Biomedical subjects
Publications and source records attributed to D W Scheifele.
We investigated multiple sclerosis in adolescents in British Columbia before and after a hepatitis B vaccination programme was begun. There was no evidence of a link between hepatitis B vaccination and multiple sclerosis or other demyelinating disease.
For infants immunized with Haemophilus influenzae type b conjugate vaccines, booster immunization is usually recommended in the second year of life, typically between 12 and 18 months. This study assessed the effect of age at booster immunization on pre-immunization antibody trough levels and on subsequent responses, for a PRP-T conjugate vaccine. Subjects were healthy children who had received PENTA vaccine (DPT-IPV/PRP-T combination) as infants. They were enrolled and given measles-mumps-rubella vaccine (MMR) at 12 months of age, then randomly assigned to receive PENTA vaccine concurrently with MMR or at 15 or 18 months of age. Parents were asked to note any adverse effects after PENTA vaccination. Blood samples were obtained prior to PENTA vaccination and 4 weeks later, and tested for antibodies to each antigen. In total 253 children received PENTA vaccine: 86 at 12 months, 85 at 15 months and 82 at 18 months. Injection site redness and swelling were least extensive in the youngest group (p < 0.001) but their rates of occurrence did not differ with age. Anti-PRP levels were similar in each age group prior to immunization; post-booster geometric mean concentrations (GMCs) ranged from 13.0 microg/ml in the youngest to 33.9 microg/ml in the oldest subjects (p < 0.0001). For each of the other antigens examined, booster responses were strongest at 18 months. We conclude that anti-PRP levels are stable between 12 and 18 months in children previously given PRP-T vaccine. PENTA boosters given at 12 months appear to cause milder injection site morbidity whereas those given at 18 months result in stronger responses to virtually every constituent antigen, although each age group responded satisfactorily.
Although immunization programs with Haemophilus influenzae type b (Hib) conjugate vaccines have dramatically reduced disease incidence, few data are available regarding the duration of protection after vaccination. We measured serum anti-polyribosylribitol phosphate (PRP) levels in healthy 4- to 5- year-old children previously given 4 doses of PRP-T vaccine (at 2, 4, 6, and 18 months) or 1 dose of PRP-D vaccine (at 19 months) during clinical trials to assess antibody persistence. Concurrent with other preschool immunizations, half of the children were randomly assigned to receive a PRP-T booster immunization to assess responsiveness. Among 136 subjects who were primed with PRP-D, the baseline geometric mean concentration of antibody was 0.7 microg/mL (95% CI 0.5 to 0.9). Concentrations were <0.15 microg/mL in 24 (17.6%) subjects. Among 212 children who were primed with PRP-T, the geometric mean concentration was 2.2 microg/mL (95% CI 1.9 to 2.5) (P <.001). Only 2 (0.9%) had concentrations <0.15 microg/mL. Four weeks after PRP-T immunization, geometric mean concentrations had increased to 98.4 and 102.0 microg/mL, respectively. Responses were strong even in those with low or undetectable preimmunization antibody levels. Spontaneous increases in antibody levels were seen in 9 (5.2%) of 172 subjects not given additional PRP-T. We concluded that among 4- to 5-year-olds, anti-PRP levels remained above 0.15 microg/mL in nearly all children after PRP-T priming and in most after PRP-D priming, and that both groups were able to respond vigorously to restimulation, consistent with persistent immune memory.
BACKGROUND: Tetanus-diphtheria toxoids (Td) booster immunization is generally recommended for Grade 9 students (14- to 16-year-olds) but targeting younger students may enhance vaccine uptake or facilitate simultaneous vaccinations. However, earlier vaccination might cause greater side effects. This study was undertaken to compare the safety of Td vaccinations in students in Grade 6 (11 to 12 years old) and Grade 9. METHODS: A controlled, sequential assessment of Td vaccine, adsorbed, was conducted in one urban school district, starting with Grade 9 students. Grade 6 students were given Td concurrently with Dose 3 of hepatitis B vaccine. Adverse effects were assessed during visits 2 days after vaccination. Participation criteria, immunization technique and assessment procedures were standardized. RESULTS: Of 410 students vaccinated, 204 in Grade 9 and 206 in Grade 6, 391 (95.4%) were assessed in person. Nineteen missed follow-up visits but telephone interviewers established that none missed school because of vaccine side effects. At follow-up Grade 6 students more often reported deltoid pain with arm movement (35.2% vs. 10.8%, P < 0.001). Injection site redness > or = 50 mm in diameter was present in 12.2% of Grade 6 and 3.6% of Grade 9 students (P < 0.001) whereas swelling > or = 50 mm diameter was present in 22.4 and 10.8%, respectively (P < 0.01). Fewer than 10% of subjects took analgesics for injection site pain. Only 5 students (1.3%) rated Td site morbidity as severe/unacceptable. Hepatitis B site morbidity was minimal in comparison. CONCLUSION: Td boosters were moderately reactogenic in adolescents. Younger students more often experienced injection site morbidity but considered it bearable. Booster immunizations can reasonably be offered within the age range of 11 to 16 years.
