Genetic Vaccination of Mice with Plasmids Encoding the NS1 Non-structural Protein from Tick-borne Encephalitis Virus and Dengue 2 Virus

Abstract

Although there is a safe, inexpensive and efficacious vaccine against yellow fever, vaccination against other flavivirus diseases is less successful. There is no licensed vaccine against dengue fever and current vaccines against tick-borne encephalitis (TBE) and Japanese encephalitis are expensive and require several injections. Furthermore novel vaccines containing only virus envelope proteins may raise fears over antibody mediated enhancement (ADE) of disease. Here we report the successful use of genetic vaccination against TBE in an experimental animal model using a plasmid containing the coding sequence of a non-structural protein (NS1). Such vaccines would provide inexpensive protection against disease, without raising concerns over inducing ADE on subsequent exposure to heterotypic infectious virus. Attempts to generate chaemeric plasmids to protect against both TBE and dengue fever were less successful. Although these chaemeric plasmids directed the synthesis and secretion of the virus NS1 protein normally, no protection was observed against either TBE or dengue fever.

Meta-analysis of All Immune Epitope Data in theFlavivirusGenus: Inventory of Current Immune Epitope Data Status in the Context of Virus Immunity and Immunopathology

“…The majority of DENV-specific T-cell epitopes are recognized by CD8 þ T cells (97). This result is not surprising given the presumed role of CD8 þ T cells in viral clearance and their potential role in immunopathology (although CD4 þ T cells have also been implicated in the latter).…”

“…And indeed, the E protein is believed to play a critical role in the induction of immunity to natural infection (38). Moreover, NS1 has also been shown to mediate protection against disease by inducing both humoral and cellular responses (41,96,97). Although there is no evidence that antibodies are associated with severe disease, non-neutralizing antibodies against E can enhance infectivity in mouse macrophages (72).…”

“…The same peptide may be present in more than one species=serotype, making the number of potential cross-reactive peptide=immunogen combinations greater than what is shown here. LGRWKAVEKSVA MKH C (78-92) KHLTSFKRELGTLID C (91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105) IDAVNKRGRKQN KRG C (96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110) KRGRKQNKRGGN EGS Epitope reactivities were defined following experimental immunization of human subjects with inactivated or attenuated dengue virus (all four serotypes), or with the commercially available YF 17D and JE-VAX vaccines. Data are shown according to immunizing virus (immunogen), and include the antigen=position and the epitope sequence.…”

Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc γ Receptor-Dependent and -Independent Mechanisms

“…Future studies using error-prone PCR mutagenesis and yeast surface display are planned to identify the amino acid contact residues for many of the individual MAbs against WNV NS1. Because some antibodies against flavivirus NS1 protect against lethal infection in vivo, immunization with purified NS1 has been proposed as an alternative vaccination strategy against flaviviruses (26,33,34,44,62,63,71,75). Indeed, immunization with a single NS1 peptide (amino acids 37 to 55) of TBE elicited antibodies that protected mice against lethal challenge (65).…”

Dengue virus non-structural protein NS1: Structure, intracellular trafficking and role as a diagnostic marker

“…Although there is a wealth of evidence suggesting protection afforded by NS1 is a result of anti-NS1 antibodies ability to fix complement (Co et al, 2002;Falgout et al, 1990;Schlesinger et al, 1986;Schlesinger et al, 1985Schlesinger et al, , 1987, it has been found protection does not always correlate with the ability of a Mabs to fix complement, suggesting other mechanisms of protection (Henchal et al, 1988;Jacobs et al, 1994;Schlesinger et al, 1993;Young, 1990). Other strategies using NS1 have also been developed including live attenuated virus, recombinant vaccinia virus, adenovirus, subunit vaccines including NS1 with other structural proteins and DNA vaccines with various immunisation schedules have been successfully used to protect mice and monkeys from TBEV, YFV, JEV and DENV (Aleshin et al, 2007;Blaney et al, 2006;Blaney et al, 2003;Calvert et al, 2006;Costa et al, 2007;Costa et al, 2006a;Costa et al, 2006b;Jacobs et al, 1992;Khoretonenko et al, 2003;Lieberman et al, 2007;Mellado-Sanchez et al, 2005;Puttikhunt et al, 2003;Simmons et al, 2006;Timofeev et al, 2004;Timofeev et al, 1998;Wu et al, 2003). The major stumbling block for NS1 vaccines is the fact that NS1 can also elicit autoantibodies that cross react with host proteins and induce damage to uninfected cells.…”