Hope and a "Queen"

By: Aziel Gangerdine, HVTN Core, Seattle, WA, USA

Communities, scientists, investigators in the field of HIV prevention, and other stakeholders are likely anticipating the announcement of the preliminary results of two large-scale HIV prevention studies later this year. Notably branded as AMP, antibody mediated prevention, both studies are designed to determine whether a broadly neutralizing antibody called VRC01 can prevent the transmission of HIV in people.

Fittingly, the NIAID-funded HIV Vaccine Trials Network (HVTN), together with its our partners at the HIV Prevention Trials Network (HPTN) and the study funder and sponsor the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), will lead discussions when the preliminary results of the Antibody Mediated Prevention (AMP) studies are shared.

Two interdependent stories will be at the heart of the announcement: the stories of science and the will and hope of communities. These stories will be told through the voices of the 4,625 AMP study participants, consisting of women in sub-Saharan Africa between the ages of 18 – 40 years, and men and transgender people between the ages of 18 – 50 years in the Americas and Switzerland who have sex with men. These stories will color a canvas set against a backdrop of the world’s HIV epicenter in a venue likely to have limited seating and an air of anticipation.   

The Story of Science

A preventive vaccine that is safe and globally effective against HIV is to HIV prevention research what a queen represents on a chessboard. On the chessboard the queen is a game changer as it moves any number of squares vertically, horizontally and diagonally. Similarly, a vaccine against HIV will change the game by offering a new long-lasting HIV prevention option, which may mitigate the need for daily medication like PrEP or post-exposure prophylaxis (PEP) for some people; could offer herd immunity that protects individual who get vaccinated and their communities; and could potentially prevent the asymptomatic transmission of HIV from an infected person who is not aware that they are infected to others.  In developing countries an HIV vaccine has the potential to alleviate pressure on poor social and health infrastructure that is already under tremendous pressure from other diseases such as Tuberculosis (TB), diabetes and cancer. The socioeconomic benefits to any one society will be tremendous if an HIV vaccine is introduced to scale and made accessible to communities. History reminds us that smallpox was eradicated by a vaccine. In the United States, a long list of diseases such as diphtheria, measles, mumps, rubella, and tetanus near eradication as a result of vaccines.

The pursuit to add the “queen” to existing HIV prevention strategies such as voluntary male circumcision, PrEP, internal and external condoms, treatment for prevention, and HIV counseling and testing is mired with challenges. Among others, HIV is a retrovirus with a high mutation rate, and it targets the same T-cells the immune system needs to activate the immune system to fight infection.   Additionally, a safe and effective HIV vaccine must prevent the transmission of the varying subtypes of HIV that are found throughout the world.          

The proof-of-concept AMP studies are not HIV vaccine studies. In HIV vaccine trials, study participants get an HIV vaccine regimen and researchers evaluate if vaccine-induced antibodies and cellular immune responses are elicited that may prevent HIV infection. The AMP studies skip that step by administering an antibody through IV infusion directly into the bloodstream of study participants, looking to see if having the antibodies will be protective. If efficacy is found, they will also help to establish the amount of antibodies one needs in order to achieve protection. By determining the amount of antibodies needed to prevent HIV, this will help vaccine researchers set a target for the amount of antibodies that a future HIV vaccine may need to elicit. Having this kind of target could help make future development of a vaccine more efficient and cost effective.   

The Will and Hope of Communities

In early February 2020, the Network stopped all vaccinations in its HVTN 702 vaccine trial. An interim analysis showed that while the vaccine was safe, it was showing no efficacy at all. Conducted in South Africa, the trial enrolled more than 5,400 HIV-negative men and women between the ages of 18-35 years. The news dashed hopes for this HIV vaccine regimen against subtype C, the predominantly circulating strain of HIV in sub-Saharan Africa. A somber mood set into communities, amongst stakeholders, and the scientific community.

In 1909 polio was discovered and in 1954 a vaccine for human use was developed. A vaccine against measles was developed in 1957 after its discovery in 1911. The scientific journeys took 47 and 46 years respectively. The discovery and introduction of vaccines to prevent the transmission of other pathogens is a test of will. The scientific community persevered and their actions embody the words of Helen Keller that “optimism is the faith that leads to achievement. Nothing can be done without hope and confidence.”

Four decades later, the HIV and AIDS pandemic continues to impact lives in spite of significant progress in treatment and prevention. In 2018 UNAIDS estimated there to have been more than 74 million HIV transmissions and 32 million deaths since the epidemic began.  The need for a safe and globally effective preventive HIV vaccine cannot be emphasized enough. 

In the future, history will remind us of the scientific and people-centered lessons learned from HVTN 702 and the other previous efficacy trials that have shown disappointing outcomes.  Equally important to those lessons will be an account of how many study participants, communities, stakeholders, and study teams remain committed to help end the epidemic and its impact the world over.

When the AMP teams’ scientists take to the podium, more than 4 years after the study’s first infusion, their voices will be amplified by the study participants from 11 countries who want to see an end to HIV. Around the world people will witness an account of the dedicated communities from Botswana, Brazil, Kenya, Malawi, Mozambique, Peru, South Africa, Switzerland, Tanzania, the United States, and Zimbabwe who were a part of a global response to end the pandemic. 

The HIV prevention field will move forward, regardless of the AMP outcome. We will learn as a global community, and remain steadfast in our commitment to the pursuit for a safe and globally effective preventive HIV vaccine. When audiences step back, hope will be the narrative that conveys the story painted on a canvas at the world’s HIV epicenter.

Image Credit: Lisa Donohue

The Science of bnAbs  

What is a Broadly Neutralizing Antibody (bnAb)?

A bnAb is an antibody that neutralizes many of different strains of HIV that are found around the world. Antibodies are proteins produced by the immune system’s B cells that can neutralize the virus, blocking it from causing infection. Antibodies can also help eliminate the virus from the body. They are shaped like the letter “Y”.

The good news is that antibodies can prevent infection. The even better news is that they have immunological memory. The first time you are infected by a virus you will develop antibodies against that virus. The next time you come in contact with that same virus, you will already have antibodies prepared to fight against that particular virus. This is what preventive vaccines try to mimic.

What is VRC01?

VRC01 is a bnAb against HIV. It stops HIV from binding to human CD4 T-cells by attaching to the virus and preventing it from infecting the T cells. The VRC01 antibody is able to bind onto HIV at the CD4 binding site on the gp120 protein, which is the same spot that HIV would ordinarily use to attach to CD4 T-cells to infect them. In animal studies, VRC01 neutralized HIV and prevented about 90% of the HIV samples that were tested from being able to attach to T-cells and infect them.

The AMP studies can:

  1. tell us what the best models are for testing candidate HIV vaccines in animals;
  2. help determine effective blood antibody levels that could prevent HIV;
  3. determine what antibody levels an HIV vaccine may need to elicit to prevent HIV infection; and
  4. make future HIV vaccine development more efficient and cost effective.  

Advancing HIV Vaccine and Prevention Efforts

In early HIV vaccine development efforts, attempts were made to induce neutralizing antibodies, but no HIV vaccines tested thus far have produced neutralizing antibodies of significance. Naturally occurring bnAbs in individuals living with HIV arise rarely, and typically take many years to develop. However, most effective licensed vaccines, such as the measles vaccine, induce neutralizing antibody responses, and they provide protection from infection via neutralization. The AMP studies are the first efficacy trials to address the question of whether a broadly neutralizing antibody against HIV could be protective against infection.

Aziel Gangerdine is the Director of Communications for the HVTN.