Overcoming Obstacles To Mrna Vaccines
In an early proof-of-concept of using gene-based therapeutics to produce the proteins needed to fight disease, published in 1990, scientists reported that in mice, cells successfully produced proteins encoded in injected RNA or DNA. The method was potentially revolutionary: It could, in theory, be used to engineer any protein the body needed to boost immunity against pathogens and fight diseases such as cancer and rare genetic conditions.
I would predict, and others have too, that this will beckon a new era for the application of mRNA towards infectious diseases, particularly as rapid response platforms to help deal with outbreaks.
Nick Jackson, Coalition for Epidemic Preparedness Innovations
Despite its promise, there are challenges associated with working with mRNA. Ordinary mRNA produces only low levels of proteins, and the molecule degrades too quickly inside the body to make it suitable as a therapeutic. On top of that, RNA can trigger an immune response thats independent of the response to the protein it encodes. If you just inject foreign RNA into people or animals, you can induce a very serious inflammatory response, Pardi says. He adds that this is our bodies defense mechanism against viruses, which can use either DNA or RNA to store their genetic information.
I think pretty much everyone acknowledges this as the big breakthrough , says Liu.
Mrna Technology: The Launch Of A New Era For Vaccines
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Vaccines have worked in the same way since they were invented more than 200 years ago: they use a weakened version of the targeted virus to create an immune response that the body remembers. Since COVID-19 appeared, a new kind of vaccine has emerged — the mRNA vaccine. The mRNA vaccine is a unique delivery system that focuses specifically on the cells that are the targets of an infection. And, as Robert Salata, MD, UH infectious disease specialist and Program Director, Roe Green Center for Travel Medicine and Global Health, explains, researchers are now studying how to use this revolutionary technology to fight other diseases such as HIV, rabies and influenza.
The Long History Of Mrna Vaccines
Messenger RNA, or mRNA, was discovered in the early 1960s research into how mRNA could be delivered into cells was developed in the 1970s. So, why did it take until the global COVID-19 pandemic of 2020 for the first mRNA vaccine to be brought to market?
In this explainer, Chris Beyrer talks us through mRNA vaccines history, development, and breakthroughs.
Theres a big gap between when the first mRNA flu vaccine was tested in mice in the 1990s and when the first mRNA vaccines for rabies were tested in humans in 2013. What was happening in the interim?
The early years of mRNA research were marked by a lot of enthusiasm for the technology but some difficult technical challenges that took a great deal of innovation to overcome.
The biggest challenge was that mRNA would be taken up by the body and quickly degraded before it could deliver its messagethe RNA transcriptand be read into proteins in the cells.
The solution to this problem came from advances in nanotechnology: the development of fatty droplets that wrapped the mRNA like a bubble, which allowed entry into the cells. Once inside the cell, the mRNA message could be translated into proteins, like the spike protein of SARS-CoV-2, and the immune system would then be primed to recognize the foreign protein.
So, what happened once they figured out this technology?
Then COVID-19 hit what happened then?
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How Long Has Mrna Technology Been Available For
There has been some concern amongst the public regarding the speed of development of mRNA COVID-19 vaccines. When in fact, researchers have been studying and working with mRNA technology for over 30 years. Since its discovery in 1961, mRNA has been the subject of research for various diseases.
Further information regarding the timeline of key discoveries and advances in the development of mRNA as a drug technology can also be seen at Nature: mRNA-based therapeutics- developing a new class of drugs.
Cautious Optimism For Trials Of Mrna
Clinical trials for mRNA vaccine against HIV begin in United States. Upcoming trials in Rwanda and South Africa will test long-term suppression of HIV. But lack of license access and production capacity may hamper pan-African rollout.
- 31 March 2022
One remarkable thing about the COVID-19 pandemic was how quickly a vaccine was developed to combat the virus. A process that normally spans a decade or more dozens of clinical trials, terse patent negotiations, complex roll-out strategies was condensed into less than one year. mRNA, messenger ribonucleic acids that elicit an immune response from cells before degrading, provided a quick and safe solution to a global health threat.
mRNA technology has been under development since the 1960s, but its success in combatting coronavirus has resulted in renewed interest in using the technology for other diseases. One of these is another pandemic that has killed an estimated 36 million people since it was recognised in 1981 human immunodeficiency virus, better known as HIV.
The United States National Institute of Allergy and Infectious Diseases announced in March the launch of a phase I clinical trial evaluating three experimental HIV vaccines based on an mRNA platform. NIAID director Anthony Fauci said that while finding an HIV vaccine had proven a daunting scientific challenge, there was now an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection.
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Safety Monitoring After Vaccination
Even after emergency use authorization has been granted, Dr. Kenyon said that the scientists will continue to collect safety data, as they will follow the participants for up to 2 years. This adds another layer of reassurance as a person shifts from a trial to a real-life setting.
The trial is tens of thousands of participants, but for the vaccine program, you are getting into the millions. While unlikely, it may uncover any undetected toxicities that were not picked up by the trial.
The V-safe .
It is a smartphone-based system where you will be contacted actively by the CDC to see how you are doing after being vaccinated and , therefore, pick up any adverse events that were not picked up in the trials, Dr. Kenyon explained.
