Tag Archives: Immune

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.

Masks made of ostrich cells make COVID-19 glow in the dark

In the two years that SARS‑CoV‑2 has ravaged across the globe, it has caused immeasurable human loss. But we as a species have been able to create monumental solutions amidst great adversity. The latest achievement involves a standard face mask that can detect COVID-19 in your breath, essentially making the pathogen visible.

A COVID-19 sample becomes apparent on a mask filter under ultraviolet light. Image credits: Kyoto Prefectural University.

Japanese researchers at Kyoto Prefectural University have created a mask that glows in the dark if COVID-19 is detected in a person’s breath or spit. They did this by coating masks with a mixture containing ostrich antibodies that react when they contact the SARS‑CoV‑2 virus. The filters are then removed from the masks and sprayed with a chemical that makes COVID-19 (if present) viewable using a smartphone or a dark light. The experts hope that their discovery could provide a low-cost home test to detect the virus.

Yasuhiro Tsukamoto, veterinary professor and president of Kyoto Prefectural University, explains the benefits of such a technology: “It’s a much faster and direct form of initial testing than getting a PCR test.”

Tsukamoto notes that it could help those infected with the virus but who show no symptoms and are unlikely to get tested — and with a patent application and plans to commercialize inspection kits and sell them in Japan and overseas within the next year, the test appears to have a bright future. However, this all hinges on large-scale testing of the mask filters and government approval for mass production. 

Remarkably, this all came with a little help from ostriches.

The ostrich immune system is one of the most potent on Earth

To make each mask, the scientists injected inactive SARS‑CoV‑2 into female ostriches, in effect vaccinating them. Scientists then extracted antibodies from the eggs the ostriches produced, as the yolk transfers immunity to the offspring – the same way a vaccinated mother conveys disease resistance to her infant through the placenta. 

An ostrich egg yolk is perfect for this job as it is nearly 24 times bigger than a chicken’s, allowing a more significant number of antibodies to form. Additionally, immune cells are also produced far more quickly in these birds—taking a mere six weeks, as opposed to chickens, where it takes twelve.

Because ostriches have an extremely efficient immune system, thought to be the strongest of any animal on the planet, they can rapidly produce antibodies to fight an enormous range of bacteria and viruses, with a 2012 study in the Brazilian Journal of Microbiology showing they could stop Staphylococcus aureus and E. coli in their tracks – experts also predict that this bird will be instrumental in fending off epidemics in the future.

Tsukamoto himself has published numerous studies using ostrich immune cells harvested from eggs to help treat a host of health conditions, from swine flu to hair loss.

Your smartphone can image COVID-19 with this simple test

The researchers started by creating a mask filter coated with a solution of the antibodies extracted from ostriches’ eggs that react with the COVID-19 spike protein. After they had a working material, a small consort of 32 volunteers wore the masks for eight hours before the team removed the filters and sprayed them with a chemical that caused COVID-19 to glow in the dark. Scientists repeated this for ten days. Masks worn by participants infected with the virus glowed around the nose and mouth when scientists shone a dark light on them.

In a promising turn, the researchers found they could also use a smartphone LED light to detect the virus, which would considerably widen the scope of testing across the globe due to its ease of use. Essentially, it means that the material could be used to the fullest in a day-to-day setting without any additional equipment.

“We also succeeded in visualizing the virus antigen on the ostrich antibody-carrying filter when using the LED ultraviolet black light and the LED light of the smartphone as the light source. This makes it easy to use on the mask even at home.”

To further illustrate the practicability of the test, Tsukamoto told the Kyodo news agency he discovered he was infected with the virus after he wore one of the diagnostic masks. The diagnosis was also confirmed using a laboratory test, after which authorities quarantined him at a hotel.

Next, the team aims to expand the trial to 150 participants and develop the masks to glow automatically without special lighting. Dr. Tsukamoto concludes: “We can mass-produce antibodies from ostriches at a low cost. In the future, I want to make this into an easy testing kit that anyone can use.”

Teeth.

Our immune systems may actually help create cavities, a new study finds

Researchers in the University of Toronto’s Faculty of Dentistry have found evidence that our own bodies could be the major driver of tooth decay and filling failure.

Teeth.

Image via Pixabay.

The study shows how the decay of dentin (the hard substance beneath our teeth’s enamel) and fillings isn’t the work of bacteria alone. Rather, they report, it’s the product of an unintentional ‘collaboration’ between bacteria and immune cells known as neutrophils. As these two do battle, our teeth suffer the collateral damage.

Carpet bombing

“No one would believe that our immune system would play a part in creating cavities,” says Associate Professor Yoav Finer, the lead author of the study and the George Zarb/Nobel Biocare chair in prosthodontics at the Faculty of Dentistry. “Now we have evidence.”

Neutrophils are a type of short-lived immune system cells that play an important role in combating inflammation throughout the body. These cells make their way into the oral cavity via the gums around our teeth, where they fight off any bacterial invaders. But as they track and engage these bacteria, neutrophils also inflict damage on the surrounding environment.

“It’s like when you take a sledgehammer to hit a fly on the wall,” Finer says. “That’s what happens when neutrophils fight invaders.”

