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ABSTRACT: An additional one to three doses of hepatitis B vaccine are recommended for nonresponders to an initial standard three-dose series. We compared the safety and immunogenicity of an investigational hepatitis B surface antigen vaccine (HBsAg-1018) with a phosphorothioate oligodeoxyribonucleotide adjuvant that targets toll-like receptor-9 to a commercially available, alum-adjuvanted hepatitis B vaccine (HBsAg-Eng) in nonresponders to three previous doses (primary study) or to four to six previous doses (substudy) of HBsAg-Eng. Both vaccines were well tolerated, although HBsAg-1018 was associated with more injection-site tenderness (63.2% vs. 18.8%, p = 0.016 in the primary study and 81.8% vs. 15.4%, p = 0.003 in the substudy). No statistically significant differences in rates of seroprotection (anti-HBs concentration ≥ 10 mIU/mL) or geometric mean antibody concentrations were found in the primary study. In the substudy, a greater proportion of HBsAg-1018 recipients achieved an anti-HBs concentration ≥ 100 mIU/mL (54.5% vs. 8.3%, p = 0.027), and those responders had higher geometric mean antibody concentrations at 4 weeks (264 vs. 46.5 mIU/mL, p = 0.021) and 52 weeks (7.0 vs. 1.2 mIU/mL, p = 0.030) than HBsAg-Eng recipients. Although this study suggests that HBsAg-1018 may have improved immunogenicity in nonresponders to hepatitis B vaccine vaccination when compared with HBsAg-Eng, larger studies are required.
Human vaccines & immunotherapeutics. 04/2013; 9(7).
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ABSTRACT: Previous studies have shown that two doses of an investigational hepatitis B vaccine consisting of hepatitis B surface antigen combined with an immunostimulatory phosphorothioate oligodeoxyribonucleotide adjuvant (HBV-ISS) given 8 weeks apart provides seroprotection sooner than 3 doses of a licensed hepatitis B vaccine over 24 weeks. A more rapid schedule with a 4-week interval could provide earlier protection and potentially greater compliance.
In this randomized, double-blind study, healthy adults received two doses of HBV-ISS at 0 and 4 or 0 and 8 weeks; saline placebo was given at week 8 for the 0-4 schedule and at week 4 for the 0-8 schedule). Adverse events were collected after each dose. Antibodies were measured at 0, 4, 8, 12, and 32 weeks.
Participants were randomized to the 0-4 (n=18) or 0-8 (n=23) weeks schedule. Rates of adverse events were similar in the two groups after the HBV-ISS injections regardless of the schedule, but more frequent than after the placebo injections. By 4 weeks post-dose-2, 94.1% of 0-4 and 100% of 0-8 recipients had protective antibody levels; geometric mean concentrations were 244 mIU/mL and 3217 mIU/mL respectively. By 32 weeks, the difference in antibody concentration had decreased (GMC 439 mIU/mL vs. 863 mIU/mL, respectively; p=0.04).
A 0-4 weeks, two-dose regimen of HBV-ISS was well-tolerated and induced an antibody response that was similar to a 0-8 weeks schedule.
Vaccine 06/2012; 30(36):5445-8. · 3.77 Impact Factor
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Joanne M Langley,
David W Scheifele,
Caroline Quach,
Otto G Vanderkooi,
Brian Ward,
Shelly McNeil,
Simon Dobson,
James D Kellner,
Susan Kuhn,
Tobias Kollman,
Donna MacKinnon-Cameron, Bruce Smith,
Yan Li,
Scott A Halperin
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ABSTRACT: Concern arose in 2010 that reactogenicity, particularly febrile seizures, to influenza A/H1N1-containing 2010-2011 trivalent seasonal inactivated influenza vaccine (TIV) could occur in young children who had been previously immunized and/or infected with the pandemic strain. We conducted a pre-season study of 2010-2011 TIV safety and immunogenicity in children 12-59 months of age to inform public health decision making.
Children immunized with 1 or 2 doses of the pandemic vaccine, with or without the 2009-10 TIV, received 1 or 2 doses of 2010-11 TIV in an observational, multicentre Canadian study. Standard safety monitoring was enhanced by a telephone call at ~24 h post-TIV when adverse events were expected to peak. Summary safety reports were rapidly reported to public health before the launch of public programs. TIV immunogenicity was assessed day 0, and 21 days after final vaccination. Clinical Trials Registration NCT01180621.
