Robert Austrian

Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.

Objective. To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. Methods. The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37 868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype‐specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. Results. In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent‐to‐treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype‐specific effectiveness was 66.7%. Conclusion. This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.

The Protective Efficacy of Polyvalent Pneumococcal Polysaccharide Vaccine

BACKGROUND Although the protective efficacy of pneumococcal polysaccharide vaccine has been demonstrated in randomized trials in young African gold miners, there has been controversy about its efficacy in older Americans at risk for serious pneumococcal infections. To assess the vaccines protective efficacy against invasive pneumococcal infections, we conducted a hospital-based case-control study of the efficacy of pneumococcal vaccine in adults with a condition recognized to be an indication for receiving the vaccine. METHODS From 1984 to 1990, adults in whom Streptococcus pneumoniae was isolated from any normally sterile site were identified by prospective surveillance in the microbiology laboratories of 11 large hospitals; those with an indication for pneumococcal vaccine were enrolled as case patients. For each case patient, one control was matched according to age, underlying illness, and site of hospitalization. We contacted all providers of medical care to ascertain each subjects history of immunization with pneumococcal vaccine. Isolates of S. pneumoniae were serotyped by an investigator unaware of the subjects vaccination history. RESULTS Thirteen percent of the 1,054 case patients and 20 percent of the 1,054 matched controls had received pneumococcal vaccine (P less than 0.001). When vaccine was given in either its 14-valent or its 23-valent form, its aggregate protective efficacy (calculated as a percentage: 1 minus the odds ratio of having been vaccinated times 100) against infections caused by the serotypes represented in the vaccine was 56 percent (95 percent confidence interval, 42 percent to 67 percent; P less than 0.00001) for all 983 patients infected with a serotype represented in the vaccine, 61 percent for a subgroup of 808 immunocompetent patients (95 percent confidence interval, 47 percent to 72 percent; P less than 0.00001), and 21 percent for a subgroup of 175 immunocompromised patients (95 percent confidence interval, -55 percent to 60 percent; P = 0.48). The vaccine was not efficacious against infections caused by serotypes not represented in the vaccine (protective efficacy, -73 percent; 95 percent confidence interval, -263 percent to 18 percent; P = 0.15). CONCLUSIONS Polyvalent pneumococcal vaccine is efficacious in preventing invasive pneumococcal infections in immunocompetent patients with indications for its administration. This vaccine should be used more widely.

Emergence of Multiply Resistant Pneumococci

Multiple antimicrobial resistance in pneumococci was detected in Johannesburg in July, 1977, and prompted an investigation of the prevalence of resistant strains in two hospitals. Carriers of Types 6A and 19A penicillin-resistant pneumococci, resistant to antibiotic concentrations ranging between 0.12 and 4 microgram per milliliter were found in 29 per cent of 543 pediatric patients and 2 per cent of 434 hospital staff members. Multiply resistant Type 19A strains, resistant to beta-lactam antibiotics, erythromycin, clindamycin, tetracycline and chloramphenicol, were isolated from 128 carriers, and were responsible for bacteremia in four patients. Isolates from 40 other carriers were resistant to penicillin alone or to penicillin and chloramphenicol or to penicillin, chloramphenicol and tetracycline. Pneumococci can be screened for penicillin resistance with a modified Kirby--Bauer technic; the strains with zones of less than 35 mm around 6-microgram penicillin disks or less than 25 mm around 5-microgram methicillin disks should be tested for sensitivity to penicillin by measurements of minimum inhibitory concentration.

Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente.

Objective: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. Methods: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. Results: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16–34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. Conclusion: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.

A radioimmunoassay for immunologic phenomena in pneumococcal disease and for the antibody response to pneumococcal vaccines. I. Method for the radioimmunoassay of anticapsular antibodies and comparison with other techniques

A radioimmunossay is described which uses a 14C biosynthetically internally labeled antigen. This modified Farr technique has been standardized by quantitative precipitation and compared with hemagglutination and mouse protection. Specificity was established by use of heterologous hyperimmune sera and by use of unlabeled pneumococcal polysaccharides for inhibition. Reproducibility has been evaluated for different preparations of antigens and varying storage conditions of sera. The system has been applied to a wide variety of studies requiring analysis of human and animal sera.

Spread of Streptococcus pneumoniae in Families. II. Relation of Transfer of S. pneumoniae to Incidence of Colds and Serum Antibody

Factors that affect the spread of Streptococcus pneumoniae and the antibody responses associated with colonization were studied in 64 families for periods of eight to 52 weeks. Surveillance included daily recording of respiratory symptoms and bimonthly pharyngeal cultures for identification of the pneumococcal carrier state. Rhinovirus cultures were included for a portion of the study period. Intrafamilial carriage of a single type of S. pneumoniae and simultaneous spread to more than one family member were commonmspread often occurred in association with an upper respiratory tract infection; simultaneous transmission of S. pneumoniae and a rhinovirus was documented. Preexisting, type-specific serum antibody did not prevent acquisition of homotypic S. pneumoniae but did appear to shorten the duration of pharyngeal carriage. Sera of all 11 adults had greater than 150 ng of antibody nitrogen/ml of homotypic serum antibody (measured by a radioimmunoassay) before colonization. In contrast, only one of 13 preschool children had homotypic antibody concentrations of this magnitude before colonization. A threefold or greater rise in the concentration of homotypic antibody occurred in 13 of 24 children (54%) after acquisition of S. pneumoniae; the increase in antibody concentration was associated with illness in six of the children. On the other hand, acquisition of S. pneumoniae in adults was not associated with an increase in concentration of homotypic serum antibody.

