Flu myths: dispelling the myths associated with live attenuated influenza vaccine

Live attenuated influenza vaccine (LAIV), commercially available since 2003, has not gained widespread acceptance among prescribers. This underuse can be traced to several misperceptions and fears regarding LAIV. This review examines both the facts (safety, immunogenicity, and effectiveness) and the most pervasive myths about LAIV. Live attenuated influenza vaccine is a safe, highly immunogenic, and effective vaccine. It is well tolerated; only mild and transient upper respiratory infection symptoms occur with LAIV vs placebo, even in higher-risk patients with asthma or the early stages of human immunodeficiency virus. It is immunogenic, especially in induction of mucosal immunity. In certain populations, LAIV is as effective as, and in some cases more effective than, inactivated influenza in preventing influenza infection. It appears to be more effective in preventing influenza infection than trivalent inactivated influenza vaccine when the vaccine virus strain does not closely match that of the circulating wild-type virus. Many myths and misperceptions about the vaccine exist, foremost among them the myth of genetic reversion. Independent mutation in 4 gene segments would be required for reversion of the vaccine strain of influenza virus to a wild type, an unlikely and as yet unobserved event. Although shedding of vaccine virus is common, transmission of vaccine virus has been documented only in a single person, who remained asymptomatic. In the age groups for which it is indicated, LAIV is a safe and effective vaccine to prevent influenza infection.     

Efficacy of a single dose of live attenuated influenza vaccine in previously unvaccinated children: A post hoc analysis of three studies of children aged 2 to 6 years

Background: Although 2 doses of influenza vaccine are recommended for children aged <9 years who have not been previously vaccinated, children may receive only 1 dose because of suboptimal adherence to national influenza vaccination recommendations.Objective: This study evaluated the efficacy and tolerability of a single dose of the live attenuated influenza vaccine (LAIV) in previously unvaccinated children aged ≥2 years, the population for which LAIV is approved.Methods: This study was a post hoc subgroup analysis of previously published studies. Three randomized, double-blind, placebo-controlled clinical trials have evaluated the efficacy of a single dose of LAIV in previously unvaccinated young children. Single-dose efficacy, as a prespecified outcome, was evaluated in the subgroup of children aged 2 to 6 years. Reactogenicity and adverse events through 10 days after vaccination were reported after 1 and 2 doses.Results: Across all studies combined, the mean (SD) ages of the children within the subgroups analyzed were 35.8 (12.1) months for LAIV recipients and 34.5 (11.3) months for placebo recipients. The groups were balanced by sex, with 51% and 50% boys in the LAIV and placebo groups, respectively. The LAIV and placebo groups were also balanced with regard to the countries of origin, as follows: United States (35% LAIV, 31% placebo), Southeast Asia (35% LAIV, 44% placebo), South America (19% LAIV, 15% placebo), and South Africa (11% LAIV, 11% placebo). In a post hoc subgroup analysis of children aged 2 to 6 years from these 3 studies, the efficacy of a single dose of LAIV compared with placebo was 71.5% (95% CI, 52.9% to 83.4%), 87.3% (95% CI, 59.2% to 96.1%), and 59.9% (95% CI, 31.1% to 77.4%). Two of the studies compared the efficacy of 1 and 2 doses of vaccine in the same season. The 1-dose efficacy of LAIV was 87% to 92% of the 2-dose efficacy. Upon revaccination in year 2 with a single dose, year-2 efficacy was not significantly different for children who received either 1 or 2 doses in year 1 (1 dose in year 1, efficacy 64.1% [95% CI, 13.1% to 85.7%]; 2 doses in year 1, efficacy 55.4% [95% CI, ?23.6% to 85.9%]; P = NS). All reactogenicity events associated with the first dose of LAIV were decreased after the second dose, with the exception of cough.Conclusions: A single dose of LAIV provided significant but not optimal protection against influenza in previously unvaccinated children. This finding may be of particular importance for children who are at risk of being partially immunized.     

