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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.

Preliminary data suggests Moderna’s mRNA flu vaccine is effective

Moderna, one of the pioneers of the COVID-19 vaccines and of mRNA vaccines, is now nearing a new breakthrough. The company recently announced results from its trial — and it seems to be safe and effective.

Digitally-colorized, negative-stained transmission electron microscopic (TEM) image depicting a number of Influenza A virions. Image credits: CDC.

With the ongoing pandemic, it’s easy to forget that influenza is also around — but it is, and it’s causing its own set of problems.

“Even before the COVID-19 pandemic, approximately three million people died each year due to respiratory infections, and many more are hospitalized or become ill as a result of these viruses,” said Moderna CEO Stephane Bancel in a statement hailing the result.

The problem with the flu is that it’s hard to make a vaccine for it. There are four main influenza viral variants (A, B, C, D), each with its own substrains, and influenza viruses, in general, mutate much faster than coronaviruses. In particular, the Influenza A virus is a fast evolver. This is why you have to take the flu vaccine every year: because it needs constant tweaking as the viruses change as well. The efficacy of existing influenza vaccines is around 40-60%, much lower than that of COVID-19 vaccines.

There’s another problem. The majority of current flu vaccines are based on inactivated viruses grown in chicken eggs. This means that you have to select the virus strains 6-9 months in advance. If a new strain were to appear in the meantime and you’d want to address that with your flu vaccine, you’d need to start over again.

But mRNA vaccines could change all that and make vaccines easier to develop (and hopefully, more efficient as well).

Before the pandemic, Moderna was already working on several mRNA vaccine candidates — of course, that had to be put temporarily on hold as resources were diverted to the COVID-19 pandemic, but Moderna hasn’t given up on its initial plans. It even announced it’s working on a double-whammy vaccine that could protect against the flu and COVID-19.

The Phase I clinical trials started in July 2021 and now, the first results are in.

Just preliminary results

The study was carried out on 180 people and produced high levels of antibodies in all participants, at all the dosage levels that were attempted (one of the main objectives of the study was to figure out the right dosage). Side effects were mild (mostly tiredness, headaches, and pain around the injection site) and were more likely to affect younger rather than older participants.

Moderna’s experimental flu shot is “quadrivalent,” meaning it focuses on four strains of flu: A/H1N1, A/H3N2, B/Yamagata and B/Victoria. These are believed to be the most prevalent and dangerous strains, according to recommendations from the World Health Organization.

However, Moderna is also working to include more strains in its vaccine. This is one of the main advantages of mRNA vaccines: they can encode defenses against different strains with relative ease. This is also why Moderna wants to mix its COVID-19 and flu shots into a single vaccine — they even want to include the respiratory syncytial virus (RSV), a common virus that causes the cold but can be threatening for infants and elderly people.

Yes, but

At first glance, this seems like good news. But analysts noted that the antibody results don’t appear to be better than that of existing influenza vaccines and in fact, appear to be somewhat inferior.

There are a few things to be said about the fine print of these results. For starters, the antibody response isn’t the only thing that drives the immune response — for instance, T cells also play a role — and these aren’t even interim results, they’re just Phase I trials. Phase I trials, sometimes called “first in humans” trials are meant to test the safety and zoom in on the right formulation and dosage, not to assess efficacy. Moderna expects results from Phase II trials in early 2022. Moderna also stresses that the main advantages of mRNA still stand: the benefit is that they can be produced quickly and customized on the fly based on what strains are prevalent in a specific year, and they can be combined with other vaccines into a single shot.

However, regardless of the results, This is a reminder that mRNA isn’t a magic fix for vaccines — or at least not yet. Immunology is like a hallway with many doors, and different doors require different types of keys; mRNA is one such key, but it’s not a master key that can open all doors, or if it is, we haven’t learned how to use it yet.

Moderna isn’t the only company in this race either. The mRNA vaccine technology went from being considered a distant possibility just a few years ago to one of the hottest topics in immunology, thanks to the success that the Pfizer/BioNTech and Moderna COVID-19 vaccines have enjoyed. Both Pfizer and BioNTech are working on their own mRNA flu vaccines, as are GSK (working with CureVac) and Sanofi (working with Translate Bio).

No doubt, we’ll be hearing a lot from these mRNA influenza vaccines in the near future, and there’s a good likelihood they’ll offer some improvement over existing vaccines. But for now, at least, mRNA isn’t shaping up to be a silver bullet.

Novel mRNA vaccine against ticks works in guinea pigs

A group of researchers from Yale University have developed an mRNA vaccine that teaches the immune system to identify saliva from tick bites. The vaccine, which proved to be effective in guinea pigs, could prevent ticks from feeding on and then transmitting tick-borne diseases to people, a growing problem in many countries. 

It's a much bigger problem than you think
Image credit: Creative Commons / Jaqueline Mattias.

The vaccine is based on the same mRNA technology that has proven effective against COVID-19. Essentially, the mRNA shot means being injected with genetic material from the target virus instead of the virus itself. The mRNA gives your body instructions to fight the targeted pathogen and then is eliminated. Researchers have been working on mRNA vaccines, but thanks to the great efforts invested in the current pandemic, we’re finally on the right path. 

“There are multiple tick-borne diseases, and this approach potentially offers more broad-based protection than a vaccine that targets a specific pathogen,” senior author Erol Fikrig and Yale researcher said in a statement. “It could also be used in conjunction with more traditional, pathogen-based vaccines to increase their efficacy.”

Lyme disease is the most famous and damaging of them all tick-borne diseases, but it’s not the only one. Lyme, as well as several other diseases, is expanding across North America and Europe, with about 40,000 reported cases in the US per year. Ticks are a potential danger to anyone outdoors, from farmworkers to hikers, and they transmit several pathogens that can cause serious health problems that can even be life-threatening.

The new vaccine is different from those developed by Valneva and Pfizer and it’s only early stages of development but moving forward. The main difference is that it targets the bacteria responsible instead of the tick carrier. They are both promising approaches that could bring a solution to a growing health concern. 

Developing a vaccine

The researchers at Yale developed a new vaccine that trains the immune system to respond to tick bites, exposing it to 19 proteins found in tick saliva. It has mRNA molecules that tell the cells to produce these proteins – just like the mRNA COVID-19 vaccine tells the cells to manufacture coronavirus proteins to shield against the virus. 

In a set of experiments, the team tested the vaccine on guinea pigs. Unlike unvaccinated animals, vaccinated guinea pigs exposed to ticks developed red rashes at the place where they were bitten, suggesting an immune response. The ticks also tended to detach early on without sucking as much blood as they normally would.

The researchers also placed ticks carrying the Lyme disease on both vaccinated and unvaccinated animals. They removed the ticks once the skin rashes appeared on the animals, something that usually happens in the first 18 hours. While none of the vaccinated guinea pigs became infected, half the unvaccinated animals did.

“The vaccine enhances the ability to recognize a tick bite, partially turning a tick bite into a mosquito bite,” Fikrig said in a statement. “When you feel a mosquito bite, you swat it. With the vaccine, there is redness and likely an itch so you can recognize that you have been bitten and can pull the tick off quickly.”

While the vaccine was successfully in guinea pigs, it wasn’t in mice – unable to get a natural resistance after infection. The researchers now plan to test it in other animals, such as rabbits, so to better understand how the immunity of ticks varies in different hosts, and slowly move on towards humans. They also want to develop in the future vaccines for other tick-borne pathogens.

The study was published in the journal Science Transnational Medicine.

How mRNA vaccines from Pfizer and Moderna work, why they’re a breakthrough and why they need to be kept so cold

As the weather cools, the number of infections of the COVID-19 pandemic are rising sharply. Hamstrung by pandemic fatigue, economic constraints and political discord, public health officials have struggled to control the surging pandemic. But now, a rush of interim analyses from pharmaceutical companies Moderna and Pfizer/BioNTech have spurred optimism that a novel type of vaccine made from messenger RNA, known as mRNA, can offer high levels of protection by preventing COVID-19 among people who are vaccinated.

Although unpublished, these preliminary reports have exceeded the expectations of many vaccine experts, including mine. Until early this year, I worked on developing vaccine candidates against Zika and dengue. Now I am coordinating an international effort to collect reports on adult patients with current or previous cancers who have also been diagnosed with COVID-19.

Promising preliminary results

Moderna reported that during the phase 3 study of its vaccine candidate mRNA-1273, which enrolled 30,000 adult U.S. participants, just five of the 95 COVID-19 cases occurred among the vaccinated, while 90 infections were identified in the placebo group. This corresponds to an efficacy of 94.5%. None of the infected patients who received the vaccine developed severe COVID-19, while 11 (12%) of those who received the placebo did.

Similarly, the Pfizer-BioNTech vaccine candidate, BNT162b2, was 90% effective in preventing infection during the phase 3 clinical trial, which enrolled 43,538 participants, with 30% in U.S. and 42% abroad

How does mRNA vaccine work?

Vaccines train the immune system to recognize the disease-causing part of a virus. Vaccines traditionally contain either weakened viruses or purified signature proteins of the virus.

But an mRNA vaccine is different, because rather than having the viral protein injected, a person receives genetic material – mRNA – that encodes the viral protein. When these genetic instructions are injected into the upper arm, the muscle cells translate them to make the viral protein directly in the body.

Moderna was founded to deveop mRNA vaccines.

This approach mimics what the SARS-CoV-2 does in nature – but the vaccine mRNA codes only for the critical fragment of the viral protein. This gives the immune system a preview of what the real virus looks like without causing disease. This preview gives the immune system time to design powerful antibodies that can neutralize the real virus if the individual is ever infected.

While this synthetic mRNA is genetic material, it cannot be transmitted to the next generation. After an mRNA injection, this molecule guides the protein production inside the muscle cells, which reaches peak levels for 24 to 48 hours and can last for a few more days.

Why is making an mRNA vaccine so fast?

Traditional vaccine development, although well studied, is very time-consuming and cannot respond instantaneously against novel pandemics such as COVID-19.

For example, for seasonal flu, it takes roughly six months from identification of the circulating influenza virus strain to produce a vaccine. The candidate flu vaccine virus is grown for about three weeks to produce a hybrid virus, which is less dangerous and better able to grow in hens’ eggs. The hybrid virus is then injected into a lot of fertilized eggs and incubated for several days to make more copies. Then the fluid containing virus is harvested from eggs, the vaccine viruses are killed, and the viral proteins are purified over several days.

The mRNA vaccines can leapfrog the hurdles of developing traditional vaccines such as producing noninfectious viruses, or producing viral proteins at medically demanding levels of purity.

MRNA vaccines eliminate much of the manufacturing process because rather than having viral proteins injected, the human body uses the instructions to manufacture viral proteins itself.

Also, mRNA molecules are far simpler than proteins. For vaccines, mRNA is manufactured by chemical rather than biological synthesis, so it is much quicker than conventional vaccines to be redesigned, scaled up and mass-produced.

In fact, within days of the genetic code of the SARS-CoV-2 virus becoming available, the mRNA code for a candidate vaccine testing was ready. What’s most attractive is that once the mRNA vaccine tools become viable, mRNA can be quickly tailored for other future pandemics.

What are problems with mRNA?

MRNA technology isn’t new. It was shown a while back that when synthetic mRNA is injected into an animal, the cells can produce a desired protein. But the progress remained slow. That’s because mRNA is not only notoriously unstable and easy to degrade into smaller components, it is also easily destroyed by the human body’s immune defenses, which make delivering it to the target very inefficient.

But beginning in 2005, researchers figured out how to stabilize mRNA and package it into small particles to deliver it as a vaccine. The mRNA COVID-19 vaccines are expected to be the first using this technology to be approved by the FDA.

After a decade of work, the mRNA vaccines are now ready for evaluation. Physicians will be watching for unintended immune reactions, which can be both helpful and detrimental.

Why keep mRNA supercold?

The most important challenge for development of a mRNA vaccine remains its inherent instability, because it is more likely to break apart above freezing temperatures.

Modification of the mRNA building blocks and development of the particles that can cocoon it relatively safely have helped the mRNA vaccine candidates. But this new class of vaccine still requires unprecedented freezer conditions for distribution and administration.

What are the refrigeration requirements?

The Pfizer-BioNTech mRNA vaccine will need to be optimally stored at minus 94 degrees Fahrenheit and will degrade in around five days at normal refrigeration temperatures of slightly above freezing.

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In contrast, Moderna claims its vaccine can be maintained at most home or medical freezer temperatures for up to six months for shipping and longer-term storage. Moderna also claims its vaccine can remain stable at standard refrigerated conditions, of 36 to 46 degrees Fahrenheit, for up to 30 days after thawing, within the six-month shelf life.

Not surprisingly, Pfizer is also developing shipping containers using dry ice to address shipping constraints.


Author: Sanjay Mishra, Project Coordinator & Staff Scientist, Vanderbilt University Medical Center, Vanderbilt University

This article is republished from The Conversation under a Creative Commons license. Read the original article.