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To determine the prevalence of hepatitis A virus (HAV) infections in children in a large urban center, a point prevalence survey was conducted using a novel, ultrasensitive assay for HAV-specific IgG in saliva. A structured sample of 224 grade-six students (5.8% of grade registrants) was obtained from 23 schools throughout Vancouver. All students provided saliva samples adequate for testing. The anti-HAV prevalence rate was 7.1% (95% confidence interval, 4.1%-11.3%). Among 167 Canadian-born students, only 5 (3%) were positive, whereas among 57 students born elsewhere, 11 (19.3%) were positive (P < .001), with circumstances in the latter group supporting infection prior to emigration. No clustering of positive persons was evident. The cumulative risk of HAV infection in Canadian-born children was low through age 11-12 years even in less affluent parts of the city, speaking against a need for routine use of HAV vaccine in this setting.
Although detection of disease-induced hepatitis A virus (HAV)-specific antibodies in saliva has been successfully utilized in a few epidemiological studies, available assays fail to detect lower salivary anti-HAV levels associated with vaccine-induced immunity. We present a new capture enzyme immunoassay which employs a three-layer antibody recognition system. Evaluation of paired saliva-serum specimens from 1,025 international travellers, 134 other volunteers, and 91 hepatitis A vaccine recipients demonstrated 99.6% (95% confidence interval, 98.4 to 99.9) specificity and 98.7% (95% confidence interval, 97.7 to 99.4) sensitivity of this salivary assay in differentiating between immune and susceptible individuals, compared with serum-based methods. We conclude that this assay is sufficiently sensitive for reliable detection of both vaccine- and infection-induced HAV-specific immunoglobulin G in saliva, even when corresponding anti-HAV levels in serum are very low (< 1 IU/ml).
As grants from agencies shrink, universities and academic researchers are pursuing work on clinical trials funded by pharmaceutical manufacturers. The author, an investigator with a nonprofit research cooperative, offers insight and advice on industry-sponsored trials. He finds that the "doorways" to industry research are hidden, as are industry priorities. Researchers with limited experience have trouble "breaking in" and, when they do work on industry-sponsored trials, are usually given the less interesting work at first. Difficulties encountered during industry-sponsored trials include lack of researcher input, unreasonable enrolment requirements, delays by the sponsor and quashing of publication of unfavourable results. On the positive side, a good experience can include stimulating research, with the researcher playing a substantial role in all phases, an adequate budget, rapid turnaround and publication of the results. To succeed in this environment, trialists should have established expertise, technical and managerial abilities, appropriate resources and strong personal attributes; a national or international reputation is an asset. Researchers can benefit from universities' industry liaison offices and from strong oversight by institutional review boards.
OBJECTIVE: To describe changes in the number of cases of Haemophilus influenzae type b (Hib) infections among Canadian children before and after the introductory phases of Hib vaccination. DESIGN: Multicentre case series. SETTING: All 10 pediatric tertiary care centres across Canada participating in the Immunization Monitoring Program, Active (IMPACT) of the Canadian Paediatric Society and the Laboratory Centre for Disease control. PATIENTS: Children with a Hib infection admitted to any of the participating hospitals from 1985 to 1994. Annual case totals from 1985 to 1990 were determined from records of hospital laboratories or coded discharge diagnoses, or both. From 1991 to 1994 intensive case surveillance was conducted on the wards in addition to thorough record searches as above. OUTCOME MEASURES: Estimated annual case totals for 1985-90. For 1991-94 intensive surveillance for quarterly case totals, yearly age distribution of cases, and proportion of recent cases that represent vaccination failures or missed opportunities to prevent infection. RESULTS: The total number of Hib cases from 1985 to 1990 was 2095; from 1991 to 1994, there were 326 laboratory-confirmed cases and 15 probably cases supported by Hib antigen detection. The annual number of cases declined from an estimated 485 in 1985 to 24 in 1994, a decrease of 95.1%. The steepest interannual decrease (63.7%) occurred between 1992 and 1993, following the introduction of infant-based vaccination programs across Canada. The number of Hib cases involving children most at risk (those 6 to 18 months old) decreased from 78 in 1991 to 4 in 1994. Of the 24 cases in 1994, 6 were categorized as preventable, 1 was fatal, and 8 were vaccine failures (2 of which involved currently used vaccines). CONCLUSION: The prevalence of Hib infections reported by the IMPACT centres has declined greatly since the introduction of vaccination programs. However, deaths and complications continue to occur, attesting to the need to vaccinate all eligible infants and children against this virulent pathogen.