Among 207 children, a general adverse event was reported by 60.9% of children post-dose one and by 58.3% post-dose two. Only severe fever (>38.5°C) was more common in two-dose compared to one dose recipients (16.7%, n=4 v. 1.0%, n=2). At baseline 99.0% of participants had A/H1N1 hemagglutinin inhibition (HAI) titers ≥10, and 85.5% had a protective titer of ≥40 (95% CI 80.0, 90.0). Baseline geometric mean titers (GMT) were higher in recipients of a 2-dose schedule of pandemic vaccine compared to one-dose recipients: 153.1 (95% CI 126.2, 185.7) v. 78.8 ((58.1, 106.8, p<0.001). At 21 days, all regulatory criteria for influenza vaccine immunogenicity were exceeded for A/H1N1 and H3N2, but responses to the B antigen were poor. No correlations between reactogenicity and either baseline high influenza titers or serologic response to revaccination were evident.
Infants and toddlers who received AS03-adjuvanted A/H1N1 2009 vaccine up to 11 months earlier retained high titers in the subsequent season but re-exposure to A/H1N1 2009 antigen in TIV resulted in no unusual adverse effects and 100% were sero-protected for A/H1N1 after receipt of the 2010-11 TIV.
Vaccine 03/2012; 30(23):3389-94. · 3.77 Impact Factor
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ABSTRACT: Two pentavalent infant vaccines that contain either 5 or 3 component acellular pertussis antigens are authorized in Canada. Because of changes in vaccine use by provinces over time and movement of families across jurisdictions, it is possible that children are exposed to different combination vaccines during the primary infant immunization schedule. The safety and immunogenicity of mixed primary infant schedules is unknown.
In a double-blind multicenter trial, 2-month-old healthy infants were randomized to 1 of 2 schedules at 2, 4, and 6 months of age (either Pediacel, Pediacel, Infanrix [PPI] or Infanrix, Pediacel, Pediacel [IPP]). Solicited local and systemic adverse events (AEs) were collected by parent diary on days 0 through 7; unsolicited AEs were collected for 31 days after each dose. Immune responses to polypolyribosylribitol phosphate capsular polysaccharide (PRP) (Haemophilus influenzae type b) and pertussis antigens were assessed before the first dose and 28 days after the 6 month (third) dose.
In all, 127 infants were randomized to IPP and 126 to PPI. The percentage of children with anti-PRP responses ≥0.15 μg/mL after dose 3 was higher in the IPP than in the PPI group (98.3, 95% CI: 94.1, 99.8 vs. 86.1%, 95% CI: 78.6, 91.7, P < 0.001). Antipertussis toxin and anti-fimbriae 2 and 3 responses were statistically significantly higher in the IPP than in the PPI group. Higher filamentous hemagglutinin responses occurred in PPI than in IPP. No difference between groups was observed in pertactin responses.Systemic AEs were similar between the 2 vaccine schedules. Irritability (67.2 vs. 51.6, P = 0.014) and mild crying (35.2% vs. 23.0%, P = 0.037) were more common after the 6-month dose in the PPI compared with the IPP group, as were overall systemic reactions (any intensity) for the PPI group after this dose (80.0 vs. 68.0, P = 0.042).
Mixed 2-, 4-, 6-month pentavalent infant vaccine schedules had different immunogenicity and reactogenicity, with a PPI schedule being more reactogenic, and less immunogenic for PRP and fimbriae 2 and 3 antigens at 7 months. It is preferable to complete the primary infant 3-dose vaccine series with the same vaccine, rather than considering infant vaccines as interchangeable.
The Pediatric Infectious Disease Journal 12/2011; 31(2):189-92. · 3.58 Impact Factor
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ABSTRACT: The two-parameter linear failure rate distribution has been used quite successfully to analyze lifetime data. Recently, a new three-parameter distribution, known as the generalized linear failure rate distribution, has been introduced by exponentiating the linear failure rate distribution. The generalized linear failure rate distribution is a very flexible lifetime distribution, and the probability density function of the generalized linear failure rate distribution can take different shapes. Its hazard function also can be increasing, decreasing and bathtub shaped. The main aim of this paper is to introduce a bivariate generalized linear failure rate distribution, whose marginals are generalized linear failure rate distributions. It is obtained using the same approach as was adopted to obtain the Marshall-Olkin bivariate exponential distribution. Different properties of this new distribution are established. The bivariate generalized linear failure rate distribution has five parameters and the maximum likelihood estimators are obtained using the EM algorithm. A data set is analyzed for illustrative purposes. Finally, some generalizations to the multivariate case are proposed.
