Gregory J. Tyrrell

Changing Epidemiology of Invasive Pneumococcal Disease in Canada, 1998–2007: Update from the Calgary-Area Streptococcus pneumoniae Research (CASPER) Study

BACKGROUND Routine infant vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) began in the Calgary Health Region (Alberta, Canada) in 2002. We measured the impact of this vaccine program on invasive pneumococcal disease (IPD). METHODS Prospective, population-based surveillance of all cases of IPD (with culture specimens obtained from sterile sites) was conducted from January 1998 through December 2007. Demographic and clinical data were collected. All viable isolates were saved and serotyped. RESULTS There were 1182 IPD cases over the 10-year period. Comparison of the vaccine period (2003-2007) with the prevaccine period (1998-2001) revealed that the incidence of IPD due to PCV7 serotypes decreased significantly by 86%, 59%, 38%, and 78% in the 6-23-month, 2-4-year, 16-64-year, and 65-84-year age groups, respectively. The total number of IPD cases decreased by 77%, 45%, and 34% in the 6-23-month, 2-4-year, and 65-84-year age groups, respectively. The incidence of IPD due to non-PCV7 serotypes increased by 183%, and the total incidence of IPD increased by 73% among adults aged 16-64 years; however, this increase was primarily attributed to a large outbreak of serotype 5 IPD among homeless adults during the period 2005-2007. There were 5 cases of IPD due to PCV7 serotypes among vaccinated children in the vaccine period. CONCLUSIONS Since the introduction of PCV7 vaccine, there has been a profound decrease in the total number of cases of IPD among children and in cases due to PCV7 serotypes among subjects of all ages in Calgary, indicating a strong direct effect and herd effect of the vaccine. The serotypes that now cause IPD have changed significantly. The magnitude and impact of replacement IPD caused by non-PCV7 serotypes is not yet known.

Extension of the Lancefield Classification for Group A Streptococci by Addition of 22 New M Protein Gene Sequence Types from Clinical Isolates: emm103 to emm124

Classic M protein serotyping has been invaluable during the past 60 years for the determination of relationships between different group A streptococci (GAS) strains and the varied clinical manifestations inflicted by these organisms worldwide. Nonetheless, during the past 20 years, the difficulties of continued expansion of the serology-based Lancefield classification scheme for GAS have become increasingly apparent. By use of a less demanding sequence-based methodology that closely adheres to previously established strain criteria while being predictive of known M protein serotypes, we recently added types emm94-emm102 to the Lancefield scheme. Continued expansion by the addition of types emm103 to emm124 are now proposed. As with types emm94-emm102, each of these new emm types was represented by multiple independent isolates recovered from serious disease manifestations, each was M protein nontypeable with all typing sera stocks available to international GAS reference laboratories, and each demonstrated antiphagocytic properties in vitro by multiplying in normal human blood.

Serotype distribution of invasive Streptococcus pneumoniae in Canada after the introduction of the 13-valent pneumococcal conjugate vaccine, 2010-2012.

The introduction of the 7-valent pneumococcal vaccine (PCV7) in Canada was very effective in reducing invasive pneumococcal disease (IPD) in children; however, increases of non-PCV7 serotypes have subsequently offset some of these reductions. A 13-valent pneumococcal vaccine (PCV13) targeting additional serotypes was implemented between 2010 and 2011, and in 2012 changes in the incidence of disease and the distribution of IPD serotypes began to emerge. The incidence of IPD in children <5 years of age declined from 18.0 to 14.2 cases per 100 000 population between 2010 and 2012; however, the incidence in ages ≥5 years remained relatively unchanged over the 3-year period, at about 9.7 cases per 100 000 population. From 2010 to 2012, PCV13 serotypes declined significantly from 66% (224/339) to 41% (101/244, p < 0.001) in children <5 years of age, and from 54% (1262/2360) to 43% (1006/2353, p < 0.001) in children ≥5 years of age. Serotypes 19A, 7F, 3, and 22F were the most common serotypes in 2012, with 19A decreasing from 19% (521/2727) to 14% (364/2620, p < 0.001), 7F decreasing from 14% (389/2727) to 12% (323/2620, p = 0.04), and 22F increasing from 7% (185/2727) to 11% (279/2620, p < 0.001) since 2010. Serotype 3 increased from 7% (23/339) to 10% (24/244) in <5-year-olds (p = 0.22) over the 3-year period. The highest rates of antimicrobial resistance were observed with clarithromycin (23%), penicillin using meningitis breakpoints (12%), clindamycin (8%), and trimethoprim-sulfamethoxazole (6%). Shifts in the distribution of IPD serotypes and reductions in the incidence of disease suggest that current immunization programs in Canada are effective in reducing the burden of IPD in children. While we acknowledge the limited data on the effectiveness of the PCV13 vaccine, to our knowledge, this study represents one of the first descriptions of the potential impact of the PCV13 vaccine in the Canadian population. Continued surveillance will be important to recognize replacement serotypes, to determine the extent of herd immunity effects in nonpaediatric populations, and to assess the overall effectiveness of PCV13 in reducing IPD in Canada.

The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007

Active surveillance was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active from 2000-2007 in children 16 years of age and younger to determine the influence of 7-valent pneumococcal conjugate immunization programs on the prevalence, serotype and antibiotic resistance patterns of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. The absolute number of reported IPD cases decreased 48% (p<0.01) over the 8-year period and 56% (p<0.01) in children 0-4 years of age. The absolute number of reported IPD cases caused by serotypes in the conjugate vaccine decreased 87.5% (p<0.01) overall and 92% (p<0.01) in children 0-4 years. Although 6 non-vaccine serotypes increased over time, only serotype 19A increased significantly (p<0.01). Overall, the proportion of penicillin resistant isolates remained unchanged at 17%. Cefotaxime/ceftriaxone resistance remained unchanged at 2% of isolates annually. Universal pneumococcal conjugate infant immunization programs have dramatically decreased cases of invasive pneumococcal disease.

Progress in the prevention of pneumococcal infection

Streptococcus pneumoniae (pneumococcus) remains an important human pathogen more than a century after its discovery, with infections occurring most commonly among young children and elderly people. It causes a wide range of invasive infections in normally sterile body sites such as blood and

Serotypes and antimicrobial susceptibilities of invasive Streptococcus pneumoniae pre- and post-seven valent pneumococcal conjugate vaccine introduction in Alberta, Canada, 2000-2006.

Alberta, Canada introduced the Streptococcus pneumoniae seven valent conjugate vaccine (PCV7) program for children less than 2 years of age in September 2002. We determined the rates of invasive pneumococcal disease in Alberta, Canada 2 years pre- and 4 years post-PCV7 introduction (2000-2006) as well as the rates of antibiotic resistance and serotype distribution in this same time period. Overall, PCV7 serotypes decreased 61% from 2000 to 2006. The greatest decrease in incidence of invasive pneumococcal disease occurred in children less than 2 years of age declining from a high of 96.7/100,000 (2000) to 25.8/100,000 (2006) (P<0.0001). Non-susceptibility of S. pneumoniae isolates to penicillin dropped significantly from 14% in 2000 to 4.6% in 2006 (P<0.0001). Non-susceptible erythromycin isolates also decreased from 8.8% (2000) to 5.8% (2006) (P=0.13). The introduction of PCV7 in Alberta, Canada has decreased the incidence of invasive pneumococcal disease in Alberta as well as resulting in a decrease in antibiotic resistance over this same time frame, principally for penicillin resistance.

Epidemiology and genotype analysis of sapovirus associated with gastroenteritis outbreaks in Alberta, Canada: 2004–2007

This study describes the epidemiology and circulating strains of sapovirus associated with gastroenteritis outbreaks in Alberta, Canada, from 2004 to 2007. Sapovirus was an important cause of gastroenteritis outbreaks, accounting for 43 (17.6%) of 244 outbreaks in which all samples tested were negative for norovirus. All 4 human sapovirus genotypes, GI, GII, GIV, and GV, were found in samples during these outbreaks. The greatest amount of sapovirus-associated outbreak activity occurred in 2007, after the emergence of genotype GIV in December 2006. The majority of sapovirus-associated outbreaks in Alberta during this period (27 [62.8%] of 43) occurred in hospitals, community long-term care facilities, and senior lodges. Adults>65 years of age were the age group most commonly affected.

Effects of Routine Infant Vaccination With the 7-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization With Streptococcus pneumoniae in Children in Calgary, Canada

