DNA-based immunization produces Th1 immune responses to hepatitis delta virus in a mouse model

Abstract

Hepatitis delta virus (HDVHepatitis delta virus (HDV) is a defective, single-stranded RNA virus that needs the supply of hepatitis B surface antigen (HBsAg) for its assembly and transmission. 1,2 HDV superinfection is one of the major causes of fulminant hepatitis in Taiwan. 3 Superinfection with HDV often results in chronic hepatitis, and many chronic hepatitis D (CHD) patients progress to cirrhosis. [4][5][6][7] In the past decade, universal hepatitis B virus (HBV) vaccination for the newborn in Taiwan has decreased the HBV carrier rate and the incidence of hepatocellular carcinoma in childhood. 8 Unfortunately, up to 5% of the adult population does not respond to the currently licensed HBV vaccines, and millions of individuals are already chronically HBV-infected. Currently, there is no effective vaccine to protect HBV carriers from HDV superinfection.Many reports have indicated that the immune mechanism plays a significant role in the pathogenesis of both HBV and hepatitis C virus infections, 9,10 but the pathogenic mechanism of HDV infection is still controversial. 11 HDV transgenic mice that expressed both large (L-HDAg) and small hepatitis delta antigen (S-HDAg) in the liver did not develop liver disease, providing evidence that HDV is not directly cytopathic. 12 A recent study showed that patients with inactive HDV infection had a significant T-cell proliferation response to HDV synthetic peptides; conversely, patients with active HDV-related hepatitis showed no significant response. 13 It is thus postulated that the host immune response might determine disease activities after HDV infection. 13 Augmentation of the host' s cellular immune response may represent an ideal way to treat chronic HDV infection.At present, there is no effective therapy for chronic HDV infection. Interferon is the only licensed drug to treat CHD, but a large dosage and a long duration of treatment are needed. 14 Furthermore, interferon is only effective in a minor proportion of CHD patients, and relapses are common after discontinuation. DNA vaccine, or nucleic acid vaccine, by means of direct injection of the vector encoding viral proteins sequence intramuscularly or intradermally, is a newly developed technique. [15][16][17][18] This approach can induce a broad range of immune responses and has been successfully used to provide protective immunity against influenza, herpes simplex, rabies, Simian immunodeficiency virus, human immunodeficiency virus, and lymphocytic choriomeningitis virus (LCMV) in different animal model systems. 15,[19][20][21][22][23][24] In the recent literature, HBV-DNA-based immunization has been shown to induce cellular and humoral immune responses in mice, duck, and woodchuck models. [25][26][27][28][29][30] Hepatitis C virus nucleic acid immunization has also been demonstrated in mice models. 17,31-33 DNA vaccination is currently a promising Abbreviations: HDV, hepatitis delta virus; HBsAg, hepatitis B surface antigen; CHD, chronic hepatitis D; HBV, hepatitis B virus; L-HDAg, large hepatitis delta antig...

VariedImmunity Generated in Mice by DNA Vaccines with Large and SmallHepatitis DeltaAntigens

“…Recombinant HDAg fusion proteins were purified as previously described (9,11,16). Recombinant L-HDAg and S-HDAg fusion proteins were both made with E. coli maltose-binding protein (MBP).…”

“…Mice were immunized at 6 to 8 weeks of age. Cardiotoxin (Sigma) was given to each mouse 1 week before immunization (11). Groups of mice were anesthetized and given intramuscular (bilateral quadriceps) injections of a total dose of 100 g of plasmid DNA dissolved in 100 l of sterilized normal saline.…”

“…DNA vaccination is a promising method for preventing and treating persistent viral infections. Previous results suggested that DNA vaccines can produce Th1 immune responses against HDV (11).…”

“…A previous study demonstrated that an L-HDAg-encoding DNA vaccine could produce low titers of anti-HDV antibodies (11). However, in a subsequent study with the HDV DNA vaccine, no HDAg-specific antibody titers were detectable by a commercial enzyme-linked immunosorbent assay (ELISA) or by a Western blot assay (17).…”

Recent updates in hepatitis vaccination and the prevention of hepatocellular carcinoma

“…A recent study has suggested that DNA vaccines against HDV can induce significant cellular immune responses with a T-helper 1 (Th1) preference in a mouse model. 33 Thus the DNAbased immunization may be a promising tool not only in the prevention of HDV superinfection in HBV carriers but also in the treatment of chronic HDV infection. More animal studies are needed to further evaluate the safety and therapeutic effects of this vaccine.…”