By Kristen Jill Kresge
Pharmexa-Epimmune Initiates Phase I AIDS Vaccine Trial
Pharmexa-Epimmune, a US subsidiary of a Danish vaccine and immunotherapy company, recently initiated a Phase I AIDS vaccine trial in partnership with the HIV Vaccine Trials Network (HVTN) to evaluate the safety and immunogenicity of two candidate vaccines given either alone or in combination. This trial, HVTN 064, will enroll 120 HIV-uninfected volunteers at 4 sites in the US (Baltimore, Rochester, and 2 sites in San Francisco) and in Lima and Iquitos, Peru.
The first candidate, known as EP HIV-1090, is a DNA plasmid vaccine comprised of antigens from Gag, Pol, Nef, and Vpr that code for proteins conserved among several HIV clades (A, B, C, D, F, and G). This candidate was tested in a previous Phase I trial with the HVTN in 42 volunteers. The second vaccine candidate, EP-1043, is a recombinant protein vaccine comprised of T helper cell epitopes from HIV clade B Env, Gag, Pol, and Vpu administered with an Alum adjuvant. This vaccine candidate is intended to interact with CD4+ T cells and cause their proliferation.
In the first part of this trial, 24 volunteers will be randomized to receive placebo or 4 injections of either a low or high dose of EP-1043. After analyzing the safety data, investigators will then evaluate the preferred dose in the second part of HVTN 064, where volunteers will be randomized to one of three groups: EP-1043 or placebo, EP-1090 or placebo, and both candidates versus placebo.
All volunteers will be monitored over 11 site visits during the course of a year. This trial is being sponsored by the US National Institutes of Allergy and Infectious Diseases within the National Institutes of Health and both vaccines are being manufactured by Pharmexa-Epimmune.
Phase I AIDS Vaccine Trial Opens in India
India started the country’s second Phase I AIDS vaccine trial in January in Chennai to determine the safety and immunogenicity of a modified vaccinia Ankara (MVA) vaccine candidate at varying doses. The vaccine candidate, TBC-M4, uses an attenuated and non-infectious vaccinia virus vector to deliver env, gag, tat-rev, and nef-RT HIV genes from clade C, the most commonly circulating in India.
The DNA coding sequences for the included genes were isolated from recently HIV-infected individuals in India by the National AIDS Research Institute in Pune (NARI). Half the volunteers enrolled in IAVI D001 will receive the low dose of TBC-M4 and safety data from this group will be evaluated by an independent advisory board before inoculating the second group with the higher dose. All volunteers will receive three injections of the candidate vaccine.
This double blind, placebo-controlled trial will enroll and follow 32 volunteers at the vaccine trial centre at the Tuberculosis Research Centre over 2 years. This newly-established center includes a clinical facility as well as an HIV immunology and virology laboratory where all trial samples will be analyzed. All clinical and laboratory staff completed training on study operations and data management, as well as on gender issues related to AIDS vaccine clinical research.
IAVI is sponsoring the trial in partnership with the Indian Council of Medical Research and the National AIDS Control Organization of India. Therion Biologics, a biotechnology company in Cambridge, Massachusetts, collaborated with IAVI on the development of TBC-M4 and is manufacturing the vaccine for use in the trial. Several other Phase I AIDS vaccine clinical trials are currently ongoing in the US and Brazil that use MVA as a vector.
India is also conducting another Phase I AIDS vaccine trial that began last year at NARI with tgAAC09, an adeno-associated virus vector vaccine manufactured by Targeted Genetics in the US. This trial is also sponsored by IAVI.
Kenya Begins Enrollment for Phase I Vaccine Trial
A Phase I AIDS vaccine trial sponsored by IAVI in collaboration with the Vaccine Research Center (VRC) at the National Institute of Allergies and Infectious Diseases (NIAID) began enrolling volunteers this January in Kenya. The trial, IAVI V001, initially started in Rwanda and was expected to enroll a total of 64 volunteers in these countries. However after early success in recruiting volunteers the target number for both countries will be increased, pending regulatory approval by the local Institutional Review Boards in Kigali and Nairobi.
