Tag Archives: B cells

The fascinating science behind the first human HIV mRNA vaccine trial – what exactly does it entail?

In a moment described as a “potential first step forward” in protecting people against one of the world’s most devastating pandemics, Moderna, International AIDS Vaccine Initiative (IAVI), and the Bill and Melinda Gates Foundation have joined forces to begin a landmark trial — the first human trials of an HIV vaccine based on messenger ribonucleic acid (mRNA) technology. The collaboration between these organizations, a mixture of non-profits and a company, will bring plenty of experience and technology to the table, which is absolutely necessary when taking on this type of mammoth challenge.

The goal is more than worth it: helping the estimated 37.7 million people currently living with HIV (including 1.7 million children) and protecting those who will be exposed to the virus in the future. Sadly, around 16% of the infected population (6.1 million people) are unaware they are carriers.

Despite progress, HIV remains lethal. Disturbingly, in 2020, 680,000 people died of AIDS-related illnesses, despite inroads made in therapies to dampen the disease’s effects on the immune system. One of these, antiretroviral therapy (ART), has proven to be highly effective in preventing HIV transmission, clinical progression, and death. Still, even with the success of this lifelong therapy, the number of HIV-infected individuals continues to grow.

There is no cure for this disease. Therefore, the development of vaccines to either treat HIV or prevent the acquisition of the disease would be crucial in turning the tables on the virus.

However, it’s not so easy to make an HIV vaccine because the virus mutates very quickly, creating multiple variants within the body, which produce too many targets for one therapy to treat. Plus, this highly conserved retrovirus becomes part of the human genome a mere 72 hours after transmission, meaning that high levels of neutralizing antibodies must be present at the time of transmission to prevent infection.

Because the virus is so tricky, researchers generally consider that a therapeutic vaccine (administered after infection) is unfeasible. Instead, researchers are concentrating on a preventative or ‘prophylactic’ mRNA vaccine similar to those used by Pfizer/BioNTech and Moderna to fight COVID-19.

What is the science behind the vaccine?

The groundwork research was made possible by the discovery of broadly neutralizing HIV-1 antibodies (bnAbs) in 1990. They are the most potent human antibodies ever identified and are extremely rare, only developing in some patients with chronic HIV after years of infection.

Significantly, bnAbs can neutralize the particular viral strain infecting that patient and other variants of HIV–hence, the term ‘broad’ in broadly neutralizing antibodies. They achieve this by using unusual extensions not seen in other immune cells to penetrate the HIV envelope glycoprotein (Env). The Env is the virus’s outer shell, formed from the cell membrane of the host cell it has invaded, making it extremely difficult to destroy; still, bnAbs can target vulnerable sites on this shell to neutralize and eliminate infected cells.

Unfortunately, the antibodies do little to help chronic patients because there’s already too much virus in their systems; however, researchers theorize if an HIV-free person could produce bnABS, it might help protect them from infection.

Last year, the same organizations tested a vaccine based on this idea in extensive animal tests and a small human trial that didn’t employ mRNA technology. It showed that specific immunogens—substances that can provoke an immune response—triggered the desired antibodies in dozens of people participating in the research. “This study demonstrates proof of principle for a new vaccine concept for HIV,” said Professor William Schief, Department of Immunology and Microbiology at Scripps Research, who worked on the previous trial.

BnABS are the desired endgame with the potential HIV mRNA vaccine and the fundamental basis of its action. “The induction of bnAbs is widely considered to be a goal of HIV vaccination, and this is the first step in that process,” Moderna and the IAVI (International AIDS Vaccine Initiative) said in a statement.

So how exactly does the mRNA vaccine work?

The experimental HIV vaccine delivers coded mRNA instructions for two HIV proteins into the host’s cells: the immunogens are Env and Gag, which make up roughly 50% of the total virus particle. As a result, this triggers an immune response allowing the body to create the necessary defenses—antibodies and numerous white blood cells such as B cells and T cells—which then protect against the actual infection.

Later, the participants will also receive a booster immunogen containing Gag and Env mRNA from two other HIV strains to broaden the immune response, hopefully inducing bnABS.

Karie Youngdahl, a spokesperson for IAVI, clarified that the main aim of the vaccines is to stimulate “B cells that have the potential to produce bnAbs.” These then target the virus’s envelope—its outermost layer that protects its genetic material—to keep it from entering cells and infecting them.  

Pulling back, the team is adamant that the trial is still in the very early stages, with the volunteers possibly needing an unknown number of boosters.

“Further immunogens will be needed to guide the immune system on this path, but this prime-boost combination could be the first key element of an eventual HIV immunization regimen,” said Professor David Diemert, clinical director at George Washington University and a lead investigator in the trials.

What will happen in the Moderna HIV vaccine trial?

The Phase 1 trial consists of 56 healthy adults who are HIV negative to evaluate the safety and efficacy of vaccine candidates mRNA-1644 and mRNA-1644v2-Core. Moderna will explore how to deliver their proprietary EOD-GT8 60mer immunogen with mRNA technology and investigate how to use it to direct B cells to make proteins that elicit bnABS with the expert aid of non-profit organizations. But readers should note that only one in every 300,000 B cells in the human body produces them to give an idea of the fragility of the probability involved here.

Sensibly, the trial isn’t ‘blind,’ which means everyone who receives the vaccine will know what they’re getting at this early stage. That’s because the scientists aren’t trying to work out how well the vaccine works in this first phase lasting approximately ten months – they want to make sure it’s safe and capable of mounting the desired immune response.

