Yellow fever (YF) is a viral disease transmitted by mosquitoes and endemic mostly in South America and Africa with 20-50% fatality. All current licensed YF vaccines, including YF-Vax (Sanofi-Pasteur, Lyon, France) and 17DD-YFV (Bio-Manguinhos, Rio de Janeiro, Brazil), are based on live attenuated virus produced in hens' eggs and have been widely used. The YF vaccines are considered safe and highly effective. However, a recent increase in demand for YF vaccines and reports of rare cases of YF vaccine-associated fatal adverse events have provoked interest in developing a safer YF vaccine that can be easily scaled up to meet this increased global demand. To this point, we have engineered the YF virus envelope protein (YFE) and transiently expressed it in as a stand-alone protein (YFE) or as fusion to the bacterial enzyme lichenase (YFE-LicKM). Immunogenicity and challenge studies in mice demonstrated that both YFE and YFE-LicKM elicited virus neutralizing (VN) antibodies and protected over 70% of mice from lethal challenge infection. Furthermore, these two YFE-based vaccine candidates induced VN antibody responses with high serum avidity in nonhuman primates and these VN antibody responses were further enhanced after challenge infection with the 17DD strain of YF virus. These results demonstrate partial protective efficacy in mice of YFE-based subunit vaccines expressed in. However, their efficacy is inferior to that of the live attenuated 17DD vaccine, indicating that formulation development, such as incorporating a more suitable adjuvant, may be required for product development.

Background Alouatta spp. are highly susceptible to yellow fever (YF) infection and develop an often fatal disease. The threat posed by an outbreak started in 2016 leads us to investigate vaccination as a potential tool in preventing YF in non‐human primates (NHP). Methods Susceptible howler monkeys were immunized with three different concentrations of the human Brazilian commercial YF17DD vaccine. Post‐vaccination viremia/RNAemia, immunogenicity, and safety were characterized. Results The vaccine did not produce YF clinical manifestations in any of the NHPs. After immunization, all animals seroconverted demonstrating the ability of the YF vaccine to induce humoral response in Alouatta species. Conclusions The present work has demonstrated the safe and immunogenic profile of the existing YF 17DD vaccine in howler monkeys. This knowledge may support further studies with other susceptible monkey species and provide a possible solution for controlling epizootics and preventing the devastation of endangered species.

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Introduction: Yellow Fever (YF) is a mosquito-borne viral hemorrhagic fever with a case fatality rate up to 50%. It is endemic in the Brazilian Amazon region, and sporadic outbreaks take place outside the endemic area in Brazil. However, Brazil has recently experienced its largest recorded YF outbreak in decades, with 1,376 confirmed cases and 483 deaths in humans, and 864 confirmed epizooties in non-human primates (NHPs) from July 2017 to June 2018. Despite the excellent safety of YF 17DD vaccine, there are rare cases of serious adverse events, which are often fatal. According to described aspects, the risk of urban YF resurgence and the absence of a vaccine available for NHPs, there is a strong demand for the development of alternative YF vaccines that are safe and efficacious for disease control. Therefore, Bio-Manguinhos/Fiocruz, in collaboration with Fraunhofer USA Center for Molecular Biotechnology, has been developing a plant-derived recombinant subunit YF vaccine (YFE-1T) to address the global demand for increasing availability and safety of the YF vaccine. YFE-1T subunit composed by the ectodomain of the E protein was transiently expressed in Nicotiana benthamiana by Agrobacterium tumefaciens-mediated gene transfer, purified and adsorbed to aluminum hydroxide adjuvant. Objective: In this study, the immunogenicity of the subunit YF vaccine in golden-headed lion tamarin (Leontopithecus chrysomelas) was evaluated by the determination of the neutralizing antibody titers (PRNT 50). Methodology: NHPs were immunized by intramuscular route with two doses of YFE-1T with aluminum hydroxide adjuvant. All animal experiments were approved by the Animal Care and Use Committee (CEUA-UNIFESO 470/2018) and environmental license was authorized by the Brazilian Ministry of the Environment (ICMBio-SISBIO 60511-2/2018). Results: YF neutralizing antibody titers were present after second dose in three of the six animals receiving YFE-1T with aluminum hydroxide. In this group, 50% individuals seroconverted and one animal had high neutralizing titers. The control groups immunized with different doses of the live attenuated vaccine (groups 1, 2 and 3) showed 100%, 40% and 83.3% of seroconversion ninety days after inoculation, respectively.These findings suggest that new studies using other antigen concentrations and adjuvants are needed to produce a robust immunogenicity. Conclusion: The results indicate the potential of this recombinant antigen for use in the development of a non-infectious YF vaccine. To evaluate the protective efficacy induced by subunit vaccine, one year after the first immunization all animals will be challenged using attenuated YF 17DD vaccine.

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