Safety and immunogenicity of fully liquid and lyophilized formulations of an investigational trivalent group B streptococcus vaccine in healthy non-pregnant women: Results from a randomized comparative phase II trial.

BACKGROUND: We evaluated the safety and immunogenicity of liquid and lyophilized formulations of an investigational trivalent group B streptococcus (GBS) vaccine in non-pregnant women and assessed the formulations' equivalence in terms of serotype-specific immune response. METHODS: This phase II, randomized, comparative, observer-blind trial enrolled healthy non-pregnant women 18-40 years of age. Women received a single dose of fully liquid (n = 529) or lyophilized (n = 521) trivalent GBS vaccine on day 1. Safety assessments were performed up to day 181 (study termination). Serotype Ia/Ib/III-specific immunoglobulin G (IgG) antibodies were measured in sera from women on day 1 (pre-vaccination) and day 31. Equivalence between the two formulations was demonstrated if the two-sided 95% confidence interval (CI) for the ratio (liquid/lyophilized) of the geometric mean concentrations (GMCs) on day 31 was contained in a (0.5, 2.0) interval for each serotype. RESULTS: Solicited and unsolicited adverse events were reported at similar rates for both formulations. Serious adverse events were reported for six (1.1%) liquid GBS and nine (1.7%) lyophilized GBS vaccinated women, none of which were considered related to vaccination or fatal. On day 31, serotype-specific IgG concentrations were 8-16-fold higher than on day 1 in both groups. Equivalence of the liquid to the lyophilized formulation 30 days post-vaccination was demonstrated as the 95% CIs of the GMC ratios were within the pre-specified interval for the three serotypes: GMC ratios were 1.02 (95% CI: 0.79, 1.32) for serotype Ia, 0.93 (0.71, 1.21) for serotype Ib and 0.99 (0.76, 1.30) for serotype III. CONCLUSIONS: Both formulations of the investigational trivalent GBS vaccine had favorable safety profiles and induced similar GBS serotype-specific antibody concentrations. This study demonstrated that the fully liquid formulation was equivalent to the lyophilized formulation in healthy non-pregnant women in terms of immunogenicity for all three serotypes. CLINICAL TRIALS REGISTRATION: NCT02270944.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine.

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 µg). All vaccines were well tolerated, apart from in the TLR7a 100 µg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56-81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 µg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

Safety and immunogenicity of a respiratory syncytial virus fusion glycoprotein F subunit vaccine in healthy adults: Results of a phase 1, randomized, observer-blind, controlled, dosage-escalation study.

INTRODUCTION: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants. An investigational vaccine using an engineered recombinant RSV fusion glycoprotein in its post-fusion conformation (RSV F subunit vaccine) has been developed to protect young infants via maternal immunization. This first-in-human, phase I, observer-blind study (NCT02298179) evaluated the safety and immunogenicity of different dosages and formulations of RSV F subunit vaccine in healthy non-pregnant women and men aged 18-45 years. METHODS: Participants were enrolled (1:1:1) in a stepwise dosage-escalation manner into three cohorts to receive RSV F subunit vaccine containing 45 µg, 90 µg and 135 µg of RSV F glycoprotein. Within each cohort, participants were randomized (1:1:1:1) to receive two doses of RSV F subunit vaccine with (aluminum hydroxide or MF59) or without adjuvant, or placebo, ≥28 days apart. Safety (until day 365 post-dose 2), anti-RSV neutralizing antibodies (NAbs) and serum total binding antibodies to RSV F protein (until day 181 post-dose 1) were evaluated. RESULTS: All formulations were well-tolerated. No vaccine-related serious adverse events were reported. All participants were seropositive for anti-RSV NAbs at baseline, with geometric mean titers (GMTs) ranging from 184 (95% confidence interval [CI]: 127-266) to 380 (95% CI: 272-531). At 28 days post-dose 1, anti-RSV NAb GMTs in vaccine recipients ranged from 893 (95% CI: 702-1,136) to 1,602 (95% CI: 1,243-2,064). No booster effect was observed, but immune responses were maintained above pre-vaccination levels for six months post-dose 1. Ratios of RSV F total binding antibodies fold changes to NAb fold changes ranged from 2.79 to 4.12 at 28 days post-dose 1. The impact of the adjuvant was limited. CONCLUSIONS: A single dose of each formulation of RSV subunit F vaccine was well-tolerated and enhanced preexisting NAb titers through six months of follow-up.