PURPOSE: To examine the evidence concerning the safety and effectiveness of the inactivated hepatitis A virus vaccine recently licensed for use in Canada. DATA SOURCES: The main source of information were papers presented at the International Symposium on Active Immunization against Hepatitis A, held in Vienna, Austria, Jan. 27-29, 1992. The bibliographies of these papers were searched for additional references. Recent articles describing the new vaccine and the epidemiologic aspects of infection with hepatitis A virus (HAV) were also reviewed. STUDY SELECTION: Peer-reviewed reports of trials approved by a government regulatory agency on the safety, immunogenic properties and efficacy of the vaccine. DATA EXTRACTION: The authors assembled key reports on adverse reactions, protection from disease and serologic assessment of immune response in vaccine recipients; data from these reports were tabulated and analysed. RESULTS OF DATA SYNTHESIS: The new vaccine contains the HM175 strain of HAV, which is adapted to grow in tissue culture. The virus is purified, inactivated with the use of formaldehyde and adsorbed onto aluminum hydroxide. The recommended dose for adults is 720 enzyme-linked immunosorbent assay (ELISA) units in a 1.0-mL dose and for children 360 ELISA units in a 0.5-mL dose, injected intramuscularly. The usual schedule is three serial doses, the second given 1 month and the third 6 to 12 months after the initial dose. Reported side effects are infrequent and minor. In healthy persons who have received two doses, the seroconversion rate is almost 100%. Protective efficacy after two doses is estimated to be 94%. However, the persistence of protective antibodies has been studied only over the short term (3 years). CONCLUSIONS: The new HAV vaccine is safe, effective and best suited to pre-exposure prophylaxis in people with an increased risk of infection for an extended period, such as travellers to areas where the disease is endemic. Further studies are needed to determine whether infants respond well to the vaccine and whether the vaccine protects recipients from subclinical infection and associated fecal shedding of HAV. Controlled trials to determine the duration of protection beyond 3 years and the effects of more rapid dosage schedules are also needed.
A booster dose of Haemophilus influenzae type b conjugate vaccine in the second year of life is the final step in the recommended series of doses to protect infants from invasive infection. This study assessed the safety and immunogenicity of PRP-T conjugate vaccine booster doses (Act-HIB, Connaught Laboratories Ltd). The participants were 367 healthy children who had taken part in a study of primary immunization with PRP-T. At 18-19 months old, subjects were randomly assigned to receive diphtheria-pertussis-tetanus (DPT) and PRP-T vaccines either mixed in one syringe (n = 183) or separately in opposite limbs (n = 184). Adverse events were monitored for 48 h after immunization. Blood was obtained prior to vaccination in half of the subjects (combined injections group) and following vaccination in all subjects to test for antibodies to each of the antigens administered. Local adverse reactions were infrequent with PRP-T alone and equally frequent at sites of DPT or DPT/PRP-T injection, except for redness > or = 25 mm in diameter which was more frequent after the combined vaccines (25.1 versus 14.1%, p < 0.01). Systemic adverse events did not differ in type or frequency between groups. Before immunization, the geometric mean anti-PRP level in those tested was 0.41 micrograms ml-1; 26.7% had levels below 0.15 micrograms ml-1. Both treatment groups responded strongly to vaccination. In those serially tested, anti-PRP levels rose by over 90-fold, to 38.1 micrograms ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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OBJECTIVE: To estimate the contribution of whole-cell pertussis vaccine to severe local reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine. DESIGN: Double-blind randomized controlled trial. SETTING: Urban community. PARTICIPANTS: Volunteer sample of 200 healthy children 4 to 6 years old who were eligible for the fifth dose of DPT vaccine. INTERVENTIONS: Children received, in both arms, either diphtheria toxoid-tetanus toxoid (DT) and monovalent pertussis vaccines (group A, 99 children) or DPT and meningococcal vaccines (group B, 101 children). All were licensed products from single lots. The children were assessed 24 hours later by a trained observer. Serum samples obtained before vaccination were tested for antibodies to tetanus and diphtheria toxins and five pertussis antigens by means of enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of severe local reactions (an area of redness or swelling or both of 50 mm or greater) 24 hours after vaccination. Relation between serum antibody levels before vaccination and rates of severe local reactions to corresponding vaccines. RESULTS: All of the subjects were followed up 24 hours after vaccination. Severe redness was present in 38% given DPT vaccine, 29% given intramuscular pertussis vaccine and 9% given DT vaccine (p < or = 0.002, three-way comparison). Severe swelling was common after vaccination with all three products. After intramuscular pertussis vaccination a relation was evident between the prevaccination levels of antibody to whole-cell pertussis bacteria and the rates of redness (p < 0.02) but not between the prevaccination subcellular antibody levels and the rates of redness. CONCLUSION: That pertussis vaccine resembled the DPT vaccine in causing severe redness suggests that it is the principal cause of such reactions after DPT vaccination. The DT vaccine was also reactogenic; thus, cumulative sensitization to one or more of its constituents may be a factor.
