HIV Vaccines: Will mRNA Be a Game Changer?
In 2020, approximately 35.9 million adults and 1.7 million children were living with human immunodeficiency virus-1 (HIV), the virus that causes acquired immune deficiency syndrome (AIDS). Two major types of HIV exist: HIV-1 – which was discovered first and is the most widespread form of the virus – and HIV-2.
Since the AIDS epidemic emerged in the mid-late 1970s, our knowledge of how HIV affects the human body has progressed. While there is no cure for HIV-1, there are treatment options available that help individuals with the infection to live longer and healthier lives. These therapies are antiretroviral therapies, or ARTS, that work to reduce the viral load within the body to an undetectable level, such that it cannot be transmitted to non-infected individuals. By the end of 2020, 27.4 million people with HIV had access to ARTs globally.
However, there are inequalities across the globe when it comes to accessing ARTs, particularly for children and individuals in low-income countries. A report published in July 2021 stated that ~ 46% of the 1.7 million children living with HIV were not receiving in 2020, and ~ 150,000 children were newly infected. We cannot provide access to the required therapeutics at a rate that overcomes the number of new infections each year. In short, ARTs alone are not sufficient to help us overcome the battle against HIV.
"HIV remains an infection which can have serious consequences," Dr. Peter English, retired consultant in communicable disease control and member of the editorial board for Vaccines Today, told Technology Networks. "While treatments are now available that mean that it [HIV] is a shadow of the problem than it used to be, they still need to be taken regularly for life. This is expensive and intrusive, and not without 'side effects'. It would be far better to be able to prevent the infection through vaccination or even, better still, be able to generate immunity that would clear the virus in people who are infected."
Challenges in HIV vaccine development
The road to developing a vaccine for HIV has often been referred to as the "biggest biomedical challenge of our generation". Unfortunately, our opponent in this challenge is a mighty one.
In 1984, the then US Secretary of Health and Human Services Margaret Heckler announced that researchers had identified the virus behind AIDS. In the now famous press conference, she also predicted that a vaccine would be developed within the next two years. This statement – which is almost 40 years old – did not age well. Why do we not yet have a vaccine for HIV? There are a whole host of reasons, including the fact that the majority of people infected with HIV do not become immune to the virus, it is incredibly good at mutating and there are difficulties in generating animal models that can predict vaccine efficacy in humans. "The body does not like to make a good immune response against HIV, and HIV is really unique among all the serious viral pathogens that we have had to deal with historically," said NIAID Director Anthony S. Fauci. As the typical approach for vaccine development is to mimic the natural immune response, this is a major obstacle.
Broadly neutralizing antibodies
In the 1990s, a discovery was made that ultimately carved the path to where we are today in the HIV vaccine research field. One percent of HIV-1 patients were found to develop potent antibodies, known as broadly neutralizing antibodies (bNAbs). These rare antibodies target specific sites on the HIV-1 virus envelope that are important for establishing infection in the body and that do not vary greatly across different strains of the virus.
Antibodies are Y-shaped proteins that are produced by B cells of the immune system in response to exposure to antigens. Antibodies contain a paratope which recognizes a specific epitope on an antigen, acting like a lock and key binding mechanism. The binding helps the body to eliminate antigens, either via direct neutralization or through a "tagging" system that provokes other arms of the immune system to respond. You can read more here.
Taking the immune system to school
This discovery provided a new blueprint for HIV vaccine development. Studying bNAbs can be used to guide the design of immunogens that are used in vaccines to trigger an immune response, such that they specifically initiate the production of bNAbs.
Immunogen vs antigen
Immunogen and antigen are terms that are often used interchangeably, but they are different. An immunogen triggers a cell-mediated immune response, whereas an antigen is something that binds to an antibody or a T-cell receptor. Not all antigens will be immunogens, but all immunogens are antigens.
Immunogen is a stimulus that produces a humoral or cell-mediated immune response, whereas antigens are any substance that binds specifically to an antibody or a T-cell receptor. All immunogens are antigens, but all antigens may not be immunogens, some very small molecules called haptens can bind to antibodies or B-cell receptor but they cannot initiate an immune response.
In 2015, Director of the National Institutes of Health Dr. Francis Collins referred to this approach – focusing on triggering bNAb production – as "taking the immune system to school": "In effect, a successful vaccine strategy has to 'take the immune system to school’ and it requires more than one lesson to pass the final exam. Specifically, what’s needed seems to be a series of shots – each consisting of a different engineered protein designed to push the immune system, step by step, toward the production of protective antibodies that will work against virtually all HIV strains." This process, however, is not easy.
The first step is to create an immunogen that is capable of "pushing" the immune system to make the bNAbs. Advances in structural biology techniques have enabled the study of large cohorts of HIV-1 infected patients, whereby bNAbs have been isolated and characterized to identify where they bind to the virus. This, in turn, informs the design of immunogens that are based on conserved regions of the virus – a method that is known as structure-based vaccine design.
One such immunogen, eOD-GT8 60mer, was developed in the lab of Professor William Schief, director of vaccine design for The International AIDS Vaccine Initiative (IAVI)'s Neutralizing Antibody Center (NAC), located at Scripps Research. “We and others postulated many years ago that in order to induce bNAbs, you must start the process by triggering the right B cells — cells that have special properties giving them potential to develop into bNAb-secreting cells,” Schief said. Targeting B cells with these "special" properties is an approach known as germline targeting. In preclinical animal studies, eOD-GT8 60mer was found to elicit antibodies that were precursors to the specialized bNAbs.
The researchers envision that this candidate could be part of a series of vaccinations that would eventually generate the required bNAbs to provide protection against HIV-1. This series of vaccines represents the "schooling" system referred to by Collins.
"The sequential vaccination is really a series of vaccinations [where] one leads to the next. Each vaccination will result in a pool of what we call memory B cells, where each B cell has an antibody on its surface, and then the next shot of the vaccine will come and trigger the memory B cells to mature, and so on.” Schief explained that the job of the final vaccine shot, is to convert the memory B cells into plasma cells which will secrete antibodies.
“In this case we need them to be secreting bNAbs against HIV, so that no matter which one of the fifty million different strains of HIV we are exposed to, the collection of all the different bNAbs that had been elicited by the vaccine would be enough to block the virus," Schief added.
As a first step, IAVI decided to test the safety of the immunogen in a Phase I trial, IAVI G001, that took place in 2018. The trial enrolled 48 healthy, HIV-negative participants that were allocated to receive two doses of either a placebo or the vaccine candidate.
"In the trial, we were testing to see whether this approach would work. The question was simply: if you vaccinate human beings with this vaccine candidate, will it bind the right naïve B cells and trigger them and cause them to expand and form memory B cells that have the right properties?" Schief explained.
Climbing on the shoulders of mRNA technology
In February 2021, Schief presented the results of the trial at the International AIDS Society HIV Research for Prevention conference. The candidate had passed its first test with flying colors. Ninety seven percent of the participants that were vaccinated developed detectable VRC01-class immunoglobulin G (IgG) B cells. “In this trial, the targeted cells were only about one in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”
IAVI and the Scripps Research scientists decided to partner with Moderna to utilize the company's mRNA technology to deliver the immunogen eOD-GT8 60mer to the body. While no mRNA vaccine had been authorized for human use prior to Pfizer–BioNTech's BNT162b2, decades of research had been conducted in this space, placing mRNA vaccines in the right place, at the right time.
How do mRNA vaccines work?
Unlike traditional methods of vaccination, whereby a part of a virus, a protein or bacterial cell is presented to the human body to trigger an immune response, mRNA vaccines are based on the "central" dogma of biology. In the case of SARS-CoV-2, mRNA code that provides the blueprint for building the "spike" protein of the virus is packaged up and delivered to the cells. Once inside the cells, this mRNA strand is translated by the host cell’s molecular machinery, to produce the antigen, consequently triggering an immune response.
A Phase I study of the vaccine candidate – known as mRNA-1644 – is set to commence. While a recent update to ClinicalTrials.gov prompted suspicion that the trial would be starting imminently, neither Moderna nor IAVI have made a public announcement.
The study will recruit 56 healthy individuals, aged 18 to 50 years, who are HIV-negative. The study hypothesis reads as follows: "sequential vaccination by a germline-targeting prime followed by directional boost immunogens can induce specific classes of B-cell responses and guide their early maturation toward broadly neutralizing antibody (bNAb) development through an mRNA platform." Both mRNA-1644 and a variant version of the candidate, mRNA-1644v2-Core also being tested in the trial, will be subject to safety and immunogenicity studies. The study is not blinded because the core focus is to ensure that the candidates are, A, safe and B, trigger some kind of immune response.
First base, but not a home run
This will be the first trial to test an mRNA-based vaccine for HIV in humans. It is hoped that the flexibility of the platform might be a gamechanger for overcoming the virus' tendency to mutate. English explained, "mRNA vaccines allow the rapid development of vaccines using different genetic sequences, and thus different antigens. This could mean developing vaccines that produce a range of different antigens, to cope with the diversity of the HIV virus; and it could allow studies to try out a wider range of antigens to see study their efficacy in initial laboratory studies."
It is very early days, however. Robin Shattock, professor of mucosal infection and immunity at the Faculty of Medicine, Imperial College London, said that, while the Moderna's clinical trial "gets you to first base" it's not necessarily a home run: "Essentially we recognize that you need a series of vaccines to induce a response that gives you the breadth needed to neutralize HIV […] "It’s quite likely that their technology may allow them to start to look at that process, but we’re a very long way away from an effective vaccine.”
The absence of a HIV vaccine is not due to science's lack of trying, but rather the complexity and conniving nature of its viral opponent. While the COVID-19 global pandemic has cast inexplicable grief and disrupt upon the world, it has also brought insight and knowledge on how we best equip ourselves to fight against ongoing and future pathogenic threats. Will this "new-era" in vaccinology see us finally solve "the biggest biomedical challenge of our generation"? Only time, and trials, will tell.
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