COVID vaccine success fans hopes of mRNA shot for cancer

London: Drew Weissman is not ready to rest on his laurels. He’s already thinking about the next coronavirus variant – the one that will come after the Indian variant, or the Kent variant, or the South African variant, and demolish the defences of our vaccines. Or rather, to give him his due, his vaccines.

Weissman, professor of medicine at the University of Pennsylvania, is noticeably reserved and softly spoken on our Zoom call. And perhaps most importantly, he has form to back his claims up, for in the past year his life’s work has transformed human health.

Dr. Drew Weissman and Dr. Katalin Karikó – the pair of scientists whose messenger RNA discovery at the University of Pennsylvania helped pave the way for the COVID-19 vaccines.Credit:Facebook/Penn Medicine

“My wife and kids get mad at me because I don’t show the enjoyment of the accomplishment,” he says, stroking the ears of his immense white cat, Xander.

That accomplishment has been to develop not just a vaccine for COVID-19, but a whole new vaccine technology which, instead of priming our immune response by injecting us with bits of virus (like the AstraZeneca vaccine), uses genetic couriers called mRNA to teach our bodies how to build those bits themselves. It effectively turns the body’s cells into tiny vaccine-making factories.

The technique, never deployed before the pandemic, has been astonishingly successful. Moderna and Pfizer vaccines, which both use it, have a 95 per cent effectiveness rate, compared with about 82 per cent for AstraZeneca.

More significantly even than that, however, is the fact that like any courier, mRNA can be loaded with new parcels while maintaining the same delivery mechanism, meaning it can be updated to carry instructions to our cells that could protect against malaria or herpes, or fight back and beat cancer and HIV. From the ashes of the pandemic’s destruction is rising the phoenix of a medical revolution. “It’s a game changer,” says Dr Zoltan Kis, at Imperial College London’s Future Vaccine Manufacturing Hub.

For a long time, however, it did not look like it was going to work at all. In the late 1990s Weissman, who was working on dendritic cells – “the cells that start all new immune reactions” – met Katalin Kariko, who was working with RNA. The pair decided to combine their projects. They realised that, if it worked, their system would be able to deliver instructions so that the body could itself build specific proteins – to calm inflammation in stroke patients, say, or deliver a vital protein called CFTR to cystic fibrosis sufferers. “We knew when we first started it had enormous potential,” says Weissman. There was just one problem. “It was unusable.”

Every time he and Kariko tested the system on mice, “the mouse got sick” with chronic inflammation. Its immune response was out of control. “We worked to solve that inflammation for seven years,” he says. In 2005, they cracked it. “We could now deliver any therapeutic protein we wanted.”

Over the past decade Weissman has been working on a variety of vaccines, with five in trials before COVID hit — including a universal flu vaccine and two for HIV. But then, in early 2020, news of a novel virus began emerging from China. Its genetic code was posted online on January 10. “We started working on COVID on January 12,” says Weissman. Vaccine development had traditionally taken years. But on March 16, just two months later, Moderna put its COVID vaccine into a clinical trial.

Speed of development is just one of mRNA’s benefits (“plug in a new variant and in days you’re ready to go,” says Weissman). A second is manufacturing. In contrast to traditional vaccines, says Kis, “there are no living cells involved in the making of the RNA. It’s synthetic. A biochemical process, simple, easy to purify it and to show quality – a much cleaner approach.” Much less also goes much further. “Ten litres of RNA could make as many doses as 1000 litres of the conventional process.”

Dr. Drew Weissman and Dr. Katalin Karikó received their first dose of the Pfizer/BioNTech vaccine together in DEcember.Credit:Facebook/Penn Medicine

Kis sees three stages to develop the potential of mRNA therapies. In the immediate term, they can be directed at infectious diseases like COVID, which Kis calls “the low-hanging fruit”. In the long term, they can be used to deliver gene-editing tools inside the body to fix inherited conditions like sickle cell. In the medium term, however, Kis sees the advent of personalised cancer vaccines.

Weissman explains how they would work: “You take out a piece of lung tumour or breast cancer or colon cancer or melanoma and sequence it” to reveal its genetic code. Such codes in cancer have many mutations, and a vaccine is based on those specific mutations, prompting the immune system to attack the cancer cells while leaving other cells unharmed. The technique has been shown to work well in melanoma, and less so in other cancers. But BioNTech already has one cancer vaccine in a phase two [of three] trial “looking at a whole bunch of different cancers”.

As with many cutting-edge techniques, the cost of such a vaccine would currently be prohibitive; “probably hundreds of thousands of dollars”, says Weissman. But as the plunging price of gene sequencing has shown, costs can tumble dramatically as breakthrough technology becomes widely adopted.

It is in genetic medicine that Weissman hopes to make the biggest breakthrough, by loading up his RNA courier with a gene-editing tool called Crispr. The problem is hitting the right target in the body – typically the particles end up in the dendritic cells or being flushed out to the liver. But Weissman says this big hurdle has now been overcome. “We can now target bone-marrow stem cells and T-cells”, a path to curing sickle cell disease and HIV, respectively.

A trickle of excitement permeates his self-contained manner as he describes such possibilities. “There is huge potential,” he says. “Not everything is going to work. But some of it will. And we and others are going to keep developing this to get as many things to work to treat these diseases.”

He is fully aware that, without the COVID-19 pandemic, his research and its spin-offs would not be receiving the money and attention they are now. “COVID has certainly catapulted RNA into everybody’s language and changed vaccine development,” he says.

The Telegraph, London

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