Background: All Streptococcus pneumoniae disease is preceded by nasopharyngeal (NP) colonization. We studied the impact of 7-valent pneumococcal conjugate vaccine (PCV7) on colonization in healthy children. Methods: Routine PCV7 vaccination began in Alberta in 2002. Six point prevalence surveys were conducted from 2003 to 2005, in 7 community health centers in Calgary where children had their routine vaccinations. A questionnaire was administered and a single NP swab was obtained for culture. Serotyping was performed on all S. pneumoniae isolates. Results: There were 3398 children with complete data, 1307, 1225, and 866 in 12-month, 18-month, and 4–6 year groups, respectively. None had received PCV7 in survey 1. From survey 2 onwards, 92–98% of 12-month-olds had 3 or more doses of PCV7, and from survey 3 onwards, 95–99% of 18-month-olds had 3 or more doses. By survey 6, only 4% of 4–6 year olds had 3 or more doses. The overall S. pneumoniae colonization rate was 20%. In all age groups, including unvaccinated 4–6 year olds, there were significant declines in PCV7 serotypes, and increases in non-PCV7 serotypes. The largest increases were serotypes 6A, 15C, and 11A. Multivariate analysis found that factors including age, siblings, daycare attendance, episodes of otitis media, and antibiotic use affected S. pneumoniae colonization but only PCV7 vaccination was associated with decreased PCV7 serotype colonization and increased non-PCV7 colonization. Conclusions: Routine PCV7 vaccination has led to significant changes in the predominant S. pneumoniae serotypes found in NP colonization in both vaccinated and unvaccinated children, indicating both a direct and herd effect.

M Types of Group A Streptococcal Isolates Submitted to the National Centre for Streptococcus (Canada) from 1993 to 1999

ABSTRACT The National Centre for Streptococcus (NCS) (Canada) determined the group A streptococcal (GAS) M types of 4,760 Canadian isolates submitted between 1993 and 1999 by classic serotyping. The 10 most frequently identified M types were M1 (26.4%), M12 (9.8%), M28 (8.9%), M3 (6.8%), M4 (6.2%), M11 (4.8%), M89 (3.1%), M6 (3.0%), M2 (2.6%), and M77 (1.9%). Nontypeable isolates accounted for 15.4% of the collection. The province of Ontario submitted 51.1% of the isolates, followed by Quebec (21.2%) and Alberta (13.9%). Together, these three provinces constituted 71.3% of the Canadian population in 1996. The numbers of M types M1, M12, M28, and M3 occurred most frequently in subjects whose ages were <1 to 15 years and 25 to 45 years, as well as in the elderly (60 to 90 years). Further analysis found that the four most frequently identified M types from blood, brain, and cerebrospinal fluid were M1 (28.2%), M28 (9.2%), M12 (9.1%), and M3 (8.2%), with 13.4% of isolates being nontypeable. The four isolates from throats most frequently identified were M1 (19.5%), M12 (15.3%), M3 (8.6%), and M28 (5%) with 19.4% of isolates being nontypeable. The sic gene of a subset of M1 strains (9.5% of the M1 collection) was sequenced. Of 36 sic types identified, the four most common were sic1.01 (22.8%), sic1.02 (14.9%), sic1.135 (10.5%), and sic1.178 (9.6%). Together these four sic types further characterized nearly 60% of the M1 strains sequenced. In summary, from the years 1993 to 1999, the NCS detected 54 M types, of which 10 different M types constituted 73.5% of the collection. M1 was the most common GAS M type circulating in the Canadian population, responsible for more than a quarter of the isolates typed. The most common throat isolates differed in M-type and proportion from those of invasive isolates. Sequencing the sic gene further characterized the most common M-type serotype 1 in a fashion that may be useful for epidemiologic investigations.

Full-Genome Dissection of an Epidemic of Severe Invasive Disease Caused by a Hypervirulent, Recently Emerged Clone of Group A Streptococcus

Group A Streptococcus (GAS) causes an exceptionally broad range of infections in humans, from relatively mild pharyngitis and skin infections to life-threatening necrotizing fasciitis and toxic shock syndrome. An epidemic of severe invasive human infections caused by type emm59 GAS, heretofore an exceedingly rare cause of disease, spread west to east across Canada over a 3-year period (2006 to 2008). By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, we discovered that a recently emerged, genetically distinct emm59 clone is responsible for the Canadian epidemic. Using near-real-time genome sequencing, we were able to show spread of the Canadian epidemic clone into the United States. The extensive genome data permitted us to identify patterns of geographic dissemination as well as links between emm59 subclonal lineages that cause infections. Mouse and nonhuman primate models of infection demonstrated that the emerged clone is unusually virulent. Transmission of epidemic emm59 strains may have occurred primarily by skin contact, as suggested by an experimental model of skin transmission. In addition, the emm59 strains had a significantly impaired ability to persist in human saliva and to colonize the oropharynx of mice, and seldom caused human pharyngitis. Our study contributes new information to the rapidly emerging field of molecular pathogenomics of bacterial epidemics and illustrates how full-genome data can be used to precisely illuminate the landscape of strain dissemination during a bacterial epidemic.