Enrollment in Merck's ongoing Phase IIb AIDS vaccine trial with the MRKAd5 vaccine candidate has been expanded to include double the number of volunteers researchers originally planned at sites in North America, South America and the Caribbean. The test of concept trial (see September 2005 Primer on Understanding Test-of-Concept Trials) started in January of this year and is a collaboration between Merck, the HIV Vaccine Trials Network (HVTN), and the National Institute of Allergy and Infectious Diseases. Final results are not due until 2008 on the vaccine candidate that uses a viral vector to carry three copies of HIV genes to the immune system.

MRKAd5 has previously generated strong cellular immune responses in humans. But because it uses Ad5, a naturally circulating strain or serotype of the virus that can cause the common cold, researchers thought it might be ineffective in those who have already developed adenovirus-directed immunity (see February 2005 Primer onUnderstanding Pre-existing Immunity). However, the results of now completed studies show that MRKAd5 is able to generate immune responses even in volunteers with high levels of pre-existing immunity to Ad5, leading the company to expand the trial to include 1,500 additional volunteers that have high levels of Ad5 antibodies at the start of the trial.

"We have found that the vaccine candidate consistently produces a detectable immune response in 60-70% of people," says Robin Isaacs, executive director of vaccine research at Merck. "If we continue to find that people with high Ad5 antibody levels have a good response to the vaccine then it may make the candidate vaccine useful for a larger number of people."

The Vaccine Research Center (VRC) and HVTN have also started a Phase II clinical trial with a two-part vaccine including a DNA-based vaccine candidate followed by a boost with an adenovirus serotype 5 vector. This vaccine candidate differs from the ongoing Phase IIb Merck trial (see above) because it uses a different version of the Ad5-based vaccine candidate and also first uses a DNA vaccination to prime the immune system. The VRC has observed an improved response when the DNA vaccine candidate and Ad5 are administered in a prime/boost manner (seeAIDS vaccine researchers find promise).

This study, HVTN 204, seeks to enroll 480 volunteers at sites in North and South America, Africa, and the Caribbean in order to determine the safety and level of immune responses generated by the candidate as compared to an inactive substance known as placebo. Volunteers that are randomly selected to receive the DNA/Ad5 candidate will receive 3 injections of the DNA and a single Ad5 boost over a period of 6 months. Half of the trial participants will be enrolled at HVTN sites in the Americas as well as in Haiti and Jamaica, while the other half will be at sites in South Africa and Botswana.

This vaccine is the first developed at the VRC to move into the second stage of clinical testing. The US-based company Vical is manufacturing the DNA portion of the vaccine and the adenovirus vector was developed by the VRC in collaboration with GenVec. The DNA/Ad5 candidate includes HIV genes from subtype A and C, which are the most prevalent forms of the virus in Africa and parts of Asia. Volunteers can not become HIV infected from this vaccine candidate.

This same candidate will be evaluated further in a series of Phase I and II clinical trials in Africa in cooperation with IAVI and the US Military HIV Research Program, pending regulatory approvals in these countries.

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All articles written by Kristen Jill Kresge

Why is voluntary counseling and testing for couples an important process for recruiting women into vaccine trials?

Voluntary counseling and testing (VCT) is the process used by community-based clinics and trial sites to offer HIV testing, education, and counseling to individuals who want to know whether they are HIV infected or not. The VCT process involves learning about how HIV is transmitted and what behaviors put a person at risk for infection, in addition to the meaning and implications of the individual's test results.

There are several different types of VCT depending on whether the service is administered at a community clinic, as an initial screening for participation in an AIDS vaccine trial, or before joining a research study (see April Primer onUnderstanding Research Voluntary Counseling and Testing). There are also different types of VCT used to target specific populations. One involves testing and counseling couples that are married or living together, rather than individuals, and is therefore referred to as couples VCT (CVCT).

What is different about a CVCT session?

During a traditional VCT session a person is given information on what can put them at risk for HIV infection. In a couples session the counselor works with the couple to find out how their behaviors work together to influence their risk. This involves opening a dialogue between partners about their sexual activities and empowering them to communicate their shared risks, which can be complicated in countries where such discussion may be taboo. Nurse counselors encourage each person to take responsibility for their behaviors and inform them about ways the can limit their risk, such as using condoms. CVCT is a complex process because counselors are working with the needs and emotions of two people whose risks for HIV infection can involve others outside of their relationship.

A couple will go through the entire process together, including completing the consent documents (see June Primeron Understanding Informed Consent), pre-test counseling, HIV testing, and post-test counseling. The consent for participation in CVCT requires that the partners agree to receive their HIV test results together, but these results remain confidential outside of the couple.

Dependent on their test results, the nurse or counselor will work with the couple during the post-test counseling to help them make a plan for the future. In testing and counseling couples there are three scenarios: both partners are HIV infected, both are uninfected, or one is infected and the other is uninfected. This last case is what researchers refer to as a discordant couple. Counselors can work closely with discordant couples to create an atmosphere where the partners support each other, both through this process and in the future, while limiting the uninfected partner's risk of becoming HIV infected.

Working with couples rather than individuals has been shown to have many positive effects, including increased condom use and a lower rate of new HIV infections between partners.

Why is CVCT an important recruitment tool for AIDS vaccine trials?

To find out if an AIDS vaccine candidate is effective at blocking HIV transmission, researchers must administer the vaccine candidate to groups or cohorts of people who are at high risk of becoming infected with HIV. This requires testing the vaccine in countries or communities where there is a high prevalence of infection. In Africa, couples are at the highest risk for HIV infection and researchers estimate that between 60-70% of HIV transmission occurs within couples that are married or living together.

African couples are therefore an important cohort for evaluating the efficacy of AIDS vaccine candidates and CVCT is one way to enroll volunteers that are at high risk of HIV infection from heterosexual transmission. This may not be true on other continents like Asia, where HIV transmission is still mainly occurring in the more traditional high-risk groups such as sex workers or injection drug users.

How can CVCT be used to recruit women for vaccine trials?

CVCT is an important way for researchers to reach out to more women about accessing counseling and testing services as well as possibly joining a vaccine trial (see AIDS vaccine researchers find promise). In recent years the number of people utilizing VCT services in some areas of sub-Saharan Africa has increased dramatically, mainly because of new treatment programs that offer people life-saving drugs if they are found to be HIV infected. Despite being more vulnerable to infection, women remain underrepresented at many VCT sites.

Counseling and testing partners together can empower women to access VCT services, while avoiding discrimination or even possible violence from their husbands or communities. At some sites counselors will invite couples who have received CVCT to come for focus groups to see how they feel about possibly enrolling in a trial. Couples can learn about the vaccine candidate being tested and find out what it is like to volunteer for an AIDS vaccine trial.

One of the earliest centers to implement CVCT was a clinic in Kigali, Rwanda run by Projet San Francisco and Susan Allen, a researcher from Emory University who has established one of the largest couples counseling centers in Africa. This site started screening couples because women requested that their husbands also be tested. Of the original 1,500 women that were seen at the Kigali center, 1,000 were able to convince their husbands or partners to join them. The nurse counselors are now preparing for the site's first AIDS vaccine trial.