The mRNA Vaccine Revolution Under Way Exponentially
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Until recently most people had never even heard of mRNA Vaccines. Now scientists believe they may be the key to solving a vast array of health problems.
Last year (2020) Anna Blakney was working in a niche field of science in a lab in London. Few people outside of her scientific circles had heard of mRNA vaccines. Because none yet existed. Attendees at an annual conference talk she gave in 2019 could be counted in the tens, not hundreds. Today, she's in high demand, i.e. an Assistant Professor at the University of British Columbia, Canada, and a Science Communicator with 253,000 followers and 3.7 Million likes on Tik-Tok. She admits she was in the right place at the right time to ride a once-in-a-generation wave of scientific progress. She even gave this new era a name: "The RNAissance".
Due to the Covid-19 pandemic, many people have now heard of – and have received – an mRNA vaccine the Big Pharmas Pfizer-BioNTech and Moderna. But when Blakney started her PhD at Imperial College London in 2016, "a lot of people were skeptical whether it could work". Now, "the whole field of mRNA is just beginning to explode. It's a game changer in medicine," she says.
Blakney goes on to say "It's such a game changer it raises some very exciting questions: could mRNA vaccines prove to be a cure for cancers, HIV, tropical diseases."
Messenger ribonucleic acid, or mRNA for short, is a single-stranded molecule that carries genetic code from DNA to a cell's protein-making machinery. Without mRNA, your genetic code wouldn't be used, proteins wouldn't be made, and your body wouldn't work. If DNA is the bank card, then mRNA is the card reader.
Billions of doses of mRNA vaccines have been administered across the globe since the Covid-19 outbreak began. (Credit: Getty Images)
Billions of doses of mRNA vaccines have been administered across the globe since the Covid-19 outbreak began. (Credit: Getty Images)
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Once a virus is inside our cells, it releases its own RNA, tricking our hijacked cells into spewing out copies of the virus – in the form of viral proteins – that compromise our immune system. Traditional vaccines work by injecting inactivated virus proteins called antigens, which stimulate the body's immune system to recognize the virus when it reappears.
The genius of mRNA vaccines is there's no need to inject the antigen itself. Instead, these vaccines use the genetic sequence or "code" of the antigen translated into mRNA. It's a ghost of the real thing, fooling the body into creating very real antibodies. The artificial mRNA itself then disappears, degraded by the body's natural defenses including enzymes that break it down, leaving us with only the antibodies.
It's therefore safer to produce more quickly and cheaply, compared with traditional vaccines. You no longer need huge bio-secure labs growing deadly viruses inside millions of chicken eggs. Instead, just one lab can sequence the proteins of the antigen and email it around the world. With that information a lab could make "a million doses of mRNA in a single 100ml test tube," says Blakney.
We've now seen that process play out in real time. On 10 January 2020, Zhang Yongzhen, a Professor at the Chinese Center for Disease Control and Prevention in Beijing, sequenced the genome for Covid-19 and published it the next day. Covid-19 was declared a pandemic by the World Health Organization (WHO) on March 11th. On March 16th, using Zhang's sequence, the first mRNA vaccine began Phase 1 Clinical Trials.
The US Food and Drug Administration approved the Pfizer-BioNTech Covid-19 vaccine on December 11, 2020, making history as not only the first ever mRNA vaccine approved for humans, but also the first to have a 95% efficacy rate in clinical trials.
Approval of the Moderna mRNA vaccine followed close behind on December 18, 2020. The previous title holder for "fastest ever vaccine", i.e. the Mumps Vaccine, in comparison took four years. The Moderna & Pfizer–BioNTech Vaccines took just 11 Months.
There weren't many people in the mRNA therapeutics world who would have imagined a 95% initial efficacy rate – Kathryn Whitehead said.
