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IAS 2017: Another HIV Vaccine Efficacy Trial Will Start This Year

A year ago, one of the biggest pieces of prevention news at the Durban International AIDS Conference was the announcement that a large HIV vaccine efficacy study would start in South Africa. HVTN 702, now running, is only the eighth human vaccine efficacy trial ever run in the history of the HIV epidemic, and the first since 2009.

[Produced in collaboration with aidsmap.com]

As of this autumn, it will have company. Researchers said at the 9th International AIDS Society Conference (IAS 2017) in Paris that HVTN 705 will start towards the end of this year. In this study, 2600 sexually active women aged 18-35 in South Africa, Zambia, Zimbabwe, Malawi, and Mozambique will be given a candidate HIV vaccine or a placebo and then followed for 3 years to see if it stops them becoming infected with HIV.

The HVTN 705 vaccine has been developed by Janssen, the pharmaceutical subsidiary of the giant drug and health company Johnson and Johnson. Whereas HVTN 702 grew out of the unexpectedly positive results of a previous vaccine trial, RV 144, the new vaccine has been painstakingly developed and refined in a number of studies conducted by Janssen.

Both vaccines are "prime-boost" in their design. This means that one or more doses are given of an initial "prime" consisting of HIV gene fragments packed inside a shell of an inert, harmless virus -- a so-called vector. The prime is then followed by a "boost" that consists of proteins from the mature HIV viral particle. The boost may or may not also contain the prime vector.

The rationale behind this design is that vectors have the machinery to act like real infections and can enter immune cells, turning on their immune response to the viral components. Thus primed, the immune response is hopefully amplified greatly by the booster doses -- to the point where, if a real viral invader appears, it is immediately recognized and neutralized.

The HVTN 702 vaccine consists of ALVAC, an HIV prime vector with a cowpox virus shell (from the same family as herpes and chickenpox), and a boost of the HIV gp140 envelope protein. It is given as 2 primes injected a month apart, then 4 more injections of the vector plus booster protein over an 18-month period.

The HVTN 705 regimen will be somewhat less onerous. It will consist of 2 doses of an adenovirus vector called Ad26. Adenoviruses are a common virus family that is mainly known for causing colds, though the vector should not do that. This is then followed by 2 more doses of the adenovirus and a booster of the gp140 envelope protein.

Janssen’s Hanneke Schuitemaker told the conference that the vaccine for the new trial had been developed by Janssen during 3 separate trials, during which different components and combinations were trialed and the best picked.

The APPROACH trial included 400 people in the U.S., Rwanda, Uganda, South Africa, and Thailand, and explored 2 different viral vectors using either the adenovirus shell or the shell of a type of MVA (modified vaccinia Ankara), another herpes cousin. In the trial, using the Ad26 vector for both prime and boost shots proved to raise the best immune response.

In a second trial called ASCENT, the choice was between different boost proteins -- either ones consisting solely of proteins from HIV subtype C, the kind found mainly in southern Africa, or adding in a mosaic of proteins from all the different viral subtypes. As HVTN 705 will only take place in southern Africa, just the clade C boost will be used, as it was not inferior to the mosaic boost according to results from the 150 people in this trial, which was conducted in the U.S., Rwanda, and Kenya.

A third study called TRAVERSE has yet to release its final results. This trial compares 2 different formulations of the prime vector and involves 198 people in the U.S. and Rwanda. When its results are published around October, the final determination of the composition of the HVTN 705 vaccine will be made.

However, the decision to go forward has already been made, as APPROACH was the crucial "Go or no-go" trial used to determine if a Phase 3 efficacy trial should go ahead.

As with HVTN 100 -- the trial used to decide whether HVTN 702 should proceed -- criteria were pre-set that APPROACH needed to attain. They were as follows:

Criterion 1: More than 90% of people given the vaccine mounted an IgG antibody response to HIV clade C.

Result: More than 92% of people mounted such a response.

Criterion 2: More than 56% of people showed a cell-killing antibody response to HIV clade C called ADCP (antibody-dependent cellular phagocytosis).

Result: After all 4 doses, 65% of people mounted this response.

Criterion 3: Over 50% of people should show a positive immune response to a pool of HIV envelope proteins, using the ELISPOT assay.

Result: After 4 doses, 80% of people had an ELISPOT response.

Criterion 4: The 2 booster doses should amplify the existing immune response caused by the prime to HIV envelope protein by at least 50%.

Result: After 4 doses, the response was magnified nearly sevenfold -- by 590%.

Criterion 5: Computer modeling from monkey studies showed that the magnitude of the immune response as measured by 2 different assays, ELISPOT and ELISA, needed to exceed a certain threshold in order for a 60% reduction in infections to be achieved. The criterion was that at least 40% of subjects had to achieve this after the third inoculation, and at least 60% after all 4.

Result: After 3 doses, 64% of subjects passed this threshold, and after 4 doses, 80% did so.

The main analyses of the results will be done 7 months after the first shot (just after the third one), at 2 years, and at 3 years. Assuming HVTN 075 does start this autumn, this indicates that the trial will finish, if all goes as expected, in late 2020, with results available in mid-2021.

South African researcher Glenda Gray, who provided an overview at the IAS symposium, said that in some countries, including her own, HIV diagnoses were continuing to rise despite considerable increases in the proportion of people on antiretroviral treatment; South African HIV diagnoses had risen by 30,000 a year between 2010 and 2015, despite HIV treatment coverage increasing from under 20% to nearly 50%.

This shows how urgently necessary an HIV vaccine is. The challenge would to be to make a simple one that provides long-term efficacy. Gray was optimistic, however, that the vaccine research pipeline was on the right path.

"I feel we have reached a pivotal moment in HIV vaccine development," she said.

8/9/17

Sources

H Schuitemaker. Progress in antibody-mediated preventive vaccine strategies. 9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Presentation MOSY0403.

G Gray. How close are we to the perfect HIV vaccine? 9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Presentation MOSY0402.