Computational Statistics & Data Analysis 01/2011; 55(1):644-654. · 1.03 Impact Factor
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ABSTRACT: The immunogenicities and efficacies of a licensed diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine and the same vaccine formulated in a liposome/oil emulsion adjuvant were compared in a mouse model of pertussis respiratory infection. A single dose of the liposome/oil emulsion-adjuvanted vaccine produced significantly higher antibody levels than one dose of the licensed vaccine and protected mice from Bordetella pertussis infection with an efficacy equivalent to that of three doses of the licensed vaccine.
Clinical and Vaccine Immunology 11/2007; 14(10):1381-3. · 2.55 Impact Factor
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ABSTRACT: In a multicenter, randomized, placebo-controlled clinical trial of pertussis immune globulin, intravenous (P-IGIV), 25 infants hospitalized with pertussis were enrolled in 24 months (15% of the target sample size) before the study was prematurely terminated because of expiration of the P-IGIV lots and unavailability of additional study product. Although well tolerated, there was no difference in the number or rate of improvement of symptoms (paroxysmal cough, whoop, apnea, bradycardia, oxygen desaturations) in P-IGIV recipients compared with placebo.
The Pediatric Infectious Disease Journal 02/2007; 26(1):79-81. · 3.58 Impact Factor
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ABSTRACT: Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups.
Healthy 18-50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune((R))). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine.
The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125mug dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations.
The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.
Vaccine 02/2007; 25(3):450-7. · 3.77 Impact Factor
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ABSTRACT: Current guidelines for screening for HIV infections in Nova Scotia recommend an opt-in approach in which patients are counselled and consent to testing. The objectives of the present study were to measure adherence to these recommendations, to explore women's knowledge, attitudes, beliefs and behaviours concerning HIV screening, and to compare these results with prenatal screening practices for rubella, hepatitis B and group B streptococcus.
All women who gave birth consecutively during a seven-week period were recruited. Study participants were interviewed to determine their knowledge, attitudes and beliefs concerning prenatal screening. Hospital and laboratory records were reviewed for information concerning prenatal screening and perinatal treatment to audit screening practices.
A total of 279 patients were enrolled in the study, representing 58% of those eligible. The HIV screening rate was 72%, compared with 95% for rubella, 89% for hepatitis B and 24% for group B streptococcus. Of the participants tested for HIV, 80% were aware of being tested. Of all the study participants, 17% indicated having received pretest counselling about HIV, 56% volunteered to be tested for HIV, 78% received the test results, and 3.8% received post-test counselling. More participants preferred an opt-out approach to HIV screening (50%), where testing is routinely performed on everyone, rather than the opt-in approach (43%). Participants displayed a similar preference for screening for the other infections.
HIV prenatal testing rates in Nova Scotia are comparable with those of other provinces that recommend an opt-in approach, but are lower than testing rates for opt-out programs. Most study participants were not screened using the recommended opt-in approach.
The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada 08/2006; 17(4):224-8. · 1.54 Impact Factor
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ABSTRACT: We studied the safety and immunogenicity of a nasally administered vaccine comprising three monovalent inactivated influenza antigens (A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Guangdong/120/2000) non-covalently associated with outer membrane proteins of Neisseria meningitidis (Proteosome) in normal, healthy adults. In a randomized, double-blind trial participants (n = 78) were allocated to placebo or a single nasal dose of vaccine containing 15, 30, or 45 microg of each of the three HA antigens, or two nasal doses containing 30 microg of each HA, separated by 2 weeks. The vaccine was generally well tolerated in all doses tested, and in a one or two-dose schedule. A shallow vaccine reactogenicity dose-response was seen. The most common local reaction was nasal congestion, which occurred in up to 48.3% of vaccine recipients in days 0-6 after vaccine but was mild and self-limiting; this reaction was not significantly more common among active vaccine recipients than placebo recipients. Mild to moderate headache was the most commonly reported systemic reactogenicity complaint in all treatment groups, and was the only solicited complaint to increase significantly in frequency after a second active dose. No severe systemic reactions occurred. A positive and statistically significant antibody response was observed, in serum and in nasal secretions, to increasing dose for all three antigens. Serum HAI titre responses and nasal secretory IgA immune responses were elicited against all three antigens. Further testing of this nasal influenza vaccine is warranted to determine its safety and immunogenicity in these populations and its efficacy in the prevention of clinical illness.