Byproducts of these engagements are the problem, the team explains. On their own, neutrophils can’t cause meaningful damage to teeth; these cells can’t produce any acid to attack the mineral-rich compounds. However, as they engage in an attack, oral bacteria do employ acids in a bid to defend themselves — and these demineralize teeth.

It’s here that the problem starts. The now-weakened teeth become susceptible to enzymes released both by bacteria and neutrophils, and these enzymes start boring through the demineralized area of teeth and tooth-colored fillings. Dentin and tooth-colored fillings sustain damage “within hours” of a bacteria-neutrophil showdown, the team reports. The research helps better explain why so many patients who had cavities filled with tooth-colored fillings face high rates of recurrence of the cavities. Most tooth-coloured fillings fail within five to seven years, costing Canadians an estimated $3 billion a year, the paper explains.

“It’s a collaboration of destruction – with different motives,” says study author Michael Glogauer, professor of the Faculty of Dentistry and acting chief dentist at the Princess Margaret Cancer Centre.

“Ours is the first basic study to show that neutrophils can break down resin composites (tooth-coloured fillings) and demineralize tooth dentin,” says master’s student and first author of the paper, Russel Gitalis. “This suggests that neutrophils could contribute to tooth decay and recurrent caries.”

While the findings may seem bleak, they actually point the way towards new potential treatment strategies. The findings may also help us develop new filling materials and test their resilience in the lab, potentially leading to much more durable fillings.

The paper “Human neutrophils degrade methacrylate resin composites and tooth dentin” has been published in the journal Acta Biomaterialia.

This one amoeba could hold the secret to fixing immune deficiencies in humans

Our immune system’s phagocytes use two mechanisms to protect our bodies: they attack and destroy pathogens either internally or externally. These mechanisms are well-studied and established in medicine, but it was believed that only humans and other complex organisms possess such defense mechanisms.

Microbiologists from the University of Geneva Switzerland (UNIGE) have now stumbled upon a species of social amoeba living in the soil of temperate forests that also employs these defensive mechanisms, and has been doing so for over a billion years. Since the amoebas employ defensive behaviors similar to the ones seen in human cells while being genetically modifiable, researchers plan to study them to understand and fight genetic diseases of the immune system.

Working in tandem with researchers from Baylor College of Medicine in Huston, USA, Professor Thierry Soldati’s team studies the social amoeba Dictyostelium discoideum. These predatory amoebas are usually very good at finding enough to eat by themselves, but when food is short they do something astonishing.

Amoeba slug

Close to 100,000 amoebas will come together into a single “mini animal,” known as a slug. This them turns into a “fruiting body” made up of a mass of spores and a central stalk. The spores can survive without food until the wind or another force carries them to a new area where they can germinate and find breakfast.

This is a slug made up of social amoebae. Reactive oxygen species produced by the sentinel cells, which are necessary for the generation of DNA nets that defend the slug, are colored in red.
Image credit Thierry Soldati, UNIGE.

In this way, the amoebas assure their survival through trying times. But it does come at a cost: around 20% of cells sacrifice themselves to create the stalk and 80% will become spores. To make sure the amoebas cash out on their investment, up to 1% of amoebas retain their phagocytic functions.

This 1% is what got the team’s science-bone a’tingling.

“This last percentage is made up of cells called “sentinel” cells. They make up the primitive innate immune system of the slug and play the same role as immune cells in animals,” explains Thierry Soldati, last author of the study.

“Indeed, they also use phagocytosis and DNA nets to exterminate bacteria that would jeopardize the survival of the slug. We have thus discovered that what we believed to be an invention of higher animals is actually a strategy that was already active in unicellular organisms one billion years ago,”

Our body’s bodyguards

Scanning electron micrograph of a neutrophil phagocytosing anthrax bacilli (orange). Photo by Volker Brinkmann.

Ok, let me give you some background. Phagocytes are one kind of immune-system cells floating around in your body. They get their name from the process of phagocytosis, which describes the act of one cell enveloping another then “digesting” it. This is done using reactive species of oxygen (hydrogen peroxide, ozone, etc) synthesized by the NOX2 enzyme.

But this hinges on the ability of a cell to envelop the pathogen. If the invader is too large to be captured, cells instead resort to the external attack method. They eject genetic material in the form of DNA that forms sticky, toxic nets called “neutrophil extracellular traps” (so the acronym for these nets is literally NETs — very handy.)

Armed with these NETs, phagocytes can bite more than they chew — pathogens get covered in these, are attacked by the same oxygen species and die, allowing our immune cells to take out threats much larger than themselves.

But immune systems don’t always work as intended. Patients suffering from granulomatous disease (CGD), for example, can’t express the functional NOX2 enzyme, so their phagocytes can’t destroy the pathogens they find. Because their cells can’t take out the invaders, they suffer from a host of recurring infections.

The team’s discovery might help researchers understand such immune system deficiencies in humans. By genetically modifying Dictyostelium discoideum, UNIGE microbiologists are able to conduct experiments on the mechanisms of their innate immune system. The team hopes that this microorganism can therefore serve as a scientific model for the research on defects in these defense processes, opening the way to possible treatments.

The full paper, titled “Social amoebae trap and kill bacteria by casting DNA nets” has been published online in the journal Nature Communications and can be read here.