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Development of a novel vaccine against Yellow Fever composed of an inactivated virus in association with a peptide from the non-structural protein NS3 and evaluation of its immunogenicity

Abstract

Yellow fever is a disease caused by the yellow fever virus (YFV), an arbovirus (arthropod-borne virus) that belongs to family Flaviviridae, genus Flavivirus, and considered the prototype of this family. Yellow fever transmission is characterized by an urban and a sylvatic cycle of transmission, depending on the vector responsible for the transmission. Similar to other flaviviruses, YFV genome consists of a positive sense, single-strand RNA that encodes a polyprotein that is cleaved into 7 non-structural and 3 structural proteins that, depending on the protein, harbor the majority of epitopes involved with the cellular and humoral immune response. The severe presentation of yellow fever is associated with failure of the multiple organs, with predominance of hepatic and renal failure, although the central nervous system, cardiopulmonary and digestive systems are also involved, the latter presenting with large bleeding ("black vomit"). The less severe clinical manifestations, independent of the transmission cycle, resemble those observed with other flavivirus infections, i. e., fever, myalgia, headache, retroorbital pain, among others. However, different from other arbovirus diseases, a live-attenuated virus vaccine (17D/17DD) is available to prevent YFV infections. This vaccine, developed in the 30's, is considered one of the most immunogenic vaccines available to date for disease prevention, but also, one of the most reactogenic as well. Therefore, in rare cases, the immunization with this vaccine can cause serious adverse effects, such as the viscerotropic or neurological disease that, in a large percentage of cases, can lead to death. In spite of that, it is the main prevention strategy available for protection against yellow fever and, due to the most recent outbreaks of sylvatic yellow fever, the Brazilian Ministry of Health recommends the yellow fever vaccination to every region of the country. However, the safety of the live-attenuated yellow fever vaccine in immunocompromised individuals is still questionable due to the higher likelihood of occurring severe post-vaccination adverse effects. The use of inactivated virus vaccines is a safe form of vaccination for this group of people and can be used in every situation, including in outbreaks, where severe adverse effects may be seen more often due to mass vaccination. However, these vaccines are usually less immunogenic than live-attenuated vaccines as they mainly elicit a humoral imune response. In this project, an inactivated yellow fever virus vaccine will be produced using a sylvatic yellow fever virus isolated in our laboratory and the safety and immunological response to this inactivated vaccine, either in its pure preparation [inactivated (iYFV)] or in combination with a recombinant NS3 peptide (iYFV+NS3Hel) to elicit a cellular immune response, will be evaluated in A129 mice. Every result obtained with the inactivated vaccines (iYFV with adjuvants or not), inactivate vaccine associated to NS3 (iYFV+NS3Hel) will be compared to those obtained with the live-attenuated yellow fever virus vaccine (17DD). Thus, depending on the results obtained here, after immunization A129 mice with the combined vaccine (iYFV+NS3Hel), this vaccine candidate can be tested in non-human primates and, eventually, in humans. (AU)