Antibodies to the RNase H domain of hepatitis B virus P protein are associated with ongoing viral replication.

Antibodies against the RNase H domain of human hepatitis B virus P protein(s) are frequent markers of acute and chronic virus infection (T. Weimer, K. Weimer, Z.-X. Tu, M.-C. Jung, G. R. Pape, and H. Will, J. Immunol. 143:3750-3756, 1989). In the present study, these antibodies were determined in serial serum samples of experimentally infected chimpanzees and naturally infected human patients with acute and chronic hepatitis B virus infection. Anti-P antibodies were found in the sera of both chimpanzees and humans early in infection shortly after the immunoglobulin M anti-HBc response; they persisted in chronic carriers with ongoing viral replication but declined and disappeared at the time of virus clearance from the sera. These data demonstrate that antibodies to the RNase H domain of the hepatitis B virus P protein are early markers of infection and a signal of ongoing virus replication. Falling titers indicate the decline or end of active virus production and may therefore be a prognostic sign of virus elimination in natural infection and after antiviral therapy.

Protective efficacy of a novel hepatitis B vaccine consisting of M (pre-S2 + S) protein particles (a third generation vaccine).

The protective efficacy of a new type of yeast-derived hepatitis B (HB) vaccine (TGP-943, subtype adr), which was formulated from modified M (pre-S2 + S; P31) protein (M-P31c) particles, was investigated in chimpanzees. Animals were injected intramuscularly three times at 4-week intervals with doses of 10 or 40 micrograms (as a protein) of TGP-943. There were no significant differences in the immunogenicity of 10 micrograms compared to that of 40 micrograms of TGP-943 in terms of anti-S antibody response, while the induction and persistence of anti-pre-S2 antibodies seemed dose-related. Chimpanzees, vaccinated with 40 micrograms of TGP-943, produced anti-pre-S2 antibodies 2 weeks after the first injection, which appeared earlier than anti-HBs (S) antibodies. A maximum level of the anti-pre-S2 antibodies was reached 2 weeks after the second injection. Apart from immunization with TGP-943, chimpanzees injected with denatured TGP-943, consisting of 10 micrograms (as a protein) of non-particulate M-P31c antigen, produced anti-pre-S2 antibodies with a non-protecting level of anti-S antibodies (less than 10 mIU ml-1). Five weeks after the third injection, all animals were challenged intravenously with 1000 chimpanzee infectious units of HBV subtype (ayw) and were protected as confirmed by normal serological markers, no signs of infection in the sera and liver biopsies, and no detection of HBV-DNA by PCR method. No side effects from inoculation with TGP-943 or denatured TGP-943 were also encountered in any animals.

Plasmodium falciparum: studies on mature exoerythrocytic forms in the liver of the chimpanzee, Pan troglodytes.

Mature exoerythrocytic forms (EEF) of Plasmodium falciparum from the chimpanzee were examined by light- and transmission electron microscopy from a liver biopsy taken on Day 6 after sporozoite inoculation. Infectivity of the sporozoites obtained from whole mosquitoes which were membrane fed on cultured gametocytes was about 4-6%. In comparison, salivary gland sporozoites added to human hepatocytes in vitro had only a developmental percentage of 0.02 to 0.05% at Day 5. The EEF found in the liver biopsy were not all at the same stage of development. Immature compact parasites were seen simultaneously with stages with fully formed merozoites, indicating a rapid final maturation or asynchrony. At Day 7.5, large numbers of rings were already seen in the peripheral blood, indicating a duration of the liver development of P. falciparum in the chimpanzee of about 5.5-6 days. The process of merogony at the fine structural level was comparable to that described for rodent and other primate parasites in vivo. Compared to the fine structure of EEF in vitro in cultured human hepatocytes, the parasites described here were much more advanced in development. There appeared to be some cell infiltration with collagen deposition around the intracellular parasite; however, no marked degeneration of EEF was observed.

Clinicopathologic study of six cases of meningitis and meningoencephalitis in chimpanzees (Pan troglodytes).

Three fatal cases of purulent meningitis and one fatal case of thromboembolic necrotizing meningoencephalitis occurred in chimpanzees from the Primate Center TNO, The Netherlands. In addition, two apes had clinical signs of meningitis and were successfully treated. The severity of the residual hemiparesis and dysphagia in one of these two apes was such that it was killed for humane reasons. The histopathological diagnosis was chronic active meningoencephalitis. Streptococcus pneumoniae was isolated from five apes and Klebsiella pneumoniae from one. In the majority of cases, the primary site of infection was the upper respiratory tract. After reducing the population density, initiating a vaccination program using a commercially available human polyvalent pneumococcal vaccine, and changing the cleaning procedure of the animal facilities, no other cases of meningitis or meningoencephalitis have occurred in the chimpanzee colony in the ensuing 3.5 years.

Antiviral and side effects of interferons produced by recombinant DNA techniques as tested in rhesus monkeys.

Human interferon type alpha 2 (HuIFN-alpha 2) produced by Escherichia coli was found to be as active as natural leukocyte interferon in protecting rhesus monkeys against intradermal vaccinia virus infection. HuIFN-beta 1 produced in E. coli had similar but less pronounced activity. HuIFN-alpha 2 induced fever but not leukopenia, while HuIFN-beta 1 had opposite effects. Concurrent treatment with acetosalicylic acid and prednisolone/azothioprine combinations did not interfere with the efficacy of the human interferons.