An experimental "mosaic" vaccine against a variety of HIV subtypes appeared promising in early-stage clinical trials, Hanneke Schuitemaker, Ph.D., of Janssen Pharmaceuticals reported at the 9th IAS Conference on HIV Science.
The trial results, presented on July 24, are the latest data available from the APPROACH study, which involves almost 400 HIV-negative study volunteers. They were randomized to one of eight arms: seven different vaccine variations and a placebo. In the most promising vaccine arm, 100% of study participants showed antibody responses and 83% had T-cell responses.
This response rate does not mean, however, that the vaccine actually protects against HIV in humans, Dan H. Barouch, M.D., Ph.D., of Harvard Medical School cautioned in a related press conference. Further research will be needed to establish that.
Details of the Mosaic Vaccine Study Results
The basic concept behind this vaccine is a "prime boost" approach, which consists of two "prime" injections of a modified virus as the delivery vehicle for antigens (i.e., the vector) and two "booster" injections carrying an additional protein. The primer injections were given three months apart, followed by boosters at six and 12 months after study start.
The vaccine candidate is called a "mosaic" vaccine because it includes snippets from a variety of different HIV subtypes, called clades. Specific clades of the virus are more common in certain parts of the world. Because it contains a variety of inserted HIV subtype snippets, a mosaic vaccine is designed to work globally against most clades.
Study participants in all vaccine arms received the same prime vaccinations, which are based on a flu virus vector, adenovirus 26 (Ad26). Participants in each arm then received the same booster shot twice, but the boosters differed by arm. Three groups received an Ad26-based vaccine, while the other three received one based on a pox virus vector, modified vaccinia Ankara (MVA). Each of these vectors was either tested by itself or combined with a low or a high dose of the gp140 protein. The seventh vaccine arm received only a high dose of the protein.
The eight arms, of about 50 volunteers each, were therefore:
- Ad26 prime + Ad26 & high-dose gp140 boost
- Ad26 prime + Ad26 & low-dose gp140 boost
- Ad26 prime + Ad26 boost
- Ad26 prime + MVA & high-dose gp140 boost
- Ad26 prime + MVA & low-dose gp140 boost
- Ad26 prime + MVA boost
- Ad26 prime + high-dose gp140 boost
- Placebo (also called "sham")
The vectors are used to prod the participant's immune system into action; the mosaic inserts theoretically cause the immune system to produce antibodies against a variety of different HIV clades; and the protein is intended to improve immunity.
Boosts with the Ad26 vector and a high dose of gp140 elicited the best immune response, making this the lead candidate vaccine. Earlier pre-clinical trials in macaque monkeys had also found that version to be the most effective. In the animal studies, it reduced the risk of seroconversion by 94% per exposure to HIV, and by 66% overall after six exposures to the virus. The functionality of the antibodies generated in the human trial was very similar to that found to confer protection against the virus in the monkey study.
Researchers compared data from the lead candidate arm to pre-set criteria for proceeding to a proof-of-concept study. "We are happy that we could tick all the boxes [for these criteria] and, at least based on this data, be optimistic to proceed to a proof-of-concept study," Schuitemaker said. She noted that researchers are waiting for results from the ongoing TRAVERSE trial before proceeding, however. That trial is comparing two versions of an Ad26-based vaccine: one with three mosaic antigens and one with four such antigens. Results are expected later this year.
Should TRAVERSE be successful, a larger Stage 2B clinical trial would begin in southern Africa. That study would enroll 2,600 women between the ages of 18 and 35 who are HIV negative and sexually active. Half would be given the lead vaccine candidate and half a placebo shot, with each volunteer receiving four injections over a period of 48 weeks. The first phase of the trial would take two years, with follow-up for another year thereafter.
Can an HIV Vaccine Get Us Over the Hump?
Globally, deaths from HIV have dropped by one-third since 2000, and the number of new HIV infections has fallen 40% during that time, according to the World Health Organization. Still, "the ultimate control of the worldwide HIV epidemic will likely require the development of a safe and effective vaccine," Barouch said.
There are different views on what constitutes an "effective" vaccine, he acknowledged. Anthony S. Fauci, M.D., the director of the U.S. National Institute of Allergy and Infectious Diseases, said that 50% to 60% effectiveness in an HIV vaccine "would have a major impact on the epidemic."
The APPROACH trial is one attempt to develop such a vaccine. Another is an ongoing Phase 3 clinical trial in South Africa that is based on an earlier study in Thailand. Called HVTN 702, the South African trial also uses a "prime boost" approach, but it is testing the efficacy and safety of a different pox-based vaccine vector, ALVAC, and another protein, gp120. Barouch welcomed this "rival" trial, saying, "We need more shots on goal" to develop a viable HIV vaccine.
The slides accompanying Schuitemaker's presentation at IAS 2017 are available online.