropositivity (VISP) in HIV-negative vaccine recipients varies substantially depending on the specific vaccine used and the participant's individual response to it. In trials conducted by the HIV Vaccine Trials Network over the last 10 years, the average chance of VISP occurring was about 42%.5 With a few vaccines, VISP has lasted for more than 15 years. For other vaccines, VISP did not occur at all. Because different types of diagnostic tests may be used, VISP can appear at any point after administration of a vaccine candidate, even after completion of the HIV vaccine study. Study volunteers in NIAID-sponsored trials are offered long-term monitoring to watch for VISP; providers should encourage their patients to ask what long-term monitoring/testing is available from the trial sponsors.

5 Cooper, C. J., Metch, B., Dragavon, J., Coombs, R.W., Baden, L. R. (2010). Vaccine-induced HIV seropositivity/reactivity in noninfected HIV vaccine recipients. JAMA, 304.

A person living with HIV who becomes pregnant typically passes HIV antibodies to their baby. This could also apply to vaccine-induced HIV antibodies, which could persist in the baby for a limited time. This has not been shown to happen, and these antibodies would not be expected to pose any risk to the baby. But while present, they could result in a false HIV diagnosis. It is important for someone to know if they have VISP so that their obstetrician can become educated about it prior to delivery so that the adult and their newborn are not mistakenly given anti-retroviral medications.

Preventive HIV vaccines contain lab-made copies of genes or proteins that appear to the immune system like those in the real human immunodeficiency virus, but they don't contain all the elements required to cause infection. Preventive HIV vaccine candidates, like other viral vaccines such as the hepatitis B vaccine, are made with different approaches that may include one or a combination of the following:

• Proteins, or pieces of proteins, such as those found on the outer coating of the virus.
• Viral vector—A way to package HIV (or other) genes inside the shell of another virus, so that the proteins coded by the HIV genes are presented to the immune system. Viral vectors are disabled so that they do not cause disease; they can be non-replicating (they do not make copies of themselves) or replicating.
• DNA vector—HIV genes or gene fragments, usually delivered in a circular DNA molecule called a "plasmid."
• Pseudovirion—Virus-like particle that resembles a virus but does not contain its genetic information and cannot replicate.
• Live bacterial vector—Bacteria engineered to carry HIV genetic material.

In addition, some HIV vaccines being studied also use adjuvants—"immune boosters" that are combined with vaccines to promote an earlier, more potent, and/or more persistent immune response to the vaccine. Adjuvants may allow for a lower vaccine dosage or fewer doses of vaccines to be given, or direct the immune system toward either a B-cell or T-cell response.

Some vaccines, like those for polio, contain whole, killed virus or live, attenuated (weakened) virus, but because of safety concerns, these types of HIV vaccines are not tested in HIV prevention trials.

Vaccine candidates are first tested for safety and activity in the laboratory and then in animals. Human clinical trials of preventive HIV vaccines then occur in three phases:

Phase I — 12 to 18 months, about 20 to 100 participants—A small group of healthy, HIV-negative participants who do not have medical issues that would interfere with evaluation of the safety of the vaccine are selected to participate in trials that evaluate vaccine safety and immune responses elicited by the vaccine.

Phase II — 2+ years, 100–400 participants—If a vaccine has promising safety and early immune response data, HIV-negative participants are enrolled in Phase II studies to continue to test safety and immune responses. The study is not intended to prove efficacy.

In recent years, researchers have done "test-of-concept" trials—also called "Phase IIb" trials—in a few thousand HIV-negative individuals. While these studies are not intended to lead directly to licensure, they can provide important clues as to what may constitute a protective immune response.

Phase III — 3+ years, several thousand participants are enrolled to test a vaccine's safety and efficacy. If data are favorable, these studies can lead to licensure.

To date, only a few Phase IIb and III HIV vaccine trials have been completed, none of which has led to licensure of the vaccines tested. One of them, RV144, a Phase III study carried out in Thailand, demonstrated modest vaccine efficacy: the rate of new HIV infections were about one third lower among participants who received the vaccine regimen compared with participants who received the placebo. These results are helping to guide the future of HIV vaccine research.

"Ownership" of a vaccine depends on the specific patents and licenses for any given vaccine being tested. Many agencies and organizations are working together to develop and test preventive HIV vaccines. These include U.S. government agencies, such as the National Institutes of Health (NIH), foreign governments, universities, charitable foundations, nonprofit organizations, and biotech and drug companies.

To help support HIV vaccine research in your community:

• Learn all you can about HIV vaccine trials in your area so you can answer patients' questions accurately.
• If any of your patients are current or former HIV vaccine trial volunteers and you wish to perform HIV testing as part of their routine health care, please instead ask them to provide you with their HIV test results from their clinical trial site, or encourage them to contact their clinical trial site to arrange for testing. This is because study vaccines can cause the immune system to produce antibodies that can be detected on common HIV diagnostic tests and can be misinterpreted as an indicator of HIV infection. The clinical trials sites use a multi-step algorithm of HIV testing to differentiate between vaccine-induced antibodies and true HIV infection. In NIAID-sponsored trials, this testing is provided free of charge to the volunteer.
• Raise awareness about the potential public health benefits of HIV preventive vaccines among the individuals who come to you for care.
• Know where to refer patients who want more in-depth information about HIV vaccine research.
• If your patients have questions about joining an HIV vaccine study, encourage them to:
• Ask the study investigator questions. A list of questions they may want answered can be found at www.clinicaltrials.gov. The clinical trial site can also provide a copy of the Informed Consent Form and a Frequently Asked Questions document describing the study.
• Carefully review the consent information with your patient to ensure that they understand the purpose of the study, the risks of participation, and their responsibilities as a study participant.
• Encourage the potential study participant to discuss the decision with family, friends, and others whom they trust. With the patient's permission, trial site staff can also talk to these people to help answer their questions.