An open-label comparison of the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal influenza vaccine in healthy adults

BACKGROUND: Many intramuscular inactivated influenza vaccines achieve suboptimal results in the prevention of respiratory disease and influenza complications. This has led to the current interest in developing effective oral or intranasal preparations. OBJECTIVE: This study compared the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal subunit influenza vaccine in healthy adults. It also assessed the immunogenicity and tolerability of 3 different production lots of the intranasal vaccine containing Escherichia coli heat-labile toxin adjuvant. METHODS: This was a multicenter, Phase I, randomized, open-label pilot study in which the primary end point was immunogenicity (hemagglutination-inhibition [HI] antibody assay on days 1 and 29). The secondary end point was the frequency of adverse events (AEs). Subjects were assigned to 4 vaccination groups: groups AI, AII, and AIII received intranasal influenza vaccine from batches that differed in the hemagglutinin and neuraminidase strains used, and group B received intramuscular virosomal subunit vaccine. Assessments of health status, hematology, biochemistry, body temperature, heart rate, blood pressure, and incidence of AEs were made on days 1, 8, and 29, and serology was assessed on days 1 and 29. RESULTS: The study enrolled 88 subjects. All 3 production lots of intranasal vaccine induced an immune response to most of the viral strains administered (A/Singapore, A/Texas, A/Wuhan, B/Beijing), with no notable immunogenic differences between lots. After intranasal vaccination, geometric mean titers (GMT) increased 2.7-fold against A/Singapore (group AI); 1.8- and 3.1-fold against A/Texas (groups AII and AIII, respectively); 1.9- to 2.4-fold against A/Wuhan; and 1.5- to 1.7-fold against B/Beijing. After intramuscular vaccination. GMT increased 11.3-, 6.3-, and 2.7-fold against A/Texas, A/Wuhan, and B/Beijing, respectively. Seroprotection (HI antibody titers > or = 1:40 in > 70% of those vaccinated) was achieved against all strains in the group that received intramuscular vaccination, against A/Wuhan in all groups that received intranasal vaccination, and against A/Texas in group AII. Both vaccine formulations were well tolerated. Intranasal vaccination was associated with a low incidence ( < 20%) of nasal AEs. CONCLUSIONS: Both the intranasal and intramuscular vaccinations elicited a systemic immune response and were well tolerated. The different batches of intranasal vaccine showed a similar immunogenic profile. Intranasal administration may be preferred to intramuscular administration by some patients.     

Tolterodine extended release is well tolerated in older subjects

Objectives: To investigate the tolerability of tolterodine extended release (ER) in older subjects with overactive bladder (OAB). Methods: This was a retrospective analysis of pooled data from five large, randomised, double‐blind, placebo‐controlled trials. Subjects with OAB symptoms, including urinary frequency and urgency (and nocturia in two studies) with or without urgency urinary incontinence, received qd treatment with tolterodine ER (4 mg) or placebo for 8–12 weeks. Data were stratified post hoc by age group: < 65 (n = 2531), 65–74 (n = 1059) and ≥ 75 years (n = 573). Tolerability was assessed by evaluating the occurrence of adverse events (AEs). AE occurrences from each study were mapped to the MedDRA coding dictionary of preferred terms. Results: Discontinuation rates were slightly higher among subjects ≥ 75 years of age vs. those < 65 years of age; however, this was observed in subjects treated with placebo as well as tolterodine ER. Overall, there were no significant differences in the occurrence of dry mouth, headache, constipation, nausea, urinary tract infection, blurred vision, dry eye, dizziness and micturition disorder in older (65–74 or ≥ 75 years) vs. younger (< 65 years) subjects treated with tolterodine ER relative to placebo (treatment × age; all p > 0.1). Dry mouth was the only AE consistently associated with tolterodine ER treatment (< 65 years, 17%; 65–74 years, 16%; ≥ 75 years, 15%). The occurrence of all other AEs was ≤ 5% in most age and treatment cohorts. Most AEs were mild or moderate in all age and treatment cohorts. Conclusion: The nature and frequency of AEs associated with tolterodine ER treatment were similar across age groups in subjects with OAB, suggesting that tolterodine ER was not associated with an increased risk of AEs in older vs. younger subjects and, thus, is a suitable first‐line pharmacotherapy treatment for OAB in this population.     