Factors influencing access of pregnant women and their infants to their local healthcare system: a prospective, multi-centre, observational study.

BACKGROUND: The successful implementation of maternal vaccination relies on results of clinical trials, considering the prenatal and postnatal attendance at selected healthcare institutions. This study evaluated factors influencing maternal/infant access to healthcare facilities to identify potential barriers to participation in future clinical trials on maternal vaccination. METHODS: In this prospective, multi-centre, observational study, pregnant women (N = 3243) were enrolled at ten sites across Panama, the Dominican Republic, South Africa, and Mozambique between 2012 and 2014. They completed questionnaires at enrolment, delivery, and infant follow-up (90 days post-partum) visits, including questions on transportation, phone accessibility, alternative childcare, gestational age at enrolment, delivery location, and health status of their infant. Logistic regression was used to identify factors significantly associated with return to study site for delivery or infant follow-up visits. RESULTS: Among 3229 enrolled women with delivery information, 63.6% (range across sites: 25.3-91.5%) returned to study site for delivery. Older women and those at later gestational age at enrolment were more likely to deliver at the study site. While heterogeneities were observed at site level, shorter travel time at delivery and increased transportation costs at enrolment were associated with increased likelihood of women returning to study site for delivery. Among 3145 women with live-born infants, 3077 (95.3%) provided 90-day follow-up information; of these, 68.9% (range across sites: 25.6-98.9%) returned to study site for follow-up visits. Women with other children and with lower transportation costs at delivery were more likely to return to study site for follow-up visits. Among 666 infants reported sick, 94.3% were taken to a healthcare facility, with only 41.9% (range across sites: 4.9-77.3%) to the study site. CONCLUSION: Although high retention was observed from enrolment through 90 days after delivery, post-partum surveillance should be broadened beyond the study sites and additional follow-up visits should be planned within the neonatal period. The factors influencing maternal/infant access to healthcare facilities and the issues identified in this study should be taken into consideration in planning future clinical studies on maternal immunisation in low- and middle-income countries. TRIAL REGISTRATION: The study was registered at ClinicalTrial.gov ( NCT01734434 ) on November 22, 2012.

Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy.

BACKGROUND: Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. METHODS: This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 µg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. RESULTS: Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%-61% and 26%-76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. CONCLUSIONS: Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. CLINICAL TRIALS REGISTRATION: NCT01193920.

Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial.

BACKGROUND: Maternal group B streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed vaccine exists. This study assessed the safety and immunogenicity of a CRM197-conjugated trivalent GBS vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. METHODS: We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28-35 weeks' gestation) women aged 18-40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational vaccine (two injections, 1 month apart, of a 20 µg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28-35 weeks' gestation of 0·5 µg, 2·5 µg, or 5·0 µg of the non-adjuvanted investigational vaccine (for each serotype), or placebo. All study participants and study staff not involved with vaccine preparation were masked to the randomisation group. The vaccine contained an equal dose (0·5 µg, 2·5 µg, 5·0 µg, or 20 µg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in µg/mL) following the two injections for cohort 1, and selection of one vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. FINDINGS: Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 µg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33-40% experienced at least one local and 54-71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 µg/mL [95% CI 7·0-18] for the GBS vaccine 0·5 µg group, 18 µg/mL [11-29] for the GBS vaccine 2·5 µg group, 22 µg/mL [13-35] for the GBS vaccine 5·0 µg group, and 0·64 µg/mL [0·42-0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the vaccine doses at any of the measured timepoints (p>0·05). INTERPRETATION: The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. FUNDING: Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.

