Membrane and envelope virus proteins co-expressed as lysosome associated membrane protein (LAMP) fused antigens: a potential tool to develop DNA vaccines against flaviviruses

Rafael Dhalia,Isabelle F.T Viana,Thomas August,Milton Maciel Jr,Fábia S.P Cruz,Mariana L Palma,Ernesto T.A Marques Jr

doi:10.1590/s0001-37652009000400005

Abstract

Vaccination is the most practical and cost-effective strategy to prevent the majority of the flavivirus infection to which there is an available vaccine. However, vaccines based on attenuated virus can potentially promote collateral side effects and even rare fatal reactions. Given this scenario, the development of alternative vaccination strategies such as DNA-based vaccines encoding specific flavivirus sequences are being considered. Endogenous cytoplasmic antigens, characteristically plasmid DNA-vaccine encoded, are mainly presented to the immune system through Major Histocompatibility Complex class I - MHC I molecules. The MHC I presentation via is mostly associated with a cellular cytotoxic response and often do not elicit a satisfactory humoral response. One of the main strategies to target DNA-encoded antigens to the MHC II compartment is expressing the antigen within the Lysosome-Associated Membrane Protein (LAMP). The flavivirus envelope protein is recognized as the major virus surface protein and the main target for neutralizing antibodies. Different groups have demonstrated that co-expression of flavivirus membrane and envelope proteins in mammalian cells, fused with the carboxyl-terminal of LAMP, is able to induce satisfactory levels of neutralizing antibodies. Here we reviewed the use of the envelope flavivirus protein co-expression strategy as LAMP chimeras with the aim of developing DNA vaccines for dengue, West Nile and yellow fever viruses.

Highlights

The family Flaviviridae is represented by several viruses of medical importance, such as Japanese encephalitis, West Nile, tick-borne encephalitis, yellow fever (Maecker et al 1998) and dengue (Barrett 2002)
Endogenous cytoplasmic antigens, typical of DNA encoded antigens, are mainly presented to the immune system through the Major Histocompatibility Complex (MHC) class I molecules, which are mostly associated with cellular cytotoxic response
The activation of CD4+ T cells requires the Antigen-Presenting Cells (APCs) with antigenic peptides loaded into the groove of MHC class II molecules

Summary

FLAVIVIRUSES AVAILABLE VACCINES

Fants less than 9 months old, pregnant women and immunodeficient subjects (Cetron et al 2002). Despite several improvements made in the manufacture and quality control process, increased severity of symptoms (Monath et al 2002) and fatal reactions (Vasconcelos et al 2001, Lefeuvre et al 2004) has been systematically associated with the YF virus-attenuated vaccination Given this scenario, the development of alternative vaccination strategies, such as DNA-based vaccines encoding specific flavivirus sequences, has been considered (Donnelly et al 1997, Lewis and Babiuk 1999, Robinson 1999, Schultz et al 2000) and presents some advantages (Table I). Endogenous cytoplasmic antigens, typical of DNA encoded antigens, are mainly presented to the immune system through the Major Histocompatibility Complex (MHC) class I molecules, which are mostly associated with cellular cytotoxic response Such responses do not elicit a satisfactory humoral response very often, which is essential for efficient virus neutralization.

Mass production

FUTURE DIRECTIONS