Elsevier

Vaccine

Volume 28, Issue 24, 28 May 2010, Pages 4073-4078
Vaccine

Changing epidemiology of invasive Haemophilus influenzae in Ontario, Canada: Evidence for herd effects and strain replacement due to Hib vaccination

https://doi.org/10.1016/j.vaccine.2010.03.075Get rights and content

Abstract

The epidemiology of invasive Haemophilus influenzae infections was evaluated in Ontario between 1989 and 2007 to assess the impact of the introduction of the conjugate H. influenzae serotype b (Hib) vaccine in the early 1990s on Hib and non-Hib serotypes in both vaccinated and unvaccinated cohorts as well as the possibility of “strain replacement” with non-vaccine H. influenzae strains. Data were collected by the provincial Public Health Laboratories-Toronto, Ontario Agency for Health Protection and Promotion, which performed almost all serotyping on invasive (blood, CSF, other sterile sites) H. influenzae strains isolated in the province during the study period. Temporal trends for Hib, other typeable strains, and non-typeable H. influenzae were evaluated by Poisson regression, controlling for the specimen submissions. Prior to infant Hib vaccination, the most commonly observed serotype was serotype b (64.9%). Subsequently, 70.3%, 13.6%, and 9.4% of isolates were non-typeable, serotype f, and serotype b, respectively. Infant Hib vaccination resulted in a decrease in Hib incidence in all age groups (pooled IRR 0.432) and marked increases of non-typeable and serotype f H. influenzae in children aged <5 years (IRR 2.4 and 3.0, respectively). Vaccination against Hib has altered the epidemiology of invasive H. influenzae infections in Ontario. Prevention of invasive Hib disease was observed in both vaccinated and unvaccinated age groups. Invasive H. influenzae infection now commonly presents as sepsis due to non-typeable H. influenzae in older individuals. However, strain replacement of Hib with serotype f and non-typeable strains in children under 5 years was documented.

Introduction

Invasive infection caused by Haemophilus influenzae, particularly serotype b (Hib), has long been a major cause of morbidity and mortality, especially in children aged <5 years [1]. Prior to the introduction of vaccines against Hib, typical invasive Hib presentations included meningitis, bacteremic pneumonia, epiglottitis, septicemia, cellulitis, and osteoarticular infections. Meningitis was most common, comprising approximately 50% of invasive Hib cases [1]. The impact of vaccination on Hib epidemiology was dramatic and rapid. Several Hib vaccines were introduced in Canada within the last 25 years: a polysaccharide vaccine was introduced in Canada in 1986, the first conjugate vaccine, PRP-D, was available in 1988 for children over 18 months of age, and the current conjugate vaccine provided to infants beginning at 2 months of age, PRP-T, was introduced in 1992. Hib vaccination dramatically reduced the incidence of infection in both vaccinated age groups and in children too young to be vaccinated in Canada and other countries [2], [3], [4], [5]. The impact on unvaccinated children implies the existence of herd effects that result from decreased pharyngeal carriage of the pathogen among vaccinated children [3], [4].

Hib is not the only serotype of H. influenzae with pathogenic potential: six H. influenzae serotypes (a–f) are distinguished based on capsular antigens, and strains may also be non-typeable. An important and as yet unanswered question related to the epidemiology of H. influenzae concerns the question of strain replacement. In particular, it is unclear whether the elimination of Hib increases the likelihood of invasive H. influenzae disease caused by other serotypes, as a result of decreased competition with Hib [6]. Limited evidence suggests that strain replacement may actually be occurring in Canada. The Immunization Monitoring Program, ACTive (IMPACT) conducts active, prospective surveillance of invasive H. influenzae infections in 12 pediatric hospitals representing all Canadian provinces and 2 territories. IMPACT recently reported that between 1996 and 2001, 60% of invasive H. influenzae infections in children were caused by non-serotype b H. influenzae with the majority due to non-typeable H. influenzae[7]. An epidemiological evaluation of invasive H. influenzae isolates from patients of all ages was recently conducted in Ontario's neighboring province Manitoba where it was observed that invasive cases are now primarily caused by non-typeable and serotype a H. influenzae and a similar picture was observed in a recent report on invasive H. influenzae in northwestern Ontario, next to the Manitoba border [8], [9]. However, public health surveillance systems in Canada currently focus only on reports of Hib, making the evaluation of strain replacement in H. influenzae, and its impact on trends in invasive disease caused by this pathogen, difficult to detect using surveillance data [8].

The Public Health Laboratory-Toronto of the Ontario Agency for Health Protection and Promotion, Toronto, Canada (PHL-T) currently performs antimicrobial susceptibility testing and capsular typing on invasive isolates of H. influenzae. Although Hib identification is the main reason why isolates are submitted to the PHL-T, the PHL-T records contain typing data on almost all of the invasive H. influenzae isolates from the primary isolating laboratories in Ontario as these are referred to PHL-T for confirmation. Thus, PHL-T records are a de facto source of population-based surveillance data on invasive H. influenzae infection in the province of Ontario. We sought to use this database in order to: (i) evaluate the epidemiology of invasive H. influenzae isolates in Ontario between 1989 and 2007; (ii) to assess the impact of the introduction of universal infant Hib vaccination on non-vaccinated age groups; and (iii) to evaluate the impact of immunization on the epidemiology of non-Hib serotypes, with a focus on the question of whether strain replacement might be occurring in Ontario.

Section snippets

H. influenzae isolate collection and identification

Between January 1, 1989 and July 1, 2007, 1455 unique invasive H. influenzae isolates were received from across Ontario for serotyping at the PHL-T. Submission of invasive H. influenzae isolates to PHL-T is voluntary; however, PHL-T received 95% of the Ontario Hib isolates reported to the Public Health Agency of Canada during the course of this study. Isolates were collected from cerebrospinal fluid (CSF), blood, and other sterile sites, including aspirates and tissue. When organisms were

Invasive H. influenzae isolates in Ontario, 1989–2007

1455 unique invasive H. influenzae isolates were analyzed. Between 47 and 112 H. influenzae isolates from sterile sites were received per year. Isolates were received from 34 of 36 health units across the province. Southern health units comprised 94.9% of the isolates and the greatest proportion of isolates was received from the Toronto Public Health Unit (29.7%).

Change in the age of patients with invasive H. influenzae infections with vaccination

Over the entire study period, the greatest number of isolates was received from adults over 65 years (37.4%) and children <5 years of

Discussion

The introduction of a conjugate vaccine against Hib represents a key public health advance of the last 50 years [5], [15], [16]. We report here that the incidence of invasive Hib disease in children, reflected in the submission of invasive Hib isolates to Ontario's Public Health Laboratory-Toronto, has fallen sharply since the introduction of the Hib conjugate vaccine. This phenomenon has been reported previously in other jurisdictions [16], [17]. Furthermore, we document herd effects acting on

Acknowledgements

H. Adam was supported by a Clinical Microbiology Fellowship from the Ontario Ministry of Health and Long Term Care (June 2006–June 2009). D. Fisman is supported by an Early Researcher Award from the Ontario Ministry of Research and Innovation, the Canadian Institutes for Health Research Catalyst Program for pandemic influenza modeling, and the MITACS Centre for Excellence.

Conflicts of interest statement: D. Fisman received matching funds for his Early Researcher Award from Sanofi-Pasteur. All

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