Maternal Immunization With an Investigational Trivalent Group B Streptococcal Vaccine: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and immunogenicity of an investigational trivalent group B streptococcal vaccine in pregnant women and antibody transfer to their newborns. METHODS: The primary outcome of this observer-blind, randomized study was to estimate placental antibody transfer rates at birth. Secondary outcomes included measurement of serotype-specific antibodies at screening, 30 days postvaccination, at delivery, and 91 days postpartum, infant antibody levels at 3 months of age, the potential effect on routine infant diphtheria vaccination at 1 month after the third infant series dose, and safety in mother and infant participants through at least 5 months postpartum. Sample size was based on 60 participants in the vaccine group giving a probability of observing at least one adverse event of 90% if the actual rate of the event was 3.8%. RESULTS: From September 2011 to October 2013, 86 pregnant women were allocated in a 3:2 ratio to receive an investigational group B streptococcal vaccine containing glycoconjugates of serotypes Ia, Ib, and III or placebo. Demographics were similar across groups. Transfer ratios were 66-79% and maternal geometric mean concentrations increased 16-, 23-, and 20-fold by delivery against serotypes Ia, Ib, and III, respectively, Women with no detectable antibodies at inclusion had lower responses than those with detectable antibodies. Three months after birth, infant antibody concentrations were 22-25% of birth levels. Antidiphtheria geometric mean concentrations were similar across groups. In the vaccine and placebo groups, 32 of 51 women (63%) and 26 of 35 women (74%) reported adverse effects, respectively. CONCLUSION: The investigational vaccine was well-tolerated without safety signals in recipients and their infants or interference with routine infant diphtheria vaccination, although further studies on safety and effectiveness are needed. The investigational vaccine was immunogenic for all serotypes, particularly among women with detectable antibody levels at baseline. Antibody transfer to neonates was at similar levels to other maternally administered polysaccharide vaccines. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01446289.

Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine manufactured with and without polysorbate 80 given to healthy infants at 2, 3, 4 and 12 months of age.

BACKGROUND: Polysorbate 80 (P80), a nonionic detergent used to solubilize proteins, is used in both oral and injectable medications including vaccines. Development studies with 13-valent pneumococcal conjugate vaccine (PCV13) showed that adding P80 resulted in a more robust manufacturing process. Before adding P80 to the formulation of PCV13, we investigated the immunogenicity and safety of PCV13 with and without P80. METHODS: Phase 3, parallel-group, randomized, active-controlled, double-blind multicenter trial was conducted at 15 sites in Poland. Healthy infants were randomized (1:1) to receive PCV13+P80 or PCV13 without P80 given at ages 2, 3, 4 and 12 months concomitantly with DTaP-IPV-Hib at 2, 3 and 4 months; hepatitis B at 2 months and measles, mumps, and rubella at 12 months. Serotype-specific antipneumococcal immune responses were evaluated using antipolysaccharide capsular immunoglobulin (Ig)G responses and opsonophagocytic activity (OPA) assay. Safety data were also collected. RESULTS: The 2 treatment groups were demographically similar. Following the infant immunization series, anticapsular IgG antibody geometric mean concentrations and OPA geometric mean titers for each serotype were within 2-fold between the 2 groups. Formal noninferiority criteria for comparison of proportion of responders (subjects with IgG titers ≥0.35 µg/mL) were met for 11 of the 13 serotypes. Overall population responses were highly similar. Anticapsular IgG responses were also within 2-fold following the toddler dose. Safety profiles were similar between the 2 groups. CONCLUSIONS: Addition of P80 to PCV13 did not adversely affect PCV13 immunogenicity or safety when compared with vaccine formulated without P80.

An open-label randomized clinical trial of prophylactic paracetamol coadministered with 7-valent pneumococcal conjugate vaccine and hexavalent diphtheria toxoid, tetanus toxoid, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b vaccine.

BACKGROUND: In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron®) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, poliovirus, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany. METHODS: Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6-8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study. RESULTS: In the intent-to-treat population, paracetamol reduced the incidence of fever ≥38°C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: -19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39°C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39°C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported. CONCLUSIONS: Paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, as events were generally mild and of no concern in either group our data support current recommendations to administer paracetamol to treat symptoms only and not for routine prophylaxis. TRIAL REGISTRATION: NCT00294294.

Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial.

