Biomedical subjects
Justen H Passwell
Publications and source records attributed to Justen H Passwell.
Use of a computerized database to study the effectiveness of an attenuated varicella vaccine.
BACKGROUND: The varicella vaccine Varilrix (GlaxoSmithKline) was introduced in Israel in June 2000 as an optional vaccination for children. METHODS: We used the database of a single health maintenance organization that serves 25% of the population in Israel to assess the effectiveness of the vaccine retrospectively. Incidence and complications of varicella were derived from the database from January 1, 1998 until December 31, 2002. RESULTS: Since licensure >30000 individuals younger than 10 years in this health maintenance organization have been immunized with the vaccine. Annual incidence of disease per 1000 in the study population was 86.6 in 1998, 74.6 in 1999, 74.0 in 2000, 37.1 in 2001 and 44.6 in 2002. This declining trend in incidence of disease was statistically significant. Complications of varicella occurred in approximately 1% of patients throughout the 5-year study period, but there was a parallel decline in the number of patients with complications corresponding to the decline in disease incidence. Vaccine effectiveness for prevention of clinical disease in this population was 92% (95% confidence interval, 91.0 to 92.7). There were varying rates of utilization within communities of varied socioeconomic class, so that in the higher socioeconomic class there was an increased utilization and a corresponding decrease of attack rate; whereas in communities where there were lower utilization rates, corresponding increased numbers of varicella cases were seen. CONCLUSION: This database enables long term follow-up of the effectiveness of this vaccine in a large population.
[Vaccines for all occasions].
The strategy of immunizing a population at risk of infectious disease has been enormously successful medically and has also proven to be cost effective. Development of effective immunogens, that induce active immunization, is a long process that requires careful monitoring and assurance of short and long term safety, induction of protective immunity and proven efficacy in preventing the disease. A successful immunization program is also dependent on delivery of the vaccine to as many susceptible individuals as possible, so as to attain herd immunity. Passive immunization with antibodies, usually used prior to the development of active vaccines has also been remarkably effective. The special circumstances of the field and crowded conditions have demanded that the Medical Corps of the Israeli army cater for the needs of our soldiers. In this issue, the past achievements and current immunization policy are outlined for the first time. Their contribution to the health of our soldiers is commendable. Close monitoring of the epidemiology of infectious disease in the special circumstances of field conditions has prompted successful programs to markedly reduce infectious hepatitis A by passive immunization with gamma globulin in the past and, nowadays, with the killed active viral vaccine. In addition, prevention of influenza by killed viral vaccine and invasive bacterial disease by Neisseria meningitidis with multivalent polysaccharide vaccines are being used. This group has also improved hygienic conditions in the field to cope with shigellosis and salmonella infections. Research in the development of effective vaccines for protection of shigellosis has also been addressed by this group. New challenges posed by the emerging infectious diseases and the possible effects of bioterrorism are certain to keep this group on their toes.
Safety and immunogenicity of Shigella sonnei-CRM9 and Shigella flexneri type 2a-rEPAsucc conjugate vaccines in one- to four-year-old children.
BACKGROUND AND OBJECTIVE: Shigella conjugate vaccines have been shown to be safe, immunogenic and efficacious in adult volunteers. We have now investigated the safety and immunogenicity of investigational Shigella sonnei and Shigella flexneri 2a conjugate vaccines in 1- to 4-year-old children, the age group at greatest risk for shigellosis. METHODS: The O-specific polysaccharides of S. sonnei and S. flexneri 2a, the two most common shigellae from patients in Israel, were bound to medically useful carrier proteins to form conjugates. Eighty healthy 1- to 4-year-olds were randomized to receive two 0.5-ml im injections 6 weeks apart of either S. sonnei-CRM(9) or S. flexneri 2a-rEPA(succ). Blood was taken before, 6 weeks after the first injection, 4 weeks after the second injections and 2 years after immunization for assay of IgG anti-lipopolysaccharide, diphtheria toxin and Pseudomonas aeruginosa exotoxin A antibodies by enzyme-linked immunosorbent assay. RESULTS: During an 8-day surveillance period after each immunization, low fever (37.8-39.0 degrees C) lasting only 24 to 48 h occurred in 2 of 40 recipients after the first injection and 4 of 40 recipients after the second injection of S. flexneri 2a-rEPA(succ) and in 2 of 38 of S. sonnei-CRM(9) after the second injection; no fever was detected after the first injection. Liver function tests were normal in all vaccinees. S. sonnei-CRM(9) elicited a >4-fold rise in IgG anti-LPS in 92.1% and S. flexneri 2a-rEPA(succ) in 85% (P < 0.0001) after the second injection; both conjugates elicited type-specific booster responses. At 2 years the geometric mean concentrations of both IgG anti-lipopolysaccharides were significantly higher than preimmunization levels. A >4-fold rise of IgG anti-diphtheria (65.8%) and IgG anti-ETA (77.5%) was observed. CONCLUSION: These experimental Shigella conjugate vaccines were safe and immunogenic in 1- to 4-year-old children.
