Lipidated dengue-2 envelope protein domain III independently stimulates long-lasting neutralizing antibodies and reduces the risk of antibody-dependent enhancement.
BACKGROUND
Dengue virus is a mosquito-transmitted virus that can cause self-limiting dengue fever, severe life-threatening dengue hemorrhagic fever and dengue shock syndrome. The existence of four serotypes of dengue virus has complicated the development of an effective and safe dengue vaccine. Recently, a clinical phase 2b trial of Sanofi Pasteur's CYD tetravalent dengue vaccine revealed that the vaccine did not confer full protection against dengue-2 virus. New approaches to dengue vaccine development are urgently needed. Our approach represents a promising method of dengue vaccine development and may even complement the deficiencies of the CYD tetravalent dengue vaccine.


RESULTS
Two important components of a vaccine, the immunogen and immunopotentiator, were combined into a single construct to generate a new generation of vaccines. We selected dengue-2 envelope protein domain III (D2ED III) as the immunogen and expressed this protein in lipidated form in Escherichia coli, yielding an immunogen with intrinsic immunopotentiation activity. The formulation containing lipidated D2ED III (LD2ED III) in the absence of exogenous adjuvant elicited higher D2ED III-specific antibody responses than those obtained from its nonlipidated counterpart, D2ED III, and dengue-2 virus. In addition, the avidity and neutralizing capacity of the antibodies induced by LD2ED III were higher than those elicited by D2ED III and dengue-2 virus. Importantly, we showed that after lipidation, the subunit candidate LD2ED III exhibited increased immunogenicity while reducing the potential risk of antibody-dependent enhancement of infection in mice.


CONCLUSIONS
Our study suggests that the lipidated subunit vaccine approach could be applied to other serotypes of dengue virus and other pathogens.
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
Chen-Yi
CY
Chiang
Chien-Hsiung
CH
Pan
Chun-Hsiang
CH
Hsieh
Jy-Ping
JP
Tsai
Mei-Yu
MY
Chen
Hsueh-Hung
HH
Liu
Shih-Jen
SJ
Liu
Pele
P
Chong
Chih-Hsiang
CH
Leng
Hsin-Wei
HW
Chen
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D019067:Antibody-Dependent Enhancement; D003715:Dengue / Q000276:immunology / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; C051821:E-glycoprotein, Dengue virus type 2; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins