Canadian vaccine research networks: Vaccine safety resources for Canada.

The Public Health Agency of Canada / Canadian Institutes of Health Research Influenza Research Network (PCIRN), established in 2009 to undertake evaluative research to inform public health decision making in Canada, is now being replaced by the Canadian Immunization Research Network (CIRN), which will retain the mandate of PCIRN but expand it to all vaccines including influenza vaccine. CIRN is organized as a network of networks focusing on undertaking research in the areas of vaccine safety, adverse events following immunization (AEFIs), vaccine hesitancy, vaccine effectiveness, and vaccine coverage. CIRN's networks include: a clinical trial network; a laboratory network; a modelling and economics network; a network of social science and humanities researchers; a vaccine safety surveillance network; a hospital-based surveillance network; a clinic network to evaluate serious AEFIs; and a network that links vaccine research capacity in provincial health agencies and departments. PCIRN has contributed to Canada's vaccine safety surveillance system and has facilitated the translation of safety research into policy. Vaccine safety surveillance and research will remain a focus of the newly formed Canadian Immunization Research Network.

The Canadian Immunization Monitoring Program, ACTive (IMPACT): Active surveillance for vaccine adverse events and vaccine-preventable diseases.

For almost 25 years the Canadian Immunization Monitoring Program, ACTive (IMPACT) has been conducting active surveillance for severe adverse events following immunization (AEFIs) and vaccine-preventable diseases in children. The network, which consists of volunteer paediatric infectious diseases investigators at 12 tertiary care paediatric hospitals, is an important component of Canada's AEFI monitoring. The network employs nurses at each of the sites to search for and report possible AEFIs to local, provincial and national public health authorities. The active nature of the surveillance ensures a high level of vigilance for severe AEFIs in children.

Safety and immunogenicity of a pentavalent combination vaccine (diphtheria, tetanus, acellular pertussis, polio, and haemophilus influenzae type B conjugate) when administered as a fourth dose at 15 to 18 months of age.

A DTaP-IPV//PRP-T combination vaccine (Pentacel) has been universally used in Canada to provide immunization against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b with single injections at 2, 4, 6 and 18 months of age. This randomized, multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age, similar to the US immunization schedule. Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and randomized to receive a fourth dose at 15, 16, 17 or 18 months. Antibody levels for each vaccine antigen were measured prior to and four weeks following booster vaccination. Overall, 1782 subjects were immunized and monitored for adverse events, and 735 were evaluated for immune responses. Preimmunization antibody levels differed minimally by age, for all antigens. The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months, as demonstrated by specific antibody geometric mean titers, seroprotection/seroresponse rates, and reverse cumulative distribution curves. The fourth dose was well tolerated in all age groups. Toddlers at 15, 16, 17 or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine.

Pelvic inflammatory disease associated with Enterobius vermicularis.

A case of pelvic inflammatory disease in a sexually non-active 13 year old girl is described, with evidence of pinworms as the cause. Albendazole treatment cleared the infestation but the patient suffered subsequent bouts of lower abdominal pain. The literature is reviewed regarding abdominal pathology associated with ectopic migration of pinworms.

Emergence of penicillin-nonsusceptible Streptococcus pneumoniae invasive clones in Canada.

