Many companies have tried and failed to make an HIV vaccine capable of preventing HIV infection, but the virus has eluded more than 30 vaccines so far.

The standard immunology approach of developing a vaccine that mimics natural infection doesn't work with HIV.

"That's the one thing that you don't want to do with an HIV vaccine because natural infection is inadequate," Anthony Fauci, director of NIH's National Institute of Allergy and Infectious Diseases (NIAID), told BioWorld. "Virtually nobody who's infected spontaneously clears the virus from the body."

The best any group has done is a prime-boost vaccine using Sanofi SA's ALVAC HIV and Vaxgen Inc.'s AIDSVAX B/E, which cut HIV infections by 31.2 percent in the phase III RV144 trial run in Thailand. (See BioWorld Today, Sept. 25, 2009.)

Rather than being discouraged, Johan Van Hoof, global therapeutics area head for infectious diseases and vaccines at the Janssen Pharmaceutical Companies of New Brunswick N.J.-based Johnson & Johnson, sees the modest protection as a sign of things to come. "It was very encouraging to see that protection was possible," he told BioWorld, noting that the trial identified biomarkers that were indicative of protection. "It also suggested how to improve activity further."

Janssen developed a mosaic vaccine capable of eliciting immune responses to different parts of the virus. A 2015 Science paper showed the most effective prime-boost regimen could reduce the risk of infection with simian immunodeficiency virus in nonhuman primates by 94 percent. After six exposures the monkeys still had 66 percent protection.

The phase I/IIa TRAVERSE trial compared trivalent mosaic antigens to a quadrivalent mosaic antigen, resulting in the selection of the four-component mosaic candidate plus a clade C gp140 soluble protein as the best vaccine to take into further testing. Preliminary data showed the vaccine produced an immune response similar to nonhuman primates with biomarkers signaling that the vaccine is working.

Last month, Janssen Vaccines & Prevention BV, together with the Bill & Melinda Gates Foundation and the NIH's NIAID, launched Imbokodo, a phase IIb trial using the quadrivalent mosaic antigen given over four doses with the final two doses also including clade C gp140 and an aluminum phosphate adjuvant to boost immune responses.

The study plans to enroll 2,600 sexually active women ages 18 to 35 in five southern African countries. Women in that age group were selected because of the prevalence of HIV infection as well as the higher likelihood that they would be compliant to the study protocol. Van Hoof estimates it'll take a year to recruit the patients, who will be followed for two years, putting a readout sometime in 2021.

A little before then, in late 2020, data will be released from HVTN 702, a phase IIb/III trial testing an HIV vaccine from Paris-based Sanofi and London-based Glaxosmithkline plc in 5,400 men and women in South Africa that was launched last year. The vaccine uses Sanofi's ALVAC-HIV and GSK's two-component gp120 protein subunit vaccine with an adjuvant to boost the body's immune response to the vaccine.

Both ALVAC-HIV and the vaccine have been modified from the versions used in the Thai RV144 trial to elicit a response to HIV subtype C, the predominant HIV subtype in southern Africa. The companies also changed the adjuvant from the one used in RV144 and added a booster shot after one year to try and prolong the protection seen in RV144.

As a mosaic antigen, Janssen may have the advantage because the vaccine may offer protection against multiple subtypes, but Fauci cautioned that the jury is still out. "I think it's too early," he said. "We've been there before, where you think you have an advantage and you don't, so the only proof of the pudding is to see how it works."

Van Hoof noted that protection of 30 percent to 50 percent could be enough to justify a vaccine's use from a global health prospective, although from an individual perspective, protection of 70 percent or higher would likely be needed to encourage widespread use.

Delivering a cure

Rather than focusing on a vaccine, Aphios Corp. is tackling the ultimate treatment: a cure for HIV infection, using its critical fluid nanosome technology to deliver small interfering RNA (siRNA).

Critical fluid nanosome technology applies pressure with supercritical fluid solvents to phospholipids to produce nanolipid particles. Unlike other nanosome technologies, the active drugs that the nanosomes encapsulate aren't impacted by heat, sheer or organic solvents, keeping the integrity of the molecule intact. The nanosomes can also be pegylated to increase circulating time and have other additions to allow for targeting to specific tissues.

"Nanosomes, when they land on the cell, become part of the cell and can release its content right into the cytoplasm and therefore have a high efficacy in terms of transfection," Trevor Castor, Aphios' president and CEO, explained to BioWorld. Nucleic acids can be delivered with viral vectors, but Castor noted that they have potential risks to patients and haven't been effective in quiescent cells.

The siRNA part of the drug will be designed to knock down genes that are required for entry of the virus into the cells. By fighting the virus from within the cell, a siRNA could end up curing a patient, unlike current antivirals that are only able to keep virus levels knocked down, but can't rid patients of the virus completely.

Earlier this month, Aphios, of Woburn, Mass., announced funding from the NIH's NIAID to help develop the drug. Castor said he thinks it'll take two to two and a half years to get the siRNA nanoparticles into the clinic.