Could mRNA make us superhuman?

Barely a year ago, Anna Blakney was working in a relatively inconspicuous, 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 hot demand: an assistant professor at the University of British Columbia, Canada, and a science communicator with 253,000 followers and 3.7 million likes on TikTok. She was, she admits, 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, from the likes of Pfizer-BioNTech and Moderna. But even when Blakney started her PhD at Imperial College London in 2016, “a lot of people were sceptical as to whether it could ever work”. Now, “the whole field of mRNA is just exploding. It’s a game changer in medicine,” she says.

It’s such a game changer that it raises some very big, exciting questions: could mRNA vaccines provide a cure for cancers, HIV, tropical diseases, and even give us superhuman immunity?

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.

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 recognise 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 defences including enzymes that break it down, leaving us with only the antibodies.

It is, 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 of zoonoses at the Chinese Centre for Disease Control and Prevention in Beijing sequenced the genome for Covid-19 and published the next day. Covid-19 was declared a pandemic by the World Health Organization (WHO) on 11 March. On 16 March, using Zhang’s sequence, the first mRNA vaccine began its phase one clinical trial. The US Food and Drug Administration approved the Pfizer-BioNTech Covid-19 vaccine on 11 December, 2020, making history as not only the first ever mRNA vaccine approved for humans but also as the first to have a 95% efficacy rate in clinical trials. Approval of the Moderna mRNA vaccine followed close behind on 18 December. The previous title holder for “fastest ever vaccine”, the mumps vaccine, took four years. The Moderna and Pfizer–BioNTech vaccines took just 11 months.

There weren’t many people in the mRNA therapeutics world who would have imagined 95% initial efficacy rates – Kathryn Whitehead

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. Even in 2019, however, mainstream mRNA vaccines 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. Or, as Blakney puts it: “Now it’s like, OK, so it’s worked for a viral glycoprotein, what other vaccines can we make with it? And what can we do beyond that?”

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, specialises 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 immunotherapy, 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 AstraZeneca, are developing mRNA therapies for severe pulmonary diseases and asthma.

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 and treatments 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 recognise and kill those cells, just like you can train your immune system to recognise and kill a virus: it’s the same idea, you just figure out what proteins are on the surface of your tumour cells and use that as a vaccine”. The idea of patient-specific, individualised medicine has been a tantalising prospect for years – this could be another door pushed wide open by mRNA, according to Blakney. In theory, “they take out your tumour, they sequence it, see what’s on the surface of it, and then they make a vaccine specifically for you”.

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 huge 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 those really tricky to treat bacteria,” 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 wellbeing applications. For example, Fu suggests that lactose intolerance – that affects hundred of millions of people of Asian origin, including himself, and indeed an estimated 68% of the global population – could one day be targeted: “I’m missing the protein that allows me to break down lactose. In the future, you could develop some way of delivering the message, the mRNA, that that will make the protein that breaks down lactose… it’s not life threatening, but I could imagine that 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 a whole bunch of different flavours… 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 neutralise 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. While it’s just speculation at present, Fu says, “you could take a whole bunch of different flavours… a cocktail of mRNAs that make different proteins selective for your particular need.” Both Moderna and Novavax already have combined Covid-19 and flu vaccines in development.

Before we get too carried away, however, questions remain around mRNA vaccines. Currently we need regular booster shots – and these shots tend to hurt your arm, 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 for.” She adds that 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: saRNA, 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 really advantageous because it allows you to use a much lower dose, usually about 100 times less saRNA compared to mRNA,” says Blakney. This means more bang for your buck, and less pain in your arm. In a tortoise versus hare race, mRNA vaccines may have run ahead to combat Covid-19, but saRNA may win out in the end – and indeed has just received $195m (£145m) backing from AstraZeneca (which compares favourably to the $29.5m (£22m) Ethris received for its pulmonary diseases vaccine development, mentioned earlier in this article).

Meanwhile, Fu, Dong, Whitehead and Blakney continue to ride – and drive – the wave of the RNAissance. Wherever it carries them, one thing is for sure: it will never again be the same niche, anonymous field of research they once knew. Especially if you put your explainer videos out on TikTok like Blakney. “My whole mission on there is to educate people about vaccines,” she laughs. “I get tonnes of random questions. But I’ve also had loads of people say things like, you are the reason why me and my partner got the vaccine. And that’s really impactful.”

Source: BBC