Human and porcine early kidney precursors as a new source for transplantation.
Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.
Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.
Treatment of chronic granulomatous disease (CGD) with myeloablative bone marrow transplantation is considered risky. This study investigated complications and survival according to different risk factors present at transplantation. The outcomes of 27 transplantations for CGD, from 1985 to 2000, reported to the European Bone Marrow Transplant Registry for primary immunodeficiencies were assessed. Most transplant recipients were children (n = 25), received a myeloablative busulphan-based regimen (n = 23), and had unmodified marrow allografts (n = 23) from human leukocyte antigen (HLA)-identical sibling donors (n = 25). After myeloablative conditioning, all patients fully engrafted with donor cells; after myelosuppressive regimens, 2 of 4 patients fully engrafted. Severe (grade 3 or 4) graft-versus-host disease (GVHD) disease developed in 4 patients: 3 of 9 with pre-existing overt infection, 1 of 2 with acute inflammatory disease. Exacerbation of infection during aplasia was observed in 3 patients; inflammatory flare at the infection site during neutrophil engraftment in 2: all 5 patients belonged to the subgroup of 9 with pre-existing infection. Overall survival was 23 of 27, with 22 of 23 cured of CGD (median follow-up, 2 years). Survival was especially good in patients without infection at the moment of transplantation (18 of 18). Pre-existing infections and inflammatory lesions have cleared in all survivors (except in one with autologous reconstitution). Myeloablative conditioning followed by transplantation of unmodified hemopoietic stem cells, if performed at the first signs of a severe course of the disease, is a valid therapeutic option for children with CGD having an HLA-identical donor.
Engraftment and differentiation of human metanephroi into functional mature nephrons after transplantation into mice is accompanied by a profile of gene expression similar to normal human kidney development.
Metanephroi, the embryonic precursors of the adult kidney, can be induced in vivo to grow and develop. Despite their potential clinical utility for transplantation, the ability of human metanephroi to differentiate after transplantation into functional mature nephrons is mostly unknown. To address this, 70-d human metanephroi were transplanted into NOD/SCID mice; global gene expression patterns that underlie development of human metanephric transplants were analyzed and compared with normal human kidney development. In addition, functionality of the grafts was assessed by dimercaptosuccinic acid radioisotope scans at different times after transplantation. The results of hybridization to cDNA arrays when RNA was derived from normal human kidneys at 8, 12, 16, and 20 wk gestation demonstrated that a subset of 240 genes changed substantially with time. The induced genes can be classified as cell cycle regulators, transcription and growth factors, and signaling, transport, adhesion, and extracellular matrix molecules. Strikingly, clustering analysis of global gene expression at 2, 6, and 10 wk after metanephric transplantation revealed an expression profile that characterizes normal human kidney development. Moreover, maturation of the transplants was accompanied by an increased uptake of dimercaptosuccinic acid. Nevertheless, expression levels of specific genes were mostly found to be suppressed in the transplants compared with the normal kidneys. These data provide insights into human kidney development and support the possibility of the transplantability of human metanephroi. Understanding of the molecular regulation of the transplanted developing metanephroi might lead to the development of strategies aimed at increasing the levels of specific genes, nephron endowment, and graft function.