Immunogenicity and Tolerability of a Heptavalent Pneumococcal Conjugate Vaccine Administered at 3, 5 and 12 Months of Age Pneumococcal conjugate vaccination does not induce a persisting mucosal IgA response in children with recurrent acute otitis media. A role for Streptococcus pneumoniae in virus-associated pneumonia Intention to treat--who should use ITT? A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine and pneumococcal polysaccharide vaccine in toddlers. Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study Immunogenicity and Reactogenicity of Four Doses of Diphtheria-Tetanus-Three-Component Acellular Pertussis-Hepatitis B-Inactivated Polio Virus-Haemophilus influenzae Type b Vaccine Coadministered with 7-Valent Pneumococcal Conjugate Vaccine Design of a group-randomized Streptococcus pneumoniae vaccine trial. Efficacy of an 11-Valent Pneumococcal Conjugate Vaccine Against Radiologically Confirmed Pneumonia Among Children Less Than 2 Years of Age in the Philippines: A Randomized, Double-Blind, Placebo-Controlled Trial Kinetics and Avidity of Antibodies Evoked by Heptavalent Pneumococcal Conjugate Vaccines PncCRM and PncOMPC in the Finnish Otitis Media Vaccine Trial Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia Impact of the pneumococcal conjugate vaccine on otitis media Heptavalent pneumococcal vaccine conjugated to outer membrane protein of Neisseria meningitidis serogroup b and nasopharyngeal carriage of Streptococcus pneumoniae in infants. Evaluation of the safety and immunogenicity of pneumococcal seven-valent conjugate vaccine (Prevenar) administered in previously unvaccinated Spanish children aged 24 to 36 months. Nasopharyngeal pneumococcal carriage after combined pneumococcal conjugate and polysaccharide vaccination in children with a history of recurrent acute otitis media. Immunogenicity and reactogenicity of a pneumococcal conjugate vaccine administered combined with a haemophilus influenzae type B conjugate vaccine in United Kingdom infants. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. The effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion at 7 and 24 months of age. Effect of the Seven-Valent Conjugate Pneumococcal Vaccine on Carriage and Drug Resistance of Streptococcus pneumoniae in Healthy Children Attending Day-Care Centers in Lisbon Evaluation of the Indirect Effects of a Pneumococcal Vaccine in a Community-Randomized Study Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial Effectiveness of Heptavalent Pneumococcal Conjugate Vaccine in Children Younger Than 5 Years of Age for Prevention of Pneumonia: Updated Analysis Using World Health Organization Standardized Interpretation of Chest Radiographs Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings Effect of Pneumococcal Vaccination on Quality of Life in Children With Recurrent Acute Otitis Media: A Randomized, Controlled Trial Efficacy of a pneumococcal conjugate vaccine against acute otitis media. Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Assessment of the compatibility of co-administered 7-valent pneumococcal conjugate, DTaP.IPV/PRP-T Hib and hepatitis B vaccines in infants 2-7 months of age. The Seven-Valent Pneumococcal Conjugate Vaccine Reduces Tympanostomy Tube Placement in Children The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Concentration of antipneumococcal antibodies as a serological correlate of protection: an application to acute otitis media. The safety, reactogenicity and immunogenicity of a 7-valent pneumococcal conjugate vaccine (7VPnC) concurrently administered with a combination DTaP-IPV-Hib vaccine. Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers. Pneumococcal conjugate vaccination in children with recurrent acute otitis media: a therapeutic alternative? Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants.
Background : The recommended vaccination schedule for the pneumococcal conjugate vaccine ( PCV ) includes 4 immunizations , according to the national programs in the United States and some European countries . Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses . Aims : The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life ( a 2 + 1 dose schedule ) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b ( Hib ) vaccine . Methods : A total of 101 healthy Swedish infants were enrolled in an open , nonr and omized , multicenter study . PCV was administered concomitantly with ( at separate sites ) a diphtheria-tetanus toxoids-acellular pertussis vaccine , inactivated polio vaccine and Hib conjugate vaccine combination at 3 , 5 and 12 months of age . IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum sample s taken at 3 , 6 , 12 and 13 months were determined with enzyme immunoassays . Local and systemic reactions were monitored for 3 days after each immunization , and serious adverse reactions were monitored for the whole study period . Results : Two doses of PCV induced satisfactory antibody responses , with the exception of serotypes 6B and 23F . The third dose evoked strong responses for all serotypes , which suggests good immunologic priming with the primary series of 2 doses . The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children . The PCV was well tolerated . Conclusion : The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule . The results suggest that the implementation of a 2 + 1 dose schedule for PCV should be considered AIM In a prospect i ve controlled study in young children with a history of recurrent acute otitis media , we analyzed the salivary IgA and IgG antibody titers upon vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV ) given once or twice , followed by a 23-valent polysaccharide booster vaccination . METHODS Salivary IgA and IgG antibody concentrations to vaccine serotype 6B , 14 , 18C and 19F were measured by enzyme immunoassay in 38 sample s of children vaccinated with PCV and 45 control sample s. In the PCV  group , 12 sample s were taken prior to vaccination , 12 sample s 4 weeks after the polysaccharide booster ( 8 months after the first conjugate vaccination ) and 14 sample s 7 months after the last vaccination ( 14 months after the first conjugate vaccination ) . In the control group 15 children were sample d at each of these three time points . RESULTS We observed an increase in salivary IgG antibody concentrations against serotype 6B , 14 , and 18C 14 months after the primary vaccination in children vaccinated with PCV twice , although this was significant for serotype 14 only . There was no increase in salivary IgG antibody in children vaccinate with PCV once nor in control children . IgA antibody titers increased significantly after 8 and after 14 months in both the pneumococcal vaccine recipients and the controls . However , the observed increase in mean antibody titers was significantly higher in control children compared to the PCV group . CONCLUSION We suggest that repeated pneumococcal conjugate vaccination is necessary to induce an increase in salivary IgG antibodies and effectuate clearance of S. pneumoniae from the nasopharyngeal mucosa of children with recurrent acute otitis media . We hypothesize that the increase in salivary IgA