Search

Introduction Individuals with an underlying malignancy have high risk of poor COVID-19 outcomes. In clinical trials, COVID-19 vaccines were safe and efficacious against infection, hospitalization, and death, but most trials excluded participants with cancer. We report results from participants with a history of past or active neoplasm (malignant or benign/unknown) and up to 6 months’ follow-up post-dose 2 from the placebo-controlled, observer-blinded trial of the 2-dose BNT162b2 mRNA COVID-19 vaccine. Patients and methods Between July 2020–January 2021, 46,429 participants aged ≥12 years were randomized at 152 sites in 6 countries. Healthy participants with pre-existing stable neoplasm could participate; those receiving immunosuppressive therapy were excluded. Data are reported for participants, aged ≥16 years for safety and ≥12 years for efficacy, who had any history of neoplasm at baseline (data cut-off: March 13, 2021). Adverse-event (AE) data are controlled for follow-up time before unblinding and reported as incidence rates (IRs) per 100 person-years follow-up. Results At baseline, 3813 participants had a history of neoplasm; most common malignancies were breast (n = 460), prostate (n = 362), and melanoma (n = 223). Four BNT162b2 and 71 placebo recipients developed COVID-19 from 7 days post-dose 2; vaccine efficacy was 94.4% (95% CI: 85.2, 98.5) after up to 6 months’ follow-up post-dose 2. This compares favorably with vaccine efficacy of 91.1% in the overall trial population after the same follow-up. AEs were reported at IRs of 95.4 (BNT162b2) and 48.3 (placebo) per 100 person-years. Most common AEs were reactogenicity events (injection-site pain, fatigue, pyrexia). Three BNT162b2 and 1 placebo recipients withdrew because of vaccine-related AEs. No vaccine-related deaths were reported. Conclusion In participants with past or active neoplasms, BNT162b2 vaccine has a similar efficacy and safety profile as in the overall trial population. These results can inform BNT162b2 use during the COVID-19 pandemic and future trials in participants with cancer. Clinical trial number: NCT04368728

Background Two phase 1/phase 2 studies assessed 2 formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) in healthy adults 50–85 years of age. Methods The QS-21 adjuvanted toxoid vaccine study randomized subjects 3:1 to 100 μg QS-21–containing C difficile vaccine or placebo administered in a shortened-month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (Days 1, 8, 30). Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A– and B–specific neutralizing antibodies. Results In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%–75.0% and 16.7%–50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen) and remained above baseline throughout follow-up. Conclusions Both formulations demonstrated robust immunogenicity. Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies.

Introduction Introduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20. Methods This phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18–49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28–42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated. Results Equivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups. Conclusions Three different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).

Background Individuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥65 years with at-risk conditions. Methods The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a double-blind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged ≥65 years received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants. Results Of the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95 years for at-risk participants; protection did not wane over the study period. Conclusions This post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. ClinicalTrials.gov identifier: NCT00744263 .

Prophylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine.Subjects received prophylactic paracetamol or ibuprofen at 0, 6-8, and 12-16 h after vaccination, or 6-8 and 12-16 h after vaccination at 2, 3, 4, and 12months of age. At 5 and 13months, immune responses were evaluated versus responses in controls who received no prophylaxis.After the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose.Prophylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration. ClinicalTrials.gov identifier: NCT01392378https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378rank=1.

Background In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. Methods This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12 months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24 months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. Results PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. Conclusions Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV’s impact on carriage density has minimal or no impact on vaccine success. ( www.ClinicalTrials.gov : NCT00508742)

Staphylococcus aureus is a leading cause of healthcare-associated infections. No preventive vaccine is currently licensed. SA4Ag is an investigational 4-antigen S. aureus vaccine, composed of capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). This Phase 1 study aimed to confirm the safety and immunogenicity of SA4Ag produced by the final manufacturing process before efficacy study initiation in a surgical population.Healthy adults (18-65years) received one intramuscular SA4Ag injection. Serum functional antibodies were measured at baseline and Day 29 post-vaccination. An opsonophagocytic activity (OPA) assay measured the ability of vaccine-induced antibodies to CP5 and CP8 to kill S. aureus clinical isolates. For MntC and ClfA, antigen-specific immunogenicity was assessed via competitive Luminex® immunoassay (cLIA) and via fibrinogen-binding inhibition (FBI) assay for ClfA only. Reactogenicity and adverse event data were collected.One hundred participants were vaccinated. SA4Ag was well tolerated, with a satisfactory safety profile. On Day 29, OPA geometric mean titers (GMTs) were 45,738 (CP5, 95% CI: 38,078-54,940) and 42,652 (CP8, 95% CI: 32,792-55,477), consistent with 69.2- and 28.9-fold rises in bacteria-killing antibodies, respectively; cLIA GMTs were 2064.4 (MntC, 95% CI: 1518.2-2807.0) and 3081.4 (ClfA, 95% CI: 2422.2-3920.0), consistent with 19.6- and 12.3-fold rises, respectively. Similar to cLIA results, ClfA FBI titers rose 11.0-fold (GMT: 672.2, 95% CI: 499.8-904.2). The vast majority of participants achieved the pre-defined biologically relevant thresholds: CP5: 100%; CP8: 97.9%, ClfA: 87.8%; and MntC 96.9%.SA4Ag was safe, well tolerated, and rapidly induced high levels of bacteria-killing antibodies in healthy adults. A Phase 2B efficacy trial in adults (18-85years) undergoing elective spinal fusion is ongoing to assess SA4Ag's ability to prevent postoperative invasive surgical site and bloodstream infections caused by S. aureus. Clinicaltrials.gov Identifier: NCT02364596.

