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Characterization of recombinant Modified Vaccinia virus Ankara delivering Zika virus nonstructural proteins NS2B and NS3pro
Characterization of recombinant Modified Vaccinia virus Ankara delivering Zika virus nonstructural proteins NS2B and NS3pro
Zika virus (ZIKV) was largely ignored for many years after it was first isolated in 1947. Unexpectedly, in 2007 ZIKV caused outbreaks in the Federate States of Micronesia, and from there spread throughout the South Pacific and to Latin America. These outbreaks were associated with neurological diseases and congenital birth disorders, which resulted in the World Health Organization (WHO) declaring the ZIKV outbreak as a “Public Health Emergency of International Concern” in 2016. To date, there are no vaccines or therapeutic agents against ZIKV licensed. As ZIKV shares similarities in immunodominant epitopes of its structural proteins with other related flaviviruses, infections with these pathogens can result in a cross-reactive antibody response. These non-neutralizing immunoglobulins can lead to increased viral replication and disease severity through the phenomenon of antibody-dependent enhancement (ADE). Moreover, flavivirus-vaccines based on structural proteins can also exacerbate the course of infection through this pathomechanism. Consequently, a new strategy to design a vaccine that avoids eliciting ADE could potentially be achieved by targeting the nonstructural proteins of ZIKV. This approach is suggested to mitigate the risk of ADE by inducing a balanced humoral and cellular immune response. However, the role of nonstructural proteins in the immune response against flaviviruses is still poorly understood. Modified vaccinia virus Ankara (MVA), a highly attenuated and replication deficient vaccinia virus with an exceptional safety profile, represents one of the most advanced recombinant viral vector platforms for the development of new vaccines against infectious diseases. This study aims to providing new approaches for a better understanding of the involvement of the cellular immune response in protection against ZIKV and thus to improve future flavivirus vaccine design. To accomplish this goal, we evaluated the safety, immunogenicity, and protective capacity of recombinant MVA-vaccine candidates expressing the ZIKV nonstructural proteins ZIKV-NS2B and ZIKV-NS3pro (MVA-NS2B and MVA-NS3pro).
MVA, Modified Vaccinia Virus Ankara, Zika virus, vaccines
Schwarz, Jan Hendrik
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Schwarz, Jan Hendrik (2021): Characterization of recombinant Modified Vaccinia virus Ankara delivering Zika virus nonstructural proteins NS2B and NS3pro. Dissertation, LMU München: Faculty of Veterinary Medicine
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Abstract

Zika virus (ZIKV) was largely ignored for many years after it was first isolated in 1947. Unexpectedly, in 2007 ZIKV caused outbreaks in the Federate States of Micronesia, and from there spread throughout the South Pacific and to Latin America. These outbreaks were associated with neurological diseases and congenital birth disorders, which resulted in the World Health Organization (WHO) declaring the ZIKV outbreak as a “Public Health Emergency of International Concern” in 2016. To date, there are no vaccines or therapeutic agents against ZIKV licensed. As ZIKV shares similarities in immunodominant epitopes of its structural proteins with other related flaviviruses, infections with these pathogens can result in a cross-reactive antibody response. These non-neutralizing immunoglobulins can lead to increased viral replication and disease severity through the phenomenon of antibody-dependent enhancement (ADE). Moreover, flavivirus-vaccines based on structural proteins can also exacerbate the course of infection through this pathomechanism. Consequently, a new strategy to design a vaccine that avoids eliciting ADE could potentially be achieved by targeting the nonstructural proteins of ZIKV. This approach is suggested to mitigate the risk of ADE by inducing a balanced humoral and cellular immune response. However, the role of nonstructural proteins in the immune response against flaviviruses is still poorly understood. Modified vaccinia virus Ankara (MVA), a highly attenuated and replication deficient vaccinia virus with an exceptional safety profile, represents one of the most advanced recombinant viral vector platforms for the development of new vaccines against infectious diseases. This study aims to providing new approaches for a better understanding of the involvement of the cellular immune response in protection against ZIKV and thus to improve future flavivirus vaccine design. To accomplish this goal, we evaluated the safety, immunogenicity, and protective capacity of recombinant MVA-vaccine candidates expressing the ZIKV nonstructural proteins ZIKV-NS2B and ZIKV-NS3pro (MVA-NS2B and MVA-NS3pro).