Vaccine 04/2006; 24(10):1601-8. · 3.77 Impact Factor
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ABSTRACT: This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate (PCV7), hepatitis B (HB) and DTaP.IPV/Hib vaccines. Infants were given DTaP.IPV/Hib and HB at 2, 4, 6 months and randomly assigned (2:1) to receive PCV7 concurrently or sequentially (at 3, 5, 7 months). Antibody levels were compared in 246 concurrent and 122 sequential vaccinees. Responses to PCV7, DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased (p=0.008) and HB responses were reduced (p=0.006) with concurrent dosing, the latter possibly from same thigh injection with DTaP.IPV/Hib. We conclude that PCV7, DTaP.IPV/Hib and HB are compatible with concurrent, separate injections.
Vaccine 04/2006; 24(12):2057-64. · 3.77 Impact Factor
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ABSTRACT: Adult formulation tetanus and diphtheria toxoids and acellular pertussis vaccines (Tdap) have been developed to prevent pertussis in adolescents and adults. There are concerns that unacceptable rates of severe injection site reactions, including Arthus-type reactions might occur if Tdap is administered too soon after a previous tetanus and diphtheria toxoid-containing vaccine formulated for infants and younger children (TD) or older children and adults (Td).
To evaluate whether adverse reactions after Tdap might be related to time since last receipt of TD/Td, we performed an open label, province-wide, clinical trial comparing the reactogenicity of Tdap given 18 months-9 years versus > or = 10 years after a previous TD/Td.
Seven thousand one hundred fifty-six children and adolescents were enrolled in the study (464-963 subjects per cohort), and 7001 had documented dates of the previous immunization within the specified intervals; adverse event data were provided by 5931 (84.7%). No whole limb swelling, Arthus-like reactions or serious adverse events related to vaccination were reported. No differences in reports of fever were found by interval since last immunization. Injection site erythema and swelling were slightly and statistically significantly increased among those participants with most recent prior TD/Td. Compared with the 10-year interval group, the maximum increase for any other group was < or = 8.6% for any erythema, < or = 6% for erythema > 10 mm, < or = 10.3% for any swelling, < or = 6.9% for swelling > 10 mm, < or = 5.2% for any pain and < or = 3.7% for moderate/severe pain.
Although there is a slight increase in injection site events with decreasing interval since a previous immunization, Tdap can be safely administered at intervals of > or = 18 months since a previous TD/Td vaccine.
The Pediatric Infectious Disease Journal 03/2006; 25(3):195-200. · 3.58 Impact Factor
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ABSTRACT: Many individuals do not respond to a three-dose series of hepatitis B vaccine (HBV) and most do not achieve a protective antibody response until after dose 2 or 3.
Healthy, seronegative 18-28 year old adults were randomly assigned in equal numbers to receive two doses of the experimental vaccine (HBV-ISS without alum) (0, 8 weeks) and placebo (24 weeks) or Engerix-B (0, 8, 24 weeks). Adverse events were collected during the first week and at 4 weeks after each injection. Antibodies were measured 4 weeks after dose 1; before, 1 and 4 weeks after dose 2, and before, 1 and 4 weeks after dose 3 and at 1 year.
Ninety-nine participants were enrolled (65% female; mean age 22.6 years). 79% of HBV-ISS and 12% of Engerix-B recipients had a protective antibody response 4 weeks post dose 1 (geometric mean concentration [GMC] 23.0 and 1.87 mIU/mL, respectively). By 1 week post dose 2, 100% of HBV-ISS and 18% Engerix-B recipients had protective levels (GMC 1603 versus 2.40 mIU/mL). Rates of adverse events were low and similar in both groups; headache and fatigue were the most common systemic adverse events in up to 1/3 of both groups. Mild injection-site tenderness was more common after HBV-ISS than Engerix-B after both doses (74-77% compared to 34-58%; p<or=0.029).
Protective levels are achieved more quickly and after fewer doses of HBV-ISS than Engerix-B. HBV-ISS is well tolerated but associated with more mild injection-site tenderness than Engerix-B.
