RESEARCH HIGHLIGHTS VACCINES Self-amplifying RNA in lipid nanoparticles: a next-generation vaccine? Photodisc Vaccines based on nucleic acids but are hampered by anti-vector Proof of concept was demonstrated (both DNA and RNA) have been immunity and safety concerns. in a model of respiratory syncytial investigated for several decades, The authors took advantage of virus (RSV) infection. The LNP–RNA but have not yet resulted in a recent advances in RNA synthesis vaccine potently induced neutralizing commercial product for human use. and nanoparticle technology. antibodies in cotton rats, as well Now, reporting in PNAS, Geall and Encapsulation of RNA in LNPs was as antigen-specific interferon- - colleagues present a new vaccine shown to protect it from enzymatic γ producing CD4+ and CD8+ T cells in platform based on self-amplifying degradation and allowed for efficient mice. These responses were comparable RNA encapsulated in synthetic lipid gene delivery after intramuscular to or exceeding those elicited by VRP nanoparticles (LNPs), which overcomes injection. Importantly, LNPs do not carry delivery of RNA or electroporation of some of the limitations of earlier vector surface proteins and are therefore pDNA and provided protection against nucleic-acid-based approaches. not limited by anti-vector immunity. subsequent RSV infection. The concept of nucleic-acid-encoded The self-amplifying RNA was derived This approach The authors point out that the vaccines was conceived over two from the genome of an alphavirus; the could provide LNP–RNA vaccine is produced in vitro in decades ago when it was found that genes encoding structural proteins were a potentially a cell-free manner, allowing large-scale, injection of mRNA or plasmid DNA replaced by genes coding for the antigen generic platform cost-effective production while (pDNA) into skeletal muscle of mice of interest, whereas the RNA replication for the rapid avoiding safety and manufacturing leads to the expression of the encoded machinery was retained. As RNA issues associated with cell culture protein. Early efforts to develop this amplification and protein expression development of of live viral vaccines, recombinant approach into a vaccine focused on take place in the cytoplasm of target potent, versatile subunit proteins and viral vectors. DNA, as it is more stable than RNA. cells, the risk of genomic integration vaccines for the Therefore, this approach could provide However, vaccination with pDNA was is eliminated and the RNA does not induction of both a potentially generic platform for the found to produce insufficient antibody need to cross the nuclear membrane humoral and rapid development of potent, versatile responses in humans, although more (this was found to be a rate-limiting cellular immune vaccines for the induction of both recent approaches to deliver pDNA by factor for DNA-based vaccines). humoral and cellular immune responses. local in vivo electroporation have shown Using a bioluminescent reporter responses. Alexandra Flemming a promising rise in efficiency. Strategies gene, it was shown that RNA delivery using pDNA, mRNA or self-amplifying by LNPs leads to antigen expression ORIGINAL RESEARCH PAPER Geall, A. J. et al. RNA delivered by viral vectors can that lasts twice as long as RNA delivery Nonviral delivery of self-amplifying RNA induce potent immune responses in by the latest viral vector technology, vaccines. Proc. Natl Acad. Sci. USA 109, non-human primates and in humans, viral replicon particles (VRPs). 14604–14609 (2012) NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | OCTOBER 2012 © 2012 Macmillan Publishers Limited. All rights reserved.