Isaac Ashkenazi

Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults

BACKGROUNDnThe aim of this double-blind randomised vaccine-controlled trial was to assess the efficacy of a conjugate vaccine composed of Shigella sonnei O-specific polysaccharide bound to Pseudomonas aeruginosa recombinant exoprotein A (S sonnei-rEPA) and of an oral, live-attenuated Escherichia coli/S flexneri 2a (EcSf2a-2) hybrid vaccine among military recruits in Israel at high risk of exposure to Shigella spp. We report here our preliminary findings on the efficacy of S sonnei-rEPA; we have not documented sufficient cases to assess the efficacy of EcSf2a-2.nnnMETHODSnBetween April, 1993, and August, 1994, male Israeli Military recruits aged 18-22 years were asked to take part in our study. We enrolled 1446 soldiers from seven separate field sites (groups A-G). Soldiers were randomly allocated one injection of S sonnei-rEPA and four doses of oral placebo (n = 576), four oral doses of EcSf2a-2 and one injection of saline placebo (n = 580), or one injection of meningococcal tetravalent control vaccine and four doses of oral placebo (n = 290). Because there were no cases of S flexneri 2a, the EcSf2a-2 and meningococcal vaccines were the control group. We defined S sonnei shigellosis as diarrhoea with a positive faecal culture for S sonnei. Each group of soldiers was followed up for 2.5-7.0 months. The primary endpoint was protective efficacy of S sonnei-rEPA against S sonnei shigellosis.nnnFINDINGSnCases of culture-proven S sonnei shigellosis occurred in four groups of soldiers (groups A-D), which comprised 787 volunteers (312 received S sonnei-rEPA, 316 received EcSf2a-2, and 159 received meningococcal control vaccine). In groups A-C, cases of shigellosis occurred 70-155 days after vaccination, whereas in group D cases occurred after 1-17 days. In groups A-C, the attack rate of shigellosis was 2.2% in recipients of S sonnei-rEPA compared with 8.6% in controls (protective efficacy 74% [95% CI 28-100], p = 0.006). S sonnei-rEPA also showed significant protection against shigellosis in group D (43% [4-82], p = 0.039). Prevaccination and postvaccination ELISA measurements of antibody to S sonnei lipopolysaccharide among recipients of S sonnei-rEPA showed that the vaccinees who developed S sonnei shigellosis had significantly lower serum IgG and IgA responses to the homologous lipopolysaccharide than those who did not (p = < 0.05).nnnINTERPRETATIONnOne injection of S sonnei-rEPA confers type-specific protection against S sonnei shigellosis. The high antibody concentration induced by the conjugate vaccine in volunteers who did not develop shigellosis suggests that there is an association between serum antibody titre and protection.

Major adverse reactions to yeast-derived hepatitis B vaccines : A review

Yeast-derived recombinant DNA hepatitis B vaccines usage became widely accepted since the early 1990s. Severe adverse events have been reported infrequently in adults and rarely in infants and children given hepatitis B vaccine in the ten years which have passed since the introduction of the vaccine. Some of the data were summarized in previous review articles. Our review of the literature revealed reports of serious adverse reactions which included immediate reactions (anaphylaxis and urticaria) as well as delayed reactions, including skin, rheumatic, vasculitic (including Systemic Lupus Erythematosus and glumerulonephritis), hematologic, ophthalmologic and neurologic reactions. These cases were summarized and a pathogenetic mechanism is offered.

