UNIVERSITY OF CALGARY. (IPD) in Adults with Underlying Comorbidities. Jason Lee Cabaj A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES

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1 UNIVERSITY OF CALGARY The Influence of Childhood Conjugate Vaccine Introduction on Invasive Pneumococcal Disease (IPD) in Adults with Underlying Comorbidities by Jason Lee Cabaj A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE GRADUATE PROGRAM IN COMMUNITY HEALTH SCIENCES CALGARY, ALBERTA SEPTEMBER, 2014 Jason Lee Cabaj 2014

2 Abstract After introduction of pneumococcal conjugate vaccine (PCV) into routine childhood immunization programs, there has been a substantial decline in vaccine-serotype invasive pneumococcal disease (IPD) in vaccinated children and in unvaccinated persons. However, indirect protection may be relatively reduced in adults with underlying comorbidities. Data from a prospective, population-based surveillance system were analyzed using an indirect cohort study design. There were 1153 adult IPD cases from January 2000 to December The proportion of cases with immunocompetent comorbidities in the post-pcv era did not differ from that in the pre-pcv period (OR 1.10; 95% CI: ). There was a non-significant increase in the proportion of cases with immunocompromising comorbidities (RRR 1.69; 95% CI: ). This observed increase, from 25.5% in the pre-pcv period to 31.1% in the post PCV-13 period, was largely due to non-pcv serotype disease. Childhood PCV programs have provided considerable benefit, but the relative burden of IPD in immunocompromised adults may be increasing. ii

3 Acknowledgements I would like to thank everyone who contributed to the development of this thesis. First, I would like to acknowledge Dr. Jim Kellner and the CASPER team for facilitating and supporting this research project. I would also like to thank the members of my thesis committee, Dr. Judy MacDonald, Dr. Alberto Nettel-Aguirre, Dr. Otto Vanderkooi (and Dr. Martin Lavoie as external examiner) for their helpful advice, criticism, suggestions, and general wisdom. In particular, I d like to express my appreciation to Dr. MacDonald for providing the initial impetus that led to this collaboration. Finally, I would also like to thank my family for tolerating my journey through all the phases of medical and academic training; they have been unfailingly supportive. Sophia, Sam, and Megan you re just a wonderful family. iii

4 Dedication To Megan, my partner in life. iv

5 Table of Contents Abstract... ii Acknowledgements... iii Dedication... iv Table of Contents...v List of Tables... vii List of Figures and Illustrations... ix List of Abbreviations and Nomenclature... xi Epigraph... xii INTRODUCTION...1 BACKGROUND...3 Pneumococcal Disease Overview...3 Risk Factors for Adult IPD...8 IPD Characteristics...12 Treatment and Antibiotic Resistance...13 Prevention of IPD...14 Literature Review...21 Study Purpose...28 METHODS...29 Data Collection...29 Study Population...30 Study Design...31 Data Analysis...38 Ethics...42 RESULTS...43 Descriptive Analysis...43 Multivariable Analysis...77 DISCUSSION...85 Summary of Results...85 Interpretation of Results...86 Strengths and Limitations...96 Future Research...97 Knowledge Translation Plan...99 Conclusions REFERENCES APPENDIX CASPER Municipalities (2010 to Current) CASPER Municipalities (Prior to 2010) v

6 APPENDIX Binomial Model Multinomial Model vi

7 List of Tables Table 1. Serotypes included in conjugate and polysaccharide pneumococcal vaccines Table 2. Literature review results: summary of changes in proportion of IPD cases with comorbid conditions Table 3. Study exposure variable Table 4. Study outcome variables Table 5. Outcome variables definitions Table 6. Study covariates Table 7. Characteristics of Adult CASPER IPD cases ( ) Table 8. CASPER IPD case frequency and incidence over study period Table 9. Overall IPD incidence per 100,000 population by age group over study year Table 10. IPD incidence per 100,000 population by vaccine group over study year Table 11. Frequency of IPD cases by age group over study year Table 12. Frequency and proportion of IPD cases with Aboriginal status over study year Table 13. Frequency and proportion of IPD cases with homeless status over study year Table 14. Frequency of pneumococcal vaccine serotypes Table 15. IPD cases by individual serotype over study year Table 16. CASPER cases characteristics and community population estimates Table 17. Proportion of IPD cases with any underlying comorbidity over PCV period for all serotypes and without outbreak serotypes Table 18. Proportion of IPD cases with an immunocompetent underlying comorbidity over PCV period for all serotypes and without outbreak serotypes Table 19. Proportion of IPD cases with an immunocompromising underlying comorbidity over PCV period for all serotypes and without outbreak serotypes Table 20. Odds ratios for immunocompetent comorbidities for the post PCV periods Table 21. Odds ratios for immunocompromising comorbidities in the post PCV periods Table 22. Unadjusted and adjusted odds ratios of any underlying comorbidity by PCV period.. 78 vii