My Patient Has A History Of Guillain
Individuals who have previously been diagnosed with GBS can receive COVID-19 vaccines. Ongoing surveillance by the TGA and other international vaccine regulators has shown growing evidence of a possible link between GBS and Vaxzevria . Specialist advice from a treating neurologist or immunisation specialist may be considered to discuss the benefits and risks of vaccination.
For more information please refer to MVEC: Guillain-Barre Syndrome and Victorian COVID-19 vaccination guidelines.
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When Should People Who Have Previously Tested Positive For Covid
A history of prior COVID-19 infection is not a contraindication to COVID-19 vaccination.
Individuals should be encouraged to be vaccinated as soon as they have recovered from acute illness. Side effects following vaccination have been reported to occur at similar or decreased rates compared with recipients who have not previously been infected with COVID-19 disease.
Some individuals may choose to delay vaccination for no more than 4 months after onset of initial symptoms as there is some evidence to suggest that immunity gained from COVID-19 infection can persist for this time. Individual risk factors for severe disease, occupation as well as amount of circulating disease should be considered when deciding to delay vaccination.
Individuals suffering prolonged symptoms can consider vaccination on a case-by-case basis in consultation with their GP.
For further information, refer to the Clinical recommendations for COVID-19 vaccines and the Victorian COVID-19 vaccination guidelines.
Basic Mrna Vaccine Pharmacology
mRNA is the intermediate step between the translation of protein-encoding DNA and the production of proteins by ribosomes in the cytoplasm. Two major types of RNA are currently studied as vaccines: non-replicating mRNA and virally derived, self-amplifying RNA. Conventional mRNA-based vaccines encode the antigen of interest and contain 5 and 3 untranslated regions , whereas self-amplifying RNAs encode not only the antigen but also the viral replication machinery that enables intracellular RNA amplification and abundant protein expression.
The construction of optimally translated IVT mRNA suitable for therapeutic use has been reviewed previously,. Briefly, IVT mRNA is produced from a linear DNA template using a T7, a T3 or an Sp6 phage RNA polymerase. The resulting product should optimally contain an open reading frame that encodes the protein of interest, flanking UTRs, a 5 cap and a poly tail. The mRNA is thus engineered to resemble fully processed mature mRNA molecules as they occur naturally in the cytoplasm of eukaryotic cells.
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Are Anthracycline Therapies Considered A Contraindication To Mrna Covi
Children who have been treated with chemotherapeutic agents including anthracyclines as part of their cancer therapy are not considered as higher risk of side effects from vaccination (including the development of myocarditis/pericarditis. Parents/guardians should speak to their treating team regarding COVID-19 vaccination based on current recommendations.
For further information refer to COVID-19 Vaccination Guidance for children 12 years and older undergoing cancer treatment and children with non-cancerous blood disorders.
It Began With Chickens
Operation Warp Speed, the private-public partnership initiated by the White House during the pandemic, may give the impression the COVID-19 vaccine developed overnight, but in actuality, it depends on research dating back nearly 100 years.
Coronaviruses were first encountered in April 1930, when a strange respiratory disease ravaged poultry farms across North Dakota and Minnesota, killing tens of thousands of baby birds, The Scientist reports. Unsure of what exactly this illness was, veterinarians Arthur Schalk and Merle Hawn of North Dakota Agricultural College, now North Dakota State University, the viral agent later named infectious bronchitis virus.
Further scientific research into IBV and recognition that it was not like influenza A, a flu virus known to cause bronchitis, would transpire over the next 30 years. In November 1968, a group of scientists wrote to the journal Nature asking for IBV, and viruses resembling it like mouse hepatitis virus discovered in 1947, to be classified as coronaviruses, a name derived from its appearance the spike proteins casting a halo around the surface, much like the sun’s corona on electron microscope imaging.
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Myth: The Side Effects Of The Covid
FACT: In April 2021, the CDC temporarily paused and then resumed use of the Johnson & Johnson vaccine. Read full story.
The Pfizer and Moderna COVID-19 vaccines can have side effects, but the vast majority are very short term not serious or dangerous. The vaccine developers report that some people experience pain where they were injected body aches headaches or fever, lasting for a day or two. These are signs that the vaccine is working to stimulate your immune system. If symptoms persist beyond two days, you should call your doctor.
If you have allergies especially severe ones that require you to carry an EpiPen discuss the COVID-19 vaccine with your doctor, who can assess your risk and provide more information about if and how you can get vaccinated safely.
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Principal Concept Of Mrna Pharmacology
The concept behind using IVT mRNA as a drug is the transfer of a defined genetic message into the cells of a patient for the ultimate purpose of preventing or altering a particular disease state.
In principle, two approaches of using IVT mRNA are being pursued. One is to transfer it into the patient’s cells ex vivo these transfected cells are then adoptively administered back to the patient. This method is being investigated for genome engineering, genetic reprogramming, T cell- and dendritic cell -based immunotherapies to treat cancer and infectious diseases, and some protein-replacement approaches. The second approach is direct delivery of the IVT mRNA using various routes. This is being developed for applications in oncology and infectious diseases, tolerization regimens to treat allergies and for other protein-replacement therapies. For both ex vivo transfection and direct vaccination, the following general principles of mRNA pharmacology apply.