Immunogenicity of single-dose Vero cell-derived Japanese encephalitis vaccine in Japanese adults

In Japan, intensive immunization against Japanese encephalitis (JE) was performed from 1967 to 1976, and regular JE immunization was performed thereafter. However, for Japanese adults facing JE risk, dates of vaccination with new inactivated Vero cell-derived JE vaccine are unavailable. This study investigated how a single dose of Vero cell-derived JE vaccine affects Japanese adults. Neutralizing antibodies were measured pre- and post-JE vaccination in 79 participants (age 40.7 ± 9.4 years), enrolled between October 2009 and March 2011, whose JE-vaccination data were gathered from vaccination records and history taking. Before vaccination, the participants' seroprotection rate (SPR) was 51.9%, whereas SPR after vaccination was 93.7%. The seroconversion rate (SCR), which measures seronegative cases that turn seropositive after vaccination, was 86.8%. The geometric mean titer (GMT) was 14.7 before vaccination and 70.1 after vaccination. Age was a significant difference between seroprotected (42.8 years) and non-seroprotected (38.7 years) groups before vaccination. Then the difference of age, SCR, pre-vaccination GMT, post-vaccination GMT and sex ratio were also significant in participants aged 25–39 years and ≥40 years, who represent generations born when Japan's JE-vaccination policy changed. SCR was 100% in participants aged 25–39 years with a vaccination recorded 55.6% in participants aged 25–39 without a vaccination record, and 96.0% in participants aged ≥40 years. Thus, more participants aged 25–39 years were seroprotected before vaccination, but SCR was higher in those aged ≥40 years. Most Japanese adults can be protected after one-dose vaccination, but this may be insufficient for people aged 25–39 years without recorded JE vaccination.     

2013-2014年季节性流行性感冒疫苗免疫血清针对我国流行株的抗体水平分析

目的 分析季节性流行性感冒(流感)疫苗免疫血清针对我国流行株的抗体水平及我国流行株与疫苗株的匹配性. 方法 采集不同年龄组人群疫苗接种前后的血清,利用流感流行株和疫苗株作为病毒抗原,应用血凝抑制试验(HI)方法对血清进行检测. 结果 三价流感疫苗对我国A(H1N1)Pdm09亚型流行株产生的抗体平均几何滴度(GMT)低于针对疫苗株病毒的GMT,血清抗体滴度 40的比例为57.0%～63.3%;对我国A(H3N2)亚型流行株产生的GMT与针对疫苗株病毒的GMT类似,血清抗体滴度超过40的比例为57.6%～63.0%;对B型流行株产生的血清抗体GMT低于针对疫苗株的GMT,不过超过了疫苗株抗体GMT的50%.不同年龄组的血清抗体反应不同,成年组相对较高. 结论 2013-2014年季节性流感疫苗与同期流行的A(H1N1)Pdm09亚型流感病毒和B型流行株Yamagata系流感病毒较为匹配;H3N2亚型疫苗与流行株的匹配性较低,有可能会导致疫苗的保护效果降低.     

Bioequivalence of zonisamide orally dispersible tablet and immediate-release capsule formulations: Results from two open-label,randomized-sequence,single-dose,two-period,two-treatment crossover studies in healthy male volunteers

Background: To make it easier for patients who are prescribed zonisamide to administer their medicine, a rapidly disintegrating oral tablet formulation has been developed.Objective: These 2 trials assessed the bioequiva-lence of a new orally dispersible tablet formulation of zonisamide (test) versus an immediate-release reference capsule.Methods: Study 1 assessed the bioequivalence of a 100-mg orally dispersible tablet versus a 100-mg reference capsule. Study 2 assessed the bioequivalence of a 300-mg test tablet versus three 100-mg reference capsules. Both trials were open-label, randomized-sequence, single-dose, 2-period, 2-treatment crossover studies in consenting healthy male volunteers aged 18 to 55 years. A 4-week washout separated treatment periods. The zonisamide test tablet was placed on the tongue and, after it had dispersed in saliva, swallowed without water. Zonisamide serum concentrations were analyzed using a validated high-performance liquid chromatography assay with tandem mass spectrome-try detection (lower limit of quantification, 10 ng/nL). Bioequivalence was concluded if the 90% CI of the ratio of AUC_0–72 and C_max were within the regulatory criteria of 0.80 to 1.25. The safety profile was assessed through adverse events (AEs) and analysis of laboratory and echocardiogram parameters.Results: In study one, 36 male subjects were enrolled and randomized (mean [SD] age, 26.1 [6.9] years; weight, 77.6 [11.0] kg; race: white, 35 [97.2%], and Asian, 1 [2.8%]). Of those, 7 were withdrawn prior to completion (5 were lost to follow-up, 1 failed the drug screening, 1 withdrew due to AEs, and 1 was excluded due to undisclosed medical history). In study two, 40 male subjects were enrolled and randomized (mean [SD] age, 31.2 [10.3] years; weight, 76.1 [9.0] kg; race: white, 38 [95.0%], black, 1 [2.5%], and other, 1 [2.5%]). Of those, 2 were withdrawn prior to completion (1 failed the urine drug screening and 1 withdrew consent). The ratios (90% CIs) of AUC_0–72 for the 100-mg and 300-mg test formulations were 1.00 (0.98–1.02) and 1.00 (0.98–1.01), respectively. The ratios (90% CIs) of C_max were 0.97 (0.94–1.00) and 0.98 (0.95–1.00). A total of 25 subjects experienced treatment-emergent AEs in study 1; of these, 8 events in 3 patients were considered to be possibly or probably related to study drug administration. A total of 21 subjects experienced treatment-emergent AEs in study 2; of these, 11 events in 6 subjects were considered to be possibly or probably related to study drug administration. All AEs and laboratory and ECG findings were similar between formulations.Conclusions: The test formulation of zonisamide met regulatory criteria for bioequivalence to the reference formulation in these healthy male volunteers. Both formulations were generally well tolerated at both dose levels.     