Vaccine 01/2006; 24(1):20-6. · 3.77 Impact Factor
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ABSTRACT: Group B Streptococcus (GBS) can be transmitted from mother to child during delivery. At the time of the study, Nova Scotia guidelines for screening pregnant women for the presence of GBS recommended using one of two testing methods. The objective of this study was to determine the level of compliance with GBS testing recommendations and to determine women's knowledge of, attitudes towards, and beliefs about prenatal screening for this infection.
All women who gave birth at a single tertiary care unit during a seven-week period were approached to participate in the study. Study participants were interviewed using a questionnaire to determine their knowledge of, attitudes towards, and beliefs about prenatal screening. Medical and laboratory records were reviewed in order to audit the prenatal screening practices.
A total of 24.5% of study participants were screened for the presence of GBS by culture of a vaginal-rectal swab taken at 35 37 weeks' gestation, and 75.5% were assessed using the risk factor approach. Of the women screened by culture, 19% were identified as needing antibiotic treatment compared with 25% of those screened by assessment of risk factors. Women were significantly less knowledgeable about GBS than about other specific infections, and they felt that the threat of GBS infection for their baby was lower than the threat of the other infections. However, many of these women were uncertain about the threat that GBS poses during pregnancy.
Screening for GBS by culture rather than by assessing risk factors would have reduced antibiotic usage in our study population by 23%. These results indicate that all women should be counselled regarding GBS infection and should be tested using the culture-based approach at 35 to 37 weeks' gestation.
Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 12/2005; 27(11):1006-12.
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Shelly A McNeil,
Scott A Halperin,
Joanne M Langley, Bruce Smith,
Andrew Warren,
Geoffrey P Sharratt,
Darlene M Baxendale,
Mark A Reddish,
Mary C Hu,
Steven D Stroop,
Janine Linden,
Louis F Fries,
Peter E Vink,
James B Dale
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ABSTRACT: Group A streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to life-threatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that cross-react with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome.
The vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS vaccine (400 microg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 vaccine antigens, and functional (opsonization) activity of M protein antibodies.
The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a >4-fold increase in the geometric mean antibody titer over baseline. The mean log2 fold-increase in serum antibody titer (+/- standard error of the mean) for all 27 antigens was 3.67 +/- 0.21. A significant mean log2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes.
On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent vaccine could have significant impact on the overall burden of streptococcal disease.
Clinical Infectious Diseases 11/2005; 41(8):1114-22. · 9.15 Impact Factor
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ABSTRACT: Although universal immunization against Bordetella pertussis (whooping cough) infection has resulted in dramatic reductions in the incidence of pertussis, outbreaks continue to occur in countries with excellent vaccine coverage. Treatment of infection may ameliorate symptom severity during the catarrhal phase of pertussis but has no effect on established paroxysms, emesis, or apnea if given during the paroxysmal or convalescent phases. Erythromycin, recommended for treatment of pertussis to prevent transmission of infection, is poorly tolerated because of gastrointestinal side effects. We compared the safety and efficacy of erythromycin with azithromycin for treatment of pertussis in a large, randomized, controlled trial that enrolled children from primary care practices in 1 American and 11 Canadian urban centers.
Children who were 6 months to 16 years of age and had cough illness that was suspected to be or was culture confirmed as pertussis were randomized to azithromycin (10 mg/kg on day 1 and 5 mg/kg on days 2-5 as a single dose) or erythromycin estolate (40 mg/kg/day in 3 divided doses for 10 days) with stratification by center. The primary outcome measure was bacteriologic cure of infection as determined by cultures of nasopharyngeal aspirates. Culture-positive participants had a second aspirate collected at the end of therapy (days 5-7 for azithromycin, days 10-12 for erythromycin) and 1 week after therapy. Bacteriologic cure was defined as negative cultures at the end of therapy. Bacteriologic relapse was defined as a positive culture 1 week after completion of therapy and after a negative end-of-therapy culture. Secondary outcomes were pertussis diagnosed by serology and polymerase chain reaction (PCR), treatment-associated adverse events, compliance, and presence of clinical symptoms at the end of the treatment course. Serology was performed using standard enzyme-linked immunosorbent assay methods. A participant was considered to have pertussis when the PCR was positive or a 4-fold increase in pertussis toxin antibody between baseline and follow-up visits was observed. PCR was performed using a 1046-bp ClaI DNA fragment from B pertussis. Adverse events (nausea, vomiting, diarrhea, any gastrointestinal complaint, or other) were determined by a parent-completed diary that was reviewed with study personnel during study visits. Compliance was measured by review of the parent medication diary during study visits and observation of medication containers by the pharmacist at study completion. Symptoms were determined by history collected by study personnel at enrollment and subsequently from the diary. The design of the study was an equivalence trial, aimed at demonstrating that the bacteriologic failure rates with the 2 therapies did not differ by >8%. For the safety analysis, all participants who received at least 1 dose of study drug were included. In the per-protocol efficacy analysis, all culture-positive participants with end-of-treatment cultures were considered.