is caused by the local boosting of the mucosal immune response by carriage and recurrent infections , which occurs less often in the PCV group compared to the control children Here we show , in a double-blind , r and omized , placebo-controlled trial in 37,107 fully immunized infants in Soweto , South Africa , that a 9-valent pneumococcal conjugate vaccine , PncCV , prevents 31 % ( 95 % confidence interval = 15–43 % ) of pneumonias associated with any of seven respiratory viruses in children in hospital . These data suggest that the pneumococcus has a major role in the development of pneumonia associated with these viruses and that viruses contribute to the pathogenesis of bacterial pneumonia . NOTE : In the version of this article originally published online , the species name was misspelled Streptococcus pnemoniae in the title of the article . The name should be Streptococcus pneumoniae . This error has been corrected for the HTML and print versions of the article In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients Children who had been r and omized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PCV ) or 23-valent pneumococcal polysaccharide vaccine ( PN23 ) at 12 , 15 , or 18 months of age were subsequently r and omized to receive a booster injection of either PCV or PN23 12 months later . For those children who received a priming dose of PCV ( N=75 ) compared to PN23 ( N=48 ) at 12 , 15 , or 18 months of age , higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested ( p<0.001 ) . Within the group of children receiving a priming dose of PCV , those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B , yet more frequent erythema ( p=0.030 ) and pain or soreness ( p=0.024 ) at the injection site compared to those boosted with PCV . In conclusion , a single dose of PCV at 12 - 18 months of age primed for responses to booster doses of either PCV or PN23 12 months later . For those children who received a priming dose of PCV , boosting with PN23 result ed in more frequent injection site pain and erythema than boosting with PCV , yet higher antibody concentrations for most of the serotypes tested BACKGROUND Pneumococcal conjugate vaccine prevents recurrent acute otitis media ( AOM ) in infants immunised at 2 , 4 , 6 , and 12 - 15 months of age . We aim ed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM . METHODS In this double-blind , r and omised study , we enrolled 383 patients aged 1 - 7 years who had had two or more episodes of AOM in the year before entry . R and omisation was stratified in four groups according to age ( 12 - 24 months vs 25 - 84 months ) and the number of previous AOM episodes ( two or three episodes vs four or more episodes ) . Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine , or hepatitis A or B vaccines . They were followed up for 18 months for recurrence of AOM . We also cultured sample s of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination . FINDINGS We noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls ( intention-to-treat analysis : rate ratio 1.25 , 95 % CI 0.99 - 1.57 ) . Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations , immediate and complete replacement by non-vaccine pneumococcal serotypes took place . INTERPRETATION These data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM Background : The 7-valent pneumococcal ( 7vPn ) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit . Methods : An open , r and omized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b ( DTPa-HBV-IPV/Hib ) vaccine and a 7vPn conjugate vaccine when coadministered at 2 , 3 and 4 months and 12–23 months of age , compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone . Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose . Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose . Results : A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine  ( 170 without and 175 with the  7vPn vaccine coadministered ) and 266 returned for booster vaccination ( 122 without and 144 with coadministration of the 7vPn vaccine ) . After primary vaccination , antibody responses against the common antigens were similar in both groups , with seroprotection rates of 93.6–100 % and with similar antibody decay before booster vaccination . The fourth dose induced a vigorous booster response , with seroprotection/vaccine response rates of 96.8–100 % . Response to the 7vPn primary and booster vaccination was within previously reported ranges . Differences in reactogenicity result ed from higher incidences of symptoms after concomitant vaccination . Rectal temperature > 39.5 ° C was observed after 1.2 % of the coadministered vaccine doses during primary vaccination and after 2.8 % of the booster vaccine doses . Conclusion : Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe A group-r and omized , double-masked , phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian population s 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 design ed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated . Thirty-eight geographically and socially distinct areas were r and omized 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-r and omized trials have challenging design and analysis features , many of which are discussed here in the context of the first such trial design ed to lead to licensure of a drug or biologic in the United States Background : Pneumococcus is a leading cause of childhood pneumonia worldwide . Pneumococcal conjugate vaccines ( PCV ) have demonstrated efficacy against childhood invasive pneumococcal disease ( IPD ) and pneumonia in the United States and Africa . No information is available from Asia on the impact of PCV on childhood pneumonia . Methods : We conducted a r and omized , placebo-controlled , double-blind trial in Bohol , the Philippines ( IS RCT N 62323832 ) . Children 6 weeks to < 6 months of age were r and omly allocated to receive 3 doses of either an 11-valent PCV ( 11PCV , sanofi pasteur , Lyon , France ) or a saline placebo , with a minimum interval of 4 weeks between doses to determine vaccine efficacy ( VE ) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life . Secondary end points were clinical pneumonia , IPD , safety , and immunogenicity . Results : Twelve thous and one hundred ninety-one children were enrolled . By per protocol ( PP ) analysis , 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients . VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9 % ( 95 % CI : −1.1 , 41.2 ; P = 0.06 ) , for the prespecified subgroups of children 3 to 11 months of age , 34.0 % ( 95 % CI : 4.8 , 54.3 ; P = 0.02 ) , and of those 12 to 23 months old , 2.7 % ( 95 % CI : −43.5 , 34.0 ; P = 0.88 ) . By intent-to-treat ( ITT ) analysis , 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients . VE against radiologic pneumonia for the ITT cohort of children < 2 years old was 16.0 % ( 95 % CI −7.3 , 34.2 ; P = 0.16 ) , for a subgroup of children < 12 months of age , 19.8 % ( 95 % CI : −8.8 , 40.8 ; P = 0.15 ) . VE against clinical pneumonia by PP was not significant ( VE 0.1 % ; 95 % CI −9.4 , 8.7 ; P = 0.99 ) . IPD was rare : only 3 cases of IPD due to vaccine serotypes were observed during the study . 