The trial in Kenya is being conducted in partnership with the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi. The trial staff are promoting initiatives to recruit women for this trial, including holding community seminars within homes or offices targeting only women.
This is one of many ongoing trials testing the safety and immunogenicity induced by a “prime-boost” vaccination regimen with a DNA plasmid vaccine and an adenovirus serotype 5 (Ad5) vector that was developed at the VRC (seeVaccine Briefs, IAVI Report 9, 5, 2005).
Trial shows HSV-2 Suppression Can Reduce HIV Shedding
Almost a dozen clinical trials are now ongoing to see if drugs to suppress herpes simplex virus-2 (HSV-2) can reduce the risk of HIV transmission and infection. These studies were initiated because of mounting evidence that a causal relationship exists between HSV-2 and HIV infection (see HIV prevention in a pill?, IAVI Report 9, 4, 2005). Researchers have hypothesized that HSV-2 infection could increase shedding of HIV in the genital tract and therefore increase both transmission and acquisition of HIV, but a relationship between these infections has not been firmly established in a randomized, controlled, clinical trial until now. At the 13th Conference on Retroviruses and Opportunistic Infections (CROI) held in February, researchers from the London School of Hygiene and Tropical Medicine (LSHTM) in the UK in collaboration with the Centre Muraz in Bob-Dioulasso, Burkina Faso presented data from the first “proof of concept” trial to show that this is in fact what happens.
This study enrolled 140 women infected with both HIV and HSV-2 in Burkina Faso and randomized them between the placebo and treatment arm, where they received a 1000 mg dose of the anti-herpes drug valacyclovir once a day for 3 months. The women were followed for a total of 9 months, 3 months prior to and for 3 months following treatment. Over 12 visits, researchers measured the levels of HIV and HSV-2 shedding in the genital tract by cervicovaginal lavage enriched by cervical swabbing, as well as the plasma viral load of HIV for each volunteer.
At baseline, the average CD4+ T cell count was 519 cells/mm3 in the treatment group and 482 cells/mm3 in the placebo arm. Any women that met the World Health Organization’s criteria for starting antiretroviral therapy were excluded from this trial and offered treatment in study ANRS 1295b, where researchers are studying the effects of combining valacyclovir and antiretrovirals (ARVs) on HIV transmission.
Throughout the course of the study, 93% of the visits were completed and Nicolas Nagot from LSHTM, who presented the results of this study at CROI, reported that the average compliance to the medication was 97%. Researchers observed that women that received valacyclovir had significantly less HIV shedding than those that received placebo. The mean reduction in the treatment group was 0.26 log copies/ml, while genital shedding actually increased in the placebo arm by 0.09 log copies/ml. Nagot also reported that HIV shedding in women on acyclovir wasn’t as persistent, with 33% of women shedding at fewer than half the visits as compared to 14% of women who were in the placebo group.
Valacyclovir also significantly reduced the level of HSV-2 shedding with only 19% of women shedding HSV-2 at least once in the treatment group compared to 54% in women who received placebo.
As a secondary endpoint researchers looked at the difference in plasma viral load between the two groups. They found that women taking valacyclovir also had a greater reduction in HIV plasma viral load than controls. The average plasma HIV load drop was 0.5 log copies/ml, while the controls had an average viral load increase of 0.1 log copies/ml. The amount of HIV RNA detected in the genital tract was also significantly lower in the women on valacyclovir and future studies will address whether this is due to the overall reduction in systemic viral load or due more directly to the action of valacyclovir on genital HIV shedding.
This is the first study to verify the causal relationship between HSV-2 infection and HIV shedding, according to Nagot. And although this study does not show a direct link between HSV-2 suppression and HIV transmission, results from ongoing trials will help establish a possible role for HSV-2 suppressive therapy in HIV prevention.