A total of 477 children were enrolled and randomly assigned to either azithromycin (n = 239) or erythromycin (n = 238). Of these children, 114 (24%) grew B pertussis from nasopharyngeal specimens (azithromycin group: 58 of 239 [24%]; erythromycin group: 56 of 238 [23%]); these children composed the efficacy cohort for the per-protocol and intention-to-treat analyses. Serology and PCR added 52 children to the number considered to have pertussis for a total of 35% (166 of 477) of all children who presented with cough illness. In the safety analysis (antibiotic side effects, compliance) and comparison of cough symptoms after treatment, all randomized children are reported in their assigned treatment group. At end of therapy, bacterial eradication was demonstrated in all 53 patients in the azithromycin group and all 53 patients in the erythromycin group with follow-up cultures available (eradication 100%; 95% confidence interval [CI]: 93.3-100). No bacterial recurrence was demonstrated in children with 1 week posttreatment nasopharyngeal cultures available (51 and 53 participants in the azithromycin and erythromycin arms, respectively [0%, 95% CI: 0-7.0; and 0%, 95% CI: 0-6.7]). No serious adverse events attributable to study drug were observed. Gastrointestinal adverse events were reported less frequently in azithromycin (18.8%; 45 of 239) than in erythromycin estolate (41.2%; 98 of 238) recipients (90% CI on difference: -29.0% to -15.7%) as a result of less nausea (2.9% vs 8.4%; 95% CI: -8.9% to -2.0%), less vomiting (5.0% vs 13.0%; 95% CI: -4.9% to -1.4%), and less diarrhea (7.1% vs 11.8%; 95% CI: -9.0% to -0.3%). Children who were randomized to azithromycin were much more likely to have complied with antimicrobial therapy over the treatment period. In the azithromycin group, 90% of children took 100% of prescribed doses, whereas only 55% of children in the erythromycin group took 100% of prescribed doses.
In this large, multicenter, randomized trial, we found that azithromycin is as effective as erythromycin estolate for the treatment of pertussis in children. Gastrointestinal adverse events were much more common with erythromycin treatment than azithromycin. Compliance with therapy was markedly better with azithromycin than with erythromycin in this study.
PEDIATRICS 07/2004; 114(1):e96-101. · 4.47 Impact Factor
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ABSTRACT: We evaluated temporal trends in hospitalization for bronchiolitis found among Canadian children for 1980-2000. The rate of hospital admission increased in all provinces over the 2 decades for all age groups but was highest in those aged <6 months. The mean length of stay decreased from 5.4 to 3.1 days (mean rate of decrease, 0.13 days/year; P<.0001). Because a concurrent increase in other respiratory diagnostic codes was not seen, it is unlikely that physician practice variation could explain this consistent trend over almost 2 decades, which may indicate a change in disease prevalence or severity.
The Journal of Infectious Diseases 12/2003; 188(11):1764-7. · 6.41 Impact Factor
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ABSTRACT: To describe the clinical course of fatal cases of pertussis and identify predictors of death at the time of presentation for medical care.
Case-control study of 16 deaths from pertussis identified by the Immunization Monitoring Program, Active (IMPACT) surveillance network (January 1991-December 2001) matched with 32 nonfatal cases by age, date, and geography. Differences were compared by Fisher exact test and logistic regression. A multivariate model was developed using stepwise logistic regression.
All 16 fatal cases were < or =6 months old; 13 were <2 months old. Fatal cases were less likely to have had cough complications during pregnancy (48% vs 14%; P=.046) and more likely to have pneumonia (63% vs 16%; P=.0024) before hospital admission and more likely to have seizures, pneumonia, leukocytosis, and hypoxemia after admission (P<.001 for all comparisons). White blood cell count and pneumonia were independent predictors of fatal outcome in the multivariate model.
