history of mrna vaccines :: Article CreatorMRNA Vaccines: Potential For Global Impact
Vaccines to prevent infectious diseases have an enormous impact on public health, and currently protect people against more than 25 different diseases. However, traditional vaccine approaches involve long, complex, and costly development and production processes. As a result, the global health community remains woefully unprepared to address rapidly emerging infectious diseases, as evidenced by the recent epidemics of Zika, Ebola, and chikungunya virus, among others. In addition, many persistent pathogens for which there are no effective vaccines continue to cause widespread sickness worldwide.
Moderna Therapeutics is addressing these challenges by pioneering a new class of vaccines made of mRNA, molecules that carry instructions copied from DNA for the assembly of proteins active in preventing or fighting disease (Fig. 1).The company's mRNA vaccines closely mimic nature by delivering mRNA to the body's cells, which in turn produce antigenic proteins as they would if the body were infected by a virus. The underlying biology of mRNA vaccines enables Moderna to pursue targets that could not be addressed previously.
In addition, unlike traditional vaccines, mRNA vaccines can be rapidly developed, because they do not require dedicated cell-culture-based and/ or fermentation-based production of weakened or killed versions of pathogens, inactivated toxins, or partial subunits of the pathogen.
Figure 1: mRNA in action, directing cellular machinery to express a protein.
All of Moderna's mRNA vaccines can be produced with a single 'plug-and-play' platform technology and manufactured at a single facility, which enables unprecedented versatility; accelerated research and early-development efforts; efficient, large-scale, standardized production; and a faster response to unanticipated threats.
"In the hundred-year history of vaccinations, mRNA offers a potential new paradigm," said Moderna's CEO Stéphane Bancel. Moderna began operations in 2011, and there are already eight mRNA prophylactic vaccine candidates in the company's pipeline, four of which are involved in clinical studies.
"We continue to invest heavily in our mRNA platform and novel infrastructure to accelerate the pace of R&D because we appreciate the acute global need for a new approach to vaccines and the potential of our mRNA vaccines to prevent disease for millions of people around the world," said Bancel.
Rapid advancement, early progress
One demonstration of the speed with which Moderna's approach can be used to address emergent global health threats is its Zika mRNA vaccine (mRNA-1325), which progressed from idea to first-in-human study in just 12 months. The Zika virus is a rapidly emerging pandemic with potential long-term public health implications. Children born to mothers infected with Zika can develop microcephaly, a disease characterized by small, incompletely developed heads, and thus severe disabilities. Zika is also thought to cause the autoimmune condition Guillain–Barré syndrome in adults.
Moderna continues to enroll healthy volunteers in the United States for a phase 1/2 study of mRNA-1325. A funding award from the Biomedical Advanced Research and Development Authority is supporting clinical studies of mRNA-1325.
Phase 1 studies are also under way for two mRNA vaccines that target influenza strains with pandemic potential: mRNA-1440 for influenza A subtype H10N8, and mRNA-1851 for influenza A subtype H7N9. Moderna recently published interim data from its ongoing phase 1 study of mRNA-1440, demonstrating the vaccine's ability to elicit robust immunity in humans with a favorable safety profile1.
A game changing pipeline
Among the other vaccines currently in development at Moderna is mRNA-1647, an mRNA vaccine for cytomegalovirus (CMV), which is the most common cause of newborn disability and can lead to deafness, microcephaly, vision loss, and mental deficiencies, among other serious complications. It is also the most frequent viral disease in transplant recipients, and often leads to transplant failure. MRNA-1647 combines six mRNAs that encode six different viral proteins: five proteins that constitute the CMV glycoprotein H (gH) pentamer complex, and one other CMV antigen, herpesvirus gB.
Another Moderna vaccine, mRNA-1653, simultaneously targets human metapneumovirus (HMPV) and parainfluenza virus (PIV3). These viruses typically cause mild respiratory illness, but symptoms can become severe in young children, the elderly, and other immunocompromised adults.
With funding from the Defense Advanced Research Projects Agency, Moderna also is developing mRNA- 1388, a chikungunya mRNA vaccine.
Currently, there are no approved vaccines for Zika, CMV, HMPV, PIV3 or chikungunya, suggesting the potential global impact that Moderna's mRNA vaccine technology could have.
In collaboration with Merck, Moderna is also conducting a phase 1 study of MRK-1777, an mRNA vaccine for an undisclosed viral indication. Moderna and Merck have a strategic collaboration to discover and develop mRNA-based vaccines and passive immunity treatments for viral diseases. The two companies also are partnering to advance mRNA-based personalized cancer vaccines in combination with Merck's anti-PD-1 therapy, Keytruda (pembrolizumab).
Moderna is partnering with the Bill & Melinda Gates Foundation to develop an mRNA antibody combination to help prevent human immunodeficiency virus (HIV) infection. Moderna's global health partnership with the foundation may also include additional mRNA-based development projects for various infectious diseases, with total funding of up to $100 million.
Beyond mRNA vaccines, Moderna is advancing mRNA therapeutics for cardiometabolic disease, immuno-oncology, and rare diseases, among other indications. The company also has existing partnerships with AstraZeneca, Alexion Pharmaceuticals and Vertex Pharmaceuticals.
