15 self amplifying mRNA vaccines These include everything found in a conventional mRNA vaccine plus all the genes that encode the RNA replication machinery This combination of genes allows one strand of synthetic mRNA to generate thousands of copies of the mRNA of interest says Jeffrey Ulmer head of preclinical research for vaccines at GlaxoSmithKline in Rockville Maryland This amplification effect he points out gives you the potential to have a much more potent immune response with the same dose of RNA or alternatively you need much less RNA to get an equivalent level of immune protection For instance BioNTech scientists working with immunologists from Imperial College London reported that mice could be fully protected from influenza using just 1 25 micrograms of self amplifying mRNA a small fraction of the 80 micrograms of a conventional mRNA vaccine needed to produce the same effect8 Late last year scientists at Imperial collaborated with the Coalition for Epidemic Preparedness Innova tions a global public private partnership based in Oslo to advance its self amplifying mRNA platform to produce vaccines against rabies the Marburg virus and H1N1 influenza Beyond vaccines mRNA technologies can be used to produce the missing or defective proteins responsible for all manner of diseases Many companies including Translate Bio of Lexington Massachusetts are pushing ahead with this kind of restorative therapeutic strategy But as Translate Bio s chief scientific officer Richard Wooster points out targeting corrective mRNA drugs to the desired organs and cell types in the body muscle say or to cancer cells is extremely difficult In addition scientists are still struggling to devise chemical formulations of mRNA that avoid unwanted immune reactions to the molecules Vaccines are not hampered by these technical complexities With vaccination you re getting a systemic effect so you don t necessarily need to have specific tissue targeting says Wooster whose company signed a deal in 2018 with Sanofi Pasteur of Paris to develop mRNA vaccines for up to five pathogens Furthermore because the goal with any vaccine is to elicit immune activity the tendency for lab made mRNA to trigger the immune system and thus serve as its own immunological enhancer becomes a feature not a problem Most of the mRNA vaccines developed so far have focused on cancer and infectious diseases But BioNTech also holds the patent rights to an mRNA vaccination platform designed to protect against allergens such as grass pollen and house dust mites I think it would be a very elegant way to prevent allergies says Richard Weiss an immunologist at the University of Salzburg Austria who helped to develop the technology His team showed that mRNA based immuni zation can completely protect mice from developing allergies against timothy grass a common cause of hay fever9 All companies have to set strategic priorities however and for now BioNTech s remain squarely rooted in oncology Last month its sci entists reported at a cancer immunotherapy conference in Paris that the company s most advanced off the shelf vaccine candidate helped to shrink or stabilize melanoma in 19 of 42 early trial participants In continued follow up investigations from the firm s first in humans study of its personalized cancer vaccine all the people who had previ ously responded favourably were still relapse free up to 41 months after treatment And those responses came without the addition of a checkpoint inhibitor BioNTech is banking on the idea that the combination that Kremer is receiving for his metastasized melanoma will yield even better results especially now that most of the kinks have been ironed out Back in February Kremer was supposed to receive his first dose of personalized vaccine shortly before taking a holiday to the Florida Keys with his wife and two teenage daughters But the treatment which BioNTech manufactures in Germany and ships to patients around the world was held up at customs The dry ice used to chill the vaccine vaporized so the product thawed out and had to be discarded Kremer says he maintained a positive outlook as he waited three weeks for the next shipment of vaccine to arrive His wife Ginny was less patient She was very upset Kremer says I don t think she slept for two months BioNTech has since developed systems to ensure that its personal ized vaccines reach people as quickly as possible a crucial feature for any cancer treatment when time is of the essence Fortunately for Kremer the delay didn t impact his prognosis He s had a remarkable response says cancer immunologist Ryan Sullivan who is treating Kremer at Massachusetts General Hospital in Boston And although there are shipping concerns that can happen and not everyone responds Sullivan adds with cases like Brad s it s easy to get excited about this type of strategy Elie Dolgin is a science journalist in Somerville Massachusetts 1 Sahin U et al Nature 547 222 226 2017 2 Alberer M et al Lancet 390 1511 1520 2017 3 Feldman R A et al Vaccine 37 3326 3334 2019 4 John S et al Vaccine 36 1689 1699 2018 5 Hekele A et al Emerg Microb Infect 2 e52 2013 6 Baeza Garcia A et al Nature Commun 9 2714 2018 7 Lutz J et al npj Vaccines 2 29 2017 8 Vogel A B et al Mol Ther 26 446 455 2018 9 Hattinger E et al J Immunol Res 2015 797421 2015 M O D ER N A S 1 2 N A T U R E V O L 5 7 4 1 7 O C T O B E R 2 0 1 9 RNA THERAPIESOUTLOOK I WAS ACTUALLY WITNESSING THE CANCER CELLS SHRINKING BEFORE MY EYES Technicians at Moderna make a personalized cancer vaccine 2019 Spri nger Nature Li mited All ri ghts reserved b i o n t e c h i m n a t u r e m a g a z i n

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