Infants too young to have begun their immunizations are at highest risk of fatal pertussis infection. Leukocytosis and pneumonia are predictors of a poor outcome; however, rapid progression of the disease may make interventions difficult.
Journal of Pediatrics 11/2003; 143(5):576-81. · 4.11 Impact Factor
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ABSTRACT: We sought to measure the anxiety felt by parents at the time of entry into a randomized controlled vaccine trial, and to determine if anxiety level was associated with parental demographic variables or past experience. The children were 2-month-old infants entering a randomized controlled clinical trial (RCT) of a diphtheria-tetanus toxoid-acellular pertussis vaccine adsorbed with Haemophilus influenzae B conjugate, or toddlers enrolling in a RCT of a Meningococcal C conjugate vaccine. Nurses interviewed parents to collect demographic data and parents self-administered the Spielberger Self-evaluation Questionnaire (State Anxiety STAI-Y-I) [Manual for the State-Trait Anxiety Inventory (Form Y) (Self-evaluation Questionnaire), Consulting Psychologists Press Inc., Palo Alto, 1983], a validated instrument measuring the temporary condition of "state anxiety." A regression tree (CART) (S-Plus) was used to identify factors associated with higher anxiety scores. Parents of 97 children enrolled. Anxiety scores ranged from 22.75 (lower anxiety) to 36.43 (higher anxiety). The regression tree identified a structured tree with six branches. The highest anxiety scores occurred in fathers with education less then grade 8, mothers with education less than high school, birth order of the child less then the third, previous serious illness in the family, or lack of experience with research. In a group of parents agreeing to enroll their infant or toddler in a vaccine study, certain attributes and experiences were associated with higher anxiety at the time of immunization in the context of a RCT. These factors should be considered by vaccine researchers in the recruitment process of clinical trials.
Vaccine 10/2003; 21(25-26):3863-6. · 3.77 Impact Factor
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ABSTRACT: Enhancement of immune function has been claimed as a benefit of some natural health products, although few have been subjected to randomized clinical trials. We evaluated the effect of an oral dietary supplement derived from the edible microalga Chlorella pyrenoidosa on immune response after influenza vaccination.
We conducted a randomized, double-blind, placebo-controlled community-based clinical trial in a convenience sample of 124 healthy adults at least 50 years of age randomly assigned to receive the study product (200 or 400 mg of a Chlorella-derived dietary supplement) or placebo. Participants took the study product or placebo once daily for 28 days. On day 21, we administered a single dose of a licensed trivalent, inactivated influenza vaccine. We obtained serum specimens to measure hemagglutination inhibition titres before and 7 and 21 days after vaccination. The primary immunological outcomes were the proportion of participants with a 4-fold or greater increase in antibodies and geometric mean antibody titres after vaccination; the proportion of participants reporting adverse events during therapy was the safety outcome.
A total of 117 (94%) participants completed all aspects of the study. There were no differences in the proportions of recipients of 200 or 400 mg of the Chlorella-derived dietary supplement or placebo who achieved at least a 4-fold increase in antibodies (proportions for the 3 virus strains ranged from 17.9% to 28.2% for the 200-mg group, from 11.1% to 22.2% for the 400-mg group and from 19.0% to 21.4% for the placebo group; p > 0.05 for all comparisons). Reports of adverse events were similar for recipients of the supplement and placebo, except with regard to fatigue, which was reported more frequently by recipients of 200 mg of the supplement (18/41 or 44%) than by those who received 400 mg of the supplement (8/40 or 20%; p = 0.032) or placebo (8/42 or 19%; p = 0.019). Recipients of 400 mg of the supplement who were 55 years of age or younger had significantly higher geometric mean antibody titres against influenza A/New Caledonia 21 days after vaccination (p = 0.047) and against B/Yamanashi 7 days after vaccination (p = 0.034); the trends were nonsignificant for titres against A/Panama. We also observed similar increases for the proportions of subjects with a 2-fold or greater or a 4-fold or greater increase in antibodies.
The Chlorella-derived dietary supplement did not have any effect in increasing the antibody response to influenza vaccine in the overall study population, although there was an increase in antibody response among participants aged 50-55 years. Adverse events were similar among those receiving the supplement and the placebo. Further studies are warranted to explore the range of clinical effects resulting from ingestion of this dietary supplement.
Canadian Medical Association Journal 07/2003; 169(2):111-7. · 8.22 Impact Factor
