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VAX-3(11)-November-2005

Vol. 03, No. 11 - November 2005

SPOTLIGHT:

Drugs that treat herpes may help reduce HIV transmission

SPOTLIGHT:

A clinical trial evaluating the safety and immune responses generated by a candidate AIDS vaccine known as tgAAC09 recently began at three sites in South Africa, including clinics in Soweto, Cape Town, and Medunsa. This is the country's first Phase II AIDS vaccine trial and investigators will enroll and follow 78 volunteers over a period of 18 months.

The vaccine candidate uses an adeno-associated virus vector to deliver HIV fragments from subtype C, the most common subtype of HIV in southern and eastern Africa, into the body. Phase I trials with tgAAC09 were conducted in Belgium, Germany, and India. Other arms of this Phase II trial will occur in Zambia and Uganda, after receiving regulatory approval in these countries.

The candidate was developed and manufactured by Targeted Genetics Corporation in Seattle based on work by Philip Johnson when he was a researcher at the Children's Hospital in Ohio. The South African trial is collaboration between Targeted Genetics and IAVI and is an important advancement in a country where 25 million people are estimated to be HIV infected.

South Africa is also hosting another important HIV prevention trial involving the microbicide candidate PRO 2000, a vaginal gel consisting of a synthetic compound that binds to HIV and may prevent it from infecting target cells. This Phase III trial will enroll over 10,000 women volunteers in South Africa, Uganda, Tanzania, and Zambia, making it the largest microbicide trial to date. This trial is being coordinated by the UK Medical Research Council.

GLOBAL NEWS

A Phase I vaccine trial of a two-part vaccine developed by the Vaccine Research Center (VRC) of the US National Institutes of Health (NIH) recently began enrolling volunteers at a site in Kigali, Rwanda. This is the first AIDS vaccine trial to take place in the country and is being conducted by the NIH, IAVI, and Project San Francisco, a research organization that has been working in Kigali for almost 20 years.

The trial will test a two-part vaccine that first uses a DNA vaccination to 'prime' the immune system. The DNA fragment carries several HIV proteins from subtypes A, B, and C, the most common in Africa and parts of Asia. This is followed by a 'boost' vaccination with an adenovirus serotype 5 (Ad5) vector carrying several HIV genes. The vaccine candidates can not cause infection with either HIV or adenovirus.

The candidates were developed at the VRC and yielded promising results in Phase I trials in the US. Several other Phase I and II trials testing the DNA/Ad5 candidates are either ongoing or expected to soon begin in several other countries including HVTN sites in North and South America, southern Africa, and the Caribbean. The prime-boost approach will also be tested at other clinical trials sites in partnership with IAVI and the US Military HIV Research Program.

"I'm really excited and pleased that these groups have taken the considerable effort to harmonize their trial plans," says Gary Nabel, director of the VRC. "Each of these organizations has a special strength," he adds, allowing the vaccine to be tested in different communities.

GLOBAL NEWS

A vaccine to protect women from infection with human papillomavirus (HPV)—a virus that causes cervical cancer and genital warts—was found to be 100% effective at preventing pre-cancerous lesions associated with the strains of the virus that are contained in the vaccine. This is the first report from a large-scale efficacy trial with Merck's HPV vaccine, known as Gardasil.

In this Phase III trial (FUTURE II) 12,167 women aged 16-26 were inoculated at 90 sites in Brazil, Colombia, Denmark, Finland, Iceland, Mexico, Norway, Peru, Poland, Singapore, Sweden, the UK, and the US. Women in the trial received up to three injections. Gardasil is a virus-like particle (VLP) vaccine consisting of a single HPV protein that self-assembles into an empty shell and closely resembles a virus particle. Proteins from 4 strains of HPV are included; strains16 and 18 are responsible for over 70% of cervical cancer cases worldwide, while 6 and 11 cause more than 90% of genital warts. The vaccine can not cause HPV infection because the whole virus is not included in the vaccine.

Merck is now in the process of preparing its application to the US Food and Drug Administration for approval and licensure to market and sell the first cervical cancer vaccine. Cervical cancer is one of the leading cancers among women and there are more than 290,000 mortalities associated with it annually. Many of these deaths occur in developing countries where there are few screening programs to provide women with regular Pap tests that can detect cervical lesions caused by the virus.

"Where the vaccine is really needed is in developing countries," says Jessica Kahn, of the Cincinnati Children's Hospital. "It could have a tremendous impact there on mortality rates." Another HPV vaccine, developed by GlaxoSmithKline Biologicals in Rixsensart, Belgium is also in Phase III clinical trials.

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All articles written by Kristen Jill Kresge

PRIMER

How can participation in an AIDS vaccine trial affect HIV test results?

