Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia.

This study aimed to determine the immunogenicity of a 9-valent pneumococcal conjugate vaccine (PCV-9) in a subgroup of Gambian children enrolled in a large vaccine efficacy trial. To place the antibody results in context, in this paper we also report previously unpublished data on serotype-specific clinical vaccine efficacy from the main trial. In the sub-study, a single 2-4 ml venous blood specimen was collected from 212 Gambian children 4-6 weeks after the administration of a third dose of PCV-9 or placebo. IgG antibodies to pneumococcal serotype 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F polysaccharides were measured by ELISA. The proportions of infants with antibody concentrations above 0.2, 0.35 and 1.0 microg/ml, and the geometric mean concentrations (GMCs) of anti-pneumococcal polysaccharide antibodies were substantially higher for each serotype in children who received three doses of PCV-9 than those in the placebo group. Among PCV-9 recipients, GMCs ranged between 2.61 and 11.09 microg/ml with the highest being against serotype 14 and the lowest against 9V polysaccharide. The estimated overall protective antibody level for all nine serotypes, based on the vaccine efficacy against vaccine-type invasive pneumococcal disease (IPD) of 77% (95% CI: 51, 90) observed in the trial, was 2.3 microg/ml (95% CI: 1.0, 5.0). The PCV-9 studied was immunogenic in a Gambian population where it was also found to be efficacious.

Design of vaccine equivalence/non-inferiority trials with correlated multiple binomial endpoints.

Immunogenicity trials that study the immune responses to vaccination are often used in the vaccine development process as alternatives to clinical efficacy trials. The comparisons of immune responses among various treatment groups are conducted in a non-inferiority or equivalence framework. When there exists a level of immune response that correlates with protection against disease, it is of interest to compare the proportion of responders as defined as response above a specific level or as a predefined increase in immune levels for post-vaccination levels above pre-vaccination levels. Since vaccines often contain several antigens, the correlations between the immune responses need to be taken into account in the analysis. In this paper, we describe appropriate testing methods for demonstrating the non-inferioritylequivalence of two treatments on each of the binomial endpoints. We conduct a comprehensive simulation study to shed light on how the Type I error and power are affected and to what extent when correlated multiple binomial endpoints are present in the vaccine trials. We also illustrate the computation of power for assessment of non-inferioritylequivalence in real studies.

Design of a group-randomized Streptococcus pneumoniae vaccine trial.

A group-randomized, double-masked, phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian populations in the southwestern United States. Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence. The trial is designed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated. Thirty-eight geographically and socially distinct areas were randomized within blocks formed by population size and geographic location. This design affords the opportunity to capture the effects of herd immunity (indirect effects) by estimating the impact of the vaccine intervention on nonimmunized infants. Group-randomized trials have challenging design and analysis features, many of which are discussed here in the context of the first such trial designed to lead to licensure of a drug or biologic in the United States.

Efficacy of a pneumococcal conjugate vaccine against acute otitis media.

BACKGROUND: Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. METHODS: We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. RESULTS: Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously. There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age. The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent (95 percent confidence interval, -4 to 16 percent [the negative number indicates a possible increase in the number of episodes]), culture-confirmed pneumococcal episodes by 34 percent (95 percent confidence interval, 21 to 45 percent), and the number of episodes due to the serotypes contained in the vaccine by 57 percent (95 percent confidence interval, 44 to 67 percent). The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent, whereas the number of episodes due to all other serotypes increased by 33 percent. CONCLUSIONS: The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine.

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.

Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers.

OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.

Morphometric measurements and RNA content of axotomized feline cervical motoneurons.

Microspectrophotometric estimates of RNA content and morphometric measurements of cytoplasmic, nuclear and nucleolar areas were made on 30 to 60 motoneurons (somal areas greater than 1000 microns2) ipsilateral and contralateral to brachial plexotomy performed unilaterally on adult cats 2-90 days before sacrifice. Nerve cells of unoperated animals were also assayed. Somal and cytoplasmic areas of axotomized motoneurons were larger than those of the corresponding, contralateral motor nerve cells 4, 6 and 75 days postoperatively. Because of between animal variability, it could not be determined, however, whether this difference was due to an increase in the area of the axotomized motoneurons or to a decrease in the area of the contralateral nerve cells. Nucleolar sizes did not change. In contrast, nuclei of axotomized motoneurons showed a temporary but unequivocal areal decrease. The cytoplasmic RNA content of axotomized motoneurons fell 14-28 days postoperatively but rose thereafter, being increased slightly but significantly 75-90 days after operation. At no postoperative interval, however, did the nucleolar RNA content of the axotomized cells deviate unequivocally from the unoperated or zero day condition. The following points may be emphasized: 1. these results differ from similar measurements of axotomized motoneurons of rodents and lagomorphs; 2. the data do not provide certain evidence of change in either morphometric parameters or RNA content of motoneurons on the side contralateral to surgery, although the possibility of a decrease in the size of these uninjured neurons should be considered; 3. morphometric and RNA measurements on axotomized peripheral (extrinsic) neurons of spinal anterior horn of cat contrast with similar measurements on axotomized central (intrinsic) neurons of cat red nucleus.

Cytologic observations on axotomized feline Betz cells. II. Quantitative ultrastructural findings.

Quantitative electron microscopic examination was made of Betz cells of two unoperated cats as well as cats subjected to left lateral funiculotomy 5, 10, 28 and 49 days before sacrifice. The percent cytoplasmic composition of chromatolyzed, right-sided Betz cells contributed by cisternal elements of RER, Golgi apparatus and dense bodies and the percent perikaryal membrane apposed by subsurface cisterns were unchanged from the normal despite marked qualitative alterations of the cytoplasm. However, 49 days postoperatively mitochondrial numerical density of axotomized, right-sided Betz cells was significantly less than at 0, 10 and 28 days post funiculotomy. Importantly, normal-appearing Betz cells ipsilateral to corticospinal tract section showed an increase in mitochondrial numerical density 5 days postoperatively. Operation did not induce change in the % perikaryal coverage by axosomatic boutons. Retraction of axosomatic boutons, though often reported for other neuronal populations undergoing axon reaction, is not a necessary feature of the axon reaction of feline Betz cells.

Hypnotic treatment of smoking: the single-treatment method revisited.

The authors replicated Spiegel's single-treatment method by treating 40 self-referred patients in a one-hour hypnosis session for smoking. Their results, a 6-month total abstinence rate of about 25%, were comparable with Spiegel's experience. They recommend future studies that include nontreatment control groups to validate the effects of the hypnotic treatment method of smoking.

Resistant ascites in alcoholic liver cirrhosis: course and prognosis.

A group of 29 patients with decompensated cirrhosis of the liver who retained a large amount of ascites under a hospital regimen during two months or longer was identified. The prognosis for this selected group of patients, while grave [during continuous hospitalization 11 out of 29 patients (= 38%) died], is not without hope: 18 patients (62%) improved and could be discharged from the hospital. Their further course was influenced by resumption of alcohol usage. Five of 11 (45.4%) who resumed drinking died due to hepatic causes within 10 months. Of the remaining six only one lost his ascites. Those who abstained (7 patients) remained alive for an average follow-up of 33 months and all lost their ascites. Alcohol resumption significantly decreased both survival (P less than 0.05) and ascites resorption (P less than 0.0015). Continued abstinence from alcohol may thus obviate the need for surgical measures to relieve ascites in these patients.