8 Table 23. Unadjusted and adjusted odds ratios of any underlying comorbidity for global post PCV period Table 24. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity by PCV period Table 25. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity for global post PCV period Table 26. Unadjusted and adjusted relative risk ratios of an immunocompromising underlying comorbidity by PCV period Table 27. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity by PCV period (excluding serotype 5 and serotype 8) Table 28. Unadjusted and adjusted relative risk ratios of an immunocompromising underlying comorbidity by PCV period (excluding serotype 5 and serotype 8) viii

9 List of Figures and Illustrations Figure 1. Alberta Health Services Zone map Figure 2. Conceptual study design Figure 3. Employed study design Figure 4. Categories for time period of disease onset relative to the introduction of routine childhood conjugate vaccine programs in Alberta Figure 5. Overall IPD incidence per 100,000 population by age group over PCV period Figure 6. PCV-13 IPD incidence per 100,000 population by age group over study period Figure 7. IPD incidence per 100,000 population by vaccine group over PCV period Figure 8. IPD incidence per 100,000 population by vaccine group over PCV period (excluding serotypes 5 and 8) Figure 9. Age distribution of adult CASPER IPD cases with and without outbreak serotypes ( ) Figure 10. Mean age over PCV period for all serotypes and non-outbreak serotypes Figure 11. Proportion of IPD cases by age group over study year Figure 12. Proportion of IPD cases of male gender over study year Figure 13. Proportion of IPD cases of male gender over PCV period for all serotypes and non-outbreak serotypes Figure 14. Proportion of IPD cases classified as homeless over study year Figure 15. Proportion of IPD cases by clinical site over PCV period Figure 16. Proportion of IPD cases classified as meningitis over PCV period Figure 17. Proportion of IPD cases by PCV group over PCV period Figure 18. Proportion of IPD cases by vaccine group over study year Figure 19. Frequency of serotypes causing IPD cases in Figure 20. Frequency of serotypes causing IPD cases in adults with immunocompromising comorbidities in Figure 21. Proportion of IPD cases with any underlying comorbidity over PCV period ix

10 Figure 22. Proportion of IPD cases with an underlying immunocompetent comorbidity over PCV period Figure 23. Proportion of IPD cases with an underlying immunocompromising comorbidity over PCV period Figure 24. Proportion of IPD cases with an underlying immunocompromising comorbidity by PCV group over PCV period x

11 List of Abbreviations and Nomenclature Abbreviation Definition ABCs Active Bacterial Core surveillance ACIP Advisory Committee on Immunization Practices (United States) CAP Community acquired pneumonia CAPiTA Community-Acquired Pneumonia Trial in Adults CASPER Calgary and Area Streptococcus pneumoniae Research CD4+ T helper cells (cluster of differentiation 4) CI Confidence interval CLS Calgary Laboratory Services COPD Chronic obstructive pulmonary disease CSF Cerebrospinal fluid EIA Enzyme Immunoassay F/P/T Federal, provincial, territorial HIV Human immunodeficiency virus HSCT Hematopoietic stem cell transplant IPD Invasive pneumococcal disease NACI National Advisory Committee on Immunization (Canada) OPA Opsonophagocytic activity OR Odds ratio PCR Polymerase chain reaction PICO Problem, Intervention, Comparison, Outcome PCV Pneumococcal conjugate vaccine (general) PCV-7 7-valent pneumococcal conjugate vaccine PCV valent pneumococcal conjugate vaccine PCV valent pneumococcal conjugate vaccine PPV valent pneumococcal polysaccharide vaccine ProvLab Provincial Laboratory for Public Health (Alberta) RRR Relative risk ratio xi

12 Epigraph I think it's much more interesting to live not knowing than to have answers which might be wrong. Richard P. Feynman xii

