14 compare the DNA sequences of the two samples and produce a list of 34 targets each encoding a different mutant protein expressed by the cancer that is predicted to be useful in training the immune system to attack the disease The technicians then take those digital sequences from the computer model and turn them into physical products First they codify the cancer specific mutations into a ring shaped DNA molecule called a plasmid They then convert the DNA into strands of mRNA before the therapeutic nucleotides are finally coated in lipid nanoparticles to make them more stable in the body Throughout this month long manufacturing process each patient s tailor made vaccine is assigned a colour red blue yellow or green and technicians wear colour coded hairnets work behind colour matched lines on the laboratory floor and use only colour coordinated equipment all as a visual precaution against mix ups We need to make sure it s one batch per patient all the way explains Jennifer White head of quality assurance at the site At the American Society of Clinical Oncology s annual meeting in June Moderna reported first in human clinical data showing that mRNA 4157 can generate mutation specific immune responses in people with cancer And when administered with a checkpoint inhibitor an antibody drug designed to further ramp up the body s cancer fighting immune activity the therapy also shrank tumours in 6 of 20 participants with metastatic disease Moderna and its devel opment partner Merck based in Kenilworth New Jersey launched a randomized 150 person follow up study in July As personalized mRNA vaccines go through trials Moderna BioNTech and CureVac based in Tübingen Germany are simulta neously developing off the shelf vaccine candidates as well These ready made vaccines are not as immunogenic as the most potent cus tomized vaccines for people with highly mutated cancers but they are potentially suitable for everyone There is no lengthy customization process no long waits often of a month or more and no added labour and manufacturing costs They are ready for anyone who needs them A NEED FOR SPEED Oncology is one important area for mRNA vaccine manufacturers but they are also developing products to tackle infectious diseases They are taking advantage of the platform s ease of manufacture to create rapid turnaround products And they are deploying the technology to combat a handful of viruses that have remained impervious to con ventional vaccine strategies One such target is cytomegalovirus CMV the most common infectious cause of neurological defects in newborns in the developed world A vaccine is desperately needed to prevent pregnant women from passing the virus to their developing fetuses But vaccine makers have struggled to recreate the virus pentameric complex a bundle of five proteins that mediate entry and exit into human cells in a way that generates a robust immune response when introduced in the body You can t make five different things in a vat purify them and then try to put them together in the lab says Tal Zaks Moderna s chief medical officer They have to be put together within the cell he says and mRNA allows researchers to do that Moderna scientists demonstrated this last year creating a multi sequence mRNA vaccine that prompted cells transfected with the mRNA to express the full pentamer on their surfaces eliciting protective anti body responses in immunized mice and monkeys4 And last month the company disclosed that participants in a phase I human trial experienced dose dependent increases in antibody levels as well Other prophylactic vaccines in Moderna s pipeline with promising early clinical data include one for respiratory syncytial virus a common cause of airway inflam mation in infants And in the case of the company s mRNA 1653 a dual vaccine against two other recalcitrant respiratory viruses metapneumo virus and a type of parainfluenza which are also responsible for severe lung infections the success of Moderna s early trials shows that you can actually now do combinations Zaks says Moderna is also working on vaccines to tackle emerging infectious diseases such as avian influenza and Zika virus for which the speed of mRNA manufacturing could be beneficial in the event of a pandemic One of the greatest advantages of this mRNA strategy is just how fast you can go from a nucleotide sequence to a vaccine product says Justin Richner a vaccine researcher at the University of Illinois College of Medicine in Chicago who has collaborated with Moderna in the past The current speed record was set in 2013 in response to an influenza outbreak in China it took scientists at Novartis just eight days to make a vaccine candidate Health officials at the Chinese Center for Disease Control and Prevention in Beijing posted gene sequences from the virus on a data sharing platform on a Sunday in late March5 By the following Sunday Andy Geall and his team at Novartis s vaccine unit in Cambridge Massachusetts were already running validation experi ments of their mRNA vaccine in hamster kidney cells It happened in real time the moment that sequence was available says Geall who is now head of formulations analytics and chemistry at Avidity Biosciences in La Jolla California For a conventional vaccine the same process could take six months or more he adds Geall continues to consult with companies and academics working on mRNA vaccines He has recently started to go beyond viruses to other pathogens Last year for example he joined forces with clinical immunologist Richard Bucala s team at Yale School of Medicine in New Haven Connecticut and successfully used mRNA to vaccinate mice against malaria6 which is caused by a single celled parasite The whole platform is very very flexible says Norbert Pardi who studies infectious diseases at the University of Pennsylvania s Perelman School of Medicine in Philadelphia He is currently working on vaccines for malaria as well as HIV hepatitis C and several other viral diseases You can use mRNA vaccines for pretty much everything he says TAKE ANOTHER SHOT Developing mRNA vaccines is not always straightforward however Moderna s initial candidate vaccine for Zika virus for example was well tolerated in people but failed to provoke much of an immune response With funding from the US government Moderna went back to the lab optimized the vaccine sequence and developed another candidate that is according to Zaks at least 20 times more potent than the first generation product in mice and monkey testing The first clinical stage mRNA vaccine from CureVac was also disappointing It was a rabies vaccine2 that could induce antibody responses in some study participants but only when administered through needle free devices and even then only around two thirds of vaccinated people achieved the recommended level of antiviral therapy CureVac has since altered its delivery platform and restarted human trials with a vaccine candidate that is encased in lipid nanoparticles As the company s scientists reported in 2017 this change enhances the cellular uptake of the mRNA sequences so the same level of antibody and T cell responses can be achieved in mice and monkeys using a tiny fraction of the dose7 But starting clinical development again cost the company valuable time in the race to bring its products to market For chief technology officer Mariola Fotin Mleczek this was an important lesson learnt the hard way Formulation makes a big impact she says What goes into the mRNA sequence matters a great deal too Some companies and non profit groups are pushing ahead with 1 7 O C T O B E R 2 0 1 9 V O L 5 7 4 N A T U R E S 1 1 RNA THERAPIES OUTLOOK YOU CAN USE MESSENGER RNA VACCINES FOR PRETTY MUCH EVERYTHING 2019 Spri nger Nature Li mited All ri ghts reserved 2019 Spri nger Nature Li mited All ri ghts reserved b i o n t e c h e i n b e t e i l i g u n g s u n t e r n e h m e n d e r m i g f o n d s

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