"We're very grateful to our partners," Bancel said. "Their support and therapeutic area expertise are enabling us to explore the expansive potential of mRNA medicines to address a broad spectrum of significant unmet needs."
No, COVID MRNA Vaccines Won't Damage Your DNA
On Wednesday Florida's state surgeon general Joseph Ladapo called for stopping the use of messenger RNA–based COVID vaccines, citing—without convincing evidence—concerns about DNA fragments from the vaccines entering the human genome. Experts, including those at the U.S. Food and Drug Administration, say the claims are unfounded and that this warning could cause great harm by preventing people from getting a potentially lifesaving vaccine.
Last December Ladapo sent a letter to the commissioner of the FDA and the director of the Centers for Disease Control and Prevention in which he questioned the safety of DNA fragments in Pfizer's and Moderna's COVID mRNA vaccines. The letter laid out unfounded concerns about these fragments entering human cell nuclei in the presence of the lipid nanoparticles that are used to deliver the mRNA to cells. He also stated concerns about DNA contamination from a virus called simian virus 40 (SV40). Ladapo suggested that if such DNA were to be integrated into cells, it could activate cancer-causing genes or cause chromosomal instability.
That month the FDA said in a response letter that, "based on a thorough assessment of the entire manufacturing process, FDA is confident in the quality, safety, and effectiveness of the COVID-19 vaccines."
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Many scientists have dismissed the risks Ladapo asserted. They include Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia, who serves on an FDA advisory committee for the COVID vaccines. The way mRNA vaccines are made does result in small amounts of DNA in the final product, Offit says—but that's true of any vaccine grown in cells, including the measles and chickenpox vaccines. "There are trace quantities" of DNA (billionths to trillionths of a gram) per vaccine dose, "which is utterly and completely harmless for several reasons," he says.
To make an mRNA vaccine against COVID, scientists start with circular pieces of DNA called plasmids that contain a gene for the spike protein of SARS-CoV-2, the virus that causes the disease. The plasmids are amplified into billions of copies inside of bacteria, and chemicals are then added to release them from the bacteria. Enzymes are used to cut the plasmids into linear pieces of DNA that encode the spike protein, and a different enzyme converts that DNA into mRNA. Another enzyme is added to chop any remaining DNA into tiny harmless fragments.
In order to enter human cell nuclei, any such residual viral DNA would first have to enter the cell's main compartment, or cytoplasm, which normally keeps foreign DNA out. Next it would have to cross the nuclear membrane; this would be impossible without an access signal, which these fragments don't have, Offit notes. The residual DNA would also have to integrate into the nuclear DNA, which would require DNA-cutting enzymes that aren't present in the mRNA vaccine. The chances that mRNA vaccination would in any way affect your DNA "are zero," Offit says.
This is not the first time Ladapo has questioned the safety of COVID mRNA vaccines. In 2022 he recommended against children age 17 or younger getting the vaccines, falsely claiming that the shots didn't help and might even cause harm.
Scientist and physician Robert Malone also made unfounded claims about the supposed dangers of DNA fragments in mRNA vaccines altering human DNA when he testified in a November 2023 committee hearing held by Republican Representative Marjorie Taylor Greene of Georgia.
Offit points out that we encounter much greater quantities of foreign DNA all the time from the bacteria we're exposed to and the plants and animals we eat. In his statement on Wednesday, Ladapo claimed that people can get other COVID vaccines that don't use mRNA. Yet the only alternative in the U.S., made by the company Novavax, is grown in moth cells—which also contain DNA. "The minute you say the word DNA, people think, 'Oh, my God, there's DNA in this? Is that going to affect my DNA?'" Offit says. "But you have better chance of becoming Spider-Man" than being harmed by DNA from the COVID vaccines.
As for the concerns about simian virus 40, the COVID vaccines do not contain SV40 proteins or any genetic material encoding them. Although SV40 was a contaminant in early polio vaccines, it has not been shown to cause cancer in humans.
Offit acknowledges that any vaccine or medicine comes with potential risks as well as benefits. The Johnson & Johnson COVID vaccine was found to cause rare and sometimes fatal blood clots in some people and was removed from the market. The mRNA vaccines, while largely safe, come with a small but nonzero risk of myocarditis, primarily in teenage boys and young men. The risk of myocarditis from COVID itself is higher, however, and COVID-related myocarditis tends to be more severe. For those concerned about mRNA vaccines, there are other vaccines available, such as the one made by Novavax.
Offit says the benefits of vaccination still clearly outweigh any risks. He recommends the primary series for everyone aged six months and older. He says getting the booster is less important for healthy young people, who are not the highest-risk group for hospitalization. People older than age 65 and people of any age with underlying health conditions that put them at risk of severe disease—including pregnant people—should definitely be up to date on their vaccine, he says. Additionally, recent studies have shown that receiving a vaccination followed by one or more boosters greatly reduces the risk of developing long COVID.
"There's no avoiding risk," Offit says. "People say, 'I'm not going to risk that vaccine.' Okay, so you're going to risk the disease. Realize that that's the risk you're taking."
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