The yellow fever 17D virus as a platform for new live attenuated vaccines

Figures & data

Figure 1. Insertion of heterologous sequences into the YF 17D genome. (A) YF genome is composed of a single positive single-stranded RNA containing 10 862 nucleotides. The major portion of the genome consists of an open reading frame flanked by a 5` and 3` untranslated region. The heterologous sequence insertion sites that have been described so far for recovering recombinant YF virus are indicated by a red arrow; (B) The translation of this large ORF produces a precursor polyprotein of 3411 amino acid residues, which are mainly co- and post-translationally processed at specific sites by the viral NS2B-NS3 proteolytic complex (white arrows) and signal peptidase (black arrows) producing the virion (structural proteins) and replicase elements (non-structural proteins). (C) Topological arrangement of YF proteins and the regions in which were possible to express heterologous sequences, indicated by red arrows. On the cytoplasmatic side, the viral proteins are processed by the viral NS2B/NS3 proteolytic complex (white arrows) whereas on the ER side by signal peptidases, furin, and an unknown protease that cleaves the carboxi-terminus of NS1.

Table 1. Expression of small heterologous sequences by the YF viral platform

Insertion: viral genomic region	Heterologous sequence (origin)	Regimen of immunization, if any	References
NS2B/NS3	SIINFEKL (chicken ovalbumin)	2 doses (mice)	MacAllister et al., 2000.^54
	SYVPSAEQIL (CSP of Plasmodium yoelii)	1 dose or with boost with irradiaded sporozoite (mice)	Tao et al., 2005.^57
	TEWETGQI (ASP-2 of Trypanosoma cruzi)	2 doses (mice)	Nogueira et al., 2011.^58
	GILGFVFTL (influenza matrix protein)	Human Dendritic cells	Barba-Spaeth et al., 2005.^55
E protein at fg loop	TEWETGQI(ASP-2 of Trypanosoma cruzi)	2 doses (mice)	Nogueira et al., 2011.^58
	DYENDIEKKI, (NANP)3, and SYVPSAEQI (CS proteins from P. falciparum and P.yoelii)	2 doses (mouse and rhesus monkeys)	Bonaldo et al., 2005^62 and 2006.^61
NS1 at 236 residue	modified influenza A M2e epitope (SLLTEVETPIRNEWGSRSNDSSD)	2 doses (mice)	Rumyantsev et al., 2010.^63

Table 2. Expression of heterologous proteins at the E-NS1 expression site of YF17D virus

Foreign gene		Immunization	Reference
reporter protein	EGFP	2 doses (mice)	Bonaldo and Galler, 2005^85; Bonaldo et al., 2007.^65
SIV	Gag 45–269	boost in rhesus monkeys primed with rBCG	Bonaldo et al., 2010^71
	Gag 44–84	prime with rYF and boost with rAdenovirus 5 (rhesus monkey)	Martins et al., 2013.^72
	Gag 76–123
	Gag 142–186
	Gag 250–415
	Vif 1–110
	Vif 102–214
	Nef 45–210
T.cruzi	ASP-2 261–380	2 doses (mice)	Nogueira et al., 2013.^56
HIV	p24	2 doses (mice)	Franco et al., 2010.^9
Lassa Virus	GPC	1 dose (guinea pigs)	Bredenbeek et al., 2006.^67
	GP1	2 doses (mice and guinea pigs)	Jiang et al., 2011.^68
	GP2	2 doses (mice and guinea pigs)	Jiang et al., 2011.^68

McAllister A, Arbetman AE, Mandl S, Peña-Rossi C, Andino R. Recombinant yellow fever viruses are effective therapeutic vaccines for treatment of murine experimental solid tumors and pulmonary metastases. J Virol 2000; 74:9197 - 205; http://dx.doi.org/10.1128/JVI.74.19.9197-9205.2000; PMID: 10982366

 PubMed Web of Science ®Google Scholar

Tao D, Barba-Spaeth G, Rai U, Nussenzweig V, Rice CM, Nussenzweig RS. Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model. J Exp Med 2005; 201:201 - 9; http://dx.doi.org/10.1084/jem.20041526; PMID: 15657290

 PubMed Web of Science ®Google Scholar

Nogueira RT, Nogueira AR, Pereira MC, Rodrigues MM, Galler R, Bonaldo MC. Biological and immunological characterization of recombinant Yellow Fever 17D viruses expressing a Trypanosoma cruzi Amastigote Surface Protein-2 CD8+ T cell epitope at two distinct regions of the genome. Virol J 2011; 8:127; http://dx.doi.org/10.1186/1743-422X-8-127; PMID: 21418577

 PubMed Web of Science ®Google Scholar

Barba-Spaeth G, Longman RS, Albert ML, Rice CM. Live attenuated yellow fever 17D infects human DCs and allows for presentation of endogenous and recombinant T cell epitopes. J Exp Med 2005; 202:1179 - 84; http://dx.doi.org/10.1084/jem.20051352; PMID: 16260489

