title: A tetravalent alphavirus-vector based dengue vaccine provides effective immunity in an early life mouse model.
abstract: Dengue viruses (DENV1-4) cause 390 million clinical infections every year, several hundred thousand of which progress to severe hemorrhagic and shock syndromes. Preexisting immunity resulting from a previous DENV infection is the major risk factor for severe dengue during secondary heterologous infections. During primary infections in infants, maternal antibodies pose an analogous risk. At the same time, maternal antibodies are likely to prevent induction of endogenous anti-DENV antibodies in response to current live, attenuated virus (LAV) vaccine candidates. Any effective early life dengue vaccine has to overcome maternal antibody interference (leading to ineffective vaccination) and poor induction of antibody responses (increasing the risk of severe dengue disease upon primary infection). In a previous study, we demonstrated that a non-propagating Venezuelan equine encephalitis virus replicon expression vector (VRP), expressing the ectodomain of DENV E protein (E85), overcomes maternal interference in a BALB/c mouse model. We report here that a single immunization with a tetravalent VRP vaccine induced NAb and T-cell responses to each serotype at a level equivalent to the monovalent vaccine components, suggesting that this vaccine modality can overcome serotype interference. Furthermore, neonatal immunization was durable and could be boosted later in life to further increase NAb and T-cell responses. Although the neonatal immune response was lower in magnitude than responses in adult BALB/c mice, we demonstrate that VRP vaccines generated protective immunity from a lethal challenge after a single neonatal immunization. In summary, VRP vaccines expressing DENV antigens were immunogenic and protective in neonates, and hence are promising candidates for safe and effective vaccination in early life.
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: muaz@globalvaccines.org.
authors.forename: Syed Muaz
authors.initials: SM
authors.lastname: Khalil
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Tonkin
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Mattocks
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Snead
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnston
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, United States.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: White
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000276:immunology*; D004666:Encephalitis Virus, Venezuelan Equine; D005260:Female; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; C084188:E protein, Dengue virus type 3; D014759:Viral Envelope Proteins
keywords: Alphavirus vector; Dengue; Dengue challenge; Dengue vaccine; Maternal antibody; Mouse model; Neonatal