Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

Abstract

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa.

Molecular and immunological characterization of a DNA-launched yellow fever virus 17D infectious clone

“…The same electroporation device was also successfully used in HIV-1 DNA vaccine human trials (Kopycinski et al, 2012;Vasan et al, 2011). Since previous studies (Bredenbeek et al, 2006;Guy et al, 2010;Jiang et al, 2011) with recombinant YFV-17D-based vaccines showed that anti-vector immunity was a minor concern during prime-boost immunization, a prime-boost vaccination regimen was adopted to further augment the immune responses. Nevertheless, in vivo delivery of YFV infectious DNA by electroporation failed to induce YFVneutralizing antibodies in HLA-A2.1 transgenic C57BL/6 mice, despite readily detectable CD8 + T-cell responses, whereas YFV-17D vaccination of BALB/c mice was reported to yield a balanced Th1-Th2 immune response (Franco et al, 2010).…”

“…YFV-17D has also been successfully exploited as a vector for the expression of foreign T-cell or B-cell epitopes, as potential vaccine candidates against malaria (Bonaldo et al, 2002;Tao et al, 2005) or as therapeutic anticancer vaccine (McAllister et al, 2000). Moreover, recombinant YFV-17D viruses expressing heterologous antigens were proposed as bivalent vaccine candidates against Lassa virus (Bredenbeek et al, 2006;Jiang et al, 2011) or as alternative vaccine vectors for malaria (Stoyanov et al, 2010) and HIV (Franco et al, 2010;Van Epps, 2005). In vitro characterization demonstrated that these recombinant viruses were viable and could express both YFV and foreign proteins.…”

“…Experiments in smallanimal models showed promising results in terms of immunogenicity and protection. Despite these encouraging results, genetic instability has been encountered for these recombinant viruses, especially with larger inserts, which is attributed to the limited packaging capacity of the icosahedral virion (Bonaldo et al, 2007;Jiang et al, 2011;Stoyanov et al, 2010).…”

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

“…56,65,66 A similar approach was employed to improve the genetic stability of Lassa virus glycoproteins expressed by recombinant YF17D viruses in this genomic site. 67,68 Interestingly, a variant of this general methodology was described in the expression of the HIV clade B consensus Gag p24 sequence by the YF17D virus. In this case, the heterologous protein was directly expressed in frame with the YF E protein and fused to the single transmembrane anchoring segment of the Sindbis virus E2 protein.…”

“…Other studies confirmed the capacity of this YF E/NS1 viral platform to elicit a T cell-specific response against other antigens. 31,56,67,68,74,75 These results point to a need of optimization of vaccination regimens as well as an improvement of the YF E/ NS1 insertion platform immunogenicity, which should be considered since the yellow fever vaccine displays outstanding immunological properties as a human immunogen. Another possibility to exploit the expression of foreign proteins by the live-attenuated YF17D virus consists of the insertion of sequences into the C gene.…”