 PubMed Web of Science ®Google Scholar

Bonaldo MC, Garratt RC, Marchevsky RS, Coutinho ES, Jabor AV, Almeida LF, Yamamura AM, Duarte AS, Oliveira PJ, Lizeu JO, et al. Attenuation of recombinant yellow fever 17D viruses expressing foreign protein epitopes at the surface. J Virol 2005; 79:8602 - 13; http://dx.doi.org/10.1128/JVI.79.13.8602-8613.2005; PMID: 15956601

 PubMed Web of Science ®Google Scholar

Bonaldo MC, Garratt RC, Freire MS, Galler R. Expression of foreign protein epitopes at the surface of recombinant yellow fever 17D viruses based on three-dimensional modeling of its envelope protein. Cell Biochem Biophys 2006; 44:313 - 24; http://dx.doi.org/10.1385/CBB:44:3:313; PMID: 16679518

 PubMed Web of Science ®Google Scholar

Rumyantsev AA, Zhang ZX, Gao QS, Moretti N, Brown N, Kleanthous H, Delagrave S, Guirakhoo F, Collett MS, Pugachev KV. Direct random insertion of an influenza virus immunologic determinant into the NS1 glycoprotein of a vaccine flavivirus. Virology 2010; 396:329 - 38; http://dx.doi.org/10.1016/j.virol.2009.10.033; PMID: 19913267

 PubMed Web of Science ®Google Scholar

Bonaldo MC, Galler R. Method for the Production of Recombinant Virus, DNA Constructs, Recombinant Virus and Vaccine Compositions BRAZIL: Fundação Oswaldo Cruz, 2005:93.

 Google Scholar

Bonaldo MC, Mello SM, Trindade GF, Rangel AA, Duarte AS, Oliveira PJ, Freire MS, Kubelka CF, Galler R. Construction and characterization of recombinant flaviviruses bearing insertions between E and NS1 genes. Virol J 2007; 4:115; http://dx.doi.org/10.1186/1743-422X-4-115; PMID: 17971212

 PubMed Web of Science ®Google Scholar

Bonaldo MC, Martins MA, Rudersdorf R, Mudd PA, Sacha JB, Piaskowski SM, Costa Neves PC, Veloso de Santana MG, Vojnov L, Capuano S 3rd, et al. Recombinant yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 gag induces SIV-specific CD8+ T-cell responses in rhesus macaques. J Virol 2010; 84:3699 - 706; http://dx.doi.org/10.1128/JVI.02255-09; PMID: 20089645

 PubMed Web of Science ®Google Scholar

Martins MA, Bonaldo MC, Rudersdorf RA, Piaskowski SM, Rakasz EG, Weisgrau KL, Furlott JR, Eernisse CM, Veloso de Santana MG, Hidalgo B, et al. Immunogenicity of seven new recombinant yellow fever viruses 17D expressing fragments of SIVmac239 Gag, Nef, and Vif in Indian rhesus macaques. PLoS One 2013; 8:e54434; http://dx.doi.org/10.1371/journal.pone.0054434; PMID: 23336000

 PubMed Web of Science ®Google Scholar

Nogueira RT, Nogueira AR, Pereira MC, Rodrigues MM, Neves PC, Galler R, Bonaldo MC. Recombinant yellow fever viruses elicit CD8+ T cell responses and protective immunity against Trypanosoma cruzi. PLoS One 2013; 8:e59347; http://dx.doi.org/10.1371/journal.pone.0059347; PMID: 23527169

 PubMed Web of Science ®Google Scholar

Franco D, Li W, Qing F, Stoyanov CT, Moran T, Rice CM, Ho DD. Evaluation of yellow fever virus 17D strain as a new vector for HIV-1 vaccine development. Vaccine 2010; 28:5676 - 85; http://dx.doi.org/10.1016/j.vaccine.2010.06.052; PMID: 20600494

 PubMed Web of Science ®Google Scholar

Bredenbeek PJ, Molenkamp R, Spaan WJ, Deubel V, Marianneau P, Salvato MS, Moshkoff D, Zapata J, Tikhonov I, Patterson J, et al. A recombinant Yellow Fever 17D vaccine expressing Lassa virus glycoproteins. Virology 2006; 345:299 - 304; http://dx.doi.org/10.1016/j.virol.2005.12.001; PMID: 16412488

 PubMed Web of Science ®Google Scholar

Jiang X, Dalebout TJ, Bredenbeek PJ, Carrion R Jr., Brasky K, Patterson J, Goicochea M, Bryant J, Salvato MS, Lukashevich IS. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs. Vaccine 2011; 29:1248 - 57; http://dx.doi.org/10.1016/j.vaccine.2010.11.079; PMID: 21145373

 PubMed Web of Science ®Google Scholar