Cost-effectiveness of influenza vaccination with a high dose quadrivalent vaccine of the elderly population in Belgium, Finland, and Portugal.

BACKGROUND: Seasonal influenza may result in severe outcomes, resulting in a significant increase of hospitalizations during the winter. To improve the protection provided by the standard dose influenza quadrivalent vaccine (SDQIV), a high-dose vaccine (HDQIV) has been developed specifically for adults aged 60 and older who are at higher risk of life-threatening complications. OBJECTIVES: The aim of this study was to determine the cost-effectiveness of HD QIV vs. SD-QIV in the recommended population of three European countries: Belgium, Finland and Portugal. METHODS: A cost-utility analysis comparing HDQIV vs. SDQIV was conducted using a decision tree estimating health outcomes conditional on influenza: cases, general practitioner and emergency department visits, hospitalizations and deaths. To account for the full benefit of the vaccine, an additional outcome-hospitalizations attributable to influenza-was also evaluated. Demographic, epidemiological and economic inputs were based on the respective local data. HDQIV relative vaccine efficacy vs. SDQIV was obtained from a phase IV efficacy randomized clinical trial. The incremental cost-effectiveness ratios (ICER) were computed for each country, and a probabilistic sensitivity analysis (1,000 simulations per country) was performed to assess the robustness of the results. RESULTS: In the base case analysis, HDQIV resulted in improved health outcomes (visits, hospitalizations, and deaths) compared to SDQIV. The ICERs computed were 1,397, 9,581, and 15,267 €/QALY, whereas the PSA yielded 100, 100, and 84% of simulations being cost-effective at their respective willingness-to-pay thresholds, for Belgium, Finland, and Portugal, respectively. CONCLUSION: In three European countries with different healthcare systems, HD-QIV would contribute to a significant improvement in the prevention of influenza health outcomes while being cost-effective.

Persistence of Hepatitis B Immune Memory Until 6 Years of Age Following Hexavalent DTaP-IPV-HB-PRP~T Vaccination in a 3-, 5- and 11- to 12-month Schedule and Response to a Subsequent Hepatitis B Challenge Vaccination.

Anti-hepatitis B (HBs) antibody persistence and hepatitis B challenge were evaluated at 6 years of age following vaccination of fully liquid DTaP-IPV-HB-PRP~T or reconstituted DTaP-IPV-HB//PRP~T at 3, 5, 11-12 months of age. At 6 years, 53.8% and 73.5% had seroprotective anti-HBs antibodies (≥10 mIU/mL), increasing to 96.7% and 95.9% postchallenge, confirming a strong anamnestic response in primed vaccinees.

Effectiveness of the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D-Conjugated Vaccine (PHiD-CV) Against Carriage and Acute Otitis Media-A Double-Blind Randomized Clinical Trial in Finland.

UNLABELLED: After administering the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D-conjugated vaccine (PHiD-CV) to children aged 2-18 months, we observed a reduction in vaccine-type nasopharyngeal carriage, resulting in a reduction of overall pneumococcal nasopharyngeal carriage, which may be important for indirect vaccine effects. We noted a trend toward reduction of acute otitis media. BACKGROUND: This trial (ClinicalTrials.gov identifier NCT00839254), nested within a cluster-randomized double-blind invasive pneumococcal disease effectiveness study in Finland (ClinicalTrials.gov identifier NCT00861380), assessed the effectiveness of the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D-conjugated vaccine (PHiD-CV or PCV10) against bacterial nasopharyngeal carriage and acute otitis media (AOM). METHODS: Infants (aged 6 weeks to 6 months) received the PHiD-CV or a control vaccine (hepatitis B) (schedule 3+1 or 2+1). Nasopharyngeal swabs were collected at 4 time points post-vaccination from all of the infants and at pre-vaccination from a subset. Parent-reported physician-diagnosed AOM was assessed from first vaccination until last contact (mean follow-up, 18 months). Vaccine effectiveness (VE) was derived as (1 - relative risk)*100, accounting for cluster design in AOM analysis. Significant VE was assessed descriptively (positive lower limit of the non-adjusted 95% confidence interval [CI]). RESULTS: The vaccinated cohort included 5093 infants for carriage assessment and 4117 infants for AOM assessment. Both schedules decreased vaccine-serotype carriage, with a trend toward a lesser effect from the 2+1 schedule ( VE across timpoints 19%-56% [3+1] and 1%-38% [2+1]). Trends toward reduced pneumococcal carriage (predominantly vaccine serotypes 6B, 14, 19F, and 23F), decreased carriage of vaccine-related serotype 19A, and small increases at later time points (ages 14-15 months) in non-vaccine-serotype carriage were observed. No effects on nontypeable Haemophilus influenzae, Staphylococcus aureus, or Moraxella catarrhalis carriage were observed. There were non-significant trends toward a reduction in the number of infants reporting AOM episodes (VE 3+1: 6.1% [95% CI, -2.7% to 14.1%] and 2+1: 7.4% [-2.8% to 16.6%]) and all AOM episodes (VE 3+1: 2.8% [-9.5% to 13.9%] and 2+1: 10.2% [-4.1% to 22.9%]). PHiD-CV was immunogenic and had an acceptable safety profile. CONCLUSIONS: We observed reduced vaccine-type pneumococcal carriage, a limited increase in non-vaccine-type carriage, and a trend toward AOM reduction.