Clinical guidance on the use of live attenuated influenza vaccine after inadvertent freezing and warming

The immediate and long-term impact of temperature deviations that may occur in clinical practice on live attenuated influenza vaccine (LAIV) potency was examined in four distinct studies that exposed vaccine to freeze/thaw cycles, warming, and heating conditions. No significant loss of vaccine potency was observed after three freeze/thaw cycles, warming of vaccine to 15°C (59°F) for 72 hours or less, exposure to room temperature (25°C/77°F) for 12 hours or less, or after heating to 37°C (99°F) for 6 hours or less. The results of these studies demonstrate that LAIV potency can potentially be maintained after exposure to temperature deviations. If a particular annual formulation of LAIV is exposed to temperatures outside of the recommended storage range, practitioners should contact the manufacturer for guidance regarding proper vaccine handling.     

A Feasibility Trial of Home Administration of Intranasal Vaccine by Parents to Eligible Children

Purpose

Intranasal vaccines are being developed for protection against many different infectious agents. The currently available intranasal live attenuated influenza vaccine (LAIV) is only approved for administration by medical personnel. We conducted a pilot study to investigate the feasibility of training parents to give LAIV to their own children.

Live Attenuated Influenza Vaccine: Is Past Performance a Guarantee of Future Results?

Live attenuated influenza vaccine (LAIV) has had a tumultuous recent history that can be difficult for many to follow and understand. Prior to 2013, LAIV had a record of accomplishment of providing equal or superior protection against influenza in children. Since 2013, concerns about the lack of protection with LAIV against pandemic H1N1 strains led to the withdrawal of any recommendation for use in the US by the Advisory Committee on Immunization Practices (ACIP). After some significant changes to the content, evaluation and production of LAIV, it has been be recommended again for use in the US in 2018-19. This commentary reviews the origin of LAIV, the events and circumstances that led to the withdrawal of any recommendation for LAIV use by the ACIP, the merits, shortcomings and repercussions of that decision and finally offers some thoughts about the future of LAIV.     

Pharmacokinetics and tolerability of rabeprazole sodium in subjects aged 12 to 16 years with gastroesophageal reflux disease: an open-label, single- and multiple-dose study