Background The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18–64 years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. Methods In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65–85 years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. Results The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. Conclusions Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65–85 years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85 years. Trial registration number: NCT01643941 .

Background A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. Methods In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64 years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). Results A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. Conclusions Single-dose vaccination of SA4Ag in healthy adults aged 18–64 years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571

Introduction Streptococcus pneumoniae is a leading cause of bacteremia, bacterial pneumonia, and meningitis, and is associated with substantial morbidity and mortality, particularly in those under 2 years of age and those over 65 years of age. While significant progress against S. pneumoniae-related disease has been made as a result of the introduction of pneumococcal conjugate vaccines (PCV7, PCV10 and PCV13), there remains value in further expanding pneumococcal vaccine serotype coverage. Here we present the first report of a 20-valent pneumococcal conjugate vaccine (PCV20) containing capsular polysaccharide conjugates present in PCV13 as well as 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) which are important contributors to pneumococcal disease. Methods This Phase I first-in-human study was a randomized, controlled, observer-blinded study with a two-arm parallel design to assess the safety, tolerability, and immunogenicity of PCV20 in adults. A total of 66 healthy adults 18–49 years of age with no history of pneumococcal vaccination were enrolled and randomized to receive a single dose of PCV20 or a licensed tetanus, diphtheria, acellular pertussis combination vaccine (Tdap) control. Local injection site reactions, select systemic symptoms, laboratory studies, and adverse events were assessed. Opsonophagocytic activity (OPA) titers and IgG concentrations were measured in sera collected prior to, and approximately one month (28–35 days) after vaccination. Results Vaccination with PCV20 elicited substantial IgG and functional bactericidal immune responses as demonstrated by increases in IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) to the 20 vaccine serotypes. The overall safety profile of PCV20 was similar to Tdap, and generally consistent with that observed after PCV13 administration. Conclusions Vaccination with PCV20 was well tolerated and induced substantial functional (OPA) and IgG responses to all vaccine serotypes. There were no safety issues identified in this Phase 1 study, and the data supported further evaluation of PCV20.

Background Clostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B. Methods Healthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 μg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A– and toxin B–specific neutralizing antibody levels in human sera. Results Local reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-μg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-μg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-μg group, peaked at month 7, and remained elevated at month 12. Conclusions The C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI. ClinicalTrials.gov identifier: NCT02725437.

Background Vaccination effectively reduces invasive disease and pneumonia caused by Streptococcus pneumoniae. However, waning antibody titers and the ability of revaccination to boost titers in older adults have been concerns. A study to describe antibody persistence after vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) and response to revaccination 5 years after the initial dose was conducted. Methods Pneumococcal vaccine–naive subjects aged 50–59 years were randomized and vaccinated with PCV13 plus trivalent inactivated influenza vaccine concomitantly or 1 month apart, then revaccinated with PCV13 five years later. Antipneumococcal polysaccharide opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) were determined before and approximately 1 month after each vaccination. Targeted local reactions and systemic events were collected for 14 days, adverse events (AEs) for 1 month, and serious AEs (SAEs) for 6 months after each vaccination. Results Of 1116 randomized subjects, 727 were revaccinated at year 5. Between the time of initial vaccination and revaccination, OPA GMTs and IgG GMCs declined but remained higher than levels before initial vaccination for 12 of the 13 vaccine serotypes. One month after revaccination, OPA GMTs and IgG GMCs were comparable with, or higher than, levels observed 1 month after initial vaccination for most vaccine serotypes. Local reactions were mostly mild. AEs were reported by

Background Based on the success of vaccination with pneumococcal conjugate vaccines (PCVs) in children, recent studies have focused on PCVs in adults. Data from a randomized, double-blind study comparing the immunogenicity, tolerability, and safety of the 13-valent PCV (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in PPSV23-naive adults 60–64 years of age have been published. The same study also included a cohort of adults aged 18–49 years that received open-label PCV13. The purpose of this cohort was to examine the immunogenicity, safety, and tolerability of PCV13 in adult subjects 18–49 years of age compared with adults 60–64 years of age for whom PCV13 is approved. Methods Adults naive to PPSV23 were grouped by age into 2 cohorts: 18–49 years (n = 899; further stratified by age into 3 subgroups 18–29, 30–39, and 40–49 years) and 60–64 years (n = 417). All subjects received 1 dose of PCV13. In both age groups, immunogenicity was assessed by antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) 1 month after vaccination. Safety and tolerability were evaluated. Results In adults aged 18–49 years, OPA GMTs and IgG GMCs were noninferior for all 13 serotypes and statistically significantly higher for all except 1 serotype (OPA GMT) and 5 serotypes (IgG GMCs) compared with adults 60–64 years. Immune responses were highest in the youngest age subgroup (18–29 years). Local reactions and systemic events were more common in adults 18–49 years compared with 60–64 years and were self-limited. Conclusion Immune responses to PCV13 are robust in adults ≥18 years of age, with highest responses observed in the youngest subgroup. Based on its safety and immunologic profile, PCV13 may serve an important therapeutic role in younger adults, particularly those with underlying medical conditions who have an increased risk of serious pneumococcal infections.

Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children5 years old worldwide. To increase serotype coverage globally, a 13-valent pneumococcal conjugate vaccine (PCV13) has been developed and approved in many countries worldwide.Assess the safety and immunogenicity of PCV13 in healthy older infants and children naïve to previous pneumococcal vaccination.This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age-appropriate catch-up schedules: Group 1 (aged 7 to12 months) received two PCV13 doses with a booster at 12-16 months of age; Group 2 (aged 12 to24 months) received two vaccine doses only; and Group 3 (aged 24 to72 months) received a single dose of PCV13. Statistical analyses were descriptive. The proportion of immunological "responders" achieving serotype-specific antipneumococcal polysaccharide concentrations ≥0.35μg/mL, 1-month after the last dose of vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events.The proportion of immunological responders was ≥88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration.Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naïve to pneumococcal vaccination.

Background Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults. Methods We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60-64 years of age. An additional group of 403 adults 50-59 years of age received open-label PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination. Results In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50-59 years of age compared to adults 60-64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers. Conclusions PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection.

BackgroundThe currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13).MethodsWe performed a randomized, modified double-blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination.ResultsFollowing the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment.ConclusionIn adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13.

Background: As 13-valent pneumococcal conjugate vaccine (PCV13) is introduced, children who began vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) may complete their vaccination with PCV13. This open-label phase 3 study evaluated immunogenicity and safety of PCV13 in Swedish infants and toddlers previously given 1 or 2 doses of PCV7 during infancy. Methods: Healthy infants previously given PCV7 at ages 3 months (group 1; n = 118) or 3 and 5 months (group 2; n = 116) received PCV13 at ages 5 (group 1) and 12 months (both groups). IgG responses were assessed 1 month after each PCV13 dose and before the 12-month dose. Local reactions and systemic events were collected for 7 days postvaccination. Other adverse events were also collected. Results: Post-5-month dose, IgG geometric mean concentrations (GMCs) in group 1 were 1.56-4.70 mu g/ml for most PCV7 serotypes except 6B (0.40 mu g/ml) and 23F (0.57 mu g/ml) and 0.72-1.88 mu g/ml for most of the 6 additional serotypes, except 6A (0.28 mu g/ml). Post-12-month dose, IgG GMCs for the PCV7 serotypes were 2.93-9.63 mu g/ml (group 1) and 3.33-9.30 mu g/ml (group 2); and for the 6 additional serotypes, 1.85-14.65 mu g/ml (group 1) and 1.34-13.16 mu g/ml (group 2). GMCs increased by >4-fold in both groups from pre- to post-12-month dose. Proportions of subjects in group 1 with pneumococcal serotype-specific IgG concentrations >= 0.35 mu g/ml (WHO-designated postprimary reference antibody level) post-5-month dose were 92.2-99.1% for most PCV7 serotypes except 6B (53.0%) and 23F (62.6%) and 80.9-100.0% for most of the 6 additional serotypes except 6A (36.8%). Local reactions and fever were mostly mild or moderate. Conclusions: PCV13 was immunogenic and safe in infants and toddlers previously partially immunized with PCV7. Even a single dose in an infant or toddler induces an immune response to the 6 additional serotypes. (C) 2013 Published by Elsevier Ltd.

Background The inclusion of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs in many countries has significantly decreased the incidence of disease caused by Streptococcus pneumoniae . However, a substantial portion of disease remained and, in some areas, there has been an increase in disease produced by serotypes not included in PCV7. A 13-valent pneumococcal conjugate vaccine (PCV13) was studied in healthy Brazilian infants in a phase 3, double-blind, randomized study. Methods Infants were randomized to receive either PCV7 or PCV13 at 2, 4, 6, (doses 1–3), and 12 (toddler dose) months of age, along with routine pediatric vaccinations (diphtheria, tetanus, whole-cell pertussis, and Haemophilus influenzae type b vaccine). Pneumococcal anticapsular polysaccharide-binding immunoglobulin G (IgG) responses and antibody responses to pertussis antigens were measured 1 month after both dose 3 of the infant series and the toddler dose. Safety and tolerability were also assessed. Results The proportion of subjects achieving a serotype-specific IgG concentration ≥0.35 μg/mL measured 1 month after the infant series was comparable in the PCV13 (≥94.2%) and PCV7 (≥93.0%) groups for the 7 serotypes common to both vaccines. The percentage of responders for the 6 additional serotypes ranged from 87.1 to 100% for PCV13. The percentage of responders varied across the pertussis antigens studied, but was not different in PCV13 and PCV7 recipients. Overall, the safety profile of PCV13 was comparable with that of PCV7. Conclusions PCV13 was comparable to PCV7 in safety and tolerability, elicited comparable immune responses to the common serotypes, and did not interfere with immune responses to concomitantly administered whole-cell pertussis vaccine. The robust immunogenicity exhibited by PCV13 for the additional serotypes suggests that it could provide significant protection against these serotypes.

Background A prior 7- and 13-valent pneumococcal conjugate vaccine (PCV7 and PCV13) study provided sufficient data ( N = 1754; Jewish, n = 1154; Bedouin, n = 595; other, n = 5) to investigate the association between nasopharyngeal (NP) acquisition of common PCV7 serotypes and cross-reacting 6A (PCV7 + 6A) and IgG concentrations. Methods Using a logistic regression model, serotype specific association between postinfant series IgG concentration (age 7 months) and new NP acquisition between ages 7 and 24 months was assessed and adjusted for ethnicity. From a subset of subjects with new NP acquisition ( n = 9–152 across serotypes studied), new acquisition percentiles and associated IgG concentrations were calculated. Results For the serotypes studied , new NP acquisition rates decreased as IgG concentrations increased. Ethnicity did not influence these associations despite differences in carriage rates. From the subset with new acquisitions, 50% of the events occurred at IgG concentrations >0.61–5.58 μg/mL; and 10% of the acquisitions occurred at IgG concentrations >2.48–17.69 μg/mL. Conclusion Remarkably high IgG concentrations are required to reduce NP acquisition. These IgG concentrations differ between serotypes. Ethnicity did not influence the association between high IgG concentrations and prevention of carriage despite differences in carriage rates. Since carriage determines transmission, these results may have important implications for herd protection. Trial registration: ClinicalTrials.gov number, NCT00508742 ; http://clinicaltrials.gov/ct2/show/NCT00508742

Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged

Healthy adults aged ≥70 years (N = 443) with no history of pneumococcal vaccination received 7- or 9-valent pneumococcal conjugate vaccine (PCV7 or PCV9) at 1× (PCV7 only), 2× (PCV7 + PCV9), or 4× (2× PCV7 + 2× PCV9) dosage in a randomised, open-label study evaluating pneumococcal protein conjugate vaccine (PnC). Controls received 23-valent pneumococcal polysaccharide vaccine (PPV). Both geometric mean concentration enzyme-linked immunosorbent assay and opsonophagocytic activity antibody titres assessed 1 month after vaccination were significantly increased over baseline titres for all PCV7 serotypes, with a trend toward a dose-dependent immune response. Local reactions for the 4× dose, but not the 2× dose, were statistically significantly higher than for the 1× dose. No treatment-related serious adverse events occurred.

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N=1160) were randomized 1:1 to receive PCV13+TIV followed by placebo, or Placebo+TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13+TIV relative to PCV13. Concomitant PCV13+TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.

Live attenuated influenza vaccine (LAIV) provides a useful tool to rapidly immunize populations in the developing world to prevent influenza outbreaks. In this noninferiority trial conducted in Asia and South America, where oral poliovirus vaccine (OPV) is still used, 2503 children aged 6 to

Introduction Clostridium difficile is a significant cause of morbidity and mortality in hospitals, nursing homes, and long-term care facilities. The bacteria can produce 3 toxins, of which the C. difficile toxin A and C. difficile toxin B are the principal virulence factors for C. difficile-associated disease. Methods A phase 1, first-in-human, placebo-controlled, dose-escalation study was performed to assess the safety and immunogenicity of an investigational vaccine candidate consisting of genetically and chemically detoxified, purified toxins A and B. The toxoids, either alone or in combination with aluminum hydroxide (Al(OH)3), were administered to healthy adults 50–85 years of age at antigen dose levels of 50, 100, or 200 μg in a 3-dose regimen administered at 0, 1, and 6 months. Results Overall, the C. difficile vaccine formulations and doses administered were generally well tolerated. Local reactions and systemic events were predominantly mild to moderate, were more common in the 50–64-year age cohort, and comprised mostly injection site pain, headache, and fatigue. In subjects who received the vaccine formulations, both the toxin A- and toxin B-specific neutralizing antibody geometric mean concentrations increased substantially at 1 month after Dose 2 and after Dose 3 compared to baseline. In the 50–64-year age cohort, geometric mean fold rises (GMFRs) in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 59.19 to 149.23 in the vaccine groups compared to 2.47 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 116.67 to 2503.75 in the vaccine groups compared to 2.48 in the control group. In the 65–85-year age cohort, GMFRs in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 42.73 to 254.77 in the vaccine groups compared to 2.03 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 136.12 to 4922.80 in the vaccine groups compared to 1.58 in the control group. Potent antitoxin neutralizing responses were still evident in immunized subjects in both age groups at Month 12. Although there was no clear dose-level response pattern, the data suggest that both the antitoxin A- and B-specific neutralizing responses were trending higher in the toxoid-only groups compared to the toxoid + Al(OH)3 groups. Furthermore, the magnitude of the immune response was similar in the 2 age cohorts. Conclusion The vaccine formulations studied in this phase 1 study were immunogenic and well tolerated. The results presented support further development of the C. difficile vaccine candidate in a larger population of subjects to determine the optimal dose and immunization schedule. Clinical trial registry NCT01706367 .

Live attenuated cold-adapted influenza vaccines (CAIVs) have been developed over the past two decades by taking advantage of the segmented RNA genome of influenza and creating attenuated reassortants containing contemporary hemagglutinin (HA) and neuraminidase (NA) genes. These vaccines have been shown to be easily administered, safe and immunogenic in adults and children. Recent trials of a trivalent live attenuated CAIV (CAIV-T, tradename FluMist, Aviron, Mt. View, CA) in children have demonstrated greater than 85% efficacy against culture positive H3N2 and B influenza illness and complications, such as otitis media. CAIV-T also prevented shedding of H1N1 virus in 83% of vaccinated subjects after a monovalent CAIV challenge. Nasal IgA and serum HA inhibition (HAI) antibody produced by these vaccines have been associated with protection against infection, but protection may exist even in the absence of identifiable antibody response. Work to date documenting phenotypic and genetic stability, low likelihood of reactogenicity, infrequent transmissibility and attenuating properties of reassortants heralds promise for the broad use of this vaccine. Targeting children to receive this vaccine may now prove practical and may serve to reduce overall influenza morbidity, given the significant contribution of the pediatric age group of children to influenza illness burden and community spread. Studies of vaccine use in community settings will aid in determining the public health future of this approach.

