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The 'Anti-Hype' Vaccine

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The 'Anti-Hype' Vaccine NEWS FEATURE The ‘anti-hype’ vaccine what do we need to do to be ready for the next pandemic,” he says. The potential of RNA vaccines to perform in After years under the radar, RNA vaccines are finally emerging as such a setting was demonstrated in 2013 during immunotherapies to combat pandemics and cancer. But as Laura an outbreak of a deadly strain of (H7N9) influ- DeFrancesco reports, clinical validation remains elusive. enza in China. The Chinese Center for Disease Control and Prevention deposited the sequence in GenBank, a web-based database, and folks at Novartis (with funding from DARPA and ‘Vaccines on demand’ is an alluring, yet mis- Rapid responses the Biomedical Advanced Research and leadingly simple, concept. Find an antigen of For many years, RNA languished as the ‘ugly Development Authority, BARDA) set out to choice against a scourge of choice. Sequence stepchild’ of nucleic acid vaccine development, see whether they could make an effective vac- and synthesize it. Formulate a product and with DNA reigning supreme. One reason for cine based on the electronic sequence. “We deliver it to a site in the body where it elicits a the slow development was that few in the were lucky enough to be collaborating with clinically meaningful immune response. Such research community considered RNA a good Craig Venter’s teams [Synthetic Genomics a vaccine would enable rapid-response agents starting point (Box 1). and Synthetic Genomics Vaccines, both based against pandemic threats. Alternatively, it In recent years, a crucial impetus for in La Jolla, California], so we made a vaccine could provide personalized cancer immu- advances in RNA vaccine technology—and in 8 days, put it in mice in 13 days and showed notherapy, with each new batch of vaccine their application to rapid response efforts— that, indeed, it works”, says Andrew Geall, who tailored to reflect the antigenic content of a has been support from the US Defense was running Novartis’s mRNA vaccine pro- patient’s evolving drug-resistant tumors. Department’s Defense Advanced Research gram until it was moved to GlaxoSmithKline RNA—long overlooked as a starting point Projects Agency (DARPA)—specifically (GSK) Vaccines in Rockville, Maryland, as 1 © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 for immunotherapy—potentially ticks many its Biological Technology Office (BTO) in part of an asset swap . (Geall currently serves of the boxes for a vaccine on demand, offer- Washington, D.C. Since 2011, DARPA has as VP of formulations at the RNAi company ing advantages in manufacture, flexibility, provided substantial funding for several early- Avidity BioSciences in La Jolla, California). By scalability and cost of goods. At the same stage RNA vaccine programs (Table 1). “We “it works,” Geall means that the vaccine raised time, clinical validation faces formidable like to think of ourselves as [funders of] early- neutralizing antibodies after one injection of 1 barriers, such as antigen discovery, prod- breakthrough, high-risk, things that would mg and all protect mice had HI titers consid- uct formulation and delivery. To emphasize not normally be funded. If you were going to ered protective after two doses. the challenge, vaccine developer CureVac do a safe biomedical research program, with DARPA could not be happier. “What you are reported in January that its prostate cancer incremental approaches to solving a problem, seeing in the field now is that using a nucleic product—the first RNA vaccine to be put that would not be us,” says Matt Hepburn, a acid to get the body to do what you want it to into humans—had failed to improve survival program manager at DARPA’s BTO. Their do, whether it’s a vaccine or other responses, over standard of care. Even so, a recent flux overriding interest is in having platforms in is really exploding. We find that profoundly of funding and research interest promises to place that can respond quickly in the case of exciting,” says Hepburn. Recently a DARPA- reinvigorate the field. a pandemic. “Our mindset, day, night, 24/7, is funded Moderna program in Zika was handed NATURE BIOTECHNOLOGY VOLUME 35 NUMBER 3 MARCH 2017 193 NEWS FEATURE program is alive and kicking, and we’re pretty LNP/RNA excited about it.” Critical elements Cytoplasmic delivery Early signs that RNA might have some use in a therapeutic setting came in 1990, with the Genomic (+) strand RNA publication of pioneering work by John Wolff, 5ʹ 3ʹ Phil Felgner and colleagues at the University Nucleus of Wisconsin–Madison demonstrating that Translation of nsPs and synthesis RDRP of complementary mRNA native RNA can be injected directly into mus- Genomic (-) strand RNA cle in mice and expressed3. CureVac’s Hoerr, at the time a PhD student at the University of Self-amplication Transcription of subgenome Tübingen, was amazed that no one picked up on in vivo administration of RNA. Although still a student, he was able to directly administer RNA, but most other researchers steered clear of RNA, Translation he says. “Nobody was trying our approach or Innate immune response (via MDA-5, RIG-I, PKR, etc.) Protein antigen taking account of what we were doing, although we published a lot of papers.” In recent years, that has been changing, particularly as ways Figure 1 Cytoplasmic delivery of a self-amplifying mRNA using a LNP non-viral delivery system. of making, delivering and expressing mRNA LNPs are taken up by endocytosis and RNA is delivered to the cell cytoplasm. Once in the cytosol, the self-amplifying mRNA co-opts host cell translation machinery to produce the RNA dependent RNA have improved and flagship companies such as polymerase (RDRP) encoded in the non-structural protein (nsP) domain (light grey boxes). This allows CureVac and Moderna have sprung up, attract- transcription of the positive strand genomic RNA into a negative strand template. Then, both full-length ing both researchers and investors to the space. genomic RNA as well as the subgenomic RNA transcripts encoding the vaccine antigen (dark grey box) The technology improvements that con- are generated. Self-amplification leads to innate immune stimulation which adjuvants the immune tribute to an effective RNA vaccine come in response to the vaccine antigen. Source: Andrew Geall, Avidity BioSciences. several forms. Modifications to the RNA mol- ecule itself improve its stability and increase its off to BARDA—which serves the application time, having combined several (up to six) flu expression upon delivery. These include add- and delivery side, as opposed to development hemagglutinin (HA) antigens in one vial. ing a cap (m7GpppG) to the 5ʹ end and tack- side, of the US government’s medical counter- According to Hoerr, it’s unusual to receive ing on a poly(A) tail to the 3ʹ end, optimizing measures program. DARPA is providing fund- immune responses against all HA antigens codon usage and GC content, providing 5ʹ and ing for preclinical development and a phase 1 at the same level in one vial. 3ʹ untranslated elements that facilitate ribosome trial of a chikungunya vaccine. Another company with an RNA vaccine binding and boost expression4. in the clinic is Argos Therapeutics, based But to get efficient translation, the RNA has to To infection and beyond in Durham, North Carolina (and known as stick around, and cells have various mechanisms Although several commercial RNA vaccine Merix until 2004). According to CEO Charles to dispose of incoming, presumably pathogenic programs are already moving forward in Nicolette, the company has been investigating nucleic acids. Upon engagement, these path- infectious disease, rapid response is not yet a the use of RNA encoding a modified form of ways—involving Toll-like receptors, the RNA theme (Table 2). Ingmar Hoerr, co-founder, the CD40 ligand protein to pretreat antigen- helicase RIG-I and protein kinase R—induce chairman and CEO of CureVac in Boston – presenting dendritic cells (DCs). Nicolette an innate immune response, which, among based CureVac, is focusing on rabies as a first notes that this protocol imitates the presence other things, shuts down the cell’s translational proof of principle. According to Hoerr, infec- of CD4+ helper T cells2. “The DC thinks it’s machinery. In 2005, Kaitlin Kariko, then at the tious disease indications offer a wealth of tra- in a healthy individual and is able to do its University of Pennsylvania in Philadelphia, ditional vaccines against which to benchmark job and generate the immune response that showed that it is possible to ‘de-immunize’ RNAs RNA vaccine responses. “There is a vaccine we want”, he says. Having a functioning DC by incorporating naturally occurring modified and [World Health Organization] guidelines that is independent of the requirement for bases5, and that the translational efficiency of + © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 for titer level.” This contrasts with cancer, CD4 T-cell help brought AIDS to mind. mRNA can be improved by replacing uridine where the lack of conventional vaccines “The [human immunodeficiency] virus has with pseudouridine6. Following this work, makes it difficult for developers to assess elevated to an art form the destruction of Derrick Rossi, a co-founder of Moderna who effectiveness of RNA as an immunogen. In CD4+ T cells; it’s what kills you in the end. is at Harvard Medical School in Boston, took infectious disease, “you can see where you So we asked the question: can we use our it a step further and showed that substituting are,” says Hoerr. RNA technology to target autologous virus pseudouridine for uridine and 5-methylcytidine CureVac’s rabies vaccine, which encodes and be able to immunize the patients effec- for cytidine works even better7.
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