OBJECTIVE: This study was conducted to characterize the pharmacokinetic and safety profile of rabeprazole sodium tablets in children and adolescents with gastroesophageal reflux disease (GERD). METHODS: This was a multicenter, open-label, single- and multiple-dose study in subjects aged 12 to 16 years with GERD. Subjects were stratified by age (12-<14 years and 14-16 years) and were randomized to receive oral rabeprazole 10 or 20 mg/d over 5 or 7 days (to accommodate weekends). The pharmacokinetic parameters calculated included C(max), T(max), AUC, t(1/2), and apparent oral clearance (day 5/7 only). Blood samples for pharmacokinetic determinations were obtained on study days 1, 2, and 5 (or 7) and at discharge on day 6 (or 8). Safety assessments, including adverse events (AEs), were performed at all study visits. RESULTS: Twenty-four subjects were enrolled in the study (12 in each dose group); they were predominantly white, had a mean age of 14.2 years, and had a mean body mass index of 24.3 kg/m(2) (the 90th percentile for adolescents of this age in the United States). Mean age and weight did not differ significantly between the 2 dose groups. On day 1, C(max) was significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.024); on day 5/7, both AUC and C(max) were significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.005 and P = 0.007, respectively). Within-period comparisons for both groups indicated that the AUC and C(max) for rabeprazole and its thioether metabolite did not differ significantly from day 1 to day 5/7. In addition, the T(max) and t(1/2) were relatively unchanged from day 1 to day 5/7 in both dose groups. Treatment-emergent signs and symptoms occurred in 11 subjects, 6 in the 10-mg group and 5 in the 20-mg group. The most frequently reported AEs were headache and nausea (16.7% and 8.3%, respectively). No statistically significant differences were observed between dose groups in terms of the number of subjects with AEs. CONCLUSIONS: Rabeprazole 10 and 20 mg were well tolerated in these children and adolescents with GERD. The results of the pharmacokinetic analyses of single and multiple oral doses indicated no apparent accumulation of rabeprazole or its thioether metabolite with the 10-mg dose. There was, however, a suggestion of accumulation with multiple dosing of rabeprazole 20 mg, which requires confirmation in larger studies.     

Allele variants of the cytochrome P450 2C9 genotype in white subjects from The Netherlands with serious gastroduodenal ulcers attributable to the use of NSAIDs

BACKGROUND: The most common serious adverse effects (AEs) associated with NSAID therapy are bleeding and perforated gastroduodenal ulcers. These AEs are dose related, and reduced oral clearance of NSAIDs associated with polymorphisms of cytochrome P450 (CYP) would, theoretically, increase the risk for AEs. OBJECTIVE: The purpose of this study was to determine whether polymorphisms of the CYP2C9 genotype are associated with the development of serious complications of NSAID-related ulcers. METHODS: We examined the records of patients with complications of serious NSAID-related ulcers who were hospitalized from November 2001 to December 2003. Diagnosis was confirmed by endoscopy or abdominal surgery, and a group of consecutive subjects was identified for genetic analysis. CYP2C9 allele frequencies were determined and compared with those in a matched cohort of subjects receiving stable weekly maintenance doses of oral coumarin anticoagulants. Allele frequencies also were compared with those in matched cohorts from earlier studies. RESULTS: All 26 subjects with serious NSAID-related ulcers were white, 15 (58%) were female, and the median age was 74.5 years (range, 32-96 years). All 87 subjects in the reference group were white, 24 (28%) were female, and the median age was 69 years (range, 48-81 years). CYP2C9 genotype frequencies did not differ significantly between subjects with serious complications of NSAID-related ulcers and subjects using oral coumarin anticoagulants. The genotype frequencies in both groups were similar to those reported in previous studies in white subjects. CONCLUSION: The CYP2C9 genotype was not a significant or clinically relevant risk factor in the development of serious NSAID-related ulcers in this group of subjects.     

Factors related to the serious adverse events in patients visiting the emergency department after ChAdOx1 and mRNA COVID-19 vaccination

IntroductionWe investigated the clinical characteristics, outcomes and factors related to the serious adverse events (AEs) of patients visiting the emergency department (ED) with various AEs after ChAdOx1 and mRNA COVID-19 vaccination.MethodsPatients with AEs who visited the ED between March 2021 and September 2021 were selected from three EDs. The clinical data of these patients were collected by retrospectively reviewing medical records. Serious adverse events (AEs) were defined as any adverse medical events that led to hospital admission.ResultsA total of 3572 patients visited the ED with AEs; 69.6% were administered mRNA vaccines, and the median (IQR) age was 48 (31–63) years. Regarding chief complaints, chest pain/discomfort (43.7%) was most common in the mRNA vaccines group, while fever (15.8%) was more commonly presented in the ChAdOx1 group. Most patients (93.9%) were discharged from the ED. In multivariate analysis, age ≥70 years, days from vaccination to ED visit ≥8 days, fever and dyspnea as chief complaints were higher independent risk factors for serious AEs (OR 27.94, OR 2.55, OR 1.95 and OR 2.18: p < 0.001, p < 0.001, p = 0.003 and p = 0.003, respectively).ConclusionMost patients who visited the ED with AEs after vaccination were discharged from the ED regardless of the type of vaccine. Emergency physicians need to differentiate serious AEs and consider factors that may require admission to the ED.     