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.

Background Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T–cell–dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations. Methods We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine–naive adults 60–64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination. Results OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose. Conclusion In pneumococcal vaccine–naive adults 60–64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations. ClinicalTrials.gov Identifier: NCT00574548 .

Background: Meta-analyses enable summarization and interpretation of data across clinical trials. When applied to safety data they allow for detection of rare events. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was approved in multiple countries worldwide for routine immunization of infants and young children. This meta-analysis was conducted to identify potentially clinically important rare safety events associated with PCV13. Objective: To summarize the safety of PCV13 compared with 7-valent pneumococcal conjugate vaccine (PCV7) administered to infants and toddlers. Methods: A meta-analysis was performed of integrated safety data from 13 infant studies (PCV13 n = 4729 and PCV7 n = 2760) conducted in 9 North American, European, and Asian countries. Local reactions at the vaccine injection site and systemic events were collected for 4–7 days after each dose into electronic diaries. Adverse events (AEs) were collected after each vaccination. Results: Overall, rates of local reactions after any dose of the infant series were similar between PCV13 and PCV7 groups: tenderness (46.7% vs 44.8%, respectively); swelling (28.5% vs 26.9%); and redness (36.4% vs 33.9%). After the toddler dose, tenderness was significantly higher among PCV7 subjects than PCV13 subjects (54.4% vs 48.8%; P = 0.005). Frequencies of fever (≥38 °C) were similar in both groups and mostly mild (≤39 °C); incidence of moderate fever (>39 °C to ≤40 °C) with PCV13 was ≤2.8% after any infant dose and 5.0% after the toddler dose, compared with ≤2.6% and 7.3%, respectively, with PCV7. Fever >40 °C was uncommon in both groups. Frequencies of decreased appetite, irritability, and sleep disturbances were similar in both groups. AEs were the types of conditions and symptoms expected in infants and children, and clinically significant differences between vaccine groups were not observed. Conclusion: PCV13 has a favorable safety profile similar to that of PCV7, a vaccine for which there is >10 years clinical experience.

Background Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations. Methods This was an extension of a previous study in pneumococcal vaccine-naive adults aged 50–64 years in which adults 60–64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50–59 were given PCV13. In this follow up study conducted about 4 years later, the 60–64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50–59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination. Results A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes. Conclusion In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses.

Background Given the concurrent administration of multiple vaccines during routine pediatric immunizations, efforts to elucidate the potential interference of any vaccine on the immune response to the concomitantly administered antigens are fundamental to prelicensure clinical research. Methods This phase 3 randomized controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) versus 7-valent PCV (PCV7) assessed immune responses of concomitantly administered meningococcal group C conjugated to diphtheria toxin cross-reactive material 197 (MnCCV-CRM 197 ) in a 2-dose infant series and 15-month toddler dose. Results 619 subjects were randomized, 315 to PCV13 and 304 to PCV7. MnCCV-CRM 197 -induced immune responses were similar between the PCV13 and PCV7 groups, with >97% of the subjects achieving a ≥1:8 meningococcal serum bactericidal assay (SBA) titer after both dose 2 and the toddler dose. Geometric mean titers were lower in the PCV13 group 191.22 (167.72, 218.02) versus 266.19 (234.86, 301.71) following dose 2 and 432.28 (361.22, 517.31) versus 730.84 (642.05, 831.91) following the toddler dose. The geometric mean (GM) meningococcal SBA titer ratios (PCV13/PCV7) were 0.72 after dose 2 and 0.59 after the toddler dose. The criteria for MnCCV-CRM 197 non-inferiority for GM titers were satisfied after dose 2. Percent responders was similar up to titers of 1:128. PCV13 elicited substantial antipneumococcal responses against all 13 serotypes, with ≥90% of the subjects achieving an antibody concentration ≥0.35 μg/mL after dose 3 in the infant series. Safety and tolerability were similar between the vaccine groups. Conclusions Immunogenicity results of MnCCV-CRM 197 for PCV13 compared with PCV7 included lower GMTs, but the clinical significance of this is unknown as the proportion of infants achieving protective MenC antibody titers was comparable in the two groups. Percent responders were similar up to titers of 1:128. PCV13 has an acceptable safety profile in infants and toddlers, while providing expanded coverage against pneumococcal disease.