The theory behind the mRNA vaccine was pioneered by University of Pennsylvania scientists Katalin Karikó and Drew Weissman, who both recently received the 2021 Lasker Award, America's top biomedical research prize. In 2019 however, mainstream mRNA vaccines development and application were believed to be at least five years away.
The pandemic fast-forwarded this field of medicine by half a decade. Kathryn Whitehead, an associate professor of chemical engineering and biomedical engineering at Carnegie Mellon University, and a key collaborator of Weissman and Karikó admits, "there weren't many people in the mRNA therapeutics world who would have imagined 95% initial efficacy rates in this emergency scenario".
But now the possibilities are seemingly endless. As Blakney puts it: "Now it's like, OK, so since it's worked for a viral glyco-protein, what other vaccines can we make with it? And what can we do beyond that?"
The pioneering work of Katalin Kariko and Drew Weissman on mRNA paved the way for the Pfizer and Moderna Covid-19 Vaccines.
At the University of Rochester, Dragony Fu, associate professor, department of biology, received expedited funding for his laboratory from the National Science Foundation to research RNA proteins. If we are currently witnessing mRNA vaccine 1.0 for Covid-19, then 2.0 will address two further categories of disease, says Fu: "one is pathogens, like Sars, but you can apply this technology to other foreign invaders such as HIV.
Already before Covid, companies were in development making mRNA vaccines against HIV." He also cites Zika, herpes and malarial parasites in the pathogens camp.
"The other category is autoimmune diseases," he says. "That is intriguing because it's verging beyond the very strict definition of a vaccine." Fu says the future could involve mRNA "treatments", for example to reduce inflammation. "In theory, that opens up so many possibilities," he says.
Yizhou Dong, associate professor of pharmaceutics and pharmacology Ohio State University, specializes in little balls of fat, or lipids, needed to house the mRNA and safely deliver it to the cells without being immediately destroyed by our body. Lipids have been described as the "unsung hero" – without lipid delivery being finally perfected and approved in 2018, there would have been no Covid-19 mRNA vaccines by 2020.
Before Covid-19, there were many research studies looking at broader applications of combining this new lipid delivery technique with mRNA Dong says, including genetic disorders, cancer immuno-therapy, infectious diseases and bacterial infections. "As long as you have the antigen and can sequence the protein, theoretically it should work".
Thanks to the combined breakthrough in lipid delivery and mRNA technology, vaccines and treatments in development include Translate Bio's mRNA therapy's for cystic fibrosis and multiple sclerosis; Gritstone Oncology and Gilead Sciences' mRNA vaccine for HIV; Arcturus Therapeutics' therapies for cystic fibrosis and heart disease; and German start-up Ethris, with Astra-Zeneca, are developing mRNA therapies for severe pulmonary diseases and asthma.
Zika is one of many diseases that there may be an mRNA vaccine for in the future. Solutions for tropical diseases are being explored too. Moderna are close to phase two (out of three) in clinical mRNA vaccine trials for both Zika and Chikungunya. Both are described as "neglected", so-called because they effect the poorest populations of the world and do not receive adequate research and funding. The speed and cost of mRNA vaccines could change that paradigm and signal the end of neglected tropical diseases.
Perhaps the first new mRNA vaccine to hit our shelves, however, will be for a more familiar foe – the flu. Influenza viruses are responsible for an estimated 290,000–650,000 deaths annually worldwide. "We're most likely to see mRNA vaccines against influenza in the near future," says Whitehead. "These mRNA vaccines have been in development for years, and clinical trials to date have been encouraging. There are currently five clinical trials for Influenza A, including one in phase two". This could be just in time.
Paul Hunter, a professor of health protection at the University of East Anglia in the UK who also consults for the WHO, has warned that some countries may be due an influenza epidemic that could lead to more fatalities than Covid-19.
Several pharmaceutical companies are also pursuing mRNA vaccines for cancer. "Cancer cells will often have certain surface markers that the rest of the cells in your body don't have," says Blakney. “You can train your immune system to recognize and kill those cells, just like you can train your immune system to recognize and kill a virus: it's the same idea, you just figure out what proteins are on the surface of your tumor cells and use that as a vaccine".