11PCV was immunogenic and well tolerated . Among 11PCV recipients , a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine , and of nonrespiratory events after the first dose . An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis . Conclusions : In PP analysis , a 22.9 % reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed ; a reduction similar as observed in other PCV trials . We could not demonstrate any VE against clinical pneumonia . Our finding confirms for the first time that in a low-income , low-mortality developing country in Asia , at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus , and thus preventable by PCV . Whether PCV should be included in national program in such setting s , however , depends on careful country specific disease burden measurement and cost-effectiveness calculation ABSTRACT The licensure of new pneumococcal conjugate vaccines ( PCVs ) relies on immunogenicity data . When defining correlates of protection , vaccine efficacy data must be included . In the FinOM Vaccine Efficacy Trial , the PncOMPC vaccine showed an efficacy profile similar to that of the licensed PncCRM vaccine despite different antibody responses after primary and booster vaccinations . We determined antibody kinetics and avidities in a subgroup of infants participating in the FinOM trial . A total of 166 infants in three vaccine groups were immunized at 2 , 4 , 6 , and 12 months of age with 7-valent PCV , PncCRM or PncOMPC , or hepatitis B vaccine . Concentrations of serum immunoglobulin G ( IgG ) against pneumococcal capsular polysaccharides were determined at 2 , 4 , 6 , 7 , 12 , 13 , and 24 months of age , and the avidity index ( AI ) to serotypes 6B , 19F , and 23F were determined at 7 , 12 , 13 , and 24 months of age by enzyme immunoassay . Both PCVs were highly immunogenic , but they demonstrated different kinetics of antibody response ; the concentration of IgG against serotypes 6B , 19F , and 23F declined faster after the third and fourth doses of vaccine in the PncCRM group than in the PncOMPC group . For both PCVs , the mean AI of anti-6B and -23F , but not of anti-19F , increased during the follow-up , which is in line with serotype-specific protection in the FinOM trial . Our data suggest that the kinetics and avidities of antibodies should be considered , in addition to antibody responses , when defining correlates of protection BACKGROUND Pneumonia is estimated to cause 2 million deaths every year in children . Streptococcus pneumoniae is the most important cause of severe pneumonia . We aim ed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children . METHODS We undertook a r and omised , placebo-controlled , double-blind trial in eastern Gambia . Children age 6 - 51 weeks were r and omly allocated three doses of either pneumococcal conjugate vaccine ( n=8718 ) or placebo ( 8719 ) , with intervals of at least 25 days between doses . Our primary outcome was first episode of radiological pneumonia . Secondary endpoints were clinical or severe clinical pneumonia , invasive pneumococcal disease , and all-cause admissions . Analyses were per protocol and intention to treat . FINDINGS 529 children assigned vaccine and 568 allocated  placebo were not included in the per- protocol analysis . Results of per- protocol and intention-to-treat analyses were similar . By per- protocol analysis , 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo . Pneumococcal vaccine efficacy was 37 % ( 95 % CI 27 - 45 ) against first episode of radiological pneumonia . First episodes of clinical pneumonia were reduced overall by 7 % ( 95 % CI 1 - 12 ) . Efficacy of the conjugate vaccine was 77 % ( 51 - 90 ) against invasive pneumococcal disease caused by vaccine serotypes , 50 % ( 21 - 69 ) against disease caused by all serotypes , and 15 % ( 7 - 21 ) against all-cause admissions . We also found an efficacy of 16 % ( 3 - 28 ) against mortality . 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo . INTERPRETATION In this rural African setting , pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease , and can substantially reduce admissions and improve child survival . Pneumococcal conjugate vaccines should be made available to African infants Objective . To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children . Methods . The heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) was given to infants at 2 , 4 , 6 and 12 to 15 months of age in a r and omized , double blind trial . 1 Children were r and omized to receive either the  CRM197 PCV ( vaccine group ) or the  meningococcal type C CRM197 conjugate vaccine ( control group ) . The primary outcome of this trial was invasive pneumococcal disease . In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient , emergency and outpatient data bases . The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified , and the original reading of their radiographs by the radiologist was obtained from automated data bases . Rates of clinical ly diagnosed pneumonia , of pneumonia with a radiograph obtained regardless of result , of pneumonia with positive radiograph ( consolidation , empyema or parenchymal infiltrate ) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups . In addition risk of disease pneumonia was evaluated by race and ethnicity . Results . The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years . A radiograph was obtained in 61 % of episodes , a positive radiograph in 21 % and perihilar findings in an additional 5 % . In per protocol follow-up of children given PCV , first episodes of all clinical ly diagnosed pneumonia were reduced by 4.3 % [ 95 % confidence interval ( CI ) , −3.5 , 11.5 % , P = 0.27 ] , episodes with a radiograph were reduced by 9.8 % ( CI 0.1 , 18.5 % , P < 0.05 ) and episodes with a positive radiograph were reduced by 20.5 % ( CI 4.4 , 34.0 , P = 0.02 ) . In the intent to treat analysis including all episodes after r and omization , episodes with a positive radiograph were reduced by 17.7 % , P = .01 ) . The greatest impact was in the first year of life with a 32.2 % reduction and a 23.4 % reduction in the first 2 years , but only a 9.1 % reduction in children > 2 years of age . Asians , blacks and Hispanics were at higher risk of pneumonia than were whites , but there was no evidence of ethnic variation in PCV effectiveness . Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group . Conclusion . The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children Context . The heptavalent pneumococcal conjugate vaccine ( PCV ) is recommended for infants to protect against invasive disease , but its impact on otitis might also have public health importance . Objective . To examine the impact of PCV on the incidence of otitis media , frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race , sex or season . Design , setting and patients .. From 1995 to 1998 , 37 868 children at Kaiser Permanente in Northern California were r and omized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999 . Interventions . Children received a primary series at 2 , 4 and 6 months of age and a booster at 12 to 15 months . Main outcome measures . Visits for otitis , frequent visits for otitis and tympanostomy tube procedures . Otitis was ascertained from diagnosis checklists routinely marked by physicians . Results . Control children averaged 1.8 otitis visits per year . Children given PCV had fewer otitis visits than control children in every age group , sex , race and season examined . Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media ( P < 0.0001 ) . In children who completed the primary series per protocol , PCV reduced otitis visits by 7.8 % [ 95 % confidence interval ( CI ) , 5.4 to 10.2 % ] and antibiotic prescriptions by 5.7 % ( CI 4.2 to 7.2 % ) . Frequent otitis was reduced by amounts that increased with otitis frequency , from a 10 % reduction in the risk of 3 visits to a 26 % reduction in the risk of 10 visits within a 6-month period . Tube placements were reduced by 24 % ( CI 12 to 35 % ) . Conclusion . In children followed up to 3.5 years , PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts BACKGROUND Streptococcus pneumoniae ( Sp ) is an important bacterial pathogen in children . Nasopharyngeal ( NP ) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease . METHODS NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine ( PCV ) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis ( vaccine serotypes : 4 , 6B , 9V , 14 , 18C , 19F , 23F ) . The vaccine was administered at 2 , 4 , 6 , and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV  and evaluated over the first 15 months of life . RESULTS Overall , Sp was isolated in 86/367 ( 23 % ) of NP cultures and 49 % of infants . Serotype 23F was significantly less prevalent in the PCV group ( 1.9 % ) than the control group ( 16.1 % ) ( P<0.05 ) . Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype . We noted , however , decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes ( 76 and 52 % reduction , respectively ) , but this did not reach statistical significance ( P=0.3 ) . Adjustment for age , daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups . CONCLUSION We did not show a significant effect of this heptavalent PCV on NP carriage . Further study of this issue , including a larger population size , is needed UNLABELLED This study evaluates the safety and immunogenicity of pneumococcal seven-valent conjugate vaccine ( Prevenar ) in 115 children , aged 2 - 3 years ( 24 - 36 months ) , who have not been previously vaccinated with Prevenar .  RESULTS SAFETY As for local reactions , 40 % of children reported erythema , 32.2 % in duration and 39.1 % tenderness at the injection site . Regarding systemic reactions , fever > or 38 C was recorded in 7 % of patients . Other commonly reported events were decreased appetite ( 24.3 % ) , restlessness ( 20 % ) , and fussiness ( 18.3 % ) . IMMUNOGENICITY After vaccination , more than 98 % of the subjects achieved antibody levels of > or = 0.15 microg/mL for all seven serotypes and more than 95 % achieved antibody levels > or = 0.50 microg/mL for all serotypes . CONCLUSIONS Pneumococcal seven-valent conjugate vaccine ( Prevenar ) was safe , well tolerated and highly immunogenic when administered in previously unvaccinated children aged 14 - 36 months BACKGROUND We recently showed that vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV7 ) followed by a 23-valent pneumococcal polysaccharide vaccine ( PPSV23 ) failed to prevent new episodes of acute otitis media ( AOM ) in previously unvaccinated toddlers and children with a history of recurrent AOM . We describe in detail the impact of pneumococcal vaccinations on nasopharyngeal carriage of S. pneumoniae in this study population . METHODS The impact of vaccination with PCV7 followed by PPSV23 on pneumococcal nasopharyngeal carriage was studied in a prospect i ve , r and omized trial involving 383 children ( age range , 1 - 7 years ) with previous AOM . Nasopharyngeal swab specimens were collected at the time of first vaccination and at 6 - 7-month intervals during the 26-month follow-up period . RESULTS Overall , pneumococcal carriage rates did not diminish , remaining at approximately 50 % in both PCV7/PPSV23 and control vaccinees . A significant shift from conjugate vaccine- to nonconjugate vaccine-type pneumococci was observed in children aged 1 - 2 years , who received the conjugate vaccine twice before the polysaccharide vaccine was administered . Conjugate vaccine serotype carriage was not influenced in older children , who received the conjugate vaccine once before receiving the polysaccharide booster . CONCLUSIONS The administration of conjugate vaccines at least twice also after 2 years of age may be m and atory for reducing the carriage of conjugate vaccine serotypes in children with recurrent AOM . Polysaccharide booster vaccination did not affect nasopharyngeal colonization with serotypes not included in the conjugate vaccine BACKGROUND Streptococcus pneumoniae is a major disease burden in young children and the incidence of antibiotic-resistant pneumococcal strains is increasing . Multivalent pneumococcal saccharide-protein conjugate vaccines have recently been developed . OBJECTIVES To assess the immunogenicity and reactogenicity of a 7-valent pneumococcal conjugate vaccine ( 7VPnC ) administered as a separate injection or as a combined injection with Haemophilus influenzae type b vaccine ( HbOC ) at 2 , 3 and 4 months of age . METHODS R and omized controlled trial of 368 healthy UK infants receiving routine vaccines only ( control group ) , routine vaccines and 7VPnC as a separate injection ( separate group ) , or routine vaccines and 7VPnC combined with HbOC ( combined group ) at 2 , 3 and 4 months . The control group received 7VPnC at 5 , 6 and 7 months . All groups received pneumococcal polysaccharide vaccine at 13 to 16 months . Anticapsular IgG antibodies to 7VPnC serotypes were measured at 2 , 5 , 13 and 14 months and safety data collected . RESULTS IgG antibody concentrations at 5 months were higher in the two treatment groups compared with the controls for all 7VPnC serotypes ( P < 0.001 ) and higher in the separate group than the combined group for five 7VPnC serotypes ( P < 0.05 ) . For both treatment groups antibody concentrations were higher at 14 months ( range , 6.6 to 25.3 microg/ml ) than at 5 months ( range , 0.6 to 2.5 microg/ml ) for all 7VPnC serotypes ( P < 0.001 ) . CONCLUSION 7VPnC was well-tolerated , safe and immunogenic when administered as a separate or as a combined 7VPnC/HbOC injection . Although antibody responses were lower in the infants who received the combination compared with those who received 7VPnC as a separate injection , marked anamnestic responses to polysaccharide challenge were observed , suggesting that both groups were immunologically primed BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the  9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo .  All children received Haemophilus influenzae type b conjugate vaccine .  Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection OBJECTIVE To explore the effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion and to search for subgroups in which the vaccine had a higher or lower effect . METHODS Analyses were performed on data from the Finnish Otitis Media Vaccine Trial , a r and omised controlled double-blind trial to evaluate the efficacy of  pneumococcal conjugate vaccination against acute otitis media . Data on the vaccination effect against otitis media with effusion were obtained by means of symptom interview and pneumatic otoscopy during pre-scheduled follow-up visits at the age of 7 and 24 months . Two endpoint definitions were considered : otitis media/tube ( otitis media or tympanostomy tube in situ ( OM/T ) ) as the primary endpoint and otitis media with effusion as the secondary endpoint . No evidence was found of an age-dependent association with vaccination effect . Therefore , the final marginal logistic regression analyses were performed on the combined data from the two follow-up visits . RESULTS The risk of otitis media tended to be lower in the pneumococcal vaccine group . The odds ratio for otitis media/tube was 0.94 ( 95 % confidence interval 0.77 - 1.14 ) and the odds ratio for otitis media with effusion was 0.90 ( 95 % confidence interval 0.69 - 1.19 ) . Presence of older siblings increased the risk of otitis media/tube and otitis media with effusion at 7 months of age . In addition , it appeared that children without older siblings and attending day-care at 24 months of age tended to benefit more from the pneumococcal conjugate vaccine . In this subgroup , the odds ratio for otitis media/tube was 0.81 ( 95 % confidence interval 0.55 - 1.20 ) and for otitis media with effusion the odds ratio was 0.43 ( 95 % confidence interval 0.22 - 0.86 ) . CONCLUSION The effect of pneumococcal conjugate vaccination on the risk of otitis media with effusion was concordant with the efficacy seen against acute otitis media , although not distinguishable from no effect in the overall analysis . In children without older siblings , vaccination appeared to reduce the point prevalence of otitis media with effusion ; this effect was not apparent in children with older siblings Aims : Prospect i ve study to evaluate the impact of the 7-valent pneumococcal conjugate vaccine ( Prevenar ) on the nasopharyngeal ( NP ) carriage of drug-resistant Streptococcus pneumoniae ( DRPn ) , by healthy children attending day-care centers ( ages 6 months–6 years ) . Methods :  Vaccinees ( 238 children ) who received vaccine and controls ( 457 children ) were followed for carriage of total S. pneumoniae and DRPn and for the serotypes and genetic background s of DRPn during 6 consecutive sampling periods between May 2001 and February 2003 . Results : We detected no significant differences between vaccinees and the control group in the total carriage rate of Pn ( average , 68 % ) or in the frequency of carriage of DRPn ( average , 38 % ) , including the frequency of penicillin-nonsusceptible strains ( average , 24 % ) . In contrast , there was a decline in the carriage of DRPn with vaccine serotypes which was compensated by the appearance and gradual increase in the frequency of DRPn expressing unusual serotypes ( 6A , 10A , 15A and 15C , 19A , 23A , 33F ) which were not present in the vaccine as well as an increase in nontypable strains . The majority of the DRPn with unusual serotypes showed different pulsed field gel electrophoresis patterns indicating replacement of the original resistant flora by other clonal types of drug-resistant bacteria . Antibiotic consumption and the frequency of respiratory tract infections were similar among the vaccinees and controls . Conclusions : Pneumococcal vaccination did not change the frequency of carriage of drug-resistant strains being the initially dominant vaccine serotypes replaced by others expressing nonvaccine serotypes . Reduction in the carriage of DRPn may require a combination of the conjugate vaccine and a decrease in antibiotic pressure When a sufficiently high proportion of a population is immunized with a vaccine , reduction in secondary transmission of disease can confer significant protection to unimmunized population members . We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-r and omized vaccine trial . A conditional logistic regression model that accounts for within-r and omization unit correlation over time is described , which models risk of disease as a function of community-level covariates . The approach is applied to an example data set from a pneumococcal conjugate vaccine study , with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects Objective . To determine the efficacy , immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) in low birth weight ( LBW ) and preterm ( PT ) infants against invasive pneumococcal disease caused by vaccine types . Methods . In a r and omized double blind trial of 37 868 infants given either PCV or meningococcal type C conjugate vaccine ( MCV ) , 1756 infants < 750 g < 2500 g ( LBW ) and 4340 infants from 32 to < 38 weeks old ( PT ) were identified . Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight ( NBW ) and full term ( FT ) infants . Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made . Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants . Results . Initiation of immunization and intervals between doses were similar for all groups . The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 ( P = 0.03 ) , and for PT compared with FT infants the risk ratio was 1.6 ( P = 0.06 ) . Vaccine efficacy for both groups was 100 % . PCV was as immunogenic in LBW and PT as in NBW and FT infants . Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child . When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3 . Isolated local and systemic reactions were more commonly seen with PCV than with MCV , a pattern similar to that in NBW and FT infants . Hospitalization rates were similar for PCV and MCV recipients . Conclusion . These data support the use of PCV in LBW infants and PT infants BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule Background : A World Health Organization ( WHO ) working group in 2001 developed a method for st and ardizing interpretation of chest radiographs in children for epidemiologic purpose s. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method . Methods : Seven-valent pneumococcal conjugate vaccine was evaluated in a r and omized , controlled study including 37,868 infants . Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading . There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers ( A and B ) ; discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists . Results : Of the 2841 radiographs , 2446 were available for scanning and were review ed using WHO-defined descriptive categories . Two hundred fifty of the 2446 radiographs were read as positive by both readers . An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the review ers . The concordance rate between the 2 review ers was 250 of 521 ( 48 % ) . Of the 271 discordant radiographs , 45 of 129 ( 34.9 % ) of reader A and 66 of 142 ( 46.5 % ) for reader B were finalized as positive by the adjudicating panel . Overall , 361 radiographs were finalized as positive ( 12.7 % ) . With these 361 images as the st and ard , the sensitivity and specificity of reader A were 82 % and 97 % , respectively , and for reader B , 88 % and 97 % , respectively . Kappa between the 2 readers was 0.58 . Of 25 control radiographs read as positive by both A and B , 80 % were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel . Using original readings by point-of-care radiologists , efficacy against first episode of radiograph confirmed pneumonia was 17.7 % ( 95 % confidence interval [ CI ] = 4.8–28.9 % ) in intent-to-treat and 20.5 % ( 95 % CI = 4.4–34 % ) in per protocol . Using the WHO method , the efficacy against first episode of radiograph confirmed pneumonia adjusting for age , gender and year of vaccination of 25.5 % ( 95 % CI = 6.5–40.7 % , P = 0.011 ) for intent-to-treat and 30.3 % ( 95 % CI = 10.7–45.7 % , P = 0.0043 ) for per protocol . Conclusion : Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity Background . Incidence and severity of respiratory infections are increased in day-care center attendees . Streptococcus pneumoniae is an important contributor to these infections . Objective . To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care . Method . In this double blind , r and omized , controlled study performed in 8 day-care centers located in Beer-Sheva , Israel , 264 toddlers ages 12 to 35 months at enrollment were r and omized to receive either a 9-valent conjugate pneumococcal vaccine ( conjugated to CRM197 ) or a control vaccine [ conjugate meningococcus C vaccine ( conjugated to CRM197 ) ] and were followed for an average of 22 months . The main outcome measures were respiratory morbidity and antibiotic use . Results . An overall reduction of 7 % in child months with ≥1 reported illness episodes was observed among vaccinees ( P = 0.008 ) , and 85 % of all episodes were related to the respiratory tract . Reductions of 15 , 16 and 17 % were observed in upper respiratory infections , lower respiratory problems and otitis media , respectively . An overall reduction of 17 % in antibiotic days was observed [ 10 % for upper respiratory infections , 20 % for otitis and 47 % for lower respiratory problems ( P ≤ 0.005 for each entity ) ] . The reduction in episodes and antibiotic use was greater for those < 36 months of age than for the older children . Conclusion . The reduction of respiratory problems , including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only Aim . We conducted a study to determine whether administration of a pneumococcal conjugate vaccine to toddlers attending day-care centers ( DCCs ) could prevent acquisition of Streptococcus pneumoniae of the vaccine serotypes ( VT ) by their younger siblings . In a double blind study , 262 DCC attendees ages 12 to 35 months were r and omized to receive a 9-valent pneumococcal conjugate vaccine ( PnCRM9;n = 132 ) , or a control vaccine ( meningococcus C vaccine;n = 130 ) . It was planned to follow the groups for 2 years with monthly nasopharyngeal pneumococcal cultures during the first follow-up year and every 2 months during the second year . Forty-six younger siblings of the above described children , age < 18 months ( 23 siblings of the PnCRM9 recipients and 23 of the controls ) , were also enrolled , and nasopharyngeal cultures were obtained monthly until the children reached the age of 18 months or started to attend DCC , if before the age of 18 months . Pneumococcal isolates were serotyped and tested for antibiotic susceptibility . Results . Of the 3748 cultures obtained from the DCC attendees , 2450 ( 65 % ) were positive for S. pneumoniae . Of 306 cultures obtained from the younger siblings , 151 ( 49 % ) were positive . Among the PnCRM9 recipients , cultures were significantly less frequently positive for the VT S. pneumoniae than among the controls ( 13 % vs. 21 % , respectively;P < 0.001 ) . The same pattern was seen in the younger siblings of PnCRM9 recipients vs. the siblings of controls ( 21 % vs. 34 % , respectively;P = 0.017 ) . The reverse trend was seen for non-VT strains in both the DCC attendees ( 44 % vs. 34 % , respectively;P < 0.001 ) and their younger siblings ( 19 % vs. 13 % , respectively;P = 0.15 ) . There was a significant decrease in the carriage rate of antibiotic-resistant S. pneumoniae in both the PnCRM9 recipients and their younger siblings . The relative risks ( and 95 % confidence intervals ) to carry S. pneumoniae penicillin-nonsusceptible , resistant to ≥1 , ≥2 and ≥3 antibiotic categories among younger siblings of PnCRM9 recipients vs. siblings of controls were 0.47 ( 0.31 to 0.70 ) , 0.49 ( 0.33 to 0.71 ) , 0.46 ( 0.30 to 0.73 ) and 0.49 ( 0.21 to 1.17 ) , respectively . When acquired , VT and antibiotic-resistant S. pneumoniae were carried for a significantly shorter period of time among siblings of PnCRM9 recipients than in siblings of controls . Conclusion . The marked effect of PnCRM9 administration to DCC attendees on carriage of VT and antibiotic-resistant S. pneumoniae among their younger household close contacts demonstrates a herd effect of the vaccine Background . Limited effectiveness of current treatment strategies for recurrent acute otitis media ( RAOM ) and increasing antibiotic resistance have diverted attention to prevention of AOM by vaccination . Pneumococcal vaccination for AOM seems to have only modest clinical efficacy . Thus far , the effects on health-related quality of life ( HRQoL ) or functional health status ( FHS ) have not been studied . Objective . To assess the effect of vaccination on HRQoL or FHS . Methods . In a double-blind , r and omized , controlled trial , 383 children 1 to 7 years old with RAOM were vaccinated with either heptavalent pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine ( pneumococcal group : n = 190 ) or with hepatitis A or B vaccines ( control group : n = 193 ) . Parents completed vali date d Dutch versions of 8 HRQoL and FHS instruments assessing generic FHS ( R and , Functional Status Question naire specific , and Functional Status Question naire generic ) , otitis media – specific FHS ( OM-6 ) , otitis media – specific child HRQoL ( Numerical Rating Scale for Child ) , family functioning ( Family Functioning Question naire ) , and otitis media – specific caregiver HRQoL ( Numerical Rating Scale for Caregiver ) . Scores were compared at baseline and at 14 and 26 months ' follow-up . Results . At baseline , the average AOM incidence in the pneumococcal and control group was 5.0 ( SD : 2.8 ) and 4.9 ( SD : 2.6 ) episodes per year , respectively , with 38.4 % and 36.8 % having suffered from ≥6 episodes per year . AOM frequency decreased 4.4 episodes per year in both groups , with a considerable and comparable improvement in HRQoL and FHS . No substantial differences in HRQoL or FHS were found between the pneumococcal and the control group at baseline or at 14 or 26 months ' follow-up . Conclusion . Pneumococcal vaccination has no beneficial effect compared with control vaccination on either HRQoL or FHS in children 1 to 7 years old with RAOM 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 r and omized , 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 Background . In the developed societies , day-care centers ( DCCs ) play an important role in the spread of antibiotic-resistant pneumococci both within the facility and from the facility to the community . This study was conducted to determine the effect of a nonavalent pneumococcal conjugate vaccine ( PCV-9 ) on the carriage of antibiotic-resistant pneumococci in the DCC . Subjects and methods . Healthy DCC attendees ages 12 to 35 months were r and omized to receive either PCV-9 or a control vaccine ( conjugate meningococcus C vaccine ) in a double blinded manner . Nasopharyngeal Streptococcus pneumoniae cultures were obtained from each subject before vaccination , monthly during the first year of follow-up and every 2 to 3 months during the second year of follow-up . For each isolate the serotype and antibiotic susceptibility were determined Results . A total of 132 and 130 evaluable toddlers received either PCV-9 or the control vaccine , respectively . In total 3748 cultures were obtained , of which 2450 ( 65 % ) were positive for S. pneumoniae . The resistance rates to penicillin , trimethoprim-sulfamethoxazole and erythromycin were 36 , 35 and 16 % , respectively . Resistance rates to ≥1 and ≥3 antibiotic categories were 52 and 9 % , respectively . Antibiotic resistance was found mainly in the 5 serotypes included in the pneumococcal conjugate vaccines ( 6B , 9V , 14 , 19F and 23F ) and in 2 related serotypes ( 6A and 19A ) . In the vaccinated group a clear and significant reduction of the carriage rate of the serotypes included in the vaccine and the related serotype 6A as well as an increase in the carriage rate of the serotypes not included in the vaccine were observed . In parallel a significant decrease in carriage rate of antibiotic-resistant pneumococci was observed . The reduction of carriage of antibiotic-resistant pneumococci was seen in all age windows but was greater in the age window < 36 months . Conclusions . The carriage rate of antibiotic-resistant S. pneumoniae , including multiply resistant S. pneumoniae , in DCC attendees is high . Pneumococcal conjugate vaccines seem to be an important tool for reducing the carriage rate of antibiotic-resistant pneumonia in DCCs 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 PNCRM7 and these other concurrently administered vaccines . METHODS This was a r and omized 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 sample s 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 result ed 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 clinical ly significant This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate ( PCV7 ) , hepatitis B ( HB ) and DTaP.IPV/Hib vaccines .  Infants were given DTaP.IPV/Hib and HB at 2 , 4 , 6 months and r and omly assigned ( 2:1 ) to receive PCV7 concurrently or sequentially ( at 3 , 5 , 7 months ) . Antibody levels were compared in 246 concurrent and 122 sequential vaccinees .  Responses to  PCV7 , DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased ( p=0.008 ) and HB responses were reduced ( p=0.006 ) with concurrent dosing , the latter possibly from same thigh injection with DTaP.IPV/Hib . We conclude that PCV7 , DTaP.IPV/Hib and HB are compatible with concurrent , separate injections Background : The novel pneumococcal conjugate vaccine , PncCRM , has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery . Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements . Methods : Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area ( 1490 of 1662 r and omized at 2 months of age ) were invited to a single visit at 4–5 years of age . The children had been vaccinated at 2 , 4 , 6 and 12 months of age with PncCRM or hepatitis B vaccine ( control ) . Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records . Additionally , tympanostomy tube placements of all children were verified from the hospital discharge registry . Vaccine efficacy ( VE ) was estimated by comparing all events of tympanostomy tube placement between vaccine groups . Results : During the vaccine trial ( 2–24 months of age ) , VE ( 95 % confidence interval ) in preventing tympanostomy tube placement was only 4 % ( – 19–23 % ) . Altogether 756 children were enrolled for the follow-up study . After 24 months of age , the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children , giving VE of 39 % ( 4–61 % ) . In the hospital-based data of all children ( N = 1490 ) , VE of 44 % was obtained ( 19–62 % ) . Conclusions : Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4–5 years of age INTRODUCTION Pneumococcal conjugate vaccine ( PnCV ) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia . METHODS This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were r and omized in a double-blind , placebo-controlled trial in South Africa . RESULTS Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia ( 61 % ; P = .01 ) , the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6 % in human immunodeficiency virus (HIV)-uninfected children and 18.8 % in HIV-infected children . Only 37.8 % of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation . A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children ( 267 cases prevented per 100,000 child-years ) and HIV-infected children ( 2573 cases prevented per 100,000 child-years ) . CONCLUSION Although outcome measures with high specificity , such as bacteremic pneumococcal pneumonia , provide a better estimate as to vaccine efficacy , the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity , such as a clinical diagnosis of pneumonia BACKGROUND For the licensing of new pneumococcal vaccines , it is vital to be able to predict their protective efficacy on the basis of immunogenicity . However , the serological correlates of protection have not been established for pneumococcal diseases . METHODS A total of 1666 children were immunized with the pneumococcal conjugate vaccine .  Acute otitis media ( AOM ) events were identified , and middle-ear fluid was cultured for pneumococci . The association between the concentration of antibodies against serotypes 6B , 19F , and 23F and the risk of AOM caused by the homologous serotypes or by the cross-reactive serotype 6A was assessed . An association model was used to predict efficacy at different geometric mean concentrations ( GMCs ) . RESULTS An association between antibody concentration and risk of AOM was found , but with large differences between serotypes . On the basis of the association , the predicted efficacy for 19F was negligible up to the highest GMC tested . In contrast , 6B was found to be highly efficacious ( > 65 % ) at a GMC of 0.5 microg/mL. CONCLUSIONS The results challenge the view that a new vaccine c and i date should always induce antibody concentrations that are not inferior to those produced by the licensed vaccine . Furthermore , the differences between serotypes caution against defining a common correlate of protection that is applicable to all serotypes To evaluate immune responses , safety and reactogenicity of the concomitant use of DTaP-IPV-Hib and the newly available 7-valent pneumococcal conjugate ( 7VPnC ) vaccines when given as the primary immunization series in early infancy . A total of 231 healthy infants were enrolled at 11 German study centers and r and omized to receive