13 INTRODUCTION Streptococcus pneumoniae (pneumococcus) is a common bacterial infection in all age groups and continues to cause a significant burden of disease worldwide. Although non-invasive infections such as non-bacteremic pneumonia, localized respiratory tract infection, and otitis media are much more common, the foremost health concern arising from pneumococcal infection is invasive pneumococcal disease (IPD), which is a leading cause of bacterial pneumonia globally and of bacterial meningitis in North America (1, 2). Invasive disease caused by S. pneumoniae can occur at numerous sites, with bacteremia, pneumonia, and meningitis being the most common manifestations. For adults, those 50 years of age and older (and especially 65 years of age and older), those in certain living circumstances, and those with underlying medical conditions have a markedly increased risk of developing pneumococcal disease (3-5). Despite advances in medical treatment, these high-risk groups have also been shown to have an increased risk of IPD-associated mortality, further underscoring the importance of adequate preventive efforts (6, 7). After introduction of pneumococcal conjugate vaccine (PCV) into routine childhood immunization programs, there has been a substantial decline in vaccine-serotype IPD in children who received the vaccine (direct effect) and in persons of all ages who did not receive the vaccine (indirect effect) (8-10). In some instances, there has also been a sizeable increase in IPD caused by non-vaccine serotypes, but an overall decline in IPD has generally been the prevailing trend in all age groups (8, 11). However, some recent international evidence has been produced suggesting that after the introduction of a 7-valent conjugate pneumococcal vaccine (PCV-7), the proportion of adults with IPD who have underlying medical conditions has increased. This finding would indicate that the indirect protection provided by conjugate pneumococcal vaccines 1

14 against vaccine-serotype disease may be lower in adults with certain medical comorbidities, leaving these groups at an even higher risk of developing IPD in comparison to healthy adults. With a 13-valent version of the conjugate vaccine (PCV-13) now incorporated into childhood vaccine programs and licensed for use in adults (50 years and older) in Canada, there is a pressing need to determine the appropriate role of conjugate pneumococcal vaccine in protecting vulnerable adults from disease caused by Streptococcus pneumoniae. The purpose of this research was to determine if the proportion of adult IPD cases with underlying comorbidities has changed after introduction of the pneumococcal conjugate vaccines (PCV-7 and PCV-13) into routine childhood immunization programs in Alberta, Canada. It was hypothesized that the introduction of childhood conjugate pneumococcal vaccines will have been associated with an increase in the proportion of IPD cases with immunocompromising and immunocompetent comorbidities. The results of this study provide timely information relevant to the Canadian context, adding to the emerging body of evidence that informs immunization policy development and program decision-making regarding the optimal approach to protecting adult populations from IPD in the conjugate vaccine era. A knowledge translation plan has been developed to guide the process of using these results inform practice and decision making. 2

15 BACKGROUND Pneumococcal Disease Overview Etiology Streptococcus pneumoniae (pneumococcus) is a gram-positive bacterium with a surface composed of complex polysaccharides. These oval/lancet shaped organisms most commonly occur in pairs (diplococci), but can also occur singularly or in short chains (12). The more than 90 recognized pneumococcal serotypes are classified based on the characteristics of the antigenic polysaccharide surface capsule, which is the primary determinant of the organism s pathogenicity and virulence (13). S. pneumoniae is of the Streptococcaceae family and forms round facultative anaerobic colonies surrounded by -hemolysis when cultured on blood agar (14). It commonly colonizes the human nasopharynx and upper respiratory tract. Asymptomatic carriage rates vary from 5-70% depending on factors such as age (carriage is generally lower in adults), circulating serotypes, host immunity, and presence of children in household (15, 16). The duration of carriage is also both age and serotype dependent. Importantly, carriage is thought to be a precursor to disease, of which there are numerous clinical manifestations (described below). There are no animal reservoirs for S. pneumoniae other than great apes (17). Pathophysiology Pneumococcal disease can be classified into invasive disease (IPD), defined as isolation of S. pneumoniae from a normally sterile site, and non-invasive (mucosal) disease, which captures the remainder of infections not fulfilling the criteria for IPD. Mucosal disease, which results from direct spread of the organism from the nasopharynx to the sinuses (sinusitis), lungs (pneumonia), and middle ear (acute otitis media), is usually less severe than IPD but considerably more common (18). Non-invasive pneumococcal infections may also become 3

16 invasive, such as when initially non-invasive pneumonia leads to infection of the bloodstream, with subsequent potential for other end-organ involvement (19). The major clinical syndromes of invasive pneumococcal disease are bacteremia, bacteremic pneumonia, and meningitis; of these, pneumonia is by far the most common manifestation of IPD in adults (20). Invasive infection also occurs less frequently at other focal sites, causing clinical illnesses such as periorbital cellulitis, conjunctivitis, endocarditis, osteomyelitis, pericarditis, peritonitis, arthritis, and soft tissue infections. The definitive method of diagnosing IPD is culture of the organism, the sensitivity of which may be reduced by delays in specimen processing or prior antibiotic use (21, 22). Polymerase chain reaction (PCR)-based assays are also useful for establishing the diagnosis of pneumococcal meningitis, as they are sensitive and specific for S. pneumoniae in cerebrospinal fluid (CSF). Other diagnostic techniques have serious drawbacks that limit their utility in most settings (23). Epidemiology Infections with S. pneumoniae are a major cause of morbidity and mortality worldwide. A precise disease burden is difficult to establish because of diagnostic and surveillance limitations in some areas, but the majority of the estimated 14.5 million episodes of severe disease and 800,000 annual deaths associated with pneumococcal infection in children under 5 years take place in developing countries (more than 60% of fatalities occur in 10 African and Asian countries) (24). Conversely, the burden of pneumococcal disease in (older) adults predominantly occurs in industrialized countries. In Europe and North America, S. pneumoniae is thought to cause approximately 30-50% of community acquired pneumonia requiring hospitalization in adults, and 10-80% of bacterial pneumonia in children (25). It is estimated that pneumococcus causes two-thirds of the more 4