Safety and Immunogenicity of Two Different Lots of the Oral, Killed Enterotoxigenic Escherichia coli-Cholera Toxin B Subunit Vaccine in Israeli Young Adults

ABSTRACT Enterotoxigenic Escherichia coli (ETEC) is one of the leading causes of diarrhea among Israeli soldiers serving in field units. Two double-blind placebo-controlled, randomized trials were performed among 155 healthy volunteers to evaluate the safety and immunogenicity of different lots of the oral, killed ETEC vaccine consisting of two doses of whole cells plus recombinantly produced cholera toxin B subunit (rCTB). The two doses of vaccine lot E005 and the first dose of vaccine lot E003 were well tolerated by the volunteers. However, 5 (17%) vaccinees reported an episode of vomiting a few hours after the second dose of lot E003; none of the placebo recipients reported similar symptoms. Both lots of vaccine stimulated a rate of significant antibody-secreting cell (ASC) response to CTB and to colonization factor antigen I (CFA/I) after one or two doses, ranging from 85 to 100% and from 81 to 100%, respectively. The rate of ASC response to CS2, CS4, and CS5 was slightly lower than the rate of ASC response induced to CTB, CFA/I, and CS1. The second vaccine dose enhanced the response to CTB but did not increase the frequencies or magnitude of ASC responses to the other antigens. The two lots of the ETEC vaccine induced similar rates of serum antibody responses to CTB and CFA/I which were less frequent than the ASC responses to the same antigens. Based on these safety and immunogenicity data, an efficacy study of the ETEC vaccine is under way in the Israel Defense Force.

Factors associated with pharyngeal carriage of Neisseria meningitidis among Israel Defense Force personnel at the end of their compulsory service.

In this 1 year cross-sectional study of personnel being discharged from compulsory military service, an available database of health-related information was used to examine the association of meningococcal carriage with socio-demographic factors. A representative, systematic sample of 1632 personnel was interviewed and had throat cultures taken. The overall meningococcal carriage rate was 16%. Serogroups B and Y accounted for 76% and 13% of the isolates respectively. In univariate analysis, carriage was associated with male gender (P < 0.0001), < 12 years school education (P = 0.002), smoking (P = 0.014), and service at a closed base, reflecting greater interpersonal contact (P < 0.0001). In multivariate analysis, only service on a closed base and male gender retained significance. School education of < 12 years remained significant for females only. Variables not associated with carriage included number of siblings, intensity of smoking, and use of the contraceptive pill. In this setting, meningococcal carriage was associated with the type of base on which soldiers served; and smoking was not an independent risk factor for carriage.

Norwalk Virus Gastroenteritis among Israeli Soldiers: Lack of Evidence for Flyborne Transmission

AbstractBackground: Paired sera collected from subjects before and after a fly-control intervention trial conducted in the Israel Defence Force (IDF) were tested for seroconversion to Norwalk virus (NV) to examine the role of NV as a cause of diarrhea in this population and to ascertain whether flies might also be implicated in transmission.nMaterials and Methods: An enzyme-linked immunosorbent assay (ELISA), using recombinant NV capsid proteins (rNV) as antigen was employed to determine the seroconversion rate in a sample of 444 subjects.nResults: During 11-week field training cycles, 18% of IDF soldiers who were tested had an NV infection defined as a ≥ 4-fold rise in antibody, yielding a cumulative incidence of nearly one infection (0.95) per soldier per year. The rate of seroconversion was nearly twice as high among soldiers who recalled having diarrhea as among those who did not, but the rates did not differ significantly between soldiers in the fly intervention areas and those in the control areas.nConclusion: NV is a common cause of enteric infections and diarrhea among Israeli soldiers who serve under field conditions, but unlike infections with Shigella and enterotoxigenic Escherichia coli, transmission of NV cannt be interrupted with an aggressive program of fly-control.

Cycle Ergometry Estimation of Physical Fitness among Israeli Soldiers

We evaluated the level of fitness among a large population-based sample of Israeli men and women ages 18-25 years, within the framework of an ongoing survey of personnel discharged from military service in the Israel Defense Force. Aerobic capacity was predicted with the Astrand-Rhyming 6-minute cycle ergometer test and maximal oxygen uptake (VO2 max) was estimated using the Astrand-Rhyming nomogram based on cardiac response to 6 minutes of constant submaximal cycle work. Mean +/- SD VO2 max values were 41.05 +/- 10.52 mL/kg/min for men (range, 15-81 mL/kg/min) and 33.84 +/- 7.60 mL/kg/min for women (range, 16-65 mL/kg/min). Smoking was found to be associated with lower VO2 max among both men and women, whereas type of military service unit was unexpectedly not associated with physical fitness level.