Distinctive international clones of penicillin-nonsusceptible and multidrug-resistant Streptococcus pneumoniae are increasingly being reported. We investigated the spread of these clones in Canada through an active surveillance that was carried out at 11 Canadian pediatric tertiary care centers from 1991 to 1998. All penicillin-nonsusceptible isolates were serotyped, tested for antibiotic susceptibility, and genotyped by pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD). Forty-five penicillin-nonsusceptible S. pneumoniae isolates were evaluated. Eleven serotype 9V isolates and six serotype 14 isolates displayed identical RAPD and PFGE fingerprint profiles. Twelve (70%) of these isolates were encountered in Quebec. The 9V/14 clone and the Spanish-French clone had similar PFGE fingerprint patterns. Eight isolates of serotype 23F and two isolates of serogroup 14 had the same fingerprint profiles and displayed resistance to three or more antibiotic drug classes. This clone was first detected in Calgary (Alberta) and in 1996 appeared simultaneously in various regions of Canada. This clone showed a PFGE fingerprint pattern similar to that of the Spanish-U.S. 23F clone. Our data show the emergence across Canada of two international clones of penicillin-nonsusceptible S. pneumoniae: (i) serotypes 9V and 14 related to the Spanish-French clone and (ii) the 23F Spanish-U.S. clone. The source of the first clone was in Quebec and the second international clone was probably originated from the United States. The exact reasons for the successful spread of these clones within Canada and their contribution to increased resistance to antibiotics have yet to be explored.

Assessment of injection site reactions to an acellular pertussis-based combination vaccine, including novel use of skin tests with vaccine antigens.

Recent reports indicate that children receiving a fifth consecutive dose of DTPa vaccine have a moderate likelihood of developing a large injection site reaction, the etiology of which remains unknown. We assessed the frequency, severity and outcome of local reactions in 205 children who had participated in earlier studies of DTPa-based vaccines and were due for a fifth dose at 4-6 years. DTPa.IPV vaccine was given intramuscularly in the deltoid. To explore the role of cell-mediated immunity in local reactions we applied epicutaneous (patch) tests at the same visit, using code-labeled solutions of DTPa.IPV, DT, Pa, IPV, alum solution and saline, leaving them in place for 48 h. Subjects were assessed by research staff on the following day. Injection site redness or swelling >/=50 mm diameter was present in 24.4 and 20.5%, respectively, but none of the subjects had fever or persistent limitation of arm movement. Large local reactions were more common in bigger children (P<0.01) but not in those with allergy/atopy. Large reactions resolved within 14 days. Positive skin tests (erythema) occurred at 85 test sites in 51 of 187 evaluable children, principally with DTPa.IPV, IPV and alum solutions. However, only DT and Pa solutions caused positive tests significantly more often in children with injection site redness > or =50 mm than in non-reactors (P < 0.05, odds ratios 5.2 and 6.1, respectively). Presence of alum in most test solutions might have confounded the results as it caused non-specific inflammation when applied alone. We conclude that local reactions to a fifth dose of DTPa-type vaccine are frequent and sometimes extensive but not incapacitating and that concurrent skin testing has potential to identify the vaccine antigens and immune mechanism contributing to local reactions with more refinement of the method.

Population-based surveillance of invasive group A streptococcal disease in British Columbia: 1996 to 1998.

OBJECTIVE: To identify and describe all cases of invasive group A streptococcal (GAS) infection occurring in British Columbia during a two-year period. DESIGN: Active, laboratory-based surveillance with supplemental case description. SETTING: Forty community and regional hospitals and the provincial laboratory participated, encompassing all health regions. POPULATION STUDIED: Entire provincial population from April 1, 1996 to March 31, 1998. MAIN RESULTS: Over the 24-month surveillance period, 182 eligible cases were identified, yielding a mean annual incidence rate of 2.3/100,000. Patients ranged in age from two to 91 years, with a mean of 39.1 years. Soft tissue infections accounted for 89 of 130 cases (68.5%) with a defined clinical syndrome, 20 of which were necrotizing fasciitis. Injection drug use was described in 55 patients, who, as a group, were younger, more likely to have soft tissue infections and less likely to die of infection than nondrug users. Other risk factors for infection included HIV infection (19 patients); skin damage (26 patients, damage independent of injection drug use); chronic illness (27 patients); and immunosuppresion (three patients). Death from GAS infection occurred in 15 of 131 (11.5%) cases with known outcome, yielding an annual case fatality rate of 1.9/million population. Among necrotizing faciitis cases, the mortality rate was 30%. CONCLUSIONS: Invasive GAS infections are rare in British Columbia and tend to involve persons with chronic illness or prior skin trauma, especially injection drug abuse, which accounted for nearly half of the cases.

