Vaccination response to tetanus toxoid and 23 ... - BioMed Central

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Arthritis Research & Therapy Vol 9 No 2 Tay et al.The impact of abatacept on humoral responses to two T-celldependentneoantigens, bacteriophage X174 and keyhole limpethemocyanin, was previously evaluated in psoriasis patientstreated with abatacept [8]. While the responses to theseneoantigens were reduced, the primary response to these T-cell-dependent antigens was not completely blocked. In addition,tertiary and quaternary responses were restored followingdiscontinuation of abatacept administration, demonstratingthat tolerance to these neoantigens was not induced [8].In the present article we describe the effect of a single dose ofabatacept on the humoral response in healthy subjects to twovaccines, tetanus toxoid vaccine and 23-valent pneumococcalvaccine. This study was carried out in normal healthy subjectsin order to evaluate the effects of abatacept on the responseto therapeutic vaccines in intact immune systems before evaluatingthe response in RA patients. Patients with active RAmay not have normal immune function parameters, and oftenreceive background disease-modifying antirheumatic drugs,many of which are immunosuppressive. It was intended thatdata from this study would guide the design of other studiesevaluating vaccine responses in patients with RA. These criticalstudies in 'real-world' RA patients are ongoing. In addition,the effect of abatacept upon two different types of antigenresponse was evaluated. The tetanus toxoid vaccine comprisesa peptide antigen, and, since most individuals in theUnited States have been vaccinated with tetanus toxoid, theresponse measured in this study can be considered a T-celldependentmemory response. Polysaccharides, however, areable to elicit responses in the absence of T-cell help, althoughthe magnitude of the response is reduced under those circumstances[9-11]. The response to pneumococcal vaccinemeasured in the present study is therefore not entirely T-cellindependent, or the response is less T-cell dependent. Finally,as a normal humoral response to T-cell-dependent antigenspeaks at around 2 weeks [12], we also analyzed the impact onhumoral response of the timing of vaccination relative to abataceptadministration.Materials and methodsStudy designThis open-label, parallel-group, controlled study was conductedat three study centers in the United States. Subjectswere randomized to one of four treatment groups (Figure 1).Group A (control group) subjects received separate 0.5 mlintramuscular (i.m.) injections of tetanus toxoid and 23-valentpneumococcal vaccines on day 1 without abatacept.Group B subjects (vaccines 2 weeks before abatacept)received separate 0.5 ml i.m. injections of tetanus toxoid and23-valent pneumococcal vaccines on day 1, followed 14 dayslater by a single intravenous (i.v.) dose of 750 mg abatacept.Serum samples were collected prior to the abatacept infusionon study day 14 and 14 days later on study day 28.Group C subjects (vaccines 2 weeks after abatacept)received a single i.v. dose of 750 mg abatacept on day 1, followed14 days later by separate 0.5 ml i.m. injections of tetanustoxoid and 23-valent pneumococcal vaccines. Serumsamples were obtained on study day 14 prior to vaccinationsand at 14 and 28 days after the vaccinations (study days 28and 42, respectively).Figure 1Patient disposition from enrollment to completion of the trial. *Abatacept administered after immunoglobulin (Ig) determination at day 14.Page 2 of 11(page number not for citation purposes)
Available online http://arthritis-research.com/content/9/2/R38Group D subjects (vaccines 8 weeks after abatacept)received a single i.v. dose of 750 mg abatacept on day 1,followed 56 days later by separate 0.5 ml i.m. injections of tetanustoxoid and 23-valent pneumococcal vaccines.Serum samples were obtained for subjects of Groups A andB at study days 14 and 28, for Group C subjects at study days28 and 42, and for Group D subjects at study days 70 and 84.Healthy male or female subjects (aged 18–65 years inclusive)with a body weight ≥ 60 kg and ≤ 100 kg were enrolled. Subjectswere excluded if they had received any live vaccine withinthe prior 4 weeks, had received a tetanus booster or pneumococcalvaccine within 5 years or if they had baseline anti-tetanusantibodies below clinically detectable levels. Anti-tetanusand anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14,19F and 23F) antibody titers were measured by ELISA at 14and 28 days after vaccination by a central laboratory. Abataceptserum concentrations were measured at the same timeas the antibody titers were determined.This study was carried out in accordance with the ethical principlesof the Declaration of Helsinki and was approved by InstitutionalReview Boards. All subjects gave informed consent.Drug administration and vaccinationAbatacept 750 mg was administered over 30 minutes by i.v.infusion using a calibrated, constant-rate infusion. Tetanus toxoidvaccine (Aventis Pasteur Inc., Swiftwater, PA, USA) and23-valent pneumococcal vaccines (Merck & Co Inc., WhitehouseStation, NJ, USA) were administered separately via i.m.injection in either the deltoid or the lateral mid-thigh.Abatacept and antibody assaysSerum samples were used to determine antibody levels. Theassay to quantify IgG anti-tetanus toxoid antibody levels wasbased on a previously described methodology [13]. The assayto quantify IgG anti-pneumococcal antibody levels was basedon the Procedures of the World Health Organization PneumococcalSerology Reference Laboratories at the Institute ofChild Health, University College, London, UK, and on the proceduresof the Department of Pathology, University of Alabamaat Birmingham, AL, USA [14]. All analyses were carriedout at the Center for Vaccine Research and Development, StLouis University Health Sciences Center, St Louis, MO, USA.The antibody response against tetanus toxoid vaccine wasexpressed as absolute titers of antibodies. Serum samples forthe quantification of abatacept were collected at baseline,prior to vaccinations, and at the time when the samples werecollected for antibody determinations [15].Safety assessmentsSubjects were monitored for adverse events (AE), serious AEand vital signs prior to dosing with abatacept and upondiscontinuation.Statistical methodsAll subjects in all four groups were included in the safety analysis.Geometric means and the percentage of the coefficientof variation were reported for antibody concentrations. Foreach antibody, point estimates and 95% confidence intervalswere constructed for the geometric mean changes from prevaccinationto postvaccination antibody levels. These constructionswere from the results of repeated-measuresanalyses of covariance on the natural logarithm of the antibodylevels, with the treatment group and the study day as factorsand the log of the baseline (prevaccination) antibody level asthe covariate. For each antibody, point estimates and 95%confidence intervals for the prevaccination to postvaccinationchanges on the log scale were exponentiated to obtain estimatesfor geometric means and ratios of geometric means(fold increase) on the original scale. A twofold or higherincrease above the baseline levels of specific antibodies wasconsidered a clinically significant or positive immune responseagainst tetanus toxoid and to each of the seven chosen serotypesof the 23-valent pneumococcal vaccine [16,17].ResultsThe baseline demographics and clinical characteristics of the80 subjects enrolled in this study were similar across the fourgroups. The mean age of subjects was 34–36 years (Table 1).Of the 80 subjects, 77 (96%) completed treatment and three(4%) discontinued early from the study.Overall, 59 AE were experienced by 29 subjects (49.2%)treated with abatacept, compared with 25 AE reported in 13subjects (65.0%) who did not receive abatacept (Group A,control group). The most frequently reported AE in Group Asubjects were injection-site pain (50.0%), headache (10.0%)and pharyngolaryngeal pain (10.0%). The most frequentlyreported treatment-emergent AE in the abatacept-treatedgroups were headache (20.3%), injection-site pain (10.2%)and viral infection (10.2%).One subject (1.7%) in Group D experienced a serious adverseevent of generalized urticaria 5 minutes after the end of thefirst abatacept infusion, which re-occurred at 90 minutespostinfusion. The investigator reported the event as moderatein intensity and probably related to the study drug. The subjectwas treated with epinephrine and diphenhydramine, remainedhospitalized overnight for observation and was discharged onstudy day 2. The event was completely resolved by study day3.Page 3 of 11(page number not for citation purposes)
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