February 8, 2007

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1.		Briefly describe this HIV vaccine trial known as HVTN 503.
		This clinical trial, known as HVTN 503, is designed to evaluate the safety and preliminary efficacy of an experimental HIV vaccine in up to 3,000 people in South Africa, making it the largest HIV vaccine trial in Africa to date. In South Africa, the trial is known as Phambili, the Xhosa word for "moving forward.”
2.		When did the trial begin?
		HVTN 503 began enrolling and vaccinating participants in January 2007.
3.		Who is conducting the trial?
		The trial is being conducted jointly by the South African AIDS Vaccine Initiative (SAAVI) and the HIV Vaccine Trials Network (HVTN). The HVTN, funded by the National Institute of Allergy and Infectious Diseases (NIAID), is a global partnership of scientists and institutions whose goal is to accelerate the search for an HIV vaccine. SAAVI was formed in 1999 to coordinate the research, development and testing of AIDS vaccines in South Africa. The study is led by Glenda Gray, MBBCH, FCPaeds (SA), of the Perinatal HIV Research Unit, University of the Witwatersrand, based at the Chris Hani Baragwanath Hospital in Soweto. James Kublin, M.D., M.P.H., of Fred Hutchinson Cancer Research Center, Seattle, serves as study co-chair.
4.		Who is supporting the HVTN 503 trial?
		HVTN 503 is supported by NIAID, part of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. The trial is also supported in part by SAAVI.
5.		What is the vaccine being studied?
		Merck & Co. Inc. (Whitehouse Station, NJ) is providing the study vaccine, called MRKAd5 HIV-1 gag/pol/nef. The vaccine is based on a weakened adenovirus, a virus that normally causes upper respiratory tract infections such as the common cold. The vaccine is a mixture of three weakened adenoviruses that act as vectors, or packaging systems, for efficiently transporting into the body and presenting to the immune system three HIV genes: gag, pol and nef. The genes are based on a subtype of HIV known as clade B. The same vaccine is currently being evaluated in a companion study, known as HVTN 502/Merck 023, that began two years ago and is ongoing in the United States, Canada, South America, Australia and the Caribbean.
6.		Can the study vaccine cause HIV infection?
		No, the study vaccine cannot cause HIV infection because it contains only three HIV genes and not the entire virus, either live or killed. In addition, the weakened adenovirus vector in the vaccine cannot cause a respiratory infection.
7.		What is the design of this trial?
		HVTN 503 is a randomized, placebo-controlled, double-blinded Phase IIb clinical trial. It is designed to further evaluate the safety of the vaccine and to obtain preliminary information on its efficacy. The trial will enroll up to 3,000 HIV-negative, sexually active men and women at high risk for HIV infection recruited at five research sites located in areas of South Africa where there is a high prevalence of HIV infection. After an initial HIV screening, confirmation of eligibility criteria, and informed consent, participants will be randomly assigned to receive either three doses of the study vaccine or placebo over the course of six months. Neither the trial participants nor the scientists will know who is getting the study vaccine and who is getting the placebo until the trial is completed. After completing the series of vaccinations, participants will be tested for HIV infection every six months for the remainder of the trial (approximately four years). All trial participants will be counseled to reduce risk behavior at each visit, given condoms, receive access to care and treatment for sexually transmitted diseases, and be linked to prevention services. In addition because recent findings indicate that medical circumcision can reduce the risk of HIV transmission from women to men, access to medical circumcision will also be provided to men in the trial who desire it. Despite all these measures, it is expected that some trial participants will become infected with HIV from engaging in risky sexual behavior. Individuals who become infected with HIV during the trial will be followed for an additional 18 months after their diagnosis and will be referred to an appropriate health care provider for access to medical care, treatment, and counseling.
8.		What is a Phase IIb clinical trial?
		HVTN 503 is known as a Phase IIb “test-of-concept” trial, the first such vaccine study in South Africa. Such a trial is designed to provide preliminary information on vaccine efficacy and how it may be attained, and thus enable researchers to decide whether or not to conduct a larger Phase III efficacy trial of the vaccine that may lead to licensure.
9.		What are the objectives of this trial?
		The primary objectives of this trial are to obtain more information about the safety of the vaccine, and to learn if the study vaccine can decrease the risk of acquiring HIV infection or lower the amount of HIV in the blood early on if a person becomes infected with HIV. In addition, the trial will investigate whether a vaccine based on one HIV subtype, or clade, might be effective in regions where another subtype is predominant. In this case, the test vaccine, based on clade B HIV, is being tested in South Africa, where clade C virus is predominant. The rationale for testing this clade B vaccine in South Africa is that data from other trials indicate that this vaccine can induce cross-clade immunogenicity in the majority of volunteers. Immune responses in the first several hundred volunteers will be assessed to ensure the vaccine induces promising immune responses in this population against the clade C virus before proceeding to full enrollment.
10.		Who is eligible to participate in this trial?