Neisseria meningitidis is a leading cause of meningitis and septicaemia, but a broadly-protective vaccine against endemic serogroup B disease is not licensed and available. The conserved, outer-membrane lipoprotein factor H binding protein (fHBP, also known as LP2086) is expressed as one of two subfamily variants in virtually all meningococci. This study investigated the safety, tolerability, and immunogenicity of a recombinant-expressed bivalent fHBP (r-fHBP) vaccine in healthy adults. Participants (N = 103) aged 18-25 years were recruited into three ascending dose level cohorts of 20, 60, and 200 mu g of a bivalent r-fHBP vaccine formulation and randomised to receive vaccine or placebo at 0, 1, and 6 months. The vaccine was well tolerated. Geometric mean titres (GMTs) for r-fHBP subfamily-specific IgG antibodies increased 19-168-fold from pre-vaccination to post-dose 2 in a dose level-dependent manner. In addition, robust serum bactericidal assay using human complement (hSBA) responses for strains expressing both homologous and heterologous fHBP variants were observed. After three vaccinations, 16-52% of the placebo group and 47-90%, 75-100%, and 88-100%, of the 20, 60, and 200 mu g dose levels, respectively, had seroprotective (>= 1:4) hSBA titres against six serogroup B strains. The bivalent r-fHBP vaccine was well tolerated and induced robust bactericidal activity against six diverse serogroup B strains in young adults at the 60 and 200 mu g dose levels. (C) 2012 Elsevier Ltd. All rights reserved.

Two randomized trials of 13-valent pneumococcal conjugate vaccine (PCV13) relative to PCV7 evaluated the immune responses of coadministered antigens comprising Infanrix(®) hexa/Infanrix(®)-IPV+Hib (diphtheria, tetanus, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b). After the 3-dose infant series, immunogenic noninferiority was demonstrated for all concomitantly administered antigens between the PCV13 and PCV7 groups. All antigens elicited good booster responses after the toddler dose except pertussis toxoid; however, 99.6% subjects achieved pertussis toxoid protective antibody level ≥5EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix-IPV+Hib as part of routine immunization schedules.

Fifty-two infants seronegative to or without prior infection with influenza type A viruses were enrolled in a study to evaluate reactogenicity and immunogenicity of three bivalent cold recombinant type A (CRA) and two trivalent inactivated influenza (TI) vaccines. Controls consisted of infants receiving normal saline by nose drops (Pli.n.) or intramuscularly (Pli.m.). CRA and TI vaccines were monitored for local and systemic reactions after vaccination. Serum specimens obtained prior to and 6 weeks postvaccination were analysed for neutralizing antibody to influenza H1N1 and H3N2 viruses. CRA vaccines and Pli.n. recipients had similar numbers of acute respiratory infections and comparable rates of illnesses during the trial. Significantly fewer CRA vaccinees without an intercurrent viral infection had fever (0/16 versus 4/10, p = 0.04) and cough (4/16 versus 9/10, p = 0.002) than CRA vaccinees with a confirmed intercurrent viral infection. Recipients of TI vaccine and Pli.m. did not develop reactions at the injection site. For each of the CRA vaccines tested, a dominant CRA virus was identified. The dominant CRA viruses were isolated from a greater number of infants or for a longer duration than the non-dominant CRA viruses. All 14 non-dominant CRA viruses were recovered from infants within the first week after vaccination; 24 of 77 dominant CRA viruses were recovered more than 7 days after vaccination. The immunogenicity of CRA vaccines was not affected by a confirmed intercurrent viral infection or low titres of influenza-specific antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Although influenza is a major public health concern among adults ≥60 years of age, few large, prospective studies of influenza vaccines have been conducted in this population. The goal of the present study was to directly compare the safety and efficacy of LAIV and TIV in adults ≥60 years of age. Materials and methods A prospective, randomized, open-label, multicenter trial was conducted in South Africa. In March–April 2002, 3009 community-dwelling ambulatory adults 60–95 years of age were randomized 1:1 to receive a single dose of LAIV or TIV. Surveillance for influenza illness was conducted through November. Serum antibody titers were evaluated in all participants, and interferon-γ enzyme-linked immunosorbent spot assay responses were evaluated in a cohort of subjects. Solicited reactogenicity and adverse events were monitored for days 0–10 postvaccination; serious adverse events were monitored for the entire study. Results Influenza illness caused by vaccine-matched strains was detected in 0.8% (12/1494) and 0.5% (8/1488) of LAIV and TIV recipients, respectively; the relative efficacy of LAIV vs TIV was −49% (95% CI: −259, 35). As expected, greater serum antibody responses were seen with TIV, and greater cellular responses were seen with LAIV (although not for influenza B). Among subjects with culture-confirmed influenza illness, post hoc analyses revealed trends toward less feverishness (LAIV, 14%; TIV, 46%; P = 0.05) and less fever (LAIV, 9%; TIV, 31%; P = 0.16) among LAIV recipients. In each treatment group, 38–39% and 24–25% of subjects had baseline hemagglutination inhibition titers of ≤4 for A/H1 and A/H3, but 7 of 8 TIV cases and 7 of 12 LAIV cases of matched-strain influenza occurred among these subjects. Runny nose/nasal congestion (+13%), cough (+5%), sore throat (+5%), lethargy (+3%), and decreased appetite (+2%) were reported by more LAIV vs TIV recipients. Injection site reactions were reported by 27% of TIV recipients. SAEs were reported by a similar proportion of LAIV and TIV recipients (9% vs 8%). Conclusions Given the low incidence of influenza in both groups, no conclusions were possible regarding the relative efficacy of LAIV and TIV. There was a trend toward less feverishness/fever among LAIV recipients who developed influenza compared with TIV recipients with influenza, consistent with results from studies comparing the vaccines in children. A disproportionate number of influenza illnesses occurred among baseline seronegative subjects, particularly for those receiving TIV, which suggests that this subgroup has the greatest need for improved influenza vaccination. The safety profiles of LAIV and TIV were consistent with results from previous studies in older adults and no significant safety concerns were identified. clinicaltrials.gov identifier, NCT00192413 .

