[Trends in research in developing new type of vaccines--aiming at efficacy and safety. Prevention and therapy of herpes simplex].
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Biomedical subjects
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The efficacy of a herpes simplex virus (HSV) component vaccine consisting of viral glycoprotein gB was examined in a mouse system. Immunization of mice with HSV type 1 (HSV-1) gB emulsified in Freund's complete adjuvant or with HSV-1 gB adsorbed to aluminum gel was fully protective against subsequent challenge with HSV-1 or HSV type 2. Latent infection in the trigeminal ganglion was also prevented by immunization with gB.
The effect of monoclonal antibody (MCA) to glycoprotein gB of herpes simplex virus (HSV) was studied in athymic nude mice inoculated with HSV intracutaneously in the midflank. HS1, the MCA used in the study, had a high neutralizing titer (1:2048) and had antibody-dependent cell-mediated cytotoxicity. HS1 was injected intraperitoneally at various intervals after HSV infection. HS1 injected 3 h after infection inhibited the development of skin lesions and most mice survived. Administration of HS1 at the time the local skin erosions appeared at the inoculated site (4-7 days after infection) was also effective, and in four of eight mice skin lesions completely healed. Furthermore, in three of four mice that survived, latent infections in the ganglia were also prevented as evidenced by the failure to detect HSV by co-cultivation with Vero cells. Administration of HS1 after the development of zosteriform skin lesions (5-9 days after infection) reduced virus in the ganglia and prolonged the survival time, though the disease was not completely arrested and all the mice died eventually.
The DNA sequence coding for herpes simplex virus type 1 glycoprotein B was placed under control of the acid phosphatase promoter of the yeast Saccharomyces cerevisiae in a plasmid capable of replicating in both yeast and Escherichia coli. Yeast transformed by the plasmid synthesized immunologically active glycoprotein B polypeptide.
To investigate the protective ability of monoclonal antibodies (MCAs) to viral glycoprotein in herpes simplex virus (HSV) infection, athymic nude mice were inoculated intracutaneously with HSV type-1 (HSV-1) in the midflank. Three hours after inoculation, one group of mice was passively immunized with one of a series of MCAs to glycoprotein gB of HSV-1, and a control group of mice was given phosphate buffered saline alone. The control mice died within 16 days after infection, whereas the mice passively immunized with any of the MCA showed suppressed development of skin lesions. Three of six mice given MCA failed to develop any visible lesions and no HSV could be isolated from the lumbar dorsal root ganglia of these mice 60 days after the challenge. BALB/c mice were also protected from infection with HSV type 2 by passive immunization with MCA to HSV-1 gB.
Dissemination of herpes simplex virus (HSV) in nude mice after intracutaneous inoculation in the midflank, and the effect of passively administered antibody on the course of infection were investigated. In untreated infected mice the skin lesions developed rapidly and HSV could first be recovered from the homogenate of the dorsal root ganglia on day 3 after infection, from the spinal cord on day 7 and from the brain on day 11. HSV could not be recovered from the blood, spleen or liver. In mice passively immunized with human gamma globulin, development of the skin lesions was rather slow and HSV could not be recovered from the homogenate of the dorsal root ganglia until day 16. From the results of explant culture of the ganglia, HSV was found to have reached the ganglia as early as 48 h after infection, even in mice administered human gamma globulin. The protective action of antibody seems to originate from the inhibition of virus growth not only at the inoculation site but also in the dorsal root ganglia.
Experiments were performed to investigate the resistance of the host due to antibody-mediated mechanisms to herpes simplex virus (HSV) infection. Transfer of hyperimmune anti-HSV mouse serum inhibited the development of skin lesions and prolonged the survival of lethally HSV-infected nude mice. Relatively high concentrations of antibody were required to achieve this protection. Antisera prepared in heterologous animals were also effective, while administration of anti-cowpox virus serum or interferon provided no protection. This type of protection is therefore due to specific antibody and cannot be attributed to interferon. In order to delineate the requirement for antibody in antibody-mediated protection, human gamma globulin preparations were transferred to lethally HSV-infected nude mice. Transfer of intact human gamma globulin (GG) was effective in controlling infection. S-sulfonation of GG did not diminish the protective ability. However, purified F(ab')2 did not have any protective action even when it was administered frequently to maintain serum neutralizing antibody titer. GG was effective in C5-deficient mice lethally infected with HSV. These results indicate that in vivo antibody-mediated protection to HSV infection requires the Fc region of the intact IgG molecule and suggest that antibody-dependent cell-mediated cytotoxicity may be operative in vivo.
The experience gained from the reconstruction of sixty-seven severely mutilated hands is applied to the analysis of the procedures of choice in three groups of injury.
The findings in fifty-nine patients with congenital constriction band syndrome and in experiments in which limb malformations resembling those of the human constriction band syndrome were successfully reproduced in rat fetuses by amniocentesis indicated that these malformations arise from excessive contraction of the uterine muscle during pregnancy, with resulting hemorrhages from the marginal blood sinuses of the digital rays. Such malformations in humans may arise during the fifth and sixth weeks counted from ovulation. It therefore was concluded that this syndrome is not hereditary but is produced by prenatal environmental factors.
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