Serotype-specific hyporesponsiveness to pneumococcal conjugate vaccine in infants carrying pneumococcus at the time of vaccination.

OBJECTIVE: To determine whether pneumococcal carriage at the time of 11-valent pneumococcal conjugate vaccine (PCV-11) administration interferes with immune response in infants. STUDY DESIGN: A total of 1111 Filipino infants recruited into an immunogenicity and carriage study, nested in an efficacy trial, received PCV-11 or saline solution placebo at 6, 10, and 14 weeks of age. Antibody concentrations to the most frequently carried vaccine serotypes 6B, 19F, and 23F were measured by enzyme immunoassay from sera obtained at 18 weeks and 9 months of age. Serotype-specific antibody concentration was compared between groups of children among PCV-11 recipients stratified according to their carriage status at 6 weeks of age. RESULTS: Antibody concentrations to 6B, 19F, and 23F were significantly lower at 18 weeks and 9 months of age among children who were carriers of the specific serotype at 6 weeks of age than among non-carriers of the serotype. The hyporesponsiveness was specific to the carried serotype. The specific antibody concentrations induced by PCV-11 among carriers did not differ significantly from those in placebo recipients, whereas the differences were highly significant among noncarriers. CONCLUSIONS: Pneumococcal carriage, prevalent in Filipino infants, interferes with serotype-specific immune response to primary series of PCV and has potential implications for immunization programs.

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.

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 randomized, placebo-controlled, double-blind trial in Bohol, the Philippines (ISRCTN 62323832). Children 6 weeks to <6 months of age were randomly 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 thousand 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 settings, however, depends on careful country specific disease burden measurement and cost-effectiveness calculation.

IgG antibody concentrations after immunization with 11-valent mixed-carrier pneumococcal conjugate vaccine in efficacy trial against pneumonia among Filipino infants.

BACKGROUND: Pneumococcal pneumonia is a major cause of morbidity and mortality worldwide. Efficacy of pneumococcal conjugate vaccines (PCV) in reducing childhood pneumonia has been estimated in four double-blind, randomized, controlled trials. An investigational 11-valent pneumococcal conjugate vaccine (11PCV) had an efficacy of 22.9% against radiologically defined pneumonia during first 2 years of life in Filipino infants. We report here the immunogenicity of the vaccine in a nested study of 1111 infants randomized 1:1 to receive 11PCV or placebo scheduled to be given according to the National EPI Program at 6, 10, and 14 weeks of age. METHODS: IgG antibody concentrations to pneumococcal capsular polysaccharides were measured by a standardized enzyme immuno-assay in serum samples drawn post-3rd dose for peak antibody response and at the time of measles vaccination at 9 months of age for persistence of the antibodies. RESULTS: The geometric mean concentrations (GMCs) of antibodies were significantly higher in 11PCV than in placebo recipients against vaccine serotypes at both sampling points. One month post-3rd dose, 93-100% of 11PCV recipients had > or =0.35microg/ml for 9 serotypes, 76% for 6B, and 87% for 23F. The same proportions varied between 24% and 97% at 9.5 months of age due to antibody decrease. GMC to vaccine-related serotype 19A, but not to 6A, was higher in 11PCV than in placebo recipients. 7-12% of the 11PCV recipients had spontaneous antibody increases to serotypes 6B, 23F, and 14 between the two sampling points. These serotypes were common in nasopharyngeal samples of the infants. CONCLUSION: The 11PCV demonstrated good immunogenicity after three doses and persistence of antibodies at least up to 9.5 months of age, comparable to other PCVs that have been evaluated for efficacy against radiologically defined pneumonia in other populations.

Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine.

