Preventive HIV Vaccine Research: Information for Health Care Providers
More than 1.1 million people in the United States are living with HIV, and more than 600,000 U.S. lives have been lost as a result of HIV/AIDS-related illness.1 Treatment can slow disease, but there is no cure for HIV/AIDS. Prevention is essential.
Biomedical research has provided valuable scientific information about the basic biology of HIV and the immune response to HIV infection. However, questions still remain about how the virus attacks the body and how the body defends itself. A more complete picture of how HIV infection occurs and the body's response to it can help in developing vaccines to prevent infection or stop the progression of illness. Such vaccines are part of a "toolbox" of HIV prevention strategies that could be used in various combinations with populations at risk for HIV infection.
Your patients trust you to provide credible, timely information—including information about HIV vaccine research.2 What you know about HIV vaccine research, and the attitude with which you convey that information, can have a tremendous influence on whether your patients support and/or participate in HIV vaccine trials.3
To help prepare you for conversations about HIV vaccine research, this fact sheet answers some of the common questions your patients—and you—might have about preventive HIV vaccine development and testing.
There is no cure for HIV/AIDS. Although the availability of antiretroviral therapy has dramatically reduced AIDS-related deaths in the United States, these treatment regimens can be complex and costly, and some people experience side effects. In addition, HIV can develop resistance to antiretroviral drugs, particularly if individuals do not take the drugs on a regular and continuous basis. Effective treatment is dependent on long-term patient compliance; 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 hope for controlling and/or ending the AIDS epidemic.
- 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.
- 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, both those at low risk and those at higher risk of contracting HIV. About 30,000 volunteers have participated in HIV vaccine research sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the NIH.4
- Most recently, in 2009, a vaccine regimen tested in Thailand cut HIV infections by about one third. This gives us hope that we can eventually find a vaccine that works well for everyone.5
- Although efforts have not yet produced an HIV vaccine that is ready for licensure, each new research discovery brings scientists closer to that goal.
On top of that, HIV presents additional scientific challenges to vaccine development:
- HIV evades neutralization and clearance by antibodies.
- There are many different types of HIV and the virus changes over time. The diversity of HIV viruses within a single infected person is greater than the diversity of influenza viruses worldwide.
- Animal models have not yet been shown to accurately predict vaccine efficacy, making selection of "promising" products for human efficacy trials difficult.
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.
- 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.
- 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.
National Institute of Allergy and Infectious Diseases: www.niaid.nih.org
Be the Generation: bethegeneration.org
HIV Vaccine Trials Network: www.hvtn.org
International AIDS Vaccine Initiative: www.iavi.org
AVAC, Global Advocacy for HIV Prevention: www.avac.org
Clinical Trial Participation
To gather the best data about vaccine safety and effectiveness, preventive HIV vaccines are tested among individuals from diverse populations—including those of different sexes, races, ethnicities, and socioeconomic backgrounds and with different environmental factors and potential routes of HIV transmission. The majority of studies (Phase I studies) enroll persons at low risk of HIV, whereas efficacy trials may be designed to enroll only persons at higher risk for HIV infection. Individuals interested in joining a study do not necessarily need to be at high risk for HIV infection.
Recruitment strategies for HIV vaccine clinical trials vary by trial purpose, location, and target population. Past recruitment strategies have included print ads, online ads, social media sites, outreach by community organizations, outreach in venues frequented by the target population (such as nightclubs), referral by friends or health care providers, and announcements in local news media. Individuals interested in participating in a clinical trial can search for studies in their area at ClinicalTrials.gov.
The age of HIV vaccine clinical trial participants varies, depending on the specific trial protocol. The usual range is 18-45 or 18-50 years of age. The age range of participants will be determined by the objectives of the study, combined with ethical and safety considerations.
The HIV/AIDS epidemic affects people from all walks of life. It is in everyone's best interest that we find an effective vaccine to prevent HIV infection that has been tested in diverse populations. Participating in vaccine research—and encouraging others who do—helps further efforts to find an effective HIV vaccine and, ultimately, control or stop the HIV/AIDS epidemic. Though we do not know whether getting the study vaccines would benefit a participant in any way, being in the study might still help participants in some ways. The counseling that a participant gets as part of the study may help him/her avoid getting HIV. Also, the lab tests and physical exams that one gets while in this study might detect health problems s/he doesn't yet know about.
All clinical trial participation carries both known and unknown risks. Like most vaccines, the HIV vaccines used in clinical trials may cause side effects such as soreness 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 staff.