17 than 40% of community-acquired pneumonia cases when no pathogen is identified (25, 26). Further, S. pneumoniae became the leading cause of bacterial meningitis in all ages after the introduction of the H. influenzae type b vaccine (27). The proportion of pneumococcal infections classified as bacteremia without focus and meningitis decline with age, and the proportion classified as pneumonia increases. There is a seasonal pattern to IPD occurrence, with infections occurring more commonly in temperate climates during the winter and spring months when influenza and respiratory syncytial viruses are in circulation (28). The rates of vaccine-type IPD in people of all ages have declined substantially after introduction of PCV-7 into childhood immunization programs. In many jurisdictions, the incidence of overall IPD dropped as well. For example, after PCV-7 was adopted in the United States (in 2000), data from the Active Bacterial Core surveillance (ABCs) showed that the overall incidence of IPD in all age groups decreased by 45% (24.4 per 100,000 population in 1999 to 13.5 per 100,000 population in 2007) and PCV-7 serotype IPD declined by 94% (15.5 per 100,000 population in 1999 to 1.0 per 100,000 population in 2007) (29). Similar reductions have been observed in other countries (30-32). A concurrent increase in the incidence of non PCV-7 serotype IPD has frequently been observed, often largely due to a greater number of serotype 19A cases. In the same United States data, non PCV-7 disease increased by 23% after conjugate vaccine introduction, from 6.1 cases per 100,000 in 1999 to 7.9 per 100,000 in 2007 (29). In adults, the observed reductions in IPD have been attributed to indirect protection from the childhood conjugate vaccine programs. The mechanism for this indirect effect is thought to be through decrease in transmission of S. pneumoniae from vaccinated children to unvaccinated children, adolescents, and adults because of the reduced presence and circulation of PCV 5

18 serotypes (33). The pattern of response for vaccine serotype disease in adults has generally been similar to that observed in children, but the relative increase in non-vaccine serotype disease has often been more substantial than in children, in some cases resulting in no significant change in overall IPD incidence in the post-conjugate vaccine era (31, 32). Using pooled data from 21 IPD surveillance datasets, Feikin et al. (2013) reported significant reductions in overall IPD 7 years after PCV-7 introduction for year-olds [RR 0.52, 95% CI ], year-olds [RR 0.84, 95% CI ], and 65 year-olds [RR 0.74, 95% CI ]) (32). In the United States, overall IPD incidence in adults 50 years of age did decline by 28% (40.8 per 100,000 population in to 29.4 per 100,000 population in ) and PCV-7 type IPD fell by 55% (22.4 per 100,000 population in to 10.2 per 100,000 population in ). Non PCV-7 disease increased by 13% after conjugate vaccine introduction, from 6.0 cases per 100,000 in 1999 to 6.8 per 100,000 in 2007 (34). Invasive pneumococcal disease became nationally notifiable in Canada in 2000 (20). Subsequently, the incidence of IPD increased for several years, likely largely due to a reporting bias related to increased awareness of the passive surveillance system. (35). PCV-7 was added to all provincial and territorial childhood immunization programs between 2002 and Large outbreaks of serotypes 5 and 8 disease resulted in elevated incidence rates in the prairie provinces in (36). Similar to other jurisdictions, much higher IPD incidence rates have been observed in both children under 5 and older adults, with the latter group accounting for a much greater proportion of cases (11% vs 40%) (20). Predictably, the largest absolute burden of IPD in Canada is found in Ontario and Quebec due to their relatively large populations. However, the greatest incidence of disease occurs in the Territories, with highly fluctuant disease activity over years of observation (37). 6