Why have group A streptococci remained susceptible to penicillin? Report on a symposium

In spite of 50 years of extensive use of penicillin, group A streptococci remain exquisitely susceptible to this antibiotic. This observation that continuing susceptibility has occurred despite the development of resistance to other antimicrobial agents prompted a day-long meeting at Rockefeller University (New York) in October 1996. Among the most likely explanations for this remarkable state of continued susceptibility to penicillin are that beta-lactamase may not be expressed or may be toxic to the organism and/or that low-affinity penicillin-binding proteins either are not expressed or render organisms nonviable. Other potential explanations are that circumstances favorable for the development of resistance have not yet occurred and/or that there are inefficient mechanisms for or barriers to genetic transfer. Recommended future actions include (1) additional laboratory investigations of gene transfer, penicillin-binding proteins, virulence factors, and homeologous recombination and mismatch repair; (2) increased surveillance for the development of penicillin resistance; (3) application of bioinformatics to analyze streptococcal genome sequences; and (4) development of vaccines and novel antimicrobial agents. Thus far the susceptibility of group A streptococci to penicillin has not been a major clinical or epidemiological problem. A similar observation, however, could have been made decades ago about Streptococcus pneumoniae. It is therefore vital for the scientific community to closely examine why penicillin has remained uniformly highly active against group A streptococci in order to maintain this desirable state.

The Antibody Responses to Pneumococcal Capsular Polysaccharides in Aged Individuals

Abstract A population of elderly individuals was studied following immunization with the pneumococcal capsular polysaccharides of types 3 and 8. The antibody responses, determined by indirect hemagglutination (IHA) and by radioimmunoassay (RIA), before and 2 weeks following immunization were compared to those in young adults. Immunoglobulin levels were measured prior to immunization. The numbers of individuals showing a significant increase in antibodies to the polysaccharides of pneumococcal types 3 and 8 were comparable in both age groups when assayed by IHA and RIA. In addition, the mean fold increases in levels of antibodies measured by IHA and by RIA were not significantly lower to either polysaccharide in the elderly group. Postimmunization levels of antibody in the elderly, determined by RIA, were lower to both polysaccharides studied than in young adults, but only those to pneumococcal polysaccharide type 3 differed at a stastically significant level. Comparison of immunoglobulin levels in elderly responders and nonresponders suggested an association between low values of serum IgM and IgA and lack of responsiveness to immunization with pneumococcal polysaccharides.

Surveillance for invasive pneumococcal disease during 2000-2005 in a population of children who received 7-valent pneumococcal conjugate vaccine

Objectives: To assess the incidence of invasive pneumococcal disease (IPD) in all children younger than 5 years of age in the Northern California Kaiser Permanente (NCKP) health care system during a 5-year surveillance period (2000–2005) after the introduction in April 2000 of routine use of 7-valent pneumococcal conjugate vaccine (PCV7). Methods: This was a laboratory-based surveillance study of all children younger than 5 years of age in the NCKP health care system from April 2000 to March 2005. The comparison group was all children younger than 5 years of age in the NCKP health care system from April 1996 to March 2000. Data obtained from clinical databases included microbiologic identification and susceptibility testing; serotyping of isolates; immunization records; and IPD diagnoses for inpatients and outpatients. IPD was defined as a positive culture of Streptococcus pneumoniae from a normally sterile body site. Results: For all serotypes, the mean annual incidence of IPD during the postlicensure surveillance period was 15.3 cases/100,000 person-years (105 p-y) compared with 62.5 cases/105 p-y in the prelicensure years of 1996–2000. The average incidence of IPD caused by vaccine serotypes was reduced from 50.1 cases/105 p-y during the prelicensure years to 4.9 cases/105 p-y during the postlicensure period. The average incidences of IPD caused by cross-reactive and by nonvaccine serotypes were 5.8 and 5.3 cases/105 p-y, respectively, during the prelicensure years and 2.5 and 6.2 cases/105 p-y, respectively, during the postlicensure period. Of the 131 IPD cases observed during the postlicensure surveillance period, bacteremia (50.4%) and pneumonia (31.3%) were the most common diagnoses. During the 5-year postlicensure surveillance period, only 3 subjects who were identified to be fully vaccinated for age with PCV7 (3 doses by 7 months of age or 4 doses by 18 months of age) developed vaccine-serotype IPD. Conclusion: The incidence of IPD has significantly decreased in a large population of children after the introduction of PCV7. Vaccine-type IPD was rare in patients who received full 4-dose immunization with PCV7. There is no clear evidence of a significant increase in nonvaccine-serotype IPD. Introduction of a 4-dose infant schedule of PCV7 into this population has resulted in a marked and sustained reduction of IPD in children.

Appropriateness of a Pneumococcal Conjugate Vaccine in Brazil: Potential Impact of Age and Clinical Diagnosis, with Emphasis on Meningitis

The distribution of pneumococcal serotypes in Brazil was analyzed by age group and clinical diagnosis, using data obtained during 20 years of national surveillance. Serotypes 1 and 5 remained among the main serotypes in all age groups, increasing in frequency with age. Serotype 14 was prevalent among children, whereas serotypes 3 and 4 were most prevalent among the adult population. The potential impact of the 7- and 9-valent conjugate vaccines on children up to age 5 years with severe pneumococcal diseases was 58.2% and 73%, respectively; the highest coverage of the 7-valent vaccine for pneumonia was achieved for children aged 7 months to 2 years (70%), whereas, for meningitis, it was observed for children aged 7 months to 5 years (58.6%). The use of conjugate vaccine may be of potential benefit by reducing the childhood sequelae and mortality of pneumococcal infection in Brazil.