HIV testing is an important first step for individuals interested in participating in an AIDS vaccine trial. All potential volunteers are tested for HIV infection because only HIV-uninfected individuals can join clinical trials of preventive vaccines. Eligible volunteers that choose to be in a vaccine trial will then be tested for HIV routinely throughout the study, which can last several years.

How does an HIV test show if a person is infected?

There are several different types of HIV tests and the type used depends on the clinic or trial site. The traditional HIV test is called an antibody test because it detects antibodies against HIV that are circulating in the blood, saliva, or urine, without actually identifying the presence of the virus. Antibodies are proteins produced by the immune system that target pathogens like viruses or bacteria. The most common tests look for HIV-specific antibodies in the blood and are the EIA (enzyme-linked immunoassay) or ELISA (enzyme-linked immunosorbent assay). Different HIV testing kits are able to detect antibodies directed toward different parts of HIV. Traditional antibody tests require full blood samples and results are usually available in a few days or weeks.

If an antibody test indicates that a person is HIV infected then a more stringent test must also be performed. This confirmation test can either be a Western Blot or an indirect immunoflourescence assay (IFA). The combined results of both the antibody and Western Blot tests are over 99% accurate. This high level of accuracy means that there are few people who are not HIV infected that have a positive test result (false positive) and few people who are HIV infected that have a negative test result (false negative).

The antibody tests are highly sensitive and can detect very small quantities of antibodies but it can take anywhere from 14 days to 6 months after a person is infected with the virus for antibodies to appear. Because of this "window period" where a person can actually be HIV infected but not have sufficient antibodies to register on a test, it is important for volunteers in a vaccine trial to be tested at regular intervals.

Recently many trial sites worldwide have started using "rapid" HIV tests. These tests require only a drop of blood from a finger prick to detect antibodies to HIV and results are available in only 15-30 minutes. The rapid tests are 99.6% accurate so there are few false-positive or false-negative results. At many vaccine trial sites nurses will conduct 2 rapid tests simultaneously to determine if the volunteer is HIV infected. If both are negative then no confirmatory test is needed, but if at least one of the rapid tests is positive then a Western Blot is required to confirm infection. There are also rapid tests that use saliva samples gathered from a cotton pad placed in the mouth instead of blood. Saliva only contains antibodies to HIV, not HIV itself, and the virus can not be transmitted through this fluid.

What if a vaccine candidate generates antibodies to HIV?

Many AIDS vaccines that are tested in clinical trials can make the immune system produce antibodies against multiple components of HIV. This is a sign that the vaccine candidate is inducing an immune response. Importantly, none of the vaccine candidates can cause HIV infection because they don't contain the whole virus but only parts of genes.

It is possible that a person who volunteers for an AIDS vaccine trial could have produced antibodies toward HIV that would be detectable by an HIV test, but without actually being HIV infected. If the antibodies are in response to the vaccine candidate then the test result is considered a false positive.

During a vaccine trial volunteers will be counseled to be HIV tested only at the study site. This is important because researchers at the study site can do specific tests to distinguish between a positive antibody test result from the vaccine candidate and one from an actual HIV infection obtained through exposure in the community. Most HIV tests are designed to identify antibodies that target certain regions of the virus, so nurses at the site can use very specific tests that only detect antibodies towards components of HIV that are not included in the vaccine.

Researchers at the study site can also do other tests known as polymerase chain reaction (RNA or DNA PCR) or p24 antigen tests that actually detect the presence of the virus and not antibodies to confirm infection. These tests measure the amount of virus in the body and can help researchers easily determine if the person was infected through exposure to HIV in their community. Any volunteer that is tested away from the trial site should notify the clinic that they have participated in an AIDS vaccine trial so that the proper tests can be performed.

What are the implications of false-positive HIV test results?

Researchers are unsure how long the antibodies generated from a vaccine candidate will last. Volunteers in vaccine trials that have positive test results, even if false, during routine testing could face potential discrimination when applying for insurance or future employment and could have difficulty with obtaining travel visas or going through immigration. People with a positive HIV test are also prohibited from donating blood and can face social stigmatization. These potential difficulties are discussed with each volunteer during the informed consent process before the vaccine trial begins. Investigators at trial sites can also provide volunteers with a letter, if requested, stating that they are participating in an AIDS vaccine trial and were not HIV infected as of a certain date.

Some organizations that are running vaccine trials will provide volunteers with a photo identification card and a contact they can call at anytime to help them to resolve conflicts over whether or not they are HIV infected. This process may not be sufficient when much larger numbers of people are participating in AIDS vaccine trials and then HIV testing policies will need to be revisited and possibly revised.