Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group.

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.

Pneumococcal otitis media and pneumococcal vaccines, a historical perspective.

Although pneumococcal otitis media was recognized in the 19th century, the illness stimulated little interest in prophylaxis until recently. Whole cell vaccines of killed pneumococci, developed to prevent pneumonia, were replaced by vaccines of capsular polysaccharides following demonstration of their antigenicity in adults. Failure of the latter to stimulate antibodies in infants and young children and demonstration of the efficacy of capsular polysaccharide-protein conjugate vaccines in preventing infection with Hemophilus influenzae type b has led to the development of polyvalent pneumococcal polysaccharide-protein conjugate vaccines. Preliminary studies have shown them to be highly effective in preventing invasive pneumococcal disease in the first 2 years of life, and studies of their impact on otitis media are currently in progress.

The pneumococcus at the millennium: not down, not out.

In the 12 decades that will have elapsed between the first isolation of the pneumococcus and the coming millennium, much of fundamental biologic importance has been learned from the study of this bacterium and the diseases it causes. Streptococcus pneumoniae is associated with the development of Gram's stain, the Quellung reaction, and many of the fundamentals of immunology. It has also played a significant role in the history of antimicrobial therapy. After a transitory period of euphoria engendered by the improved prognosis of pneumococcal pneumonia resulting from therapeutic advances, recognition that the newer treatments could not bring about the recovery of those sustaining early irreversible physiologic injury led to renewed interest in immunoprophylaxis. Added impetus to this approach has been fostered by the recent rapid increase in the number of pneumococcal isolates resistant to antimicrobial agents and in the magnitude of their resistance. Pneumococcal vaccines are increasingly relevant.

A brief history of pneumococcal vaccines.

Attempts to control pneumococcal infection by vaccination, undertaken initially in 1911, have gone through 3 phases during the subsequent 8 decades. Initially, vaccines of killed pneumococcal cells prepared in a variety of ways were used in epidemic settings with inconclusive results, although administered to approximately 1 million recipients. The discovery that adults injected with small amounts of purified capsular polysaccharide developed antibodies to the homologous capsular type led to the trial of a tetravalent vaccine that showed conclusively its ability to prevent infection by the types represented in it. With the advent of penicillin and other effective antipneumococcal drugs, interest in prophylaxis waned. Interest in vaccination was revived only after demonstration that some segments of the population remained at high risk of death if infected and after the emergence of multidrug-resistant pneumococci. Infants and young children, among whom the incidence of pneumococcal infection is high, respond poorly to purified bacterial polysaccharides but develop satisfactory responses to bacterial polysaccharides when these are linked chemically to a protein. The early results of trials with such polysaccharide protein conjugate vaccines give promise that control of a significant portion of pneumococcal infection in the paediatric population will soon be feasible.

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.

Characteristics of Isolates Streptococcus pneumoniae from Middle-Aged and Elderly Adults in Brazil: Capsular Serotypes and Antimicrobial Sensitivity to Invasive Infections.

Pneumococcal infection cause frequent, serious problems among middle aged and elderly populations worldwide. Efforts to prevent mortality caused by pneumococci are based mainly on rapid diagnosis of the infection and appropriate antimicrobial therapy. Vaccination is considered to be the best approach to prevent the disease in at risk populations and the current 23-valent pneumococcal polysaccharide vaccine is recommended for people >e;65 years of age. To evaluate the present antibiotic sensitivity patterns and the potential for vaccine use to prevent this disease in Brazil, 94 isolates of pneumococci from normally sterile body sites from patients >e;50 years of age were analyzed for capsular serotypes and antimicrobial resistance. Among the total isolates, 7.4% (n = 7) of the isolates showed intermediate level resistance to penicillin (IR). Among the IR isolates, 6 were also resistant to trimethoprim-sulfamethoxazole. All isolates were susceptible to cefotaxime, chloramphenicol, erythromycin, and vancomycin. Twenty-eight serotypes were identified and the serotypes included in the 23-valent vaccine accounted for 81.7%. By adding the cross-reacting serotypes, the percentage of vaccine preventable infections was 90.3%. Each of intermediate level resistant strains were among the 23 serotypes included in pneumococcal vaccine. This preliminary data on the distribution of serotype of S.pneumoniae among those >e;50 years of age in Brazil, and the potential for increased antimicrobial resistance to penicillin and trimethoprim-sulfamethoxazole, support the use of pneumococcal vaccine in this population.

Distribution of serotypes of Streptococcus pneumoniae isolated from invasive infections over a 16-year period in the greater São Paulo area, Brazil.

Capsular types of pneumococci from normally sterile body sites of 1,622 patients in Brazil were analyzed. Of 1,477 isolates from cerebrospinal fluid, 76.1% were of types represented in the currently available pneumococcal vaccine. The importance of age, time, and place in determining the optimal formulation of pneumococcal vaccine is considered.

Penicillin-resistant and multidrug-resistant Streptococcus pneumoniae in a pediatric hospital in Zagreb, Croatia.