19 The impact of PCV-7 introduction on the incidence of IPD in Canada was similar to that seen in the United States and has been described in reports from several regional pneumococcal surveillance systems. A previous study by the Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) group reported that the incidence of IPD due to PCV-7 serotypes decreased by 86% (6-23 months), 59% (2-4 years), 38% (16-64 years), and 78% (65-84 years) from the pre-vaccine period ( ) to the post-vaccine period ( ) (8). In Quebec, which employed a three (2+1) (rather than four) dose PCV-7 program, a marked decline in overall IPD incidence was seen in children under 5 years of age, from 67 per 100,000 ( ) to 32 per 100,000 ( ) to 24 per 100,000 population ( ), with elimination of PCV-7 serotype disease in this age group in 2011 (38). However, there was no change in IPD incidence seen in adult groups, with relative risks for IPD of 1.09 (20-59 years), 1.04 (60-79 years), and 1.03 (80+ years) from to (38). In the Nunavik region of Quebec, however, there were substantial declines in PCV-7 serotype IPD incidence following PCV-7 introduction for both persons <5 years, from 162 per 100,000 in to 10 per 100,000 in , and for 5 years (including adults), from 15 per 100,000 in to 3 per 100,000 in (39). There were concurrent increases in non-vaccine type IPD for both age groups, from 29 per 100,000 to 109 per 100,000 (<5 years) and 0 per 100,000 to 9 per 100,000 ( 5 years), respectively (39). IPD incidence in the predominantly Aboriginal population of Northern Canada (from the International Circumpolar Surveillance network) fluctuated considerably from 2000 to 2010, but the proportion of IPD due to PCV-7 serotypes in all age groups decreased from 44% of cases in 2000 to 7% in 2010; 50% of IPD cases since 2008 were due to non-vaccine serotypes (37). Finally, in Ontario there was a 77% reduction in PCV-7 serotype IPD in cohorts eligible for the vaccine and a 60% reduction in non-eligible persons 7

20 from 2008 to 2010; an increase in non-pcv7 serotypes was also seen over this limited study period (40). Economic Burden The overall societal cost attributed to invasive and non-invasive cases of pneumococcal disease prior to conjugate vaccine introduction in Canada was $193 million in 2001, of which 82% was due to health care system expenditures and 18% to familial costs (41). In the United States, the total annual cost (indirect and direct) of pneumococcal disease in adults 50 years of age after PCV introduction has been estimated to be $5.5 billion in 2008 dollars, with IPD being responsible for $1.8 billion (42). Similarly in Europe, IPD was projected in 2003 to be associated with > 6 billion in direct (in-patient care, outpatient care and drugs) and > 3.5 billion in indirect (lost work days) annual costs (43). Risk Factors for Adult IPD Comorbidities Independent of age, invasive pneumococcal disease occurs more frequently in persons with comorbid medical conditions, particularly those that compromise integrity of the immune system. In the United States, the incidence of IPD in healthy adults was 9 per 100,000 population in , but was much higher for adults with hematological cancers (503 per 100,000), HIV/AIDS (422 per 100,000), solid cancers (300 per 100,000), chronic heart disease (94 per 100,000), chronic lung disease (63 per 100,000), and diabetes (51 per 100,000) (44). Notably, the elevated risk of IPD in persons with HIV is particularly high for those individuals with low CD4+ counts and those not on antiretroviral therapy (45, 46). Individuals with functional or anatomic asplenia, cochlear implants, and transplant recipients also have substantially increased 8

21 risks of IPD, with a reported incidence of 146 cases per 100,000 adult transplant recipient person-years reported for the latter group (47-51). It is difficult to determine the influence of asthma on IPD risk independent of tobacco smoking, and studies to date have not always found an association (52, 53). However, the preponderance of recent data suggests asthma may be an independent risk factor for IPD (separately from prolonged steroid use, COPD, or smoking status) and thus has recently been added as an indication for adult pneumococcal vaccination by both the National Advisory Committee on Immunization (NACI) in Canada and the Advisory Committee on Immunization Practices (ACIP) in the United States (54-56). The presence of multiple comorbidities further increases the risk of developing IPD relative to IPD risk for those having a single comorbid condition (7). Age As with many communicable diseases, age is a major risk factor for IPD, with young children and older adults most commonly affected. Within the adult population, incidence and mortality rates increase with age, with adults 65 years and older comprising one-third of IPD cases and approximately half of IPD-associated deaths (57-59). The vulnerability of older adults is thought to be due to factors related to the aging process as well as an increased presence of underlying comorbidities (60). Immunosenescence, the complex series of changes associated with the aging process that results in gradual deterioration of the innate and adaptive immune system, increases susceptibility to infectious diseases and decreases responsiveness to vaccines (61, 62). The type of underlying comorbidities most commonly observed in IPD cases varies with age, with HIV/AIDS, alcoholism, and diabetes highest for year olds, diabetes, COPD, 9