There is NO risk of getting HIV from the preventive vaccines being tested in people because they do not contain the HIV virus. They contain only pieces of HIV that are not sufficient to cause infection.8 We do not know if study vaccines will decrease, increase, or not change a participant's chance of becoming infected with 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 getting HIV as people who did not get the vaccine. In one study, people who got the vaccine seemed to have a lower risk of getting HIV than people who did not get the vaccine. In another study, some men who got the vaccine had a higher risk of getting 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 HIV infection; participants in the study who were infected with HIV got the virus from another person who was infected.
Until vaccine candidates are more advanced in their development, pregnant women will not be accepted as volunteers in HIV vaccine clinical trials, and women who plan for a pregnancy should postpone becoming pregnant until after the trial. Pregnancy tests are done as part of the screening process and before each immunization. Women of childbearing age must agree to use an adequate method of birth control before and during the immunization period. Women who become pregnant during a trial continue to be monitored for safety, but are no longer vaccinated.
Preventive HIV vaccines contain genes or proteins that appear to the immune system like those in the real HIV 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:
- Viral surface proteins—Proteins that make up 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 towards 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-uninfected people.
Test-of-concept and efficacy trials enroll HIV-negative individuals who are at risk for HIV infection. Participants are randomly assigned to receive either a vaccine candidate or a placebo control. Current trials are designed and conducted with a "double blind"—that is, neither the participants nor the researchers know who gets the vaccine and who gets the placebo until the end of the trial. All participants receive ongoing HIV risk-reduction counseling and other proven HIV prevention measures, such as condoms. Even so, some participants become HIV-infected over the course of the trial. When the trial ends, researchers compare the HIV infection rates among participants who received the vaccine candidate with infection rates among participants who received a placebo to see if there were fewer infections among the group who received the vaccine.
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.
"Ownership" of a vaccine depends on the specific patents and licenses for any given vaccine being tested.
Preventive HIV vaccines are intended for individuals who are not infected with HIV, to prevent such infection. Vaccines are also being tested in HIV-infected individuals to see if they can help the immune system to slow disease progression and delay the onset of AIDS. A vaccine used in this way is called a "therapeutic" vaccine. The biology of preventive and therapeutic vaccines is different, as HIV alters and ultimately destroys the immune system after infection. Different immune responses may be responsible for controlling viral replication as compared to preventing new infections. Therefore, we don't know if a vaccine that prevents HIV infection would also be therapeutic for HIV-infected individuals, and vice versa. To find out whether a vaccine works for any given population, researchers must thoroughly test it in appropriate clinical studies. Researchers are working to find therapeutic as well as preventive vaccines.
When a safe and effective preventive HIV vaccine becomes available, at what age will vaccination start?
A preventive HIV vaccine would be effective in preventing infection only if given before exposure to HIV. A person can be infected with 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 HIV-infected mothers who continue to breastfeed.
Research Safety and Ethics
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 are at low risk for getting HIV and who do not have other medical problems that 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.
Participants in these studies can be at low or high risk for HIV
infection, but the study is not intended to prove efficacy.
- In recent years, researchers have done "test-of-concept" trials—also called "Phase IIb" or "intermediate-sized" trials—in a few thousand HIV-negative, at-risk 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—In this final and most time-consuming phase, thousands of at-risk 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: HIV infections dropped by about one third among participants who received the vaccine compared with participants who received the placebo.5 These results are helping to guide the future of HIV vaccine research.
How do I know that the research is following local and international cultural and ethical standards?
Because of the history of unethical research in some communities,
people in minority populations may be distrustful of clinical trial
participation. Today's research studies in people, however, have
safeguards in place to protect the safety and well-being of research
participants. Participant safety is of utmost importance.7
- Clinical trial researchers have to follow strict ethical and legal standards. In addition, most clinical research must follow federal laws that protect study participants.
- Participants can leave the study at any time.
- All of the known or anticipated risks as well as the possibility of unknown risks are fully described as part of the informed consent process. All participants must sign a consent form before the clinical trial starts. Participants are encouraged to ask questions before signing the consent form and discuss their potential study participation with others prior to enrollment.
- A clinical trial follows a carefully designed protocol, a study plan that details what researchers will do. The protocol undergoes rigorous review by several regulatory bodies, including a local Ethics Committee or Institutional Review Board.
- A local group of independent experts regularly reviews the clinical trial to oversee patient safety and makes sure the researchers follow the protocol.
- Researchers report the results of the trial at scientific meetings, to medical journals, and to various government agencies. Participants' names are not included in any of these reports.