Figure 2: Principles of antigen-encoding mRNA pharmacology.
The primary compartment of the pharmacodynamic activity of IVT mRNA is the cytoplasm. In contrast to natural mRNA that is produced in the nucleus and enters the cytoplasm through nuclear export, IVT mRNA has to enter the cytoplasm from the extracellular space.
Once IVT mRNA has entered the cytoplasm, its pharmacology is governed by the same complex cellular mechanisms that regulate the stability and translation of native mRNA.
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Mrna Vaccines Are Newly Available To The Public But Have Been Studied For Decades
Researchers have been studying and working with mRNA vaccines for decades. Interest has grown in these vaccines because they can be developed in a laboratory using readily available materials. This means vaccines can be developed and produced in large quantities faster than with other methods for making vaccines.
mRNA vaccines have been studied before for flu, Zika, rabies, and cytomegalovirus . As soon as the necessary information about the virus that causes COVID-19 was available, scientists began designing the mRNA instructions for cells to build the unique spike protein into an mRNA vaccine.
Future mRNA vaccine technology may allow for one vaccine to provide protection against multiple diseases, thus decreasing the number of shots needed for protection against common vaccine-preventable diseases.
Beyond vaccines, cancer research has used mRNA to trigger the immune system to target specific cancer cells.
Would Mrna Vaccines Work In People
The Pfizer-BioNTech and Moderna vaccines deployed the same clever mechanism. A shot of specially coded mRNA would instruct certain cells to manufacture the notorious COVID-19 spike protein, enabling the cells to briefly masquerade as the virus and teach the immune system to recognize it. Within weeks of injection, the mRNA would break down naturally without a trace, leaving in its wake a powerful immunity against the coronavirus.
Although Weissman was confident in the sciencehe had worked on 20 different vaccines in animal models with great successhe was anxious to see the results of the human trials. In science, we know that what works in mice rarely works in humans, and what works in sometimes works in humans, Weissman says. So I was very nervous whether it would work in people.
Results from the human clinical trials showed the vaccines to be remarkably safe, with 95 percent efficacy in preventing COVID-19 infection. Weissman was elated. In December 2020, he and Karikó received their first vaccine shots together at the University of Pennsylvania.
It was an emotional moment, he says, reflecting on their long struggle to show the world the promise of this extraordinary molecule. There were a lot of down times, a lot of soul-searching, a lot of figuring out why things werent working. But we never lost hope because we both saw the incredible potential that mRNA had.
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Are There Any Concerns Regarding Covid
People who have previously been diagnosed with Bells Palsy can receive COVID-19 vaccines. Cases of Bells Palsy following immunisation have been identified in participants in mRNA COVID-19 vaccine candidate clinical trials. However, as the rate of occurrence was not above the background rate expected in the general population, they are not considered to be caused by vaccination.
For more information refer to CDC: Vaccine Considerations for People with Underlying Medical Conditions.
Concerns Over Mrna Vaccine
According to Dr. Kenyon, misinformation surrounding mRNA vaccines stems from a concern that the vaccine infects people with the virus.
Nobody is getting infected with a COVID-19 vaccine. It is only the surface protein that would be replicated because we have given you the messenger RNA. It is not the entire virus, he explained.
One misconception is that an mRNA vaccine would not be useful when the virus mutates.
A July 2020 study that appears in Frontiers in Microbiology confirms that the virus mutates. After analyzing 48,635 samples of SARS-CoV-2, the researchers identified an average of 7.23 mutations per sample.
While mutations are a certainty, Dr. Sun said that this should not be a cause for alarm.
There has been an estimated 250,000 variants or strains of SARS-CoV-2 sequenced in the lab. For the most part, the virus has a low mutation rate compared to the mutation rate of the influenza virus , Dr. Sun explained. The spike protein is important for the ability of the virus to infect humans cells. I think it would not mutate enough for the vaccines to be ineffective.
Another concern is whether natural immunity would be more effective than a vaccine. However, a CDC study from November 2021 found that COVID-19 mRNA vaccines are about five times more effective in preventing hospitalization than a previous infection.
Dr. Kenyon said that before any clinical trial can start, a data monitoring and safety board must approve a study protocol.
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What Did This Research Do
There are many different coronaviruses. SARS-CoV-2, the virus that causes COVID-19, is just one others can cause illnesses like the common cold.
Years before the COVID-19 pandemic began, experts at the NIH Vaccine Research Center were studying coronaviruses to find out how to protect against them. The scientists chose to focus on one prototype coronavirus and create a vaccine for it. That vaccine could then be customized to fight different coronaviruses. It was important that this vaccine be three things:
- Fast. If a pandemic began like the COVID-19 pandemic did in late 2019 researchers would need to be able to adapt the vaccine and produce a lot of doses very quickly.
- Reliable. The vaccine had to be extremely effective in humans.
- Universal. The vaccine would have to work for many different coronaviruses, since it is not always possible to predict which viruses will spread quickly or become dangerous.