22 and cancer most frequent for year olds, and cardiac disease, COPD, and diabetes most common among 65 year olds (63). Gender Male sex has been demonstrated to be independently associated with an increased risk of IPD across the age spectrum (4, 64). The factors contributing to the greater susceptibility of men to IPD are not well understood, but may be related to the combination of immunological, physiological and lifestyle risk factors more common in men than in women (65). In some settings women have been over-represented among healthy adults with IPD, a finding that is thought to be due to increased contact with children and/or high rates of cigarette smoking (66). Aboriginal Status Aboriginal peoples are often at a substantially increased risk of pneumococcal disease. In Canada, analysis of data from the International Circumpolar Surveillance network found that yearly IPD incidence rates were 2-16 times higher in Aboriginals compared to non-aboriginals (37). Similar results have been reported for Aboriginal groups in other countries (67, 68). The increased risk for Aboriginal populations is hypothesized to result from factors such as crowded living conditions, lower socioeconomic status, and higher rates of other risk factors such as medical comorbidities and smoking (37). The effect of conjugate vaccine introduction on the epidemiology of IPD in Aboriginal populations has been mixed. While there have been significant reductions in IPD in the American Navajo nation population and in Australian Aboriginal children, either no change or an increase in overall IPD (with a large increase in non PCV-7 type disease) was seen in adult Australian Aboriginal populations after PCV-7 introduction (69-71). 10

23 Alcohol and Tobacco Use Excessive alcohol intake has been shown to be associated with an increased risk of pneumococcal pneumonia and meningitis, with the risk of IPD being up to 10-fold greater for alcoholics than for non-alcoholics (44, 72). High weekly alcohol consumption and intermittent heavy drinking are associated with an increased risk of hospitalization due to pneumococcal disease (73). Furthermore, alcoholic individuals are more likely to develop complications of IPD than are non-alcoholics (74). Alcohol abusers commonly have concurrent chronic or immunosuppressive underlying disease, but are also over-represented (i.e. more prevalent among IPD cases than in the general population) among otherwise healthy adults with IPD (66). Similarly, cigarette smoking has been identified as a strong independent risk factor for invasive pneumococcal disease in immunocompetent adults. Both active smoking, and passive second hand smoking among non-smokers, have positive dose-response relationships with risk of IPD, and the overall IPD risk in smokers is at least 2-fold higher than in non-exposed nonsmokers (4, 75). A plausible mechanism for the increased risk in smokers is impaired pulmonary clearance due to reduced complement-mediated phagocytosis by alveolar macrophages (76). Notably, half of otherwise healthy adults with IPD in some populations are cigarette smokers, and a majority do not have chronic lung disease or other indications for vaccination (75, 77). Illicit Drug Use and Homelessness Disadvantaged groups such as homeless populations have high rates of respiratory infections, including those caused by S. pneumoniae (78). During two recent overlapping outbreaks of IPD in Calgary, Alberta, illicit drug use and homelessness were identified as key risk factors for developing IPD (36). In 2008, the National Advisory Committee on 11

24 Immunization (NACI) recommended that persons who use illicit drugs should be considered for vaccination with the polysaccharide pneumococcal vaccine (79). IPD Characteristics Clinical Site Bacteremic pneumonia, which is a frequent complication following influenza, is the most common presentation of IPD in adults, accounting for over 70% of IPD cases overall and over 80% of IPD cases in older adults (80). Bacteremia with no identified focus is the most common form of IPD in children and accounts for approximately 15% of cases in adults. Meningitis occurs relatively infrequently in adult patients with IPD (~5% of cases), but it is associated with a high mortality rate (~30%) and neurological complications such as hearing loss, cognitive impairment, motor abnormalities, and seizures, occur in a significant number of those who survive (81). Serotypes The pathogenicity of pneumococcal infection and clinical manifestation of invasive pneumococcal disease varies by capsular serotype (82). Ninety-three immunologically distinct serotypes of S. pneumoniae have been identified and have been categorized into 46 serogroups (83). However, the vast majority of disease caused by S. pneumoniae is related to approximately 25 serotypes, the distribution of which varies with patient age, geography, and climate (83-85). A wider range of serotypes are responsible for disease in adults than children, where a majority of disease is caused by four to five serotypes (23). Prior to the introduction of conjugate vaccines, serotypes 1, 5, 6B, 14, 19F, and 23F were the most common serotypes globally in children under 5 years of age and the PCV-7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) were responsible for 12

25 more than 80% of IPD in North America (86-88). Serotypes 1, 5, and 7 are less common in the developed world, but universally cause more severe disease (83). Although the microbiological mechanisms that cause certain serotypes to be more pathogenic are not fully understood, it has been shown that comorbid medical conditions influence the serotype distribution causing IPD (89). Serotypes with a high potential for invasive disease in children tend to affect relatively healthy adults, whereas adults with less physiologic reserve are more often affected by serotypes with a lower invasive potential (e.g. 3, 6A, 6B, 8, 19F, 23F), which often have higher carriage rates, thicker polysaccharide capsules, and have been associated with higher rates of mortality (90-92). Certain serotypes may be preferentially found in particular clinical syndromes; for instance, serotypes 6, 10, and 23 are more often isolated from the CSF, serotypes 1, 4, and 14 from the blood, and serotypes 1 and 3 from patients with severe pneumonia (84, 93). However, all serotypes have the potential to cause disease in all sterile sites (83). Treatment and Antibiotic Resistance The primary treatment for patients with IPD is appropriate antibiotic therapy. Penicillin has been first line for community-acquired pneumonia since the 1940s; resistance to this and other antibiotics, such as macrolides, cephalosporins, and co-trimoxazole has grown in the last several decades (94, 95). Further, despite the majority (>95%) of pneumococcal strains remaining susceptible to penicillin by recently revised guidelines, the case fatality rate for hospitalized IPD patients has consistently been about 12% since the 1950 s in spite of appropriate antibiotic therapy and intensive care (7, 96, 97). Antibiotic resistance rates in healthy adults are often lower than in patients with comorbidities due to greater frequency of infection with susceptible serotypes and less prior 13

26 antibiotic use (66). Serotypes that frequently colonize and cause acute otitis media (AOM) in children (e.g. 6B, 9V, 14, 19A, 19F, and 23F) are more likely to be associated with antibiotic resistance (98). Overall, population pneumococcal immunization programs have led to a reduction in the circulation of drug-resistant strains as the highest resistance strains are included in conjugate vaccines and their shared serogroups, and the reduced carriage of conjugate vaccine type strains has resulted in less opportunity for exposure to selective pressure of antibiotics (98). However, the ongoing concern about increased resistance in non-vaccine serotypes was reaffirmed by the observed development of serotype 19A (a PCV-13 but not PCV-7 serotype) resistance to multiple antibiotics after PCV-7 introduction (98). Prevention of IPD The persistent high disease incidence and mortality of IPD, and the high cost and limitations associated with treatment of S. pneumoniae provide a strong rationale for a role for immunoprophylaxis in the prevention of pneumococcal disease (64). Polysaccharide Vaccine A 23-valent pneumococcal vaccine (PPV-23) is currently recommended in Canada by the National Advisory Committee on Immunization (NACI) for the prevention of invasive pneumococcal disease in persons with clinical conditions or other risk factors considered to be associated with the greatest risk for IPD. It contains purified capsular polysaccharides of the 23 pneumococcal serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F) most commonly isolated from adults in Europe and North America (83) (Table 1). In Canada, the two 23-valent pneumococcal formulations available are Pneumovax 23 (Merck Canada Inc.) and Pneumo 23 (Sanofi Pasteur SA). 14

27 Table 1. Serotypes included in conjugate and polysaccharide pneumococcal vaccines Serotype PCV-7 PCV-10 PCV-13 PPV A 6B 7F 8 9N 9V 10A 11A 12F 14 15B 17F 18C 19A 19F 15

28 Serotype PCV-7 PCV-10 PCV-13 PPV F 23F 33F Immunogenicity The two main serologic techniques for assessing antibody response induced by pneumococcal vaccination are IgG quantification by enzyme immunoassay (EIA) and measurement of opsonophagocytic activity (OPA) of antibodies from the sera of vaccinated individuals (23). OPA (functional) assays are theoretically preferred because opsonin-dependent phagocytosis is the primary host defense against S. pneumoniae, and antibody binding assays have reduced specificity as they also detect non-functional anticapsular antibodies. In adults, definitive correlates of protection have not been established, and EIA and OPA assay results only provide information on the relative magnitude of immune responses (23). The pneumococcal polysaccharide vaccine has been shown to be immunogenic in both healthy adults and those with immunocompetent comorbidities (99). Antibody levels decline rapidly after the first year and are back to baseline in 4-7 years, but the clinical significance of this decline has not been determined due to limited data on duration of PPV-23 induced clinical protection (100). The magnitude of immune response to PPV-23 is lower and/or there is a more rapid antibody decline in older adults and most immunocompromised persons, particularly those with untreated HIV infection, recent hematopoietic stem cell (HSCT) or solid organ transplant, chronic renal disease, hematologic neoplasm, splenectomy, and many immunosuppressive 16

29 medications (23, ). Immunization with polysaccharide vaccine induces a T-cell independent response and thus does not provide an anamnestic, or booster, response to revaccination (104). Hyporesponsiveness, or blunting of the immune response on revaccination to the same polysaccharide antigens, is a concern after use of polysaccharide vaccine for first vaccination against pneumococcal disease (105). Lower immune responses to revaccination have been demonstrated, but it is not clear if lower antibody levels correlate with inferior protection (100). Efficacy and Effectiveness The seminal controlled trials in South African gold miners provided evidence for pneumococcal polysaccharide vaccine efficacy against pneumococcal pneumonia (106, 107). Since that time, further clinical trials have produced equivocal results, largely due to methodological challenges in assessing non-bacteremic pneumonia, but a number of observational studies have demonstrated some protective effects of PPV-23 against IPD in adults, and have shown cost-effectiveness in IPD prevention (57, 108). However, studies on the efficacy of the polysaccharide vaccine among persons with immunocompromising conditions (notably those with HIV) and in some minority groups have produced only limited support for a protective effect of the vaccine ( ). Despite recent improvements in coverage for target groups, approximately 85% of IPD was still caused by PPV-23 serotypes prior to the introduction of childhood conjugate programs in the United States (34). Conjugate Vaccine Several conjugate vaccines, in which polysaccharides from pneumococcal capsules are covalently linked to carrier proteins, have been developed to address limitations of the polysaccharide vaccine. The first conjugated pneumococcal vaccine (PCV-7) that incorporated 17

30 the serotypes responsible for the majority of childhood IPD in North America (4, 6B, 9V, 14, 18C, 19F, 23F) was introduced in the United States in 2000 and in Canada in By 2006, PCV-7 had been introduced into all Canadian provincial and territorial programs; it was then replaced in 2011 by PCV-13, which has also been licensed for adult use in those 50 years of age and older (35). In Canada, the previously used 7-valent, and currently used 13-valent vaccines (Prevnar and Prevnar 13) are manufactured by Pfizer Canada Inc.; a 10-valent vaccine (Synflorix by GlaxoSmithKline) is also licensed and was briefly adopted in some regions, but was superseded by PCV-13. Immunogenicity Although they contain fewer serotypes than the polysaccharide vaccine, current conjugate vaccines provide several advantages: they elicit a T-cell dependent response that provides a booster effect upon subsequent antigen exposure, they are immunogenic in children under two years of age, and they can reduce nasopharyngeal colonization with vaccine serotypes (34). The immunogenicity of conjugate vaccines in immunocompromised individuals is generally preserved, with one exception being HIV patients with low CD4 counts (112). Although duration of immune response after receipt of conjugate vaccine has not yet been determined, repeated doses have been shown to have comparable immunogenicity to the first dose (113). The contribution of immunologic memory to long term vaccine-induced protection from pneumococcal disease remains unsettled. Efforts to establish correlates of protection have been limited by the lack of established correlations for mucosal disease and the importance of indirect protection in determining overall vaccine effectiveness (24). 18

31 Efficacy and Effectiveness Multiple large randomized trials have confirmed the efficacy of conjugate vaccines against IPD ( ). Some efficacy has also been demonstrated against pneumonia and acute otitis media (120, 121). In contrast to non-conjugate vaccines, PCV has been shown to reduce colonization of vaccine serotypes (and potentially increase carriage of non-vaccine serotypes) in vaccinated children (122). There is also evidence that adult carriage is altered by pediatric vaccination with conjugate vaccines, again leading to a decrease in vaccine serotypes and variable degrees of increase in non-vaccine serotypes (123, 124). This reduction of carriage and potential for subsequent transmission is thought to be the mechanism for the indirect protection provided by the conjugate pneumococcal vaccines (see Discussion) (125). As described above, after introduction of the 7-valent pneumococcal conjugate vaccine (PCV-7) in the routine childhood immunization schedule beginning in 2002, there was a dramatic decline in vaccine serotype invasive pneumococcal disease (IPD) in Canadian children who received the vaccine (direct effect) and in persons of all ages who did not receive the vaccine (indirect effect) (8-10). Although there has been some increase in IPD caused by nonvaccine serotypes after conjugate vaccine introduction, an overall decline in IPD has been the predominant trend in most jurisdictions (126). In some locations, IPD caused by PCV-7 serotypes has been eliminated in vaccine-eligible young children and nearly eliminated in other age groups (127). Promisingly, the initial results from a large randomized trial recently carried out in the Netherlands supported the