Sixty-four penicillin-resistant Streptococcus pneumoniae isolates [benzylpenicillin minimal inhibitory concentrations (MICs) between 0.05 and 1.6 micrograms/ml] recovered at the Pediatric Hospital "Dr. Fran Mihaljevic" in Zagreb, Croatia between October 1990 and March 1993 were analyzed for serotype, antibiotic susceptibility patterns, and chromosomal relatedness using pulsed-field gel electrophoretic (PFGE) analysis of chromosomal DNA fragmented by digestion with the SmaI endonuclease. Hospital "Dr. Fran Mihaljevic" services the capital of Croatia and its vicinity. Most of the isolates were from nasopharyngeal carriage, but several isolates were from otitis media, sinusitis, and meningitis. Most isolates belonged to either serotype 23F (36/64) or 19F (12/64); the rest, including three 15C isolates, were in 11 additional distinct serotypes. The overwhelming majority (25/36) of the serotype 23F isolates had penicillin MIC values of 1-2 micrograms/ml and shared variants of a common PFGE pattern, closely related to the PFGE identified in multiresistant pneumococci of the same serotype with wide geographic spread to Spain, Portugal, France, and the United States. This group of bacteria was also resistant to tetracycline, chloramphenicol, and sulfamethoxazole/trimethoprim. In contrast to the relative genetic and phenotypic homogeneity of the more highly penicillin resistant isolates, pneumococci with penicillin MICs between 0.5 and 0.4 microgram/ml (29/64) were distributed in 13 different serotypes and as many as 20 distinct PFGE patterns.

Novel penicillin-resistant clones of Streptococcus pneumoniae in the Czech Republic and in Slovakia.

Seventy-two penicillin-resistant Streptococcus pneumoniae isolates collected from clinical specimens in the Czech and Slovakian Republics between 1990 and 1992 were analyzed by a variety of molecular techniques. Most of the highly resistant isolates (40/72) (penicillin MIC between 1 up to 16 micrograms/ml) were represented by two distinct pneumococcal clones, and most of these isolates (35/40) were also resistant to at least two other antibiotics (tetracycline plus chloramphenicol or erythromycin). All 17 isolates belonging to the first clone were of serotype 14, had very high penicillin MICs (8-12 micrograms/ml), shared a common, abnormal penicillin-binding protein (PBP) pattern and one of two related pulsed-field gel electrophoretic (PFGE) patterns. The 15 isolates belonging to the second clone were all of serotype 19A, had penicillin MICs between 1 and 4 micrograms/ml, shared a unique, abnormal PBP pattern, and could be divided into two subgroups on the basis of PFGE patterns, one of which was indistinguishable from the PFGE pattern of a multiresistant capsular type 19A clone of S. pneumoniae already identified earlier in Hungary. Thirty-two of the 72 pneumococcal isolates had lower penicillin MICs (0.1-0.5 microgram/ml), and these isolates differed from the more highly resistant ones in several respects: They belonged to seven different serotypes, showed large variation in PFGE patterns (20 patterns in 32 isolates) and most of them (21/32) were resistant to penicillin only. Tentative explanations for these findings, in terms of epidemiological and molecular mechanisms, are considered.

Phase variation in pneumococcal opacity: relationship between colonial morphology and nasopharyngeal colonization.

When colonies of encapsulated isolates of Streptococcus pneumoniae are viewed with oblique, transmitted light on a transparent surface, they are heterogeneous in appearance because of variation in opacity. There is spontaneous phase variation among at least three discernible phenotypes at frequencies from 10(-3) to 10(-6). The ability to detect differences in opacity varies according to serotype, but variation is independent of capsule expression. Electron microscopy shows no difference in chain length but suggests that autolysis occurs earlier in the growth of the transparent variant. There was no identifiable difference in membrane protein profiles of opaque and transparent variants of the same strain. In an infant rat model of nasopharyngeal carriage, there was no significant colonization by opaque variants. Efficient and stable colonization by the transparent variants was observed, suggesting a selective advantage for this phenotype in the nasopharynx. In contrast, there was no difference in the incidence of bacteremia or in the 50% lethal dose among the variants following their intraperitoneal inoculation. These results suggest that phase variation which is marked by differences in colonial morphology may provide insight into the interaction of the pneumococcus with its host.

Serotypes responsible for invasive Streptococcus pneumoniae infections among children in Connecticut.

Active prospective surveillance to identify the serotypes of Streptococcus pneumoniae responsible for invasive infections among children in Connecticut was conducted from July 1984 through March 1993. S. pneumoniae isolates (722) recovered from normally sterile sites (98% from blood, 7% from both blood and cerebrospinal fluid) were serotyped by the Quellung reaction; 70% of the isolates were from children < 2 years old. Serotype 14 caused 29% of the infections. Seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) were responsible for 84% of the invasive infections overall and for 86% of the invasive infections among children < 2 years old. Formulations of polysaccharide-protein conjugate pneumococcal vaccines designed to prevent invasive infections in children in the United States should include these commonly isolated serotypes.

The pneumococcus and some men who came to Yale: the Dorothy M. Horstmann Lecture.

Yale has been fortunate indeed to have had Dorothy Horstmann as a member of its faculty for all but one of the last 50 years. It has had also the wisdom to take cognizance of her value as an individual and of her contributions to biomedical science and human welfare on two occasions in recent years. Her studies of poliomyelitis, hepatitis, and rubella, executed with perceptiveness, rigor and modesty, have benefited countless numbers; and for her many achievements all are in her debt. I am beholden to her colleagues for this opportunity to pay tribute to a wise and gracious friend. In casting about for a subject befitting this occasion, the thought occurred that it might be of interest to examine the contributions of some former and present members of Yale's faculty to the subject of a group of infections still endemic in all human societies, namely those caused by Streptococcus pneumoniae or the pneumococcus. The list is doubtless not exhaustive but includes such notables as Winternitz, Blake, Paul, Trask, Eaton, and Beeson of former days, as well as reflecting ongoing investigations today by Eugene Shapiro and his colleagues. In reviewing some of this earlier work, it will be my endeavor to place it in the context of contemporary understanding. In the interest of some semblance of order, the material will be examined in topical rather than in chronological order, dealing with bacteriologic and immunologic, pathogenetic, therapeutic, and prophylactic considerations in that sequence.

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 vaccine's 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 subject's history of immunization with pneumococcal vaccine. Isolates of S. pneumoniae were serotyped by an investigator unaware of the subject's 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.