An open-label,nonrandomized, single-center,prospective extension,clinical trial of booster dose schedules to assess the safety profile and immunogenicity of recombinant outer-surface protein A (OspA) Lyme disease vaccine

BACKGROUND: An efficacy trial of an outer-surface protein A (OspA) Lyme disease vaccine demonstrated tolerability and efficacy against laboratory-confirmed Lyme disease after a primary series of 3 doses at 0, 1, and 12 months.OBJECTIVES: This extension of the efficacy study assessed the immunogenicity and tolerability of booster vaccinations administered at 24 and/or 36 months after the first vaccination. METHODS: This open-label, nonrandomized, single-center, prospective extension, clinical trial was conducted in the general community in New Haven, Connecticut, where Lyme disease is endemic. Blood samples (to determine anti-OspA titer) were collected before administration of the booster doses at months 24 and 36, and at 1 and 12 months after each booster dose was administered. Immune response was assessed via total immunoglobulin G (IgG) anti-OspA antibody titers and the proportion of subjects with titers >or=1400 EL.U/mL. Adverse events (AEs) were recorded by the study volunteers on diary cards. RESULTS: A total of 318 volunteers (173 women and 145 men) received at least 1 booster dose of Lyme disease vaccine, administered at 12 or 24 months after the third vaccination of the primary series (months 24 and 36, in relation to the primary series). Eighty-eight subjects of those who received a month-24 booster received a second booster dose at month 36 (12 months after the first booster). Overall, the mean age of the volunteers was 55 years (range, 19 to 73 years). The demographic characteristics of the groups were similar. Most AEs were limited induration and were rated by investigators and subjects as mild to moderate in severity. Administration of I or 2 booster doses did not elicit any patterns of AEs different from those reported in the efficacy trial. After the first booster dose, all volunteers had an anamnestic response and positive test results for total IgG antibody. Geometric mean titers increased at least 12-fold 1 month after the first booster dose at month 24 or 36. More than 96% of volunteers had titers>1400 EL.U/mL and 100% had titers >400 EL.U/mL (minimum seroprotective level) 1 month after the booster dose at month 24 or 36. CONCLUSIONS: All booster doses were well tolerated, and the incidence of AEs did not increase after the second booster dose. The immune response generated after the 3-dose primary series waned; booster doses administered at 12 and/or 24 months after the primary series increased antibody levels above seroprotective levels.     

Pharmacokinetics,safety, and tolerability of varenicline in healthy adolescent smokers: A multicenter,randomized, double-blind,placebo-controlled,parallel-group study

Background: Varenicline is approved as an aid to smoking cessation in adults aged ≥18 years.Objective: The goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers.Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12? to 16-year-old smokers (≥3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (≤55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling.Results: The high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C_max ~30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC_0–24, was 197.0 ng · h/mL for varenicline 1 mg BID and 95.7 ng · h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng · h/mL for varenicline 0.5 mg BID and 60.1 ng · h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by ≥1 subject in any treatment group, ≥92% were mild in intensity. No subject discontinued the study because of an AE.Conclusions: Varenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (≤55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.     

A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults

BACKGROUND: Guanfacine is an alpha(2)-adrenoreceptor agonist used to treat children and adults with attention-deficit/hyperactivity disorder. An extended-release formulation of guanfacine is currently under development. OBJECTIVE: The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-release (GXR) tablets after oral administration in healthy adults. METHODS: This was a Phase I, randomized, open-label, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of CmaX, AUC(0-t), and AUC(0-infinity) were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings. RESULTS: The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medications. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within the reference range at completion of the study, with no significant changes from baseline. CONCLUSIONS: In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported.     

Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2-year randomized controlled clinical trial

OBJECTIVE: To evaluate the immunogenicity, reactogenicity, and tolerability of a prototype human papillomavirus (HPV) 16 viruslike particle (VLP) vaccine directed against the L1 capsid protein. SUBJECTS AND METHODS: We enrolled healthy nonpregnant women aged 18 to 26 years into a 2-year, double-blind, dose-ranging multicenter trial (October 12, 1998, to September 30, 2001). Subjects were assigned to study groups to receive a 3-dose regimen (day 0, month 2, and month 6) of 1 of 4 vaccine doses: 10 microg, 20 microg, 40 microg, or 80 microg or placebo. Serum anti-HPV 16 L1 antibody (sL1Ab) geometric mean titers (GMTs) were measured at day 0, at month 3, at month 7, and every 6 months for a total of 2 years using a radioimmunoassay. The primary immunogenicity analyses evaluated GMTs at month 7 in L1Ab-seronegative subjects at baseline. Vaccine tolerability was also assessed. RESULTS: A total of 480 subjects were randomized to receive placebo (n=52) or 10 microg (n=112), 20 microg (n=105), 40 microg (n=104), or 80 microg (n=107) of HPV 16 L1 VLP vaccine. At baseline, 75% of subjects were L1Ab seronegative. All vaccine doses produced a statistically significant sL1Ab response vs placebo (P<.001). At the completion of the vaccination regimen, sL1Ab GMTs in baseline-seronegative subjects were 36- to 78-fold higher than the sL1Ab GMT at day 0 observed in subjects who had mounted an immune response to HPV 16 infection before enrollment. Serum L1Ab GMTs remained high throughout the 1.5-year postvaccination period. Postvaccination sL1Ab GMTs were 1.1- to 2.4-fold higher in women who had detectable sL1Ab levels at enrollment compared with those in baseline-seronegative subjects, particularly in the persistence phase. The vaccine was generally well tolerated with no statistically significant differences in injection site or systemic adverse experiences among treatment groups. CONCLUSION: Immunization with this novel HPV 16 L1 VLP vaccine was well tolerated and produced an immunogenic response that persisted for at least 1.5 years after the final dose.     

陕西省铜川市健康人群流行性乙型脑炎中和抗体水平监测结果分析

目的 了解陕西省铜川市健康人群流行性乙型脑炎(乙脑)抗体水平,为有效防控乙脑提供参考依据。 方法 采用整群随机抽样的方法,选择铜川市宜君县2岁、3~5岁、6~10岁、11~15岁、16~45岁、46~60岁和60岁组共216人,用微量中和试验检测乙脑病毒中和抗体。 结果 铜川市健康人群乙脑中和抗体阳性率为24.07%,抗体几何平均滴度(GMT)为1 ∶ 3.04;2岁组人群抗体阳性率及GMT 均最高,为63.33%和1 ∶ 11.06,其他年龄组的抗体阳性率为6.45%~31.03%,抗体GMT 为1 ∶ 1.78~1 ∶ 3.95。各年龄组抗体阳性率及GMT差异有统计学意义。 结论 铜川市健康人群乙脑抗体阳性率及GMT均较低,具有引发乙脑流行的风险,应加强乙脑疫苗免疫接种工作,提高人群免疫覆盖率。     

Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine

BACKGROUND: Solid organ transplant (SOT) recipients are a priority group for influenza vaccination and strategies enhancing immunogenicity are needed. METHODS: We determined adverse reactions, changes in biomarkers of graft function and immune responses to two doses of the AS03-adjuvanted influenza A/09/H1N1 vaccine in 216 SOT recipients and in 138 controls after one dose. Antibody responses were measured by haemagglutination inhibition and confirmed by microneutralization. We calculated geometric mean titres (GMT) and seroprotection rates (GMT≥40). RESULTS: Adverse reactions were fewer than in controls and graft function remained unaffected. Seroprotection was achieved by only 70.3% of SOT recipients, with significant differences between groups (lung 43.6%, heart 72.0%, kidney 83.3%, liver 83.3% and pancreas 85%), compared to 87% of controls (P<0.001). The weakest responses (seroprotection 43.5%) were elicited in lung transplant recipients. GMT remained threefold lower (115 versus 340) in SOT recipients than controls. Multivariate analyses identified increasing age, type of transplant and increasing blood levels of mycophenolate as independently associated to weaker responses. In contrast, even high blood levels of calcineurin inhibitors remained without significant influence on vaccine responses. CONCLUSIONS: The squalene-based adjuvanted A/09/H1N1 vaccine was safe in SOT recipients. However, even two doses of this adjuvanted influenza vaccine did not provide adequate protection for lung transplant recipients and those with high mycophenolate blood levels. Additional prophylactic measures should, therefore, be considered for these high-risk groups.