Antibody persistence and booster response in adolescents and young adults 4 and 7.5 years after immunization with 4CMenB vaccine.

BACKGROUND: Data on duration of protection against invasive meningococcal disease post-vaccination with the recombinant, 4-component, meningococcal serogroup B vaccine (4CMenB) are limited. We evaluated bactericidal activity persistence in adolescents/young adults up to 7.5 years post-primary vaccination with 4CMenB, and response to a booster dose compared with vaccine-naïve controls. METHODS: This open-label, multicenter study (NCT02446743) enrolled 15-24 year-old-previously vaccinated participants from Canada, Australia (group Primed_4y) 4 years post-priming with 4CMenB (2 doses; 0,1-month schedule), and Chile (Primed_7.5y) 7.5 years after priming with 4CMenB (2 doses; 0,1/0,2/0,6-month schedule) and vaccine-naïve participants of similar age (Naïve_4y and Naïve_7.5y groups). Primed participants received a booster dose; vaccine-naïve participants received 2 catch-up doses of 4CMenB, 1 month apart. We evaluated antibody persistence and immune responses using hSBA in terms of geometric mean titers and percentages of participants with hSBA titers ≥4, the kinetics of bactericidal activity post-booster (previously vaccinated) or post-2 doses (vaccine-naïve), and safety. RESULTS: Antibody levels declined at 4 (Primed_4y) and 7.5 (Primed_7.5y) years post-primary vaccination, but remained higher than in vaccine-naïve participants at baseline (≤44% vs ≤ 13% [fHbp]; ≤84% vs ≤ 24% [NadA]; ≤29% vs ≤ 14% [PorA]) for all vaccine antigens except NHBA (≤81% vs ≤ 79%). One month post-booster and post-second dose, 93-100% of primed and 79-100% of vaccine-naïve participants had hSBA titers ≥4 for all antigens. Kinetics of the antibody response were similar across groups with an early robust response observed 7 days post-booster/second dose. No vaccine-related serious adverse event was reported. CONCLUSION: For all antigens except NHBA, a higher proportion of primed participants had hSBA titers ≥4, at 4 and 7.5 years post-vaccination, compared with vaccine-naïve participants. A more robust immune response after booster compared to a first dose in vaccine-naïve individuals, showed effective priming in an adolescent/young adult population. No safety or new reactogenicity issues were identified.

Meningococcal B Vaccine Immunogenicity in Children With Defects in Complement and Splenic Function.

BACKGROUND: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these "at-risk" children are missing. METHODS: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen). RESULTS: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 "other"), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant. CONCLUSIONS: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.

Immune Responses to Booster Vaccination With Meningococcal ABCWY Vaccine After Primary Vaccination With Either Investigational or Licensed Vaccines: A Phase 2 Randomized Study.

BACKGROUND: Current meningococcal prime-boost vaccination schedules include separate vaccines for serogroups ACWY and B. An investigational combined serogroups ABCWY vaccine (MenABCWY) was developed to protect against clinically important Neisseria meningitidis serogroups. METHODS: In this phase 2, randomized, observer-blind, extension study (NCT01272180), participants 10-25 years of age received 1 booster dose of MenABCWY vaccine at 24 months (M) postprimary series of MenABCWY (2 doses), 4CMenB (2 doses) or MenACWY-CRM vaccine (1 dose). Immune responses to booster dose (1M postbooster) and antibody persistence (24M, 36M postprimary series) were assessed using bactericidal assay with human complement (hSBA). Reactogenicity and safety were evaluated. RESULTS: One hundred ninety participants were vaccinated. At 1M after the MenABCWY booster dose, seroresponse rates against serogroups ACWY ranged between 85% and 96%, 73% and 100% and 83% and 95% for participants previously receiving MenABCWY, 4CMenB and MenACWY-CRM, respectively. At 12M postbooster dose, ≥67% of participants across all groups had hSBA titers ≥8 for serogroups ACWY, except in 4CMenB-primed individuals for serogroup Y (45%). Across MenABCWY and 4CMenB-primed groups, hSBA titers ≥5 across serogroup B test strains were observed in 82%-100% and 29%-100% of participants at 1M and 12M postbooster, respectively. Geometric mean titers against serogroups ACWY increased from pre- to 1M postboosting with MenABCWY and persisted at 12M. The reactogenicity and safety profile of MenABCWY was similar to that of 4CMenB. CONCLUSIONS: MenABCWY may be suitable for prime-boost schedules against meningococcal disease, including regimens involving a primary series of either 4CMenB or MenACWY-CRM licensed vaccines.

Safety and immunogenicity of a CRM or TT conjugated meningococcal vaccine in healthy toddlers.

BACKGROUND: MenACWY-CRM (Menveo(®); GlaxoSmithKline) and MenACWY-TT (Nimenrix(®); Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited. METHODS: The reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12-15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement. RESULTS: A total of 202 children aged 12-15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high. CONCLUSION: Despite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified.

A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized, controlled trial.

BACKGROUND: A meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM. METHODS: A total of 484 healthy 10-25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters. RESULTS: Seroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90-92% vs. 73%; C: 93-95% vs. 63%; W: 80-84% vs. 65%; and Y: 90-92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported. CONCLUSIONS: Both investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified.

Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months.

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351.

Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin's lymphoma.