And even though there is much hype around this trial, experts caution that “Moderna are testing a complicated concept which starts the immune response against HIV,” says Robin Shattock, an immunologist at Imperial College London, to the Independent. “It gets you to first base, but it’s not 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. The mRNA technology may be key to solving the HIV vaccine issue, but it’s going to be a multi-year process.”

And after this long period, if the vaccine is found to be safe and shows signs of producing an immune response, it will progress to more extensive real-world studies and a possible solution to a virus that is still decimating whole communities.

Still, this hybrid collaboration offers future hope regarding the prioritization of humans over financial gain in clinical trials – the proof is that most HIV patients are citizens of the third world.

As IAVI president Mark Feinberg wrote in June at the 40th anniversary of the HIV epidemic: “The only real hope we have of ending the HIV/AIDS pandemic is through the deployment of an effective HIV vaccine, one that is achieved through the work of partners, advocates, and community members joining hands to do together what no one individual or group can do on its own.”

Whatever the outcome, money is no longer a prerogative here, and with luck, we may see more trials based on this premise very soon.

Rat Hippocampus.

Dormant, berserk antibodies could hold the key for HIV vaccine

A class of antibodies known to attack the body itself could prove to be the last line of defense against threats that the immune system can’t engage.

Rat Hippocampus.

Rat hippocampus stained with NeuN antibodies (unrelated to this study, green), myelin basic protein (red), and DNA (blue).
Image credits EnCor Biotechnology Inc. via GerryShaw / Wikimedia.

In a world first, researchers from Sydney’s Garvan Institute of Medical Research report that a population of ‘bad’ antibodies — which are usually inactivated, because they tend to attack the body’s tissues and cells — form a vital last line of defense against invading microbes.

Mr. Hyde

The group of antibodies is usually seen in an inactive form in the body — which prompted most researchers to consider them a relic of our immune systems, discarded and permanently decommissioned by our bodies when they outlived their usefulness. And, at least on first glance, there seems to be a very valid reason for this: the antibodies, when active, attack the body’s own tissues and can lead to autoimmune diseases.

New research shows that the antibodies’ unbridled aggression may actually be by design. The study shows that they become active when a disease overcomes the immune system’s other defenses, or when pathogens try to imitate the body’s cells to stay safe. The antibodies also go through a rapid genetic modification process upon activation, following which they no longer threaten the body. However, they do remain very good at killing pathogens that disguise themselves to look like normal body tissue.

“We once thought that harmful antibodies were discarded by the body — like a few bad apples in the barrel — and no one had any idea that you could start with a ‘bad’ antibody and make it good,” says Professor Chris Goodnow, who lead researcher.

“From these new findings, we now know that every antibody is precious when it comes to fighting invading microbes — and this new understanding means that ‘bad’ antibodies are a valuable resource for the development of vaccines for HIV, and for other diseases that go undercover in the body.”

Certain pathogens, such as Campylobacter or HIV, have evolved to appear almost identical to the body’s cell and can thus fly under the immune system’s radar. Even if detected, these adaptations ensure the viruses are protected, because our bodies systematically avoid using antibodies that are capable of binding (i.e. attacking) its own structures.

Goodnow’s previous research aimed at understanding how our immune systems recognize these threats — some 30 years ago, his search led to a group of mysterious antibodies hidden inside silenced ‘B cells’. These are the immune cells that don’t engage pathogens directly; rather, they’re more like advanced weapon factories, producing biochemical defenses and releasing them into the bloodstream. Unlike your more run of the mill B cells, however, the group his team identified produces antibodies that can pose a danger to the body — so they’re kept on standby, in a silenced state known as ‘anergy’.

Dr. Jekyl

“The big question about these cells has been why they are there at all, and in such large numbers,” Prof Goodnow says. “Why does the body keep these cells, whose antibodies pose a genuine risk to health, instead of destroying them completely, as we once thought?”

Goodnow’s new paper reports that these cells can, in fact, be re-activated to fight off threats other B cells can’t — but only after they’ve been genetically ‘re-tooled’ for the task.

Working with a preclinical mouse model, the team showed that this group of cells starts producing antibodies when they run into pathogens that appear highly similar to the body’s own cells. Before they engage, however, they go through tiny alterations in their DNA sequence — which, in turn, alter the antibodies’ behavior. This step is crucial: the new model of antibodies no longer attacks the body, but become up to 5000 times more effective in murdering the invaders, the team reports.

In the model they tested, this antibody retooling only involved three DNA changes in the genomes of the B cells. The first change prevented the compounds from binding to the body’s own cells, while the other two were solely aimed at increasing their ability to bind to the invader.

Antibody.

Schematic of an antibody’s structure.
Image credits Mamahdi14 / Wikimedia.

In experiments carried out at the Australian Synchrotron, the team showed how these three DNA changes rearrange the structure of the antibodies (which use tip-like structures to bind to other cells or pathogens) to make them better stick to invaders. One change of note they report on is that the altered antibodies’ tips fit neatly on a nanoscale ‘dimple’ that’s present on the pathogens but not the body’s cells. Another important find is that these antibodies are actually super effective: the results, Goodnow noted, show that they “can be even better than those developed through established pathways”.

It’s important to note that, being drawn from observations on mouse models, the results may not be directly translateable to human biochemistry — although it likely is, further research will be needed before we can say for sure. Regardless, the team hopes their work will pave the way to new and improved vaccines based on these B cells — particularly against pathogens such as HIV, which the rest of the immune system can’t engage.

The paper “Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination” has been published in the journal Science.