Practical vaccination guidelines for children with cancer.

The paediatrician or family physician usually provides primary care for children diagnosed with cancer. Immunizations are an important facet of this care, but guidelines for the immunization of these immunocom-promised children are difficult to locate and cumbersome to follow. The authors have developed immunization guidelines for children receiving chemotherapy for cancer that will hopefully facilitate the care of this group of children. Before initiating any immunizations in this group of children, communication with a cancer specialist is recommended. There is little evidence-based literature to support immunization guidelines in immunocompromised hosts; thus, the recommendations presented are derived from the available literature, existing guidelines and expert opinion.

Evaluation of ready-to-use and multi-dose influenza vaccine formats in large clinic settings.

Large immunization clinics are commonly held to deliver influenza vaccine to seniors and others. Vaccine is typically dispensed from multi-dose vials but pre-filled syringes are now available, offering time savings for vaccinators. To determine if the higher purchase price of such syringes is offset by savings in time and injection supplies, we did a controlled comparison of syringe and vial formats in two large, concurrent, community-based influenza vaccination clinics. Vaccine preparation and immunization times were carefully documented along with costs for vaccine purchase, storage and injection supplies. Servicing 1,000 clients required 27 nurse hours using syringes and 36 hours using vials but the savings for personnel ($234) and supplies ($1,190) using syringes were exceeded by higher vaccine cost ($2,090 premium) and extra storage costs ($260) for bulkier packaging. Depending upon product and packaging style, programs using vials are cheaper by $709-$926 per 100 doses delivered compared to using pre-filled syringes.

School-based hepatitis B vaccination programme and adolescent multiple sclerosis.

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.

Extended follow-up of antibody levels and antigen responsiveness after 2 Haemophilus influenzae type b conjugate vaccines.

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.

A comparative study of PENTA vaccine booster doses given at 12, 15, or 18 months of age.

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.

Effect of reminder notices on the timeliness of early childhood immunizations.

OBJECTIVE: To determine whether reminder notices would improve the timeliness of toddler-age vaccinations. DESIGN: Prospective, randomized, controlled trial. POPULATION STUDIED: Two convenience cohorts of 320 children due to receive either measles-mumps-rubella (MMR) vaccine (at 12 months of age) or diphtheria-pertussis-tetanus (DPT)-inactivated polio (IPV)- Haemophilus influenzae type b (Hib) booster vaccine (at 18 months of age). SETTING: Suburban community. INTERVENTIONS: Parents of the identified children were randomly assigned either to a group to receive a reminder notice of pending vaccinations or a control group that did not receive a notice at a ratio of 1:1. Immunization uptake was assessed eights weeks after the initial due date for vaccination. RESULTS: Information was obtained for 224 children in the MMR group and 227 children in the DPT-IPV-Hib booster group. MMR uptake within eight weeks of the due date was about 90% in both the test and control groups, probably because of publicity surrounding a local college-based measles outbreak. In the DPT-IPV-Hib group, reminder notices had no effect; the uptake rates within eight weeks of the due date were 73.7% to 75.2%. Delays in immunization resulted mostly from parents' scheduling problems and provider-recommended delays. More than half of the parents whose child had delayed immunization did not recall receiving the reminder notice. CONCLUSIONS: Mailed reminders did not increase on-time immunization rates in the second year of a child's life. A telephone call or a more memorable reminder notice may be better suited to catch the attention of parents.

Comparative safety of tetanus-diphtheria toxoids booster immunization in students in Grades 6 and 9.

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.

Hepatitis A virus infections in urban children--are preventive opportunities being missed?

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.

Clinical trials and tribulations: a personal view of interacting with pharmaceutical manufacturers.

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.

New, ultrasensitive enzyme immunoassay for detecting vaccine- and disease-induced hepatitis A virus-specific immunoglobulin G in saliva.

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).