- Side effects are reported to the study investigator, who takes any medical action needed. Side effects are also reported to study reviewers who monitor the study closely for participant safety.
- Any study conducted in the United States with a research product such as an experimental HIV vaccine must be reviewed by the U.S. Food and Drug Administration for the safety of the product and the soundness of the study questions and design.
Will an investigational vaccine make someone test positive for HIV antibodies, and what does that really mean?
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 are not
infected with HIV.9 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. There are other tests conducted by vaccine staff that
measure HIV presence directly to determine whether or not someone with
VISP is truly infected with HIV. To avoid confusion, please request HIV
test results from the study site rather than testing your patient using
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 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 infection using methods that distinguish HIV infection from VISP. With the patient's permission, results on the individual's HIV status can be shared with health care providers.
HIV vaccine-induced seropositivity (VISP) in uninfected HIV 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%.11 With a few vaccines, VISP has lasted for more than 15 years. For other vaccines, VISP did not occur at all. VISP can appear at any point after administration of a vaccine candidate, even after completion of the HIV vaccine study. Volunteers should be 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.
Will a woman who participates in HIV vaccine research and later becomes pregnant pass the HIV antibodies to her children?
A woman with HIV infection typically passes HIV antibodies to her
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
There is no evidence that participation in HIV vaccine research leads individuals to engage in behaviors that increase their HIV risk.10 In fact, data from several trials completed to date shows that risk behaviors usually decline overall, particularly during the vaccination period when study visits are more frequent. Participants in clinical trials are continually counseled on how to reduce their risk of being exposed to HIV.
It is important to remember that once there is a vaccine, it may not be 100% effective. Any HIV vaccine—even one that is highly effective in preventing HIV—should be offered along with other state-of-the-art prevention tools to increase protection against HIV.
1 Centers for Disease Control and Prevention (2008). HIV Surveillance Report, Vol. 20. Retrieved from http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.
2 Alexander, S. A. (2009). Attitudes and awareness of HIV vaccine research in HIV uninfected MSM in four U.S. cities: Rochester, Boston, San Francisco and Philadelphia. Retrovirology , 6(3). Retrieved from http://www.retrovirology.com/content/6/S3/P229.
3 Stone, V. E., Mauch, M. Y., Steger, K. A. (1998). Provider attitudes regarding participation of women and persons of color in AIDS clinical trials. Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology, 19(3). Retrieved from http://journals.lww.com/jaids/Abstract/1998/11010/Provider_Attitudes_Regarding_Participation_of.6.aspx. 4 Source: NIAID, [provide date information was last updated]
5 National Institute of Allergy and Infectious Diseases. HIV Vaccine Regimen Demonstrates Modest Preventive Effect in Thailand Clinical Study. (September 24, 2009). Retrieved from http://www.niaid.nih.gov/news/newsreleases/2009/pages/thaivaxstudy.aspx.
6 College of Physicians of Philadelphia. The History of Vaccines: A Project of the College of Physicians of Philadelphia. Retrieved from http://www.historyofvaccines.org/content/timelines/all.
7 National Institute of Allergy and Infectious Diseases. Clinical Studies and Vaccine Safeguards. (August 2010). Retrieved from http://www.niaid.nih.gov/Volunteer/VRC/Pages/safeguards.aspx.
8 National Institute of Allergy and Infectious Diseases. HIV Vaccines Explained. (August 2010). Retrieved from http://www.niaid.nih.gov/Volunteer/VRC/Pages/safeguards.aspx.
9 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.
10Bartholow, B. N., Buchbinder, S., Celum, C., Goli, V., Koblin, Beryl, Para, M., Marmor, M., Novak, R. M., Mayer, K., Creticos, C., Orozco-Cronin, P., Popovic, V., Mastro, T. D. (May 1, 2005). HIV sexual risk behavior over 36 months of follow-up in the world's first HIV vaccine efficacy trial. Journal of Acquired Immune Deficiency Syndromes, 39 (1). Retrieved from http://journals.lww.com/jaids/Abstract/2005/05010/HIV_Sexual_Risk_Behavior_Over_36_Months_of.13.aspx11Cooper, C.J., Metch, B., Dragavon, J., Coombs, R.W., Baden, L.R., NIAID HIV Vaccine Trials Network (HVTN) Vaccine-Induced Seropositivity (VISP) Task Force. (2010). Vaccine-Induced HIV Seropositivity/Reactivity in Noninfected HIV Vaccine Recipients. The Journal of the American Medical Association, 304(3), 275-83.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Institute of Allergy and Infectious Diseases
Division of AIDS