Immunogenicity of a new Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB).

Haemophilus influenzae type b is responsible for an estimated 15,000 to 20,000 cases of meningitis per year in the United States, mainly in children 2 months to 5 years old. The mortality rate from meningitis due to H influenzae type b infections ranges from 5% to 10%. Despite antibiotic treatment, up to 35% of survivors have permanent neurologic sequelae. In addition to meningitis, H. influenzae type b is responsible for other invasive infections, including epiglottitis, septicemia, cellulitis, septic arthritis, osteomyelitis, pneumonia, pericarditis, and otitis media; approximately 30,000 cases H influenzae diseases occur annually in the United States. The diseases peak in incidence between 6 and 12 months of age, with almost one half of the cases occurring before 1 year of age. About 75% of disease caused by H influenzae type b occurs in children younger than 24 months old. The incidence of disease is higher in children of certain groups, including blacks, Hispanics, Eskimos and Native Americans, young children attending day-care facilities, patients with asplenia or antibody-deficiency syndromes, and children of lower socioeconomic status. There is considerable evidence that antibody to the capsular polysaccharide (polyribosylribitol-phosphate [PRP] of H influenzae type b is protective.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB): clinical evaluation.

Although systemic infections caused by Haemophilus influenzae type b occur worldwide, detailed epidemiologic data are available in but a few countries. The public health impact of morbidity, mortality, and serious sequelae from disease caused by H influenzae type b has stimulated the search for control strategies. In the United States now, active immunoprophylaxis is largely favored over treatment of prophylaxis with antibiotics. This preference stems from three major observations: that high mortality and morbidity persist despite the availability of potent antimicrobial agents, that antibiotic-resistant strains of H influenzae type b have emerged, and that implementation of antimicrobial prophylaxis on a large scale has been unsatisfactory. Moreover, universal vaccination has been projected as offering a higher economic benefit than other control strategies. A matter of more proximate importance, however, is the search for H influenzae type b vaccines that will confer protection to all age groups, including infants younger than 18 months of age and subpopulations specifically at risk for invasive disease caused by H influenzae type b. Haemophilus b conjugate vaccine (meningococcal protein conjugate), PedvaxHIB (PRP-OMPC), is a conjugate H influenzae type b vaccine developed at Merck Sharp & Dohme Research Laboratories that now is undergoing extensive clinical evaluation to assess its prospects for disease control when first administered in early infancy. This is an interim report of results obtained in studies conducted in diverse locations throughout the United States.

Extracting dynamical structure from unstable periodic orbits.

The topological recurrence algorithm provides a fast and robust method for detecting the presence of unstable periodic orbits (UPO's) in short, noisy experimental data files. We present here a technique for improving this method by using a matrix fitting algorithm to extract dynamical information about the system from these UPO's. This method greatly increases the sensitivity of the algorithm, and also provides a method for identifying false positive results.

Surrogate for nonlinear time series analysis.

We present a surrogate for use in nonlinear time series analysis. This surrogate algorithm has significant advantages over the most commonly used surrogates, in that it provides a more robust statistical test by producing an entire population of surrogates that are consistent with the null hypothesis. We will show that for the currently used surrogate algorithms, although individual surrogate files are consistent with the null hypothesis the population of surrogates generated is not. The surrogate is tested on a linear stochastic process and a continuous nonlinear system.

Diverse serologic response to rotavirus infection of infants in a single epidemic.

Eight infants with onset of gastroenteritis occurring within a 32-day period were examined for stool rotavirus antigen and serum antibody response to rotavirus. Each infant presented evidence of rotavirus infection but no single test for rotavirus-specific antigen or antibody was positive for every infected individual. Rotavirus was identified in the stools of five infants; in the others rotavirus etiology was determined by a specific immune response only. The neutralizing antibody response to each of four human rotavirus serotypes and to bovine rotavirus Nebraska calf diarrhea virus ranged from totally negative to a specific response to up to four serotypes. Three originally seropositive infants each showed an increase in neutralizing antibody titer to two or more serotypes. However, two of five originally seronegative infants also developed antibody to two or more serotypes. No consistent pattern of responses to different serotypes was detected.