The long-term immunogenicity and vaccine efficacy (VE) of a 9-valent conjugate pneumococcal vaccine was studied in HIV infected and HIV non-infected children. VE against vaccine-serotype invasive pneumococcal disease following 6.16 years of follow-up persisted in HIV non-infected children (77.8%; 95% CI 34.4-92.5 compared to 83% after 2.3 years of follow-up), and declined from 65% to 38.8% (95% CI -7.8 to 65.2) in HIV infected children. HIV non-infected vaccinees had equal (serotypes 4, 6B, 14, 19F) or greater (serotypes 9V, 18C, 23F) proportions of serotype-specific antibody concentrations of > or =0.2microg/ml to vaccine-serotypes analyzed compared to HIV infected vaccinees at 5.3 years of age.

Response and persistence of antibodies to PRP-T and DTwP vaccines with concomitant administration of conjugate vaccines.

We first studied the immunogenicity of PRP-T and DTwP vaccines in Filipino infants given at 6, 10 and 14 weeks concomitantly with either an aluminum adjuvanted eleven-valent pneumococcal conjugate vaccine (11PncTD) or a meningococcal diphtheria-conjugated vaccine as compared to a control group that received only DTwP/PRP-T. The GMCs and proportions of infants achieving protective antibody concentrations to DTwP and PRP-T vaccine antigens were similar among the groups. In the second phase, the control group received 11PncTD at 18 weeks and the antibody concentrations were measured at 9 months in all children; 11PncTD induced a booster response to diphtheria in the control group. There was no negative interference from concomitant administration of new conjugate vaccines. In contrast, 11PncTD can boost the antibody response to the carrier proteins.

Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study.

BACKGROUND: Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS: We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS: Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS: Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.

Specificities and opsonophagocytic activities of antibodies to pneumococcal capsular polysaccharides in sera of unimmunized young children.

An enzyme immunoassay (EIA) for antibodies to pneumococcal capsular polysaccharides (Pnc PSs) detects in some cases antibodies that are cross-reactive within different Pnc PSs. Recently, it has been suggested that for detection of only serotype-specific antibodies, EIA can be modified by removing cross-reactive antibodies by absorption with an irrelevant PS, e.g., the type 22F PS. The opsonophagocytosis assay measures the functional activities of antibodies in vitro, and the results of that assay correlate with in vivo protection better than measurement of the antibody concentration by EIA. We compared these different methods for measuring antibodies to type 1, 6B, 11A, 14, 19F, and 23F Pnc PSs in the sera of unimmunized young children who had been monitored for pneumococcal carriage, acute otitis media, and acquisition of antibodies to Pnc PSs from 2 to 24 months of age. Serum samples with antibody increases after contact with a pneumococcus of a homologous serotype contained specific antibodies and often had opsonophagocytic activity (OPA) (20 of 46). In samples with antibody increases from children who had not had contact with a pneumococcus of a homologous serotype, the antibodies found to be type specific by conventional EIA were usually cross-reactive and infrequently had OPA (10 of 68). When type 22F PS absorption was used in the EIA, most of the false antibody increases were eliminated, but most of the true antibody increases were still detected and the association between the antibody concentration detected by EIA and OPA was improved. However, there were serotype-dependent differences in the frequency of OPA. Use of absorption with a heterologous PS in EIA should be encouraged, and both the specificity of EIA and the sensitivity of opsonophagocytic assays should be further evaluated and improved.

Antibody response to pneumococcal capsular polysaccharides in children with acute otitis media.

BACKGROUND: To describe the antibody response to pneumococcal capsular polysaccharides in children <2 years of age with pneumococcal acute otitis media (AOM) caused by serotypes 6A, 6B, 11A, 14, 19F or 23F. These serotypes were commonly found in both nasopharyngeal carriage and AOM in children of the study population in Finland. METHODS: Serum antibody concentrations to pneumococcal capsular polysaccharides of types 6B, 11A, 14, 19F and 23F were measured by enzyme immunoassay in acute and convalescent sera from children with AOM. RESULTS: Responses (at least 2-fold increase of antibody concentration) were relatively infrequent and varied with both the age of the child and the serotype of the Streptococcus pneumoniae isolated from the middle ear fluid. Children older than 12 months were more likely to have antibody responses than were younger children. Responses were seen only infrequently to types 6A, 6B or 19F (1 of 14, 1 of 9 and 2 of 25, respectively), more often to types 11A and 14 (2 of 8 and 3 of 8) and relatively frequently to type 23F (8 of 18). However, the convalescent antibody concentrations to type 23F were low and usually declined after the infection, whereas responders to 14 AOM had antibodies that persisted at a high concentration through the follow-up. CONCLUSIONS: The results emphasize the differences between Streptococcus pneumoniae serotypes in their immunogenicity and quantitative and qualitative differences of antibodies produced after infection.