		Participants must be healthy adults between 18 and 35 years old, sexually active in the last six months, and HIV-negative. All participants must meet certain medical and non-medical criteria for eligibility. Volunteers are carefully screened to make sure they meet the eligibility requirements. Pregnant or breastfeeding women are not allowed to join the trial. Women who join the trial must agree to avoid pregnancy (use an effective contraception) starting at least 21 days before they get their first injection and continuing until one month after their last study injection, which is six months after joining the study.
11.		Where are the clinical trial sites located?
		The study plans to recruit volunteers at five sites in South Africa located in Soweto, Cape Town, Klerksdorp, Medunsa and Durban.
12.		Has this vaccine been studied before and found to be safe?
		This vaccine has already been studied for safety in Phase I and Phase II trials in the United States, Canada, Australia, the Caribbean and South America. As of January 2007, more than 1,800 individuals have received at least one injection of the MRKAd5 vaccine in trials that have enrolled more than 3,000 people. Some people who received the study vaccine experienced pain, redness, tenderness or swelling at the injection site. Some also experienced fever, nausea, headache, chills, tiredness and sore throat. These symptoms, which all resolved, are common reactions to vaccinations and are not a safety concern. Some trial participants who received the vaccine had a temporary lowering of their white blood count. However, these changes did not cause symptoms, and white blood cell levels generally returned to their usual values without treatment. While scientists believe that there are no serious safety risks, unexpected problems could arise. This is why the study vaccine, like any new drug or vaccine, needs to be tested in a controlled clinical setting with careful monitoring of participants.
13.		How will the safety of the participants be monitored?
		All participants will be closely monitored for any adverse reactions, and any possible safety concerns will be addressed immediately. Several groups have reviewed this study protocol to make sure the trial is being done according to appropriate scientific, regulatory and ethical standards. These groups include the Medicines Control Council of South Africa; the U.S. Food and Drug Administration; the South Africa Department of Agriculture; the NIAID; the HVTN; Merck & Co. Inc.; and the institutional biosafety and ethics committees at each trial site. In addition, the independent NIAID Data and Safety Monitoring Board (DSMB) will also review the unblinded data on safety, immune responses and efficacy from HVTN 503 on an ongoing basis and may recommend the trial be modified should there be a significant safety concern or should a result be reached.
14.		How long will it take to find out the study results?
		HVTN 503 is expected to last four years. The results will be available after the study is completed.
15.		How has the local community been involved in the design and development of this trial?
		Community members have been involved throughout the trial planning process to ensure that the rights and needs of participants are being met. Community members serve on community advisory boards (CABs) associated with sites participating in this study. In addition, CAB members have access to general data on the safety of and immune responses to the vaccine.
16.		What factors might affect whether or not this trial continues?
		Because HVTN 502 is currently studying the same vaccine as HVTN 503, data generated from that trial may affect the course of HVTN 503 and how scientists plan to further study the investigational vaccine. Data from HVTN 502, if and when significant, will be shared with the NIAID DSMB to help guide and determine the direction of HVTN 503. In addition, after approximately 600 volunteers have been enrolled in HVTN 503, the NIAID DSMB will conduct a preliminary review of the trial data on the immune responses to the vaccine. Based on this preliminary analysis, the NIAID DSMB will make a recommendation about whether the trial should continue to completion.
17.		If this candidate vaccine is already being studied in HVTN 502, why is this study (HVTN 503) being done?
		Because some vaccine studies have observed potentially significant cross-clade immunogenicity, a primary objective of HVTN 503 is to determine whether the study vaccine, which is based on clade B HIV, could potentially be effective in regions where clade C virus is predominant. HVTN 502 is testing the study vaccine in a region where clade B is predominant, whereas HVTN 503 is being conducted in a region where clade C is predominant.  Additionally, the South African study is likely to provide important new data on how the test vaccine might work in a predominantly heterosexual HIV epidemic. Most participants in HVTN 502 were men who have sex with men, but the trial also enrolled heterosexual men and women. In contrast, HVTN 503 plans to enroll equivalent numbers of heterosexual men and women, which will enable researchers to evaluate the vaccine’s performance by gender. In addition, research using the study vaccine has already provided some promising results from smaller clinical trials. Researchers are now interested in studying the vaccine in a larger group of participants to determine whether it can decrease the risk of acquiring HIV infection or if it can lower the amount of HIV in the blood early on in infection. This is an important step in the process of developing an effective HIV vaccine and will provide a preliminary assessment of the efficacy of this vaccine needed to determine whether this candidate vaccine should move to a Phase III trial that may lead to licensure.

Media inquires can be directed to the NIAID News and Public Information Branch at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

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