OBJECTIVE: To assess the side effects and immune responses after three serial doses of a new inactivated hepatitis A vaccine in people 40 years of age or more. DESIGN: Open, noncomparative trial. SETTING: A hospital, a regional laboratory and public health units in British Columbia. PARTICIPANTS: A volunteer sample of 64 healthy adults aged 40 to 61 years who were seronegative for hepatitis A virus (HAV). All were staff or associates of the health facilities. Exclusion criteria included elevated serum alanine and aspartate aminotransferase levels, a history of liver disease and recent travel to areas of high risk for HAV infection. INTERVENTION: A formalin-inactivated, alum-adsorbed vaccine containing 720 ELISA (enzyme-linked immunosorbent assay) units of antigen from HAV strain HM175 per 1.0-mL dose was injected intramuscularly into the delgoid area. The second and third doses were given 1 and 6 months later respectively. MAIN OUTCOME MEASURES: A detailed diary of any adverse effects for 3 days after each dose. HAV antibody levels in blood samples taken before and 30 days after each dose. RESULTS: All subjects completed the planned series of vaccinations and blood tests; symptom diaries were returned after 190 (99%) of 192 vaccinations. Local symptoms, most often soreness, were reported after 46% of the vaccinations but were mild and usually resolved within 24 hours. A temperature of more than 38.0 degrees C was never reported. Seroconversion occurred in all cases after the two primary doses, and the subjects were still seropositive at 6 months. After the booster dose the geometric mean titre was 2380 mIU/mL, all values being 200 mIU/mL or greater. CONCLUSION: In healthy adults 40 years of age or more the HAV vaccine was well tolerated and highly immunogenic. Final antibody levels were much higher than reported in people passively immunized against HAV with immune serum globulin.
OBJECTIVE: Influenza immunization is recommended for children with chronic conditions and children receiving chronic acetylsalicylic acid therapy. Our study assessed the safety and immunogenicity of this vaccination in children with chronic arthritis. METHODS: The frequency of possible adverse reactions following influenza vaccination, and virus specific HI antibody levels prior to and 4 weeks after vaccination with an inactivated split virus vaccine prepared for the 1991/92 season, were assessed in a prospective open study of children with chronic arthritis. Thirty-four patients were assessed clinically at vaccination and one month later. Local symptoms at the injection site and systemic symptoms were assessed by diary in 26 patients and 13 immunized healthy control children. RESULTS: Tenderness and/or redness at the injection site, and fever occurred equally in patients and controls. Malaise/nausea occurred in 12 patients and 3 controls (p = 0.3), but patients had more symptomatic days than controls (p = 0.01). No child with inactive arthritis developed a swollen joint following immunization. There were no significant differences between the 2 visits for a.m. stiffness, pain (VAS), global assessment, joint count or erythrocyte sedimentation rate (ESR). More patients improved than deteriorated by each measure. Three patients deteriorated by global assessment, 7 patients had an increased joint count. At least 95% of patients developed presumably protective levels of antibodies (HI titers > or = 40) to each virus. Preimmunization titers, seroresponse rates (4 x rise or rise from < 20 to > or = 40) and final titers were the same between patients (whether or not they were taking prednisone or a second line antirheumatic drug) and controls. CONCLUSION: There was no convincing evidence that influenza vaccination is associated with significant adverse reactions or arthritis flares in children with chronic arthritis. Children with chronic arthritis appeared to respond adequately to influenza vaccination.
