HIV vaccines: An unprecedented surge in activity

HIV vaccines: An  unprecedented surge in activity

Vaccines, the most powerful public health tools available, are set to play a powerful role in ending the scourge of the AIDS epidemic, researchers say. 

There is an unbridled sense of optimism in the HIV prevention field. The efficacy of two HIV vaccine candidates is currently being tested in large-scale trials. 

Uhambo for clade C

One is a Phase IIb/III trial called HVTN 702, or Uhambo, to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 in preventing HIV-1 infection, and involves 5,400 South African men and women. 

This regimen was adapted from the Thai vaccine used in the RV144 trial for the sub-Saharan African region where HIV subtype C is prevalent. The new study aims to improve vaccine efficacy by increasing the magnitude and duration of vaccine-elicited immune responses beyond those of RV144.

Results from an early-phase clinical trial, HVTN 100, showed that all volunteers who completed the first four vaccinations developed antibody responses two weeks after the fourth vaccination. Similarly, cellular immune responses were strong. HVTN 100 met all four pre-specified immunological (go/no-go) criteria, thereby qualifying the regimen for efficacy testing in HVTN 702s

“At least 12 clades of HIV exist in the world. HVTN 702 is testing a vaccine designed to prevent clade C, the most common HIV clade in Southern Africa,” says Glenda Gray MD, Protocol Chair for HVTN 702 & HVTN 705, HIV Vaccine Trials Network (HVTN), a non-profit organization focused on the development of vaccines to prevent HIV/AIDS, headquartered at the Fred Hutchinson Cancer Research Center in Seattle.

Should HVTN 702 demonstrate efficacy in HIV prevention in sub-Saharan Africa, which carries the largest burden of HIV in the world, additional adaptations of the HIV genetic components of the vaccine might be possible in the future to potentially broaden its application. 

Towards a global ‘mosaic’ vaccine

The second trial is called HPX2008/HVTN 705, or Imbokodo.

Preclinical trials data showed that regimens with mosaic-based vaccines, which aim to prevent multiple clades, were highly efficacious in protecting nonhuman primates against infection with HIV-like viruses. 

The mosaic-vaccine regimen has been designed with the goal of achieving a global vaccine that could prevent HIV infection due to multiple viral strains. The mosaic immunogens in the vaccine are designed to protect against a “mosaic” of these strains, including the most prevalent strains such as clade C, which dominates sub-Saharan Africa and India, and clade B, which is found mostly in the Americas, Western Europe and Australasia.

The mosaic vaccines were tested extensively in phase 1/2a human studies, HVTN 117/HPX2004 (TRAVERSE) and more recently in HVTN 118/HPX2003 (ASCENT).  

ASCENT was initiated to test whether adding a mosaic Env protein to the clade C Env protein given in the last two vaccinations will broaden the immune response for clade B and other non-clade C HIV-1 viruses. Results from ASCENT were presented as a late-breaker at the International AIDS Society (IAS) 2019.     

TRAVERSE data also showed that this regimen is improved when two types of mosaic envelopes are included in the adenovirus-based vaccine.

Positive outcomes from the APPROACH and TRAVERSE studies led to the initiation of a large efficacy study, the 2,600-person phase 2b trial HVTN 705/HPX2008 or Imbokodo, in at-risk women in southern Africa, in November 2017.

“APPROACH trials showed that the best combination for a mosaic vaccine is an adenovirus-based viral vector with an HIV mosaic envelope insert given four times, with the addition of an HIV-1 clade C Env protein added to the last two vaccinations,” says Larry Corey MD, Principal Investigator for HVTN. 

HVTN 705 is a multicentre, randomized, double-blind, placebo-controlled phase 2b efficacy study of a heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and aluminum phosphate-adjuvanted clade C gp140 in preventing HIV-1 infection in women in sub-Saharan Africa.   

Imbokodo uses the adenovirus mosaic construct Ad26.Mos4.HIV four dose regimens with clade C Env protein added to the last two doses, and initial results are anticipated in 2021.

Mosaico (HVTN 706/HPX3002) is a multi-centre, randomized parallel-group, placebo-controlled, double-blind, Phase 3 study. The vaccine regimen studied in ASCENT containing mosaic Env protein will be evaluated in this study to see if it protects against HIV acquisition, according to Dr Corey.

With each new study, Janssen Sciences has worked to optimise the components of the vaccine regimen. 

In Mosaico, a new version of the clade C gp140 protein that is given in the second two doses of the regimen is being tested. The new protein is a combination clade C + mosaic gp140 protein, with the goal of optimising the strength and breadth of immune responses, including to clade B.

Efforts to design vaccines that generate broadly neutralizing antibody responses are underway.

In the non-neutralising HIV vaccine arena, the mosaic-based vaccines are designed to elicit broad cross-subtype responses. 

An HIV vaccine that is broadly and globally effective is an ultimate goal of the HIV vaccine field, points out Dr Corey. 

Envelope protein trimer 

The International AIDS Vaccine Initiative announced the start of a Phase I clinical trial (IAVI W001) to test BG505 SOSIP.664 gp140 candidate in March.

The experimental vaccine is based on the HIV envelope protein (Env), which is shaped like a three-pronged spike. This configuration, known as a trimer, is a target for antibodies produced by the human immune system after infection. Some of these antibodies are able to block viral entry into cells.

This is one of the first clinical trials of a native-like Env trimer.

Previous vaccine trials involving Env concepts have tested the immunogenicity of only a portion of the Env structure or proteins that do not resemble the native structure. 

Investigators hope to see a similar specific response in humans too. Results of the IAVI W001 trial are expected in 2020.

PrEPVacc

PrEPVacc, a combination effect study of two DNA-MVA- or DNA- Env protein
HIV-1 vaccine regimens with pre-exposure prophylaxis (PrEP), is expected to begin in early 2020, enrolling 1,688 men and women from general and key population groups in four African countries.

Phase IIb clinical trial that will test two combination regimens each containing multiple clades.  

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