Metabolic syndrome: a risk factor for high intraocular pressure in the Israeli population.

AIMnTo evaluate the association among elevated intraocular pressure (IOP), the metabolic syndrome (MetS), body mass index (BMI), and some of their components in the Israeli population.nnnMETHODSnWe retrospectively reviewed the charts of 12 747 soldiers of the Israeli Defense Forces, aged 35y or older, who underwent a routine periodical medical examination between 1991 and 2004. None of the subjects received medical treatment for either glaucoma or ocular hypertension. High IOP (>21 mm Hg) was correlated with age, sex, arterial blood pressure, total blood cholesterol levels, triglyceride levels, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking, BMI and MetS.nnnRESULTSnA statistically significant difference was found between the IOP of subjects with a low risk and higher risk for the development of MetS (P<0.0001 for males, P=0.0026 for females). A statistically significant positive correlation was found in male subjects between high BMI and elevated IOP (r=0.11677, P<0.0001).nnnCONCLUSIONnMetS and BMI were significantly more prevalent in subjects with increased IOP levels. We suggest that both should be taken into consideration in the assessment of glaucoma suspects.

Meningococcal Polysaccharide Vaccination of Military Recruits in Israel: Preliminary Assessment of Vaccine Effect

Meningococcal disease in the Israel Defense Force is caused mainly by serogroups C and Y. Immunization of recruits with quadrivalent polysaccharide vaccine was introduced in November 1994. The person-time incidence rate dropped from 1.33 cases per 100,000 person-years for the preceding decade to 0 for the 32 months following immunization (p = 0.025).

Clinical Trials of Shigella Vaccines in Israel

Shigellosis or bacillary dysentery is caused by organisms belonging to genus Shigella, divided into four species (S. dysenteriae, S. boydii, S.flexneri and S. sonnei). With the exception of S. sonnei which has a single serotype, each species is divided into several serotypes according to the O-polysaccharide antigen of the cell wall (S. dysenteriae has 12 serotypes, S. flexneri has 6 serotypes, and S. boydii has 18 serotypes). Shigella spp. are invasive organisms that penetrate into the enterocytes of the colon epithelium, escape very quickly from the phagocytic vacuole and multiplicate intracellularly. Although non-motile, shigellae can move on an actin skeleton and spread to adjacent cells. The inflammatory process is usually limited to the lamina propria and does not involve the spread of Shigella deeper, into the submucosa. Pathogenesis in Shigella spp. is associated with a constellation of genes encoded on both the chromosome and a large 140 MDa virulence plasmid. These genes can be divided into two groups: regulatory genes and structural genes. The 140 MDa plasmid encodes for all the genes essential for invasion of Shigella into the epithelium of the colon. Regulatory genes are located on the virulence plasmid or on the chromosome.

Anticapsular polysaccharide meningococcal antibodies in Israeli military recruits: immune status and the effect of simultaneous administration of immune globulin on the response to polysaccharide vaccine.

The effect of the administration of immune globulin (Ig), given during summer months to prevent hepatitis A, on the immune response to a simultaneously administered quadrivalent meningococcal polysaccharide vaccine (QMPV) was studied in Israeli military recruits. Data were obtained for the first time regarding the immune status of an Israeli population. Anticapsular polysaccharide antibodies were determined using a standardized ELISA assay before, 2 weeks and 3 months after QMPV immunization with or without Ig in two groups of recruits chosen to span the date determining seasonal administration or non-administration of Ig. Pre-vaccination antibody concentrations were > or = 2 microg/ml in 98.4 and 38.9% of subjects against serogroups A and C meningococci, respectively. These levels are consistent with the extremely low incidence of disease due to serogroup A in Israel, and with the previously documented occurrence of serogroup C disease in servicemen and women. Co-administration of Ig was associated with some reduction in antibody concentrations 3 months after vaccination, especially against serogroup A meningococci (P<0.05), but not to an extent likely to be of clinical significance.