OBJECTIVE: To quantify accurately the rate of adverse reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine and to test the hypothesis that large local reactions are attributable to the diphtheria toxoid. DESIGN: Double-blind randomized controlled trial. SETTING: Suburban community public health unit. PARTICIPANTS: Healthy children 4 to 5 years of age with a history of having received four doses of adsorbed DPT vaccine. INTERVENTIONS: Subjects were given either the standard DPT vaccine (with 25 Lf units of diphtheria toxoid) or a modified DPT vaccine (with 10 Lf units of diphtheria toxoid). They were assessed 24 hours later by a nurse. Serum samples obtained before vaccination were tested for diphtheria and tetanus antitoxin levels by means of neutralization assay and enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of large local reactions (an area of redness or swelling or both of 5 cm or greater) 24 hours after vaccination in the two groups. Relation between serum antitoxin levels before vaccination and the rate of large local reactions in each group. RESULTS: Of the 250 subjects enrolled 124 received the standard vaccine and 126 the modified one. Large local reactions occurred in 71% of the subjects receiving the standard vaccine and 52% of those receiving the modified one (p less than 0.01). In the former group large erythematous reactions occurred significantly more often in those with an elevated prevaccination diphtheria antitoxin level than in those without an elevated level; no relation was found between such reactions and the prevaccination tetanus antitoxin level. Reduced arm movement was evident in 45% of the children in the two groups. Few had systemic adverse reactions. CONCLUSIONS: Large local reactions occur frequently after the preschool administration of the DPT vaccine. These reactions are uncomfortable but not serious. They result in part from the large amount of diphtheria toxoid in the standard DPT vaccine.
OBJECTIVE: To compare the adverse effects, particularly generalized aching, of a trivalent, inactivated whole-virion vaccine (WVV) and split-virion vaccine (SVV) for influenza in hospital personnel. DESIGN: Recipient-blinded study; first-time vaccinees were randomly assigned to receive either of the vaccines from one manufacturer in the 1989-90 influenza season. Subjects were asked to complete a symptom questionnaire during the 48 hours after immunization. SETTING: Annual influenza program for staff of a tertiary care children's hospital. PARTICIPANTS: Volunteers were sought among approximately 2200 members of the hospital staff. Of the 358 vaccinated for the first time, 333 (93%) returned the questionnaire. RESULTS: During the 48 hours after vaccination 13% of the SVV recipients reported generalized aching, as compared with 26% of the WVV recipients (p less than 0.01). Also, the SVV group reported fewer visible local reactions and more transient arm soreness, but the actual differences between the two groups were small. The occurrence of mild symptoms was equally common in the two groups (local reactions in at least 70% of cases, systemic reactions in at least 33%). In each group 1% of the subjects reported missing work because of the vaccination. CONCLUSIONS: The use of SVV reduces the rate of the most objectionable of the common adverse effects of influenza vaccination. Therefore, as with children, it might be more acceptable to health care workers than the current use of WVV.
Reactogenicity of trivalent influenza vaccine prepared for the 1988-89 season was assessed as part of a first-time voluntary influenza prevention program among hospital staff. Of approximately 500 full-time workers in areas with the highest concentrations of patients at high risk for influenza complications offered the vaccine 288 accepted. Of these, 266 (92%) returned a questionnaire regarding any symptoms experienced within 48 hours after vaccination; 238 (90%) of the respondents reported adverse effects. Soreness at the injection site was described by 229 subjects, 58 (25%) of whom had constant aching and 123 (54%) soreness with arm movement. Symptoms resolved in 1 to 2 days, and only 21 (9%) of those who reported symptoms said they took analgesic medication. Systemic adverse effects were described by 130 subjects (49%). Intercurrent illness accounted for some of these complaints, but 65 people (24%) described at least two of the following symptoms: generalized aching, tiredness, nausea, chills or onset of fever within 12 hours after vaccination (a symptom complex previously attributed to influenza vaccine). Systemic symptoms resolved within 0.5 to 2 days. Thirteen subjects (5%) reported missing work because of arm soreness (1 subject) or systemic symptoms (12). Adverse effects were encountered more often than expected, probably because most of the workers were young and lacked immunity to influenza. Acceptability of the program could likely be improved by using a split-virus vaccine.