Population-based surveillance of Hib invasive infections in children in British Columbia Alberta and Ontario - 1995 to 1997

OBJECTIVE:

To assess vaccine effectiveness through enhanced disease surveillance following the change in childhood immunization programs in 1995, when all provinces and territories chose to use polyribosyl ribitol phosphate-tetanus protein (PRP-T) Haemophilus influenzae type b (Hib) conjugate vaccine, generally in combination with diphtheria-pertussis-tetanus inactivated polio vaccine (DPT-IPV) (as PENTA vaccine) because the protective efficacy of this regimen had not been directly measured.

DESIGN:

Prospective, active, laboratory-based Hib case surveillance was implemented in British Columbia and Alberta, and enhanced, stimulated laboratory surveillance in Ontario during 1995 to 1997, centred on invasive infections in children. Case details and immunization histories were uniformly collected and centrally collated.

MAIN RESULTS:

Thirty-eight Hib cases were detected, but only 12 cases arose among PENTA-eligible children, an attack rate of 0.85 cases/100,000 child-years of observation. Annual case totals declined from 20 in 1995 to seven in 1997, when only one to three cases were encountered in each province and the incidence rate in children under age five years was 0.6/100,000. Only four cases occurred after primary immunization with PENTA, a failure rate of 0.28 cases/100,000 child-years of observation. Three cases among PENTA-eligible children reflected parental refusal of infant vaccinations, accounting for 25% of cases in eligible children.

CONCLUSIONS:

PRP-T conjugate vaccine was highly effective when given in combination with DPT-IPV vaccine. Provincial programs that used this regimen resulted in the near elimination of invasive Hib disease in children, but unimmunized children remain at risk.Key Words: Children, Epidemiology, Haemophilus influenzae, Infection, Prevention, VaccineHaemophilus influenzae type b (Hib) was, until recently, the principal cause in children of purulent meningitis, and its sequelae of deafness and mental impairment (1,2). Hib also accounted for most cases of epiglottitis and a substantial proportion of the cases of pneumonia, bacteremia, cellulitis and septic arthritis (3,4).The control of Hib infections through immunization has been one of the major public health advances of the past decade (5,6). Disease control was achieved with a series of increasingly effective vaccines, starting with a plain capsular polysaccharide vaccine licensed in 1986 (7). The polysaccharide vaccine, containing polyribosyl ribitol phosphate (PRP), was able to protect by eliciting bactericidal and opsonizing antibodies but could not do so in children younger than 24 months of age, the group at greatest risk of Hib infection.In 1988, a novel PRP Hib diphtheria toxoid conjugate vaccine (PRP-D) (ProHIBit, Pasteur Mérieux Connaught, Toronto, Ontario) was licensed for use in children from 18 months of age (8,9). It was incorporated into routine childhood immunization programs in all provinces and territories except Manitoba. In 1992, the current generation of Hib conjugate vaccines was licensed in Canada (10), including PRP-tetanus (PRP-T) (Act-HIB, Pasteur Mérieux Connaught), PRP-meningococcal (PRP-OMP) (PedvaxHIB, Merck Frosst Canada Inc, Kirkland, Quebec), and CRM₁₉₇ oligosaccharide (HbOC) (HibTITER, Wyeth-Ayerst Canada Inc, Ste-Laurent, Quebec) Hib conjugate vaccines, all of which were immunogenic enough to use in infants as young as two months of age. Each product initially found a market in one or more jurisdictions, but in 1995, all provinces and territories chose to use PRP-T vaccine, generally in combination with diphtheria-pertussis-tetanus inactivated polio vaccine (DPT-IPV) (as PENTA, Pasteur Mérieux Connaught) (11). Manitoba opted to use a combination of DPT and PRP-T with oral poliomyelitis vaccine.When PRP-T vaccine was selected for use by all provinces and territories, evidence for its protective efficacy was indirect, based on studies of immune responses (12,13). Efficacy was assumed because responses elicited by PRP-T matched or exceeded responses elicited by other Hib vaccines with demonstrated protective efficacy. Whether protection would be reduced by combining PRP-T with DPT-IPV was uncertain because serum anti-PRP levels were somewhat lower after the combination than after the separately injected vaccines (13). Also of concern was the observation that anti-PRP levels in serum declined substantially following completion of the three-dose primary series at six months of age. By the time of the recommended booster dose at 18 months of age, anti-PRP levels were undetectable or low (less than 0.15 μg/mL) in 27% to 45% of children (14,15). The possibility existed that breakthrough infections might occur during this serum antibody nadir, although the minimum antibody level required for protection has not been determined for Hib conjugate vaccines. Some experts argued that because such children responded strongly to booster immunization, evidence of persistent immunological memory, susceptibility to infection was unlikely (16).In 1994, Pasteur Mérieux Connaught sponsored several postmarketing surveillance projects to gauge the effectiveness of PRP-T vaccine given as the PENTA combination product. The study described here involved an innovative collaboration between three provinces and the Canadian Paediatric Society/Laboratory Centre for Disease Control Immunization Monitoring Program, ACTive (IMPACT) (17). The latter had been conducting Hib case surveillance at paediatric tertiary care centres across Canada since 1992 (6). The purpose of this study was to assess program and vaccine effectiveness during the initial three years of PENTA vaccine use in a large population.