Hepatitis: Kuschner RA

Shrestha MP, Scott RM, Joshi DM, Mammen MP, Thapa GB, Thapa N, Myint KS, Fourneau M, Kuschner RA, Shrestha SK, David MP, Seriwatana J, Vaughn DW, Safary A, Endy TP, Innis BL. · Walter Reed-Armed Forces Research Institute of Medical Sciences Research Unit Nepal, Kathmandu, Nepal. · N Engl J Med. · Pubmed #17329696 links to  free full text

Abstract: BACKGROUND: Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial. METHODS: In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses. RESULTS: A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P=0.03). CONCLUSIONS: In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469 [ClinicalTrials.gov].).

He J, Kuschner RA, Dewar V, Voet P, Asher LV, Vaughn DW. · Armed Forces Institute of Pathology, 1413 Research Boulevard, Rockville, MD 20850, USA. · J Biomed Sci. · Pubmed #17487571 No free full text.

Abstract: Twenty-seven monoclonal antibodies (Mabs) recognizing the open reading frame 2 structural protein of the Pakistan strain of hepatitis E virus (HEV) were generated by conventional hybridoma technique. These Mabs were characterized by ELISA, affinity-capture reverse transcriptase-polymerase chain reaction (AC/RT-PCR), immune electron microscopy (IEM), and a RT-PCR based seroneutralization assay. Twenty-seven Mabs were positive by ELISA. By AC/RT-PCR, 24 Mabs bound to Pakistan and Namibia HEV strains. Thirteen Mabs were examined by IEM. Nine Mabs, positive by ELISA and AC/RT-PCR, bound and aggregated to Mexican HEV strain. We tested five Mabs that were positive by ELISA, AC/RT/PCR, and IEM by a RT-PCR based seroneutralization assay. Only one Mab (Mab 7) showed activity that inhibited the ability of HEV to attach to Alexander hepatoma cells (PLC-PRF-5). When Mab 7 was diluted to 1: 160, its inhibition activity persisted suggesting that Mab 7 might be a potential candidate for further evaluation in primates (passive protection experiments).

Myint KS, Endy TP, Shrestha MP, Shrestha SK, Vaughn DW, Innis BL, Gibbons RV, Kuschner RA, Seriwatana J, Scott RM. · Department of Virology, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok 10400, Thailand. · Trans R Soc Trop Med Hyg. · Pubmed #16542692 No free full text.

Abstract: A cohort of 62 Nepalese adults with acute hepatitis E was identified and total Ig as well as IgM levels to hepatitis E virus (HEV) capsid protein were determined using the Walter Reed Army Institute of Research (WRAIR) immunoassay. An antibody profile was constructed from serial serum specimens collected up to 14 months following the onset of illness. The decline in total Ig was rapid for the first 3 months. There followed a slow, sustained decline, but antibodies remained above the seropositive level of 20 WRAIR units. The decline of IgM was steeper than total Ig for the first 3 months, but IgM remained detectable after 14 months in 25% of cases. Study data contribute to an understanding of the pathophysiology of human hepatitis E and set an antibody response pattern to be targeted as a part of HEV vaccine development.

Endy TP, Narupiti S, Myint KS, Suntayakorn S, Kuschner RA, Vaughn DW. · Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. · Southeast Asian J Trop Med Public Health. · Pubmed #12041559 No free full text.

Abstract: TT virus is a novel DNA virus widely distributed in the general population. We examined the prevalence of TTV infection in a population with acute non-A to E hepatitis and in comparison groups located in Northern Thailand. The prevalence of TTV in subjects with non-A-E hepatitis was 19% (21/112), 6% (4/72) in healthy volunteers, 17% (12/72) in those with hepatitis A or B, and 17% (8/48) in hospitalized patients with non-hepatitis illnesses. A significant association with TTV infection and non-A-E hepatitis was seen in all groups (OR 3.9, p = 0.02) and in children (OR 25.8, p = 0.001). Among subjects with non-A-E hepatitis, TTV was associated with higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (significant for AST, p = 0.02). Our observations suggest that TTV in our study population may be associated with non-A-E hepatitis and that children in particular may be at risk of hepatocellular injury as a result of TTV infection.

