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Two New HIV Vaccine Trials Launched in Recent Weeks

By Regina McEnery

Two New HIV Vaccine Trials Launched in Recent Weeks

Two preventive Phase I AIDS vaccine trials were launched recently, testing two different DNA-based AIDS vaccine candidates. In one trial that began in December, investigators from the UK began enrolling 36 women ages 18-45 at low risk of HIV infection in a randomized controlled trial comparing the safety and immunogenicity of a DNA-based vaccine candidate containing fragments of HIV’s spiky outer-surface protein that were isolated from a clade C virus, the most dominant strain circulating in sub-Saharan Africa and the one responsible for infecting half of the world’s 34 million people living with HIV.

The trial, known as MUCOVAC2, will be examining three different routes of vaccination. The first group of twenty women will receive a high or low dose of the candidate by intramuscular injection, administered along with the adjuvant glucopyranosyl lipid adjuvant (GLA), which was developed by the Seattle-based non-profit Infectious Disease Research Institute (IDRI), a product-development partnership that is working to develop new technologies that target diseases in developing countries. GLA appears to have the ability to boost both antibody and cellular immune responses.

Another six women will receive the vaccine candidate intranasally in the form of drops, administered together with the adjuvant chitosan, which is derived from the outer skeleton of shellfish and insects and has been found to improve the immunogenicity of other vaccines that are administered mucosally.

Another group of 10 women will receive an intramuscular injection of the vaccine candidate in conjunction with vaginal application of the candidate formulated into a gel. The vaginal gel will be applied nine times in a one-month cycle. This gel version of the vaccine candidate, which has been tested previously in clinical trials on its own, does not contain an adjuvant. Catherine Cosgrove, honorary consultant in infectious disease and general medicine at St. George’s University of London, who is leading the study, says the combination of an intramuscular injection with vaginal gel application aims to induce a more focused mucosal immune response.

“This is the first time the [candidate] is being used intranasally or intramuscularly,” adds Cosgrove. Studies in mice, rabbits, and rhesus macaques showed the vaccine candidate was safe and immunogenic. A consortium that includes St. George’s, Imperial College, Hull York Medical School, the Medical Research Council Clinical Trials Unit, and IDRI contributed to developing the vaccine candidate. The trial is being funded by the Wellcome Trust.

In another Phase I trial that began enrollment in December, investigators will evaluate the safety and immune responses induced by a DNA-based HIV vaccine candidate, developed by Profectus BioSciences, in a prime-boost regimen. The DNA candidate encodes multiple HIV proteins and is being co-delivered with the adjuvant interleukin-12 (IL-12)—a protein secreted by immune cells in response to viruses or bacteria—to help boost the immune response. The DNA candidate is being followed by vaccination with a viral vector-based candidate that uses an inactivated strain of the cold virus (adenovirus serotype 35; Ad35) to deliver HIV fragments.

Investigators plan to recruit 75 volunteers ages 18-50 from Rwanda, Kenya, and Uganda in this study, known as B004. The trial, which is being sponsored by IAVI, employs a novel technique called electroporation to deliver the DNA vaccine candidate (see It's Electric, below). The goal of electroporation, which delivers the vaccine candidate intramuscularly through a series of electric pulses, is to get more of the vaccine into cells.

Enrollment in B004 began in Rwanda in December, with vaccinations slated to begin in Kenya and Uganda in early 2012, pending regulatory approvals. By using Ad35, researchers are hoping to circumvent issues with pre-existing immunity to the viral vector. In the STEP trial, which showed that an Ad5-based vaccine candidate failed to prevent transmission or slow disease progression in vaccinated volunteers, data suggested that male volunteers who received the vaccine had a higher risk of acquiring HIV if they were uncircumcised and had pre-existing antibodies against the Ad5 vector (see VAX Oct.-Nov. 2007 Spotlight article A Step Back). Ad35 is less prevalent worldwide than Ad5, and therefore there should be less pre-existing immunity to the vector.

 It's Electric!
What is electroporation? 
Electroporation (EP) is a vaccine delivery technique that induces temporary pores in the membranes of muscle or skin cells so that these cells can take up the vaccine more easily. Vaccine candidates are delivered using a small hand-held EP device that uses a needle to inject the vaccine and four thin wires to administer electrical pulses that are milliseconds in length.

How is it useful in vaccination? 
EP has been shown to enhance immune responses induced by DNA-based vaccine candidates in clinical trials.

Why is electroporation used for DNA vaccines? 
DNA-based vaccine candidates, while safe and effective, are weakly immunogenic due to poor DNA uptake into cells. EP is one way of improving the efficiency of delivery.

What are the risks? 
The same EP device being tested in the B004 trial was tested in a Phase I trial involving 40 volunteers in the US and found to be safe and well tolerated. Possible adverse events that may occur following EP include a brief twitching of muscles at the vaccination site and a tingling sensation in the arm and fingers for up to one hour after injection. Mild or moderate muscle soreness, redness, bruising, and pain can also occur one to three days afterward. More severe reactions such as dizziness and fainting are rare.

Is electroporation a new technique? 
EP was discovered in 1970 and has been used in human studies since the early 1990s. Along with preventive vaccines, EP is also being studied in conjunction with therapeutic vaccines and gene therapy. —RM