An enzyme-linked immunosorbent assay for quantitation of Haemophilus Influenzae type b polysaccharide-specific IgG1 and IgG2 in human and infant rhesus monkey sera.

An enzyme-linked immunosorbent assay (ELISA) has been developed and validated to quantitate IgG1 and IgG2 antibody to polyribosyl-ribitol phosphate (PRP), the capsular polysaccharide of Haemophilus influenzae type b (Hib). The sera of children and infant Rhesus monkeys immunized with an Hib conjugate vaccine composed of Hib PRP covalently linked to an outer membrane protein complex (OMPC) from Neisseria meningitidis serogroup B (PedvaxHIB, PRP-OMPC, Merck, Sharp and Dohme Research Laboratories). The solid-phase antigen employed in the ELISA is a conjugate of PRP to human serum albumin. The enzyme-labeled antibody is alkaline phosphatase-conjugated mouse monoclonal (mAb) anti-human IgG1 or IgG2. A human serum standard was calibrated using parallel titrations with a known antibody standard. The geometric mean titer (GMT) of the anti-PRP IgG1 response to one dose of PedvaxHIB was 3.87 micrograms/ml (n = 82), 11.80 micrograms/ml (n = 62) and 14.57 micrograms/ml (n = 74) in infants and children 12 to 17 months, 18 to 23 months and greater than or equal to 24 months old, respectively. Infants 2 to 11 months old responded with an IgG1 anti-PRP response of 7.10 micrograms/ml while infant monkeys responded with a GMT of 150.65 (n = 9) after two doses of vaccine. The anti-PRP IgG2 GMT responses in all groups were less than 0.25 micrograms/ml, except for humans greater than or equal to 18-months old who exhibited a GMT of greater than or equal to 0.40 micrograms/ml (n = 75). PedvaxHIB, immunization of human infants and children and infant Rhesus monkeys elicits primarily an IgG1 response to PRP. The monkey model appears to be a reliable indicator of the human immune response.

Response of adult human volunteers to oral administration of bovine and bovine/human reassortant rotaviruses.

Small groups of adult volunteers, in sequence, were inoculated orally with inactivated purified bovine rotavirus of strain NCDV, with live NCDV purified or unpurified and with two different NCDV X human rotavirus reassortant viruses. One of five volunteers given 200 micrograms of ultravioletinactivated NCDV developed a virus-neutralizing (VN) and a binding antibody response detected by enzyme-linked immunosorbent assay (ELISA). Four of 10 volunteers given from 1 X 10(6) to 1 X 10(8) p.f.u. of live NCDV developed VN antibody, but nine of 10 responded when ELISA, HAI and radioimmuno-precipitation tests for serum antibody were also considered. Two different NCDV X human serotype 1 Wa strain virus reassortants, each containing Wa gene segment 9 and the serotype 1 neutralization phenotype, were administered orally in doses up to 10(6) p.f.u. The reassortants were relatively ineffective in eliciting a serum antibody response at the dosage level employed.

Epidemiology of rotavirus electropherotypes determined by a simplified diagnostic technique with RNA analysis.

The incidence and RNA electropherotypes of rotavirus in stools or rectal swabs of children with diarrhea were studied for three rotavirus seasons (1981 through 1984) in Philadelphia, Pa. We used a simplified RNA analysis method involving polyacrylamide gel electrophoresis followed by silver staining. Phosphate-buffered saline suspensions of the stools and swab eluates were examined directly by polyacrylamide gel electrophoresis-silver staining analysis and enzyme-linked immunoadsorbent assay (Rotazyme; Abbott Laboratories); electron microscopy was performed on solid stool specimens. The RNA analysis results were compared with electron microscopy and enzyme-linked immunosorbent assay results and exhibited a sensitivity and specificity greater than or equal to that of electron microscopy or the enzyme-linked immunosorbent assay. Ten different electropherotypes were detected among the 68 rotavirus RNA-positive specimens examined over the 3-year study. The predominant electropherotype was different in each season. Our results indicate that the polyacrylamide gel electrophoresis-silver nitrate strain RNA analysis of simple unextracted stool suspensions is a uniquely useful diagnostic technique; it rapidly provides both a definitive positive result and immediate determination of the RNA electropherotype, which is of value for epidemiological study.