TY - JOUR

T1 - Vaccination with Replication Deficient Adenovectors Encoding YF-17D Antigens Induces Long-Lasting Protection from Severe Yellow Fever Virus Infection in Mice

AU - Bassi, Maria R

AU - Larsen, Mads Andreas Bay

AU - Kongsgaard, Michael

AU - Rasmussen, Michael

AU - Buus, Søren

AU - Buus, Anette Stryhn

AU - Thomsen, Allan R

AU - Christensen, Jan P

PY - 2016/2

Y1 - 2016/2

N2 - The live attenuated yellow fever vaccine (YF-17D) has been successfully used for more than 70 years. It is generally considered a safe vaccine, however, recent reports of serious adverse events following vaccination have raised concerns and led to suggestions that even safer YF vaccines should be developed. Replication deficient adenoviruses (Ad) have been widely evaluated as recombinant vectors, particularly in the context of prophylactic vaccination against viral infections in which induction of CD8+ T-cell mediated immunity is crucial, but potent antibody responses may also be elicited using these vectors. In this study, we present two adenobased vectors targeting non-structural and structural YF antigens and characterize their immunological properties. We report that a single immunization with an Ad-vector encoding the non-structural protein 3 from YF-17D could elicit a strong CD8+ T-cell response, which afforded a high degree of protection from subsequent intracranial challenge of vaccinated mice. However, full protection was only observed using a vector encoding the structural proteins from YF-17D. This vector elicited virus-specific CD8+ T cells as well as neutralizing antibodies, and both components were shown to be important for protection thus mimicking the situation recently uncovered in YF-17D vaccinated mice. Considering that Ad-vectors are very safe, easy to produce and highly immunogenic in humans, our data indicate that a replication deficient adenovector-based YF vaccine may represent a safe and efficient alternative to the classical live attenuated YF vaccine and should be further tested.

AB - The live attenuated yellow fever vaccine (YF-17D) has been successfully used for more than 70 years. It is generally considered a safe vaccine, however, recent reports of serious adverse events following vaccination have raised concerns and led to suggestions that even safer YF vaccines should be developed. Replication deficient adenoviruses (Ad) have been widely evaluated as recombinant vectors, particularly in the context of prophylactic vaccination against viral infections in which induction of CD8+ T-cell mediated immunity is crucial, but potent antibody responses may also be elicited using these vectors. In this study, we present two adenobased vectors targeting non-structural and structural YF antigens and characterize their immunological properties. We report that a single immunization with an Ad-vector encoding the non-structural protein 3 from YF-17D could elicit a strong CD8+ T-cell response, which afforded a high degree of protection from subsequent intracranial challenge of vaccinated mice. However, full protection was only observed using a vector encoding the structural proteins from YF-17D. This vector elicited virus-specific CD8+ T cells as well as neutralizing antibodies, and both components were shown to be important for protection thus mimicking the situation recently uncovered in YF-17D vaccinated mice. Considering that Ad-vectors are very safe, easy to produce and highly immunogenic in humans, our data indicate that a replication deficient adenovector-based YF vaccine may represent a safe and efficient alternative to the classical live attenuated YF vaccine and should be further tested.

KW - Adenoviridae

KW - Animals

KW - Antibodies, Viral

KW - Antigens, Viral

KW - CD8-Positive T-Lymphocytes

KW - Female

KW - Genetic Vectors

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Vaccination

KW - Viral Proteins

KW - Yellow Fever

KW - Yellow Fever Vaccine

KW - Yellow fever virus

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pntd.0004464

DO - 10.1371/journal.pntd.0004464

M3 - Journal article

C2 - 26886513

VL - 10

JO - P L o S Neglected Tropical Diseases (Online)

JF - P L o S Neglected Tropical Diseases (Online)

SN - 1935-2735

IS - 2

M1 - e0004464

ER -