He J, Hayes CG, Binn LN, Seriwatana J, Vaughn DW, Kuschner RA, Innis BL. · Department of Virus Diseases, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Silver Spring, MD 20910, USA. · J Biomed Sci. · Pubmed #11287754 No free full text.

Abstract: Injection of an expression vector pJHEV containing hepatitis E virus (HEV) structural protein open reading frame 2 gene generates a strong antibody response in BALB/c mice that can bind to and agglutinate HEV. In this study, we tested for immunologic memory in immunized mice whose current levels of IgG to HEV were low or undetectable despite 3 doses of HEV DNA vaccine 18 months earlier. Mice previously vaccinated with vector alone were controls. All mice were administered a dose of HEV DNA vaccine to simulate an infectious challenge with HEV. The endpoint was IgG to HEV determined by ELISA. Ten days after the vaccine dose, 5 of 9 mice previously immunized with HEV DNA vaccine had a slight increase in IgG to HEV. By 40 days after the vaccine dose, the level of IgG to HEV had increased dramatically in all 9 mice (108-fold increase in geometric mean titer). In contrast, no control mice became seropositive. These results indicate that mice vaccinated with 3 doses of HEV DNA vaccine retain immunologic memory. In response to a small antigenic challenge delivered as DNA, possibly less than delivered by a human infective dose of virus, mice with memory were able to generate high levels of antibody in less time than the usual incubation period of hepatitis E. We speculate that this type of response could protect a human from overt disease.

He J, Innis BL, Shrestha MP, Clayson ET, Scott RM, Linthicum KJ, Musser GG, Gigliotti SC, Binn LN, Kuschner RA, Vaughn DW. · Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. · J Clin Microbiol. · Pubmed #16517936 links to  free full text

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He J, Innis BL, Shrestha MP, Clayson ET, Scott RM, Linthicum KJ, Musser GG, Gigliotti SC, Binn LN, Kuschner RA, Vaughn DW. · Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. · J Clin Microbiol. · Pubmed #12454141 links to  free full text

Abstract: Hepatitis E virus (HEV) is an important cause of enterically transmitted hepatitis in developing countries. Sporadic autochthonous cases of hepatitis E have been reported recently in the United States and other industrialized countries. The source of HEV infection in these cases is unknown; zoonotic transmission has been suggested. Antibodies to HEV have been detected in many animals in areas where HEV is endemic and in domestic swine and rats in the United States. There is evidence supporting HEV transmission between swine and humans. Nevertheless, HEV has not been detected in wild rodents. We tested murid rodents and house shrews trapped in Nepal's Kathmandu Valley, where hepatitis E is hyperendemic, for HEV infection. The most commonly trapped species was Rattus rattus brunneusculus. Serum samples from 675 animals were tested for immunoglobulin G against HEV by enzyme-linked immunosorbent assay; 78 (12%) were positive, indicating acute or past infection. Antibody prevalence was higher among R. rattus brunneusculus and Bandicota bengalensis than in Suncus murinus. Forty-four specimens from 78 antibody-positive animals had sufficient residual volume for detection of HEV RNA (viremia) by reverse transcription-PCR. PCR amplification detected four animals (9%; three were R. rattus brunneusculus and one was B. bengalensis) with viremia. Phylogenetic analysis of the four genome sequences (405 bp in the capsid gene) recovered showed that they were identical, most closely related to two human isolates from Nepal (95 and 96% nucleotide homology, respectively), and distinct from HEV sequences isolated elsewhere. These data prove that certain peridomestic rodents acquire HEV in the wild and suggest that cross-species transmission occurs, with rodents serving as a virus reservoir for humans.