BACKGROUND/AIMS: Prevalence of HCV infection in non-Hodgkin's lymphoma is high. The impact of antiviral therapy on the natural history of this subgroup of lymphomas after a successful chemotherapy regimen is still an argument of debate. METHODS: We retrospectively examined 343 chemotherapy-treated patients referred to our centre for five consecutive years. Clinical and histological characteristics, disease free-survival (DFS) and overall-survival (OS) were compared in HCV-positive (69/343) and HCV-negative (274/343) patients. Twenty-five HCV-positive patients received antiviral treatment following chemotherapy discontinuation. Uni- and multivariate analyses were performed. RESULTS: 20% of lymphomas were HCV-positive. Indolent histology was prevalent in the HCV-positive group (p<0.05); no significant differences in OS or DFS were found between the two groups; in HCV-positive subjects, antiviral therapy, was associated with a longer DFS (p<0.05); none of the HCV-positive subjects who achieved a virological response experienced any lymphoma relapse; 29% of non responders did; at multivariate analysis, the independent factors related to a better clinical outcome were: indolent histology at the onset of lymphoma and antiviral therapy. CONCLUSIONS: Antiviral treatment in HCV-positive non-Hodgkin's lymphoma may be an important strategy to reinforce the results of a successful chemotherapy regimen; further studies are needed to validate this combined approach.

Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer.

INTRODUCTION: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD. METHODS: We identified 101 patients treated between July 2000 and January 2007. Nineteen were still receiving the first-line trastuzumab-based treatment without evidence of PD and were not included in this analysis. Of the remaining 82 patients, 59 retained trastuzumab for one or more additional lines of chemotherapy after PD, according to our institution policy. Twenty-three patients who changed treating institution and stopped trastuzumab at first progression were used as a control group. RESULTS: For patients retaining trastuzumab, the median follow-up was 39.6 months. Clinical outcomes showed the typical degradation between first and second lines of therapy which we would expect by halting trastuzumab at first progression. Response rates were 35% and 16% and median times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy, respectively. The median overall survival (OS) rates were 70 months for patients who retained trastuzumab and 56 months for patients who halted the drug (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.51 to 1.18; P = 0.52). If we consider OS from the start of trastuzumab therapy, the figures are 53.9 and 34.8 months, respectively (HR 0.78, 95% CI 0.58 to 1.32; P = 0.2). CONCLUSION: A nonstatistically significant trend of improved survival for patients retaining trastuzumab is observed. This is in line with most retrospective analyses and recent randomized data. Retaining trastuzumab after progression is a reasonable option, but further randomized data are warranted to better define its role in comparison with other available options.

Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials.

PURPOSE: We conducted a meta-analysis of randomized trials that evaluated the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer (EBC). We aimed to determine whether this approach improves disease-free survival (DFS) and overall survival (OS) and whether benefits are maintained across relevant patient subgroups. METHODS: Studies were retrieved by searching the PubMed database and the proceedings of major conferences. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model. RESULTS: Thirteen studies were included in the meta-analysis (N = 22,903 patients). The pooled HR estimate was 0.83 (95% CI, 0.79 to 0.87; P < .00001) for DFS and 0.85 (95% CI, 0.79 to 0.91; P < .00001) for OS. Risk reduction was not influenced by the type of taxane, by estrogen receptor (ER) expression, by the number of axillary metastases (N1 to 3 v N4+), or by the patient's age/menopausal status. Sensitivity analysis showed that taxanes given in combination with anthracyclines, unlike sequential administration, did not significantly improve OS. However, the test for interaction showed that HR did not differ between the two schedules (P = .54). Taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS and 3% for OS. CONCLUSION: The addition of a taxane to an anthracycline-based regimen improves the DFS and OS of high-risk EBC patients. The DFS benefit was independent of ER expression, degree of nodal involvement, type of taxane, age/menopausal status of patient, and administration schedule.

Estimation of bulky lymph nodes by power Doppler ultrasound scanning in patients with Hodgkin's lymphoma: a prospective study.

The accuracy of standard methods in estimating bulky lesions requires validation. We used clinical/computed tomography (CT) evaluation and power Doppler ultrasound (US) to detect bulky disease in 137 consecutive Hodgkin's lymphoma patients, and analyzed the prognostic relevance of each method. Bulky disease was detected by clinical/CT evaluation in 47% of the patients and by power Doppler US in 20%. After treatment, at multivariate analysis power Doppler US-selected bulky disease was the parameter that best correlated with freedom from treatment failure (p<0.001). Power Doppler US, a readily available imaging technique, provides a better prognostic classification by detecting true bulky disease more accurately.

Capecitabine plus weekly oxaliplatin in gastrointestinal tumors: a phase I study.

OBJECTIVE: To investigate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of capecitabine plus oxaliplatin. MATERIALS AND METHODS: Oxaliplatin was given by 2-hour iv infusion on days 1 and 8, and capecitabine was given orally, from day 1 to 14, every 3 weeks. We tested 4 levels of doses: 1) capecitabine 1650 mg/m2 + oxaliplatin 50 mg/m2; 2) capecitabine 2000 mg/m2 + oxaliplatin 50 mg/m2; 3) capecitabine 2000 mg/m2 + oxaliplatin 60 mg/m2; and 4) capecitabine 2500 mg/m2 + oxaliplatin 60 mg/m2. Patients with gastrointestinal neoplasm were eligible for the study. RESULTS: Thirty-two patients were enrolled. At dose level 4, 3 patients had unacceptable toxicity (grade 3 diarrhea, grade 4 diarrhea, and grade 3 mucositis, respectively), thus, level 4 was the MTD. Apart from DLT, overall toxicity was mild: grade > or =3 nonhematological toxicity occurred in 3 patients, and hematological toxicity was sporadic. CONCLUSION: This study demonstrates that clinically relevant doses of capecitabine (2000 mg/m2 from day 1 to 14) plus oxaliplatin (60 mg/m2 on days 1 and 8) every 3 weeks can be given without causing unacceptable toxicity.

A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer.

PURPOSE: Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting. We have conducted a meta-analysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer. EXPERIMENTAL DESIGN: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method. RESULTS: Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results. CONCLUSIONS: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.