The idea of patient-specific individualized medicine has been a promising prospect for years – this could be another door opening wide by mRNA vaccine technology, according to Blakney.
In theory, "they take out your tumor, sequence it, see what's on the surface of it, and then make a vaccine specifically for you".
From cancer to HIV, tropical diseases to antibiotic resistance, scientists believe there could be a huge range of mRNA vaccine solutions.
If treatments for cancer, HIV, and tropical disease are coming along with mRNA 2.0, then what could be even further down the line with 3.0?
One area of concern for modern medicine is antibiotic resistance. "Potentially you could envision actually making a vaccine against a bacterial antigen such as C. Difficile or some of the others difficult to treat bacterias," says Blakney. There are no trials yet, but scientific journals such as Frontiers have explored this idea.
There's also potential for more general commercial health and well being applications. For example, Fu suggests that lactose intolerance – that affects hundred of millions of people of Asian origin, and an estimated 68% of the global population – could one day be targeted: "I'm missing the protein that allows me to break down lactose. He goes on to say that in the future you could develop a way of delivering the message that mRNA vaccines will make the protein that breaks down lactose and it's not life threatening, but I could imagine it being a billion-dollar industry."
At Ohio State, Dong has even run a successful mouse trial targeting cholesterol. People with high levels of the protein PCSK9 tend to have high cholesterol and develop heart disease early. "We noticed that after one treatment [in mice], we can reduce the PCSK9 protein level by over 95%.
That's definitely a very important research direction." At least one biotech company is planning a clinical trial using mRNA to inhibit PCSK9 according to Dong. You could take scores of different flavors… a cocktail of mRNAs that make different proteins selective for your particular need – Dragony Fu
All this raises the question: could mRNA therapeutics give us almost superhuman immunity? Already Covid-19 mRNA vaccines lead some people to produce very high levels of antibodies, able to neutralize several variants of Covid-19 at once.
There's also the potential to mix various mRNA vaccines together into a single health booster vaccine, which could ward off cancers and viruses at the same time.
Both Moderna and Novavax already have combined Covid-19 and flu vaccines in development. Self-amplifying mRNA vaccines may ultimately prevail. They reduce the need for painful boosters.
However questions remain around mRNA vaccines. Currently we need regular booster shots – and these shots tend to hurt, sometimes with fatiguing side effects. At the time of writing, we are less than a year into real-world use.
Anaphylactic reactions (albeit with no deaths) have been observed in approximately 2 to 5 people per million vaccinated in the United States: slightly higher, 4.7 per million, with the Pfizer–BioNTech vaccine compared to 2.5 per million vaccinations from the Moderna vaccine. According to one analysis, while still low, this is 11 times higher than with the flu vaccine.
"We're still working to understand how long the antibody response lasts for as well as the cellular response," says Blakney. "There's good indication now that you do get a really good memory T-cell response from the mRNA vaccines, but since these trials are a year and a half old in most cases we're still understanding how long that immunity lasts." Furthermore, most people, "don't really want to get multiple vaccines every year that knock you out for three days afterwards".
Blakney's lab at UBC is however working on an answer: sa-mRNA, or self-amplifying mRNA. It has the same structural components as normal mRNA, except once inside a cell it can make copies of itself. "This is advantageous because it allows using a much lower dose about 100X less saRNA compared to mRNA," says Blakney.
This means more bang for your buck, and less arm pain. In a tortoise versus hare race, mRNA vaccines may have run ahead to combat Covid-19, but sa-mRNA may win out in the end – and indeed has just received $195M backing from Astra-Zeneca.
Fu, Dong, Whitehead and Blakney continue to ride the wave of mRNA as it's transitioning into expanded applications for treating infectious diseases and cancers.