either 7VPnC plus DTaP-IPV-Hib vaccines concomitantly into opposite limbs at age 2 , 3 , 4 and 11 - 15 months ( 7VPnC group ) or DTaP-IPV-Hib vaccine at the same ages plus a 7VPnC " catch-up vaccination " at ages 6 , 7 , 8 and 11 - 15 months ( Control group ) . Blood sample s were drawn before and 4 weeks after the first three vaccine doses and 4 weeks after the fourth dose . Local and general side effects ( i.e. safety ) were solicited by diary cards . Immune responses were determined by ELISA except for antibodies to polioviruses ( neutralization assay ) . Post-dose 3 , a significant antibody response against all seven pneumococcal vaccine-serotypes was observed in the 7VPnC group only . Post-dose 4 geometric mean concentrations ( GMCs ) were similar in both groups . GMCs for other vaccine antigens were comparable between groups except for diphtheria ( higher in the 7VPnC group ) and pertactin ( lower in the 7VPnC group ) , although after three vaccine doses there was a 28-fold rise in GMCs from baseline . Both vaccines were generally well-tolerated although there were minor differences in the frequency of local reactions and somewhat more fever or drowsiness in the 7VPnC group . The use of DTaP-IPV-Hib and the 7VPnC vaccine was safe , well-tolerated and immunogenic when given concomitantly at age 2 , 3 and 4 months or when given separately with 7VPnC as a catch-up vaccination at age 6 , 7 , 8 months and as a concomitant booster immunization at age 11 - 15 months A double-blind , r and omized study involving 264 toddlers attending day care centers was conducted to document the effect of a 9-valent pneumococcal conjugate vaccine on the carriage rate of pneumococci . Of 3750 cultures done on nasopharyngeal sample s obtained from subjects during a 2-year follow-up period after  vaccination  , 65 % were positive for Streptococcus pneumoniae . In all age windows , the rate of carriage of vaccine-type pneumococci was lower among subjects who received the pneumococcal vaccine than among control subjects , because the acquisition rate was lower in the former group . The effect was most pronounced among subjects aged < or = 36 months . The sample size enabled us to study protection against carriage of S. pneumoniae serotypes 6B , 9V , 14 , 19F , and 23F ; significant protection against all serotypes except 19F was seen in the pneumococcal-vaccine group . The rate of carriage of serotype 6A ( not included in the vaccine ) was also reduced significantly , but the rate of carriage of serotype 19A ( not included in the vaccine ) was not . The rate of carriage of non-vaccine-type pneumococci ( excluding serotype 6A ) was higher in the pneumococcal-vaccine group than in the control group BACKGROUND Based on two clinical trials in healthy infants the American Academy of Pediatrics ( AAP ) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media ( AOM ) . OBJECTIVE To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences , its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media . METHODS In this double-blind , r and omized study , 74 Belgian children , aged 1 - 7 years , with at least 2 clinical ly diagnosed episodes of acute otitis media in the previous year were enrolled . Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine . Total follow-up was 26 months . RESULTS Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes , no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group ( rate ratio : 1.16 ; 95 % CI : 0.69 - 1.96 ) . Overall nasopharyngeal pneumococcal carriage remained stable . However , a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination . CONCLUSION Clinical ly no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PncOMPC ) against  acute otitis media ( AOM ) , 1666 infants were r and omly assigned to receive either PncOMPC or control vaccine ( hepatitis B vaccine ) at 2 , 4 , 6 , and 12 months of age . Of the 835 children assigned to receive PncOMPC , 187 received a 23-valent pneumococcal polysaccharide vaccine ( PncPS ) at 12 months of age instead . Whenever AOM was diagnosed , middle ear fluid was aspirated for bacterial culture . In the PncOMPC and control groups , there were 110 and 250 AOM episodes , respectively , in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes , which indicates a vaccine efficacy of 56 % ( 95 % confidence interval , 44%-66 % ) . The serotype-specific efficacy ranged from 37 % for 19F to 82 % for 9V . The 2 boosters seemed to provide equal protection against AOM , but PncPS induced markedly higher antibody concentrations . The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine OBJECTIVE To evaluate the safety and immunogenicity of two lots of a heptavalent Streptococcus pneumoniae conjugate vaccine ( PCV ) containing seven capsular polysaccharide serotypes ( 4 , 6B , 9V , 14 , 18C , 19F , and 23F ) conjugated to the outer membrane complex of Neisseria meningitidis serogroup B ( OMPC ) and administered to infants at 2 , 4 , 6 , and 12 months of age . METHODS One hundred twenty infants were r and omly assigned to concurrently receive PCV-OMPC and one of two Haemophilus influenzae type b ( Hib ) conjugate-DTwP combination vaccines : ( 1 ) Hib with a heterologous protein carrier ( CRM(197 ) , TETRAMUNE , Group 1 ) or ( 2 ) an experimental Hib-hepatitis b combination vaccine with the homologous carrier ( OMPC , Group 2 ) . All infants in Groups 1 and 2 received PCV-OMPC ( lot 1 ) at 12 months of age . Another separate group of 120 infants ( Group 3 ) received a different lot of PCV-OMPC concurrently with Hib-CRM(197 ) ( TETRAMUNE ) at 2 , 4 , and 6 months of age and then were r and omized to receive either PCV-OMPC or a 23-valent polysaccharide ( PS ) pneumococcal vaccine at 12 months of age . RESULTS Each PCV-OMPC lot was generally well tolerated and no vaccine-related serious adverse events were reported . Following the primary series , serotype-specific anti-pneumococcal geometric mean concentrations ( GMC ) were highest for serotypes 14 , 19F , and 4 and lowest for serotypes 6B and 23F . GMC and seroconversion rates in Group 3 ( lot 2 ) were lower than in Group 1 ( lot 1 ) for serotypes 6B , 14 , 18C , and 23F . Antibody responses to serotypes 6B , 14 , and 18C were significantly lower in Group 2 compared to Group 1 . Following a booster dose of PCV-OMPC at 12 months of age , each lot was immunogenic with at least a 5 - 10-fold increase in antibody levels , and responses were significantly higher among those who received the PS vaccine . CONCLUSIONS PCV-OMPC is generally safe in infants , displays variable immune response by serotype , and concomitant receipt of Hib vaccine with homologous carrier may impact on its immunogenicity
BACKGROUND Pneumonia , caused by Streptococcus pneumoniae , is a major cause of morbidity and mortality among children in low-income countries .
The effectiveness of pneumococcal conjugate vaccines ( PCVs ) against invasive pneumococcal disease ( IPD ) , pneumonia , and mortality needs to be evaluated .
OBJECTIVES To up date the 2004 review on the efficacy of PCVs in preventing vaccine-serotypes IPD ( VT-IPD ) , X-ray defined pneumonia among HIV-1 negative children , and other new outcomes .