THANKS, DARPA:

Messenger RNA vaccines instruct cells to create proteins that induce an immune response to an invader such as the SARS-CoV-2 virus, training the immune system to attack future infections of the actual pathogen. They are easier to produce in large quantities than conventional protein therapies (genetically engineered versions of natural human or pathogen proteins) and monoclonal antibody therapies (lab-produced molecules that attack viruses in the same way that human antibodies do). And once a reliable manufacturing facility is built, it can quickly switch to a new mRNA vaccine or drug--unlike protein or monoclonal facilities, which must reengineer production from the ground up for each new therapy.

Success has inspired researchers, companies and government labs to pursue mRNA therapies for many infectious diseases, including influenza, cytomegalovirus, herpes simplex virus 2, norovirus, rabies, malaria, tuberculosis, dengue, Zika, HIV, hepatitis C and the entire family of coronaviruses. In each case, researchers are determining exactly how mRNA-LNP vaccines induce potent antibody responses.

Work on mRNA vaccines is also expanding to certain cancers, food and environmental allergies, and autoimmune diseases. Positive results against ATTR amyloidosis, a fatal condition that involves the liver, have already been produced in a phase 1 clinical trial. Although protein-based medications for certain illnesses are expanding quickly, large doses are typically required, and production is often difficult and expensive; mRNA delivery of therapeutic proteins could help. The approach has already worked in animals for issues as disparate as bone repair and asthma, and human clinical trials are underway. The Defense Advanced Research Projects Agency is even experimenting with mRNA delivery of monoclonal antibodies that could be tailored for previously unidentified infectious diseases, with the goal of supplying reliable manufacturing of such remedies within 60 days.

The concentrated COVID-19 work has also helped make mRNA a leader in nucleic acid therapeutics--approaches that can produce nearly any protein made by a specific cell. The technique is starting to be applied, and it could fight diseases in more convenient, less invasive and less expensive ways. For example, the FDA has approved gene therapy for sickle cell anemia, and it is working in the U.S., although it requires marrow to be extracted from a person's bone, treated and reinserted; mRNA therapy could be delivered to marrow with a straightforward injection into a person's arm. If that works, sickle cell treatment could be greatly expanded in countries where the condition is widespread.

In similar fashion, mRNA therapeutics could revolutionize treatment of many infectious diseases in developing countries, greatly improving health-care equity.

Thanks in part to Moderna's success, the potential of mRNA vaccines also captured the attention of Big Pharma. In 2018, Pfizer signed a partnership deal worth up to $425m with BioNTech, a German group. At the time, BioNTech was mostly focused on using mRNA to develop cancer drugs injected directly into tumours.

Kariko, who now works at BioNTech, recalls that chief executive Ugur Sahin felt a responsibility to research jabs for infectious diseases as well, but worried that they would be unprofitable. "He told me, in 2015, 'Kati, it is a moral obligation for us to do infectious ­disease ­vaccines. Those are a money-sucker, but it is a moral obligation.'"

In this next stage of the story of the Covid-19 mRNA vaccines, the torch passed to Moderna and BioNTech. But such vaccines still might not have happened were it not for the intervention of the US government: lots of promising discoveries made in academic labs do not end up being commercialised for human use because of a reluctance among investors to plough money into medical research that may result in expensive failure.

In Moderna's case, the gap was filled in part by officials at a unit of the US Department of Defense known as the Defense Advanced Research Projects Agency or Darpa. Set up in 1958, in response to the launch a year earlier of Russia's Sputnik 1, the first artificial earth satellite, Darpa has been credited with fostering some of the biggest technological advances in history, from the creation of the internet to the GPS.

In 2013, the US government issued a string of grants to private companies, including up to $25m for Moderna to work on an mRNA drug to combat Chikungunya -- a potentially deadly virus spread by mosquitoes that affects millions of people mostly in Africa, Asia and the Indian subcontinent. That funding from Darpa, though tiny by comparison with the billions Bancel had raised in private funding, nudged the company into the field of infectious diseases, an unloved area among biotech investors who prefer to put money into more profitable endeavours.

"It's not even clear that, without some pretty heavy pressuring, this activity -- even at Moderna -- would have been pursued versus other potential applications for mRNA that had a much clearer path to monetisation, such as cancer treatment," says Regina Dugan, the former director of Darpa, who signed off on the grants.

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