BACKGROUND: A 2-, 4-, and 12-month schedule of a novel 13-valent-pneumococcal conjugate vaccine (PCV13), containing serotype 1, 3, 4, 5, 6A, 6B 7F, 9V, 14, 18C, 19A, 19F, and 23F polysaccharides individually conjugated to CRM197 was evaluated in a randomized, double-blind, controlled infant study. METHODS: Two hundred eighty-six healthy infants received PCV13 or the 7-valent-pneumococcal conjugate vaccine (PCV7) at 2, 4, and 12 months of age, alongside a serogroup C meningococcal (MenC) vaccine (2 and 4 months of age), DTaP-IPV-Hib (2, 3, and 4 months), and a Hib-MenC vaccine (12 months). Specific antibody responses were assessed at age 5, 12, and 13 months. RESULTS: At 13 months of age, >97% of PCV13 recipients had pneumococcal serotype-specific serum IgG concentrations ≥0.35 µg/mL for each vaccine serotype except serotype 3 (88.2%), and at least 93% of PCV13 recipients had OPA titers ≥1:8 for each serotype. At 5 months, 110/114 (96.5%) of PCV13 recipients and 100/102 (98.0%) of PCV7 recipients had serum anti-PRP (Hib) IgG concentration ≥0.15 µg/mL (difference, 1.5%; CI, -7.1%­3.7%), while 119/120 (99.2%) and 117/118 (99.2%), respectively, had MenC serum bactericidal assay titers of ≥1:8. All PCV13 recipients and 110/113 (97.3%) of PCV7 recipients had IgG concentrations against fimbrial agglutinogens of ≥2.2 EU/mL; IgG concentrations for the remaining pertussis antigens were ≥5 EU/mL for all participants. Local reactions and systemic events were similar in the PCV13 and PCV7 groups. CONCLUSIONS: A 2-, 4-, and 12-month course of PCV13 was immunogenic for all 13 vaccine serotypes and was well tolerated.

Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine.

OBJECTIVE: Invasive pneumococcal disease rates have declined since immunization with 7-valent pneumococcal conjugate vaccine (PCV7) (Prevenar/Prevnar [Wyeth Pharmaceuticals, Philadelphia, PA]) became routine. Certain nonvaccine Streptococcus pneumoniae serotypes (1, 3, 5, 6A, 7F, and 19A) still cause significant morbidity and mortality. The safety and immunogenicity of PCV7 were compared with those of 13-valent PCV (PCV13), which contains saccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F conjugated to CRM(197). PATIENTS AND METHODS: Infants were randomly assigned to receive PCV13 or PCV7 at ages 2, 4, and 6 months with other vaccines. Post-third-dose antibodies to each pneumococcal polysaccharide were measured by immunoglobulin G enzyme-linked immunosorbent assay. Antibacterial functional antibodies were measured by opsonophagocytic assay (OPA). RESULTS: Subjects received PCV13 (n = 122) or PCV7 (n = 127). All PCV13 serotypes were immunogenic, with 88% to 98% of infants achieving antibody concentrations of > or =0.35 microg/mL to shared PCV7 serotypes. For the 6 additional serotypes, 97% to 100% of PCV13-vaccinated infants achieved antibody concentrations of > or =0.35 microg/mL. Geometric mean antibody concentration for PCV13 recipients ranged from 1.32 microg/mL (serotype 23F) to 4.26 microg/mL (serotype 14). The ratio of OPA geometric mean titers for the 7 shared serotypes (PCV13:PCV7) ranged from 0.6 to 1.4, suggesting no clinically meaningful differences. For PCV13-only serotypes, OPA geometric mean titers were significantly higher in the PCV13 group than in the PCV7 group. Local reactions and systemic events were similar between groups. CONCLUSIONS: PCV13 was well tolerated and immunogenic, with most infants developing antipolysaccharide antibody concentrations of > or =0.35 microg/mL, as well as OPA responses, to each of the 13 serotypes.

Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany.

13-valent pneumococcal conjugate vaccine (PCV13) was compared to PCV7 in infants administered 4 doses. For the 7 common serotypes, PCV13- and PCV7-elicited responses showed comparable percent responders achieving 0.35mug/mL IgG threshold (exception 6B, 77.5% versus 87.1%, respectively) and OPA titers of 1:8; IgGs were lower than PCV7 but functional responses were generally comparable. For the 6 additional serotypes, PCV13-elicited IgG and functional OPA responses were notably greater than PCV7. The toddler dose boosted immune responses. Vaccines were comparable with regard to safety. PCV13 should be as effective as PCV7 in preventing pneumococcal disease caused by the common serotypes and may provide protection against the additional serotypes.

Influenza vaccine concurrently administered with a combination measles, mumps, and rubella vaccine to young children.

Children aged 11 to <24 months received 2 intranasal doses of live attenuated influenza vaccine (LAIV) or placebo, 35+/-7 days apart. Dose 1 was administered concomitantly with a combined measles, mumps, and rubella vaccine (Priorix). Seroresponses to measles and mumps were similar between groups. Compared with placebo, response rates to rubella in LAIV+Priorix recipients were statistically lower at a 15 IU/mL threshold (83.9% vs 78.0%) and the prespecified noninferiority criteria were not met. In a post hoc analysis using an alternate widely accepted threshold of 10 IU/mL, the noninferiority criteria were met (93.4% vs 89.8%). Concomitant administration with Priorix did not affect the overall influenza protection rate of LAIV (78.4% and 63.8% against antigenically similar influenza strains and any strain, respectively).

Phase 1 trial of 13-valent pneumococcal conjugate vaccine in Japanese adults.

BACKGROUND: A 7-valent pneumococcal conjugate vaccine (7vPnC) has markedly reduced invasive pneumococcal disease (IPD) in routine use in the USA and is in clinical development in Japan. But a 13-valent pneumococcal conjugate vaccine (13vPnC) would cover even more serotypes. Because vaccines are administered to children by s.c. injection in Japan but by i.m. injection in the USA, a phase I study of s.c. injected 13vPnC in healthy Japanese adults was appropriate before commencing trials in Japanese children and older adults. METHODS: This was a randomized comparison in healthy Japanese adults of s.c. administered 13-valent pneumococcal conjugate vaccine and s.c. administered 23-valent plain polysaccharide pneumococcal vaccine (23vPn). Local and systemic reactions were recorded in a daily diary for 14 days after injection. IgG antibodies to serotype-specific capsular polysaccharide were measured on enzyme-linked immunosorbent assay on samples taken before and approximately 1 month after immunization. RESULTS: A total of 15 subjects were evaluable for safety review in each treatment group. There was a trend towards more local reactions in the 13vPnC group, which may be associated with s.c. administration of aluminum-containing vaccines as used routinely in Japan; but the local reactogenicity was mostly mild or moderate. Both 13vPnC and 23vPn were immunogenic for all types, with the exception of 6A, which is not included in 23vPn and for which only 13vPnC was immunogenic. CONCLUSIONS: Overall, immunogenicity and tolerance was adequate to lead to studies of 13vPnC in both infants and older adults in Japan, using the s.c. route if appropriate.

A clinical trial examining the effect of increased total CRM(197) carrier protein dose on the antibody response to Haemophilus influenzae type b CRM(197) conjugate vaccine.

CRM(197) is a carrier protein in certain conjugate vaccines. When multiple conjugate vaccines with the same carrier protein are administered simultaneously, reduced response to vaccines and/or antigens related to the carrier protein may occur. This study examined responses of infants who, in addition to diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) received either diphtheria CRM(197)-based Haemophilus influenzae type b conjugate vaccine (HbOC) or HbOC and a diphtheria CRM(197)-based combination 9-valent pneumococcal conjugate vaccine/meningococcal group C conjugate vaccine. Administration of conjugate vaccines with CRM(197) carrier protein load >50 microg did not reduce response to CRM(197) conjugate vaccines or immunogenicity to immunologically cross-reactive diphtheria toxoid.

Phase 1 trial of a 13-valent pneumococcal conjugate vaccine in healthy adults.

In a Phase 1 study, 15 healthy subjects were randomized to receive a 13-valent pneumococcal conjugate vaccine (PCV13) and 15 to receive a 23-valent pneumococcal polysaccharide vaccine (23vPS). Antibody responses were measured immediately before and approximately one month after vaccination. Serotype-specific antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) and an opsonophagocytic assay (OPA) for functional antibodies. PCV13 was as immunogenic or more immunogenic than 23vPS and was well tolerated.

Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies.

Estimates of minimum protective antibody concentrations for vaccine preventable diseases are of critical importance in assessing whether new vaccines will be as effective as those for which clinical efficacy was shown directly. We describe a method for correlating pneumococcal anticapsular antibody responses of infants immunized with pneumococcal conjugate (PnC) vaccine (Prevenar) with clinical protection from invasive pneumococcal disease (IPD). Data from three double blind controlled trials in Northern Californian, American Indian and South African infants were pooled in a meta-analysis to derive a protective concentration of 0.35 microg/ml for anticapsular antibodies to the 7 serotypes in Prevenar. This concentration has been recommended by a WHO Working Group as applicable on a global basis for assessing the efficacy of future pneumococcal conjugate vaccines. The WHO Working Groups anticipated that modifications in antibody assays for pneumococcal anticapsular antibodies would occur. The principles for determining whether such assay modifications should change the protective concentration are outlined. These principles were applied to an improvement in the ELISA for anticapsular antibodies, i.e. absorption with 22F pneumococcal polysaccharide, which increases the specificity of the assay for vaccine serotype anticapsular antibodies by removing non-specific antibodies. Using sera from infants in the pivotal efficacy trial in Northern California Kaiser Permanente (NCKP), 22F absorption resulted in minimal declines in pneumococcal antibody in Prevenar immunized infants but significant declines in unimmunized controls. Recalculation of the protective concentration after 22F absorption resulted in only a small decline from 0.35 microg/ml to 0.32 microg/ml. These data support retaining the 0.35 microg/ml minimum protective concentration recommended by WHO for assessing the efficacy of pneumococcal conjugate vaccines in infants.

Characteristics of substance abuse treatment programs providing services for HIV/AIDS, hepatitis C virus infection, and sexually transmitted infections: the National Drug Abuse Treatment Clinical Trials Network.

Illicit drug users sustain the epidemics of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), hepatitis C (HCV), and sexually transmitted infections (STIs). Substance abuse treatment programs present a major intervention point in stemming these epidemics. As a part of the "Infections and Substance Abuse" study, established by the National Drug Abuse Treatment Clinical Trials Network, sponsored by National Institute on Drug Abuse, three surveys were developed; for treatment program administrators, for clinicians, and for state and District of Columbia health and substance abuse department administrators, capturing service availability, government mandates, funding, and other key elements related to the three infection groups. Treatment programs varied in corporate structure, source of revenue, patient census, and medical and non-medical staffing; medical services, counseling services, and staff education targeted HIV/AIDS more often than HCV or STIs. The results from this study have the potential to generate hypotheses for further health services research to inform public policy.

A placebo-controlled screening trial of celecoxib for the treatment of cocaine dependence.

AIMS: To conduct a medication screening trial study on the efficacy of celecoxib versus placebo for the treatment of cocaine dependence. DESIGN: A modified blinded, parallel group study in an outpatient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Twenty-three participants were enrolled in the treatment phase of the study. INTERVENTION: After a 2-week screening period, subjects were assigned randomly to receive either celebrex (200 mg/day) or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs and extrapyramidal side-effects tests. RESULTS: Study retention was similar across both treatment groups and safety measures indicated that celecoxib was moderately tolerated. Cocaine use, as measured by self-report and urine BE levels at end of treatment, indicated weaker improvement in the celecoxib group. Reductions in the intensity of cocaine craving were also weaker in the celecoxib group. Cocaine abstinence rates, global impression scores and all other related psychometric measures did not differ significantly between treatment groups. CONCLUSION: This study does not support the effectiveness of celecoxib for the treatment of cocaine dependence.

A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence.

AIMS: To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence. DESIGN: A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study. INTERVENTION: After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests. RESULTS: Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed. CONCLUSION: This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence.