Is the Mosaic Vaccine the HIV Breakthrough We’ve Been Waiting For?

Only the Fifth Human Efficacy Trial in 35 Years

Used under a Creative Commons license at https://www.flickr.com/photos/iavi_flickr/9317042338/

International AIDS Vaccine Initiative (IAVI)

Scientists have been trying for more than 35 years to develop an HIV vaccine but have, to date, only seen four progress to human testing. Of these, only one—a dual vaccine approach tested in the RV144 trial in Thailand in 2006—demonstrated even partial efficacy.

The challenges of HIV vaccine development are well known and mainly include the virus' ability to elude the body’s immune defenses.

HIV's ability to rapidly mutate has resulted in a vast multitude of viral strains that single or even dual vaccines have yet to be able to neutralize.

It is for this reason that the new vaccine model—known as a mosaic-based regimen—is reigniting hopes among researchers after the much-publicized failures of the AIDVAX trial in 2003, the STEP trial in 2007, and the HVTN505 trial in 2013.

About Mosaic Vaccines

This new preventive vaccine approach diverges from previous models in that it is not constrained to only predominant viral strains. Instead, the mosaic vaccine takes pieces of different HIV viruses and combines them to elicit a broader immune response.

The leading candidate, developed by Janssen Pharmaceuticals, incorporates three immune-stimulating proteins (called mosaic antigens) created from the genes of many different HIV strains. The antigens are housed in a disabled cold virus—known as adenovirus serotype 26 (Ad26)—and delivered via injection into a muscle.

Positive results from early-stage trials have led to the fast-track approval of what is only the fifth phase II efficacy trial in 35 years. Known alternately as the HTVN705, or Imbokodo trial, the mosaic Ad26 vaccine will be tested on 2,600 non-infected women, ages 18 to 35, in South Africa, Malawi, Mozambique, Zambia, and Zimbabwe.

("Imbokodo" is the Zulu word for "grindstone" used popularly in an anti-apartheid resistance song.)

It is hoped that the mosaic vaccine candidate will improve upon the 31 percent efficacy of the RV144 trial, the results of which were considered inadequate for large-scale HIV prevention.

Scientific Evidence

The excitement surrounding the mosaic Ad26 vaccine was instigated in large part by research published in The Lancet in 2018 which evaluated the effects of the vaccine in both humans and rhesus monkeys.

Known as the APPROACH trial, the phase I/II human study involved 393 non-infected adults, ages 18 to 50, from 12 clinics in East Asia, South Africa, Thailand, and the U.S. Each participant was randomly chosen to receive one of seven vaccine combinations or a placebo.

An initial injection was given a month before the study and then again at 12, 24, and 48 weeks. In some cases, an additional vaccine was incorporated, including one—called a gp140 vaccine—that is similar in design to an RV144 vaccine candidate.

The APPROACH investigators reported that, after 96 weeks, the mosaic vaccine was not only well tolerated but triggered an anti-HIV immune response irrespective of the combination of vaccines used.

The most robust response was seen in those given both the Ad26 and gp140 vaccines.

Even more promising were the results see in the parallel simian study. For this, 76 rhesus monkeys were injected with the mosaic Ad26 vaccine and exposed on six different occasions to SIV, the simian version of HIV. Despite the high-risk exposure, 67 percent of vaccinated monkeys were able to remain SIV-free.

So far, the trial results seen both in humans and monkeys were mostly positive.

Challenges and Limitations

Following the success of the APPROACH study, the HTVN705/Imbokodo trial will utilize both the mosaic Ad26 and gp140 vaccines.

Each participant will be given a total of six vaccinations—an initial dose at enrollment followed by another dose at month three and a double-dose at months six and 12.

Each woman will be routinely monitored for 24 to 36 months, checking for treatment side effects or HIV seroconversion (infection). Results are not expected until 2021.

Based on what we know, it is unlikely that the dual vaccines will be fully protective. Given the vast diversity of HIV, it is likely that some variants will escape neutralization and establish havens (known as reservoirs) in cells and tissues of the body.

What researchers are hoping is that the mosaic antigens will "teach" the immune system to identify and block some of the more virulent viral strains even as they mutate.

If the trial proves to be even moderately successful—preventing HIV by more than 50 percent—the impact on the new infection rate could be enormous.

Even today, around 1.8 million people are infected with HIV annually, or roughly 50,000 new infections per day. While 36.7 million people are currently living with the disease, only 21 million are receiving antiretroviral therapy. With monetary contributions to global HIV dwindling, a vaccine—even a moderately effective one—is considered by some to be the only realistic hope to finally ending the pandemic.

It is within this context that the HTVN705/Imbokodo trial is considered crucial.

Other Vaccine Trials

While much of the media focus has been placed on the Imokodo trial, there are other equally important investigations underway. Some are focused on the development of a preventive vaccine, while others are meant to be therapeutic (meaning they are able to help control HIV, ideally, without the need for drugs).

In addition to the Imbokodo study, human trials are underway for two preventive vaccine concepts—one known as antibody-mediated protection (AMP) and the other that uses a vaccine known as ALVAC, previously used in the RV144 trial.

Antibody-Mediated Prevention (AMP)

Antibody-mediated prevention (AMP) is an approach by which scientists aim to identify and replicate a subset of naturally occurring immune cells, known as broadly neutralizing antibodies (bNAbs), that are able to kill a wide range of HIV subtypes.

The most advanced of these investigations involve the VRC01 antibody which is known to kill over 90 percent of HIV strains in test tube studies. While early investigations into the passive immunization of VRC01 antibodies have underperformed—providing only short-term control of infection—other potentially stronger bNAbs are being explored (including the N6 antibody which is able to neutralize 96 percent of all variants).

Another study into the use of VRC01 antibodies as a means of HIV prevention, known as HIV pre-exposure prophylaxis (PrEP), is currently underway in 10 countries on three continents.

Known as the AMP study, the investigation will involve two separate phase IIb studies—one involving gay, bisexual, and transgender men in Brazil, Peru, and the U.S. and the other involving women in sub-Saharan Africa. Results are expected in 2020.

RV144 Follow-Up

The RV144 trial, despite its shortcomings, revealed some of the key mechanisms by which current vaccine models are being developed. This study involved two vaccines—the AIDSVAX vaccine (a type which failed on its own in 2003) and a second, newer vaccine called ALVAC (delivered in a disabled canarypox virus). Together, the dual vaccines provided the first evidence of significant protection in non-infected people.

Sadly, the RV144 and subsequent RV305 trials proved that the effect was short-lived, declining from a rate of 60 percent by 12 months to 31 percent by 42 months.

With that said, specific immune responses from the ALVAC vaccine proved so compelling that a new study, called the HVTN702 or Uhambo (Zulu for "Journey") trial, is currently underway in South Africa. The aim of the study is to test the efficacy of the ALVAC vaccine in preventing HIV when combined with a gp120 vaccine booster.

The phase IIb/III trial, underway since November 2016, included 5,400 non-infected men and women. The ALVAC will be delivered in an initial intramuscular injection followed by a booster 12 months later. Results are expected by 2020.

HIV Cure Research

In addition to prevention, scientists are continuing to explore both functional cures and sterilizing cures for HIV. Both take a similar approach in that they involve two theoretic steps:

  • Firstly, the purging of latent reservoirs where HIV hides
  • Secondly, the use of a drug, vaccine, or immunotherapeutic agent to control or kill the fully exposed virus

A functional cure is one in which a treatment (or likely a combination of treatments) controls rather than eradicates the virus. A sterilizing cure is one that completely releases and kills all viral particles (a strategy popularly known as "kick-kill").

While we have made progress in establishing which tools are needed to achieve the cures, the tools themselves have fallen short in research. For example, HDAC inhibitors used to treat cancer have proven to be effective at "kicking" HIV from its reservoirs but, thus far, have been only able to achieve partial clearance. For the drugs to be effective, dosages would need to be increased to toxic levels and, even then, there is no assurance that all particles would be released.

Similarly, we are years away from developing any pharmaceutical, vaccine, or immunotherapeutic agent (or combination of agents) able to fully neutralize HIV in all its forms.

Newer, innovative drug candidates are currently under investigation, including ABX464 (which achieved a 25 percent to 50 percent clearance of HIV reservoirs in early-stage human trials) and the HIV Conserv vaccine (an immune-stimulating drug which provided evidence of functional HIV control).

View Article Sources