13-Valent pneumococcal conjugate vaccine (PCV13) administered as a 4-dose series in infants, and as a toddler dose in infants previously vaccinated with PCV7 elicited comparable vaccine serotypes IgG responses to the seven common serotypes. PCV13 elicited functional responses to the six additional serotypes in both schedules after the toddler dose. The toddler dose boosted immune responses. The two regimens had comparable safety profiles. A toddler dose of PCV13 given in children previously vaccinated with PCV7 should be effective in preventing pneumococcal disease caused by common serotypes, providing protection against the additional serotypes, and supporting the transition from PCV7 to PCV13.

13-valent pneumococcal conjugate vaccine (PCV13) includes polysaccharide conjugates from six pneumococcal serotypes in addition to those in the licensed 7-valent vaccine, thereby offering expanded protection against pneumococcal disease. The phase 3 trial reported here was conducted per a regulatory requirement to evaluate the immunogenicity, safety, and tolerability of two lots of the final PCV13 formulation that differed with respect to production scale but not the manufacturing process. The anti-pneumococcal polysaccharide immunogenicity and safety/tolerability were found to be similar between the two PCV13 vaccine lots.

A randomised, open-label study compared the immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) and meningococcal C conjugate vaccine (MnCC vaccine) administered concomitantly and individually. Infants received PCV7+MnCC vaccine (n=265), PCV7 alone (n=268) or MnCC vaccine alone (n=178). PCV7 was administered at 2, 3½, 6 and 12 months, and MnCC vaccine at 2, 6 and 12 months. For the 7 pneumococcal serotypes tested (4, 6B, 9V, 14, 18C, 19F and 23F), proportions of subjects with pneumococcal serotype-specific immunoglobulin G (IgG) antibody concentrations ≥0.35 μg/mL post-infant series were non-inferior for the PCV7+MnCC vaccine (91.5-99.6%) and PCV7 (89.0-99.6%) groups. Proportions of subjects achieving serogroup C meningococcal serum bactericidal assay titres ≥1:8 post-infant series were non-inferior for the PCV7+MnCC vaccine (99.6%) and MnCC vaccine groups (98.8%). Pneumococcal IgG antibody levels were similar in the PCV7+MnCC vaccine and PCV7 groups at each time point. Post-infant and post-toddler meningococcus C serum bactericidal assay titres and IgG levels were similar in the PCV7+MnCC vaccine and MnCC groups, although pre-toddler, the levels were lower in the PCV7+MnCC vaccine group than the MnCC vaccine group. Immune response rates to diphtheria antigen approached 100% for all vaccine groups. Local reactions were mostly similar among the treatment groups. The MnCC vaccine group had lower rates of some systemic events than the PCV7+MnCC vaccine group. Immune responses to PCV7+MnCC vaccine were non-inferior compared with those seen with each vaccine administered alone.

Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged2 years. While individual conjugate vaccines are available to protect this age group against these pathogens, availability of a vaccine combining these antigens into a single injection is desirable. This study randomized 467 healthy infants to receive 4 doses of combination 9-valent pneumococcal and meningococcal serogroup C conjugate vaccine (9vPnC-MnCC) or 9-valent pneumococcal conjugate vaccine (9vPnC). Percentages of subjects achieving immunoglobulin G (IgG) antibody concentrations ≥0.35μg/mL and geometric mean IgG concentrations for each pneumococcal serotype in the 9vPnC-MnCC group were noninferior compared to the 9vPnC group. Both vaccines were well-tolerated.

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.

This randomized, double-blind, placebo-controlled study investigated the efficacy, safety, and immunogenicity of LAIV in community-dwelling ambulatory adultsor =60 years of age in South Africa in 2001. Nose and throat swabs were obtained for influenza virus culture based on the symptoms of influenza-like illness. A total of 3242 subjects were enrolled, with a mean age of 69.5 years. The efficacy of LAIV against influenza viruses antigenically similar to the vaccine was 42.3% (95% CI, 21.6-57.8%). Efficacy against A/H3N2 viruses was 52.5% (95% CI, 32.1-67.2%); vaccine efficacy was not observed against antigenically similar B strains. In post hoc analyses, efficacy in subjects 60 to70 years of age was 41.8% and -22.7% against A/H3N2 and B, respectively and 65.7% and 9.9%, respectively, for subjectsor =70 years. Reactogenicity events were higher among LAIV than placebo recipients during 11 days postvaccination (P=0.042), including runny nose/nasal congestion, cough, sore throat, headache, muscle aches, tiredness, and decreased appetite. Rates of serious adverse events were similar for LAIV and placebo recipients. This was the first demonstration of statistically significant protection by LAIV against culture-confirmed influenza in adultsor =60 years of age. These results suggest that LAIV may provide an additional public health tool in the prevention of influenza in the elderly. (ClinicalTrials.gov identifier, NCT00217230.).

Children aged 11 to

This randomized trial compares safety and immunogenicity when vaccinating infants with a pneumococcal-meningococcal conjugate vaccine in two doses vs. three doses. Infants (N=223) received 9vPnC-MnCC (CRM197-conjugated pneumococcal serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F and meningococcal C polysaccharides) either at 3 and 5 or 3, 4 and 5 months and a booster with either 9vPnC-MnCC or 23-valent pneumococcal-polysaccharide vaccine (23vPPS) and CRM197-MnCC, at 12 months. Safety was monitored and IgG measured at 3, 6, 12 and 13 months in all subjects and serum bactericidal activity (SBA) in half. The 9vPnC-MnCC vaccine was safe and induced significant IgG to all components. Three doses induced higher antibody GMCs (geometric mean concentrations) at 6 months to seven of nine pneumococcal serotypes. This was most significant for 6B and 23F (p0.001), that also showed lower rate of responders0.35 (6B, 23F) and0.5 microg/mL (6B). Antibody GMCs remained lower following 9vPnC-MnCC booster in subjects primed with two doses although only significant for serotype 18C. Significant memory responses were observed 1 week after the 23vPPS toddler dose. MnCC-IgG GMC was lower after two doses, however with comparable SBA. This study shows that the 9vPnC-MnCC vaccine is safe and induces successful immunological memory, whether given in two or three primary doses.

Early in the development of respiratory syncytial virus (RSV) vaccines severe disease occurred in children after receipt of formalin-inactivated RSV vaccine. Continuing efforts to develop an appropriately attenuated and immunogenic live RSV vaccine have given opportunities to assure that live vaccines are safe through surveillance of children after vaccination. In the present study, the rate of RSV-associated upper respiratory tract illness in 388 children was lower in RSV vaccinated children than in controls (14% versus 20% in a 6-24 month old group and 16% versus 25% in infants). Additionally, there was no evidence that vaccination predisposed to more severe lower respiratory tract illness. Thus infection with a series of live attenuated RSV vaccines did not result in enhanced disease upon infection with wild type RSV. The impact of RSV during this surveillance will inform the design of future efficacy studies with RSV vaccines.

Background This study examined the transmissibility between young children of an intranasally administered live attenuated human parainfluenza virus type 3 (HPIV3)- cp 45 vaccine candidate. Methods Eighty subjects were enrolled in playgroups among whom there was at least one infected vaccinee in close contact with a seronegative placebo recipient over 21 days without a confounding infection with wt HPIV3. Following vaccination viral cultures were obtained on nine occasions to detect shedding and transmission of HPIV3 cp 45. Serum antibody titers were measured before and 7 weeks after vaccination. Results No child fulfilled the criteria for transmission of HPIV3 cp 45 giving a risk of transmission of 0.04 (95% CI 0.01–0.19), hence establishing that HPIV3 cp 45 is less infectious than wt HPIV3 and risk of transmission is not a limitation to further clinical development of this vaccine candidate.

Intranasal trivalent, cold-adapted, live attenuated influenza vaccine (CAIV-T) is a promising alternative to inactivated vaccine for protection against influenza in children. However, correlates of immunity are not well defined. To determine the mucosal immune response to CAIV-T, 19 children ages 15-55 months were randomized to receive two doses of CAIV-T or placebo. Influenza-specific IgA to the haemagglutinin of each of three contemporary strains was measured in nasal washes collected pre- and postvaccination using a kinetic enzyme-linked immunosorbent assay. After two doses of study drug, 62, 69 and 85% of CAIV-T recipients demonstrated a mucosal IgA response to influenza A/H1N1, A/H3N2, and B strains respectively; in comparison, 33, 0 and 17% of placebo recipients demonstrated an IgA response to the same strains (p = 0.35, 0.01 and 0.01). Overall, seropositive vaccinees were 4.5 times more likely to develop a mucosal immune response than an HAI response (p = 0.015). Two doses of CAIV-T induce a mucosal IgA response to all three influenza vaccine antigens in the majority of children. In addition, a mucosal antibody response may be the only indication of a vaccine take in a seropositive child.

1126 children, 2 months to 3 years old, received a single intranasal dose of 10 4 , 10 6 , or 10 7 TICD 50 of cold adapted (ca) A/Kawasaki/9/86 (H1N1) and A/Beijing/352/89 (H3N2) or placebo, in a double blind, placebo-controlled, safety and immunogenicity trial. No reactogenicity attributable to vaccine was demonstrated. A single bivalent 10 6 or 10 7 dose produced high rates of seroconversion to H1N1 (77%) and H3N2 (92%) in seronegative children > 6 months old; serologic responses were lower to H1N1 ( P P = 0.01) in younger infants. A single 10 6 dose of bivalent ca influenza A vaccine can be immunogenic in children, but response is age dependent.

BackgroundStaphylococcus aureus is a common cause of healthcare-acquired morbidity and mortality and increased healthcare resource utilization. A prophylactic vaccine is being developed that may reduce this disease burden.MethodsVolunteers in good general health aged 50–85 (n=312) and 18–24 (n=96) years were randomized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S. aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 and CP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA). Safety, tolerability, and immunogenicity were evaluated.ResultsAt day 29 post-vaccination, robust immune responses were observed in both age cohorts at all three SA3Ag dose levels. In the primary analysis population, the 50- to 85-year age stratum, geometric mean-fold-rises in competitive Luminex® immunoassay antibody titers from baseline ranged from 29.2 to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P