Do you want to know more about mRNA before your COVID injection?

Doctors will begin rolling up their sleeves in just a few weeks to receive their first doses of COVID-19 vaccines, which use mRNA technology to induce an immune response.

For those who want to learn more about the history and science of vaccines and mRNA therapeutics before getting their injection, here’s an introduction.

How does it work

Biologically, messenger RNA is transcribed from DNA and travels to the cytoplasm of a cell, where ribosomes translate it into proteins.

For the Pfizer / BioNTech and Moderna vaccines, the synthesized mRNA is wrapped in a lipid nanoparticle to evade the immune system when injected. Once inside a cell, ribosomes will go to work pumping out the SARS-CoV-2 spike protein.

The immune system then generates a response to that protein, which confers immunity to the virus without having been infected by it.

Essentially, instead of pharmaceuticals making proteins through a costly and difficult process, mRNA enlists the body to do the job. The ability to produce mRNA so rapidly is one reason these vaccines are at the forefront in the global race for a COVID-19 vaccine.

Has it never been done before?

That’s not true at all. While an mRNA vaccine has never been on the market anywhere in the world, mRNA vaccines have been tested before in humans for at least four infectious diseases: rabies, influenza, cytomegalovirus, and Zika.

In 2017, German biotech CureVac published results in The lancet for a phase I trial of its rabies mRNA vaccine, and in January of this year the company released the results via a press release of a phase I trial of its low-dose rabies mRNA vaccine.

Last year, Moderna and German researchers published the results of phase I of two mRNA flu vaccines. In January, Moderna announced the results of its phase I study of an mRNA vaccine against cytomegalovirus, and last April, when the pandemic was raging, the company reported interim data on its mRNA vaccine against Zika.

On a role in Nature Reviews Drug Discovery, Drew Weissman, MD, PhD, of the University of Pennsylvania in Philadelphia and a pioneer of mRNA technology, and their colleagues wrote that the first results of mRNA vaccines against rabies and flu “were somewhat modest, leading to to more cautious expectations about translating preclinical to clinical success. “

The team noted that in both trials, immunogenicity was “more modest in humans than expected based on animal models, a phenomenon that was also seen with DNA-based vaccines, and the side effects were not trivial.”

Some evidence of immunogenicity can also be obtained from COVID vaccine trials. Final first-line results with Pfizer / BioNTech showed 95% effectiveness in preventing symptomatic infections within 2 months of the second dose. Moderna’s vaccine showed an efficacy rate of 94.1% in final phase III results. Both products seemed very effective in preventing serious illnesses and more moderate cases.

The durability of these effects remains an open question. However, follow-up data from a phase I study of Moderna’s product, spanning 4 months after the first dose, showed a persistent neutralizing antibody response, albeit with modest decreases during that period, particularly in older participants.

What do we know about security?

While the flu and rabies vaccines appeared to be “safe and reasonably well tolerated,” Weissman and colleagues wrote, the trials showed “moderate systemic or injection site reactions and in rare cases severe.”

Their main safety concerns, which they said should be closely monitored in future trials, were local and systemic inflammation, as well as control of “expressed immunogen” and any self-reactive antibodies.

“A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity,” they wrote. “Therefore, identifying individuals at increased risk for autoimmune reactions prior to mRNA vaccination may allow reasonable precautions to be taken.”

The authors also noted that extracellular RNA could contribute to edema, citing a study that showed it “promotes blood clotting and pathological thrombus formation.”

“Therefore, safety will need ongoing evaluation, as different mRNA modalities and delivery systems are being used for the first time in humans and tested in larger patient populations,” they wrote in the article, which was published in 2018. .

Systemic effects have definitely been seen with the two COVID mRNA vaccines, with news reports citing participants complaining of symptoms such as “severe flu.” While Pfizer / BioNTech did not report serious safety concerns with their COVID-19 vaccine, patients experienced grade 3 fatigue and headache at rates of 3.8% and 2%, respectively.

Moderna did not release adverse event figures when announcing final final results, but said there were “no new serious safety concerns.” Interim data from the company’s phase III trial, analyzed when 95 infections had been recorded, included rates of adverse events: fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%). %) and erythema / redness at the injection site (2.0%).

Why did previous vaccines stagnate?

“An important factor is that there is no sense of urgency,” said Dennis Burton, PhD, of the Scripps Translational Research Clinic in La Jolla, California. MedPage today.

Zika has been relatively contained; rabies vaccines are already effective enough; and influenza remains a difficult target, Burton said.

While tolerability may have been an issue, safety was not, he said. “There is no risk of incorporation into the host chromosomes, and the levels of mRNA and proteins will drop and disappear.”

“We know in general that the general approach is quite safe,” Burton said, but noted that it was important that adverse events be monitored and followed up.

He warned that just based on the large number of people who will be vaccinated against COVID-19, events will occur and most will probably not be related to the vaccine. If people feel that concerns about those events are adequately addressed, they should be less likely to harbor reservations about vaccination and more inclined to help achieve the levels of herd immunity needed to end the pandemic.

“One of the things that worries us the most is that people will not get vaccinated,” he said. “But the risks of this disease will be much higher than the risks associated with vaccination.”

What else do I need to know?

The introduction of synthetic mRNA into cells also shows promise as a type of replacement therapy for diseases in which the production of vital proteins is inadequate or defective. So it could have advantages over gene therapies and protein replacement: less risky than the first, less frequent dosing than the second, and cheaper than either.

Preclinical work on therapeutic mRNA dates back to at least 1990, and successful protein production was observed in mice. Two years later, a study showed that mRNA injected into the hypothalamus of rats with a genetic mutation allowed vasopressin production and reversed their diabetes.

But those early results did not spark substantial interest in mRNA therapeutics because of concerns about mRNA instability, high innate immunogenicity, and inefficient delivery, Weissman and colleagues wrote. “Instead, the field sought DNA- and protein-based therapeutic approaches.”

Finally, in 2005, Weissman and Katalin Kariko, who is now senior vice president at BioNTech, modified mRNA so that it could evade immunological detection and stimulate protein production, according to an article in STAT. This is considered one of the groundbreaking moments in mRNA therapeutics, experts said. STAT.

Since then, the technology has been used not only in vaccines for infectious diseases, but also as a means to boost the immune system to fight cancer. The mRNA can target tumor-associated antigens expressed primarily by cancer cells, such as certain growth factors. These therapeutic, rather than prophylactic, vaccines have been tried in a variety of cancers, including acute myeloid leukemia, multiple myeloma, glioblastoma, melanoma, prostate cancer, and others.

There are fewer trials of regular therapies, but one that has drawn attention is an mRNA therapy for heart failure being developed by Moderna and AstraZeneca that encodes vascular endothelial growth factor A. Preclinical studies showed the creation of new blood vessels and improved cardiac function, and a phase I study in diabetic patients published in Communications from nature in 2019 it showed improved blood flow, which could indicate a “therapeutic potential for regenerative angiogenesis.”

Whether the apparent success of the Pfizer and Moderna vaccines will spark a wave of mRNA therapeutic development remains to be seen, but Burton cautioned that the coronavirus spike protein “appears to be a particularly easy target.”

“Will RNA work for all vaccines? I don’t think we can say that yet,” Burton said. “It is a big step forward. It is very quick to do and it has many advantages. But I think SARS-CoV-2 is an easy test relative to some of the other viruses that we have to deal with.”