Vaccines ‘on demand’: science fiction or a future reality

Figures & data

Table 1. Time-line of critical discoveries and developments that led to the recent progress on the non-viral delivery of self-amplifying mRNA vaccines.

Year	Critical discovery or event	Ref.
1990	Direct injection of mRNA or pDNA into skeletal muscle of a mouse resulted in expression of the encoded protein	[10]
1993	mRNA elicited an antigen-specific immune response in mice	[23]
1994	Unformulated ‘naked’ self-amplifying mRNA demonstrated potential for use as a nucleic acid vaccine	[24]
1998	Discovery of the RNA interference pathway, the subsequent development of clinically suitable, safe and efficient systemic drug delivery systems for the cytoplasmic delivery of siRNA	[25]
2000	Optimization of mRNA vaccines for cancer applications, leading to human clinical trials and development of GMP compliant production methods	[26]
2012	Proof of concept that a clinically suitable siRNA LNP delivery system could be used to deliver a self-amplifying mRNA and match the potency of viral delivery	[13]
2013	Demonstration that modern synthetic biology tools could be used to rapidly produce a self-amplifying mRNA against H7N9 virus using an electronic gene sequence	[15]
2014	Proof of concept that a CNE delivery system could be used to deliver a self-amplifying mRNA and induce a potent immune response in multiple species	[14]
2014	A 50 µg dose of a CNE delivered self-amplifying mRNA vaccine was immunogenic in NHPs	[16]

CNE: Cationic nanoemulsion; LNP: Lipid nanoparticle; NHPs: Non-human primates; pDNA: Plasmid DNA.

Figure 1. Rapid production of a self-amplifying mRNA vaccine against the H7N9 influenza virus. Time-line of events from electronic gene sequence posting to production of RNA prior to formulation and release for in vivo testing.

Figure 2. Projected production capacity from a 1-l transcription reaction (human doses/liter). The model assumes an RNA yield of 6 mg/ml, with a 20% loss during purification. A human dose from the current NHP data is predicted to be 100 µg RNA, but with additional improvements in vector design and delivery it could be reduced to between 1 and 10 µg.

Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science 1990;247(4949 Pt 1):1465-8

 PubMed Web of Science ®Google Scholar

Martinon F, Krishnan S, Lenzen G, et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur J Immunol 1993;23(7):1719-22

 PubMed Web of Science ®Google Scholar

Zhou X, Berglund P, Rhodes G, et al. Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 1994;12(16):1510-14

 PubMed Web of Science ®Google Scholar

Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 2009;8(2):129-38

 PubMed Web of Science ®Google Scholar

Hoerr I, Obst R, Rammensee HG, et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol 2000;30(1):1-7

 PubMed Web of Science ®Google Scholar

Geall AJ, Verma A, Otten GR, et al. Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci USA 2012;109(36):14604-9

 PubMed Web of Science ®Google Scholar

Hekele A, Bertholet S, Archer J, et al. Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice. Emer Microbes Infect 2013;2:8

 Google Scholar

Brito LA, Chan M, Shaw CA, et al. A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines. Mol ther 2014;22(12):2118-29

 PubMed Web of Science ®Google Scholar

Bogers WM, Oostermeijer H, Mooij P, et al. Potent immune responses in rhesus macaques induced by non-viral delivery of a self-amplifying RNA vaccine expressing HIV-1 envelope with a cationic nanoemulsion. J Infect Dis 2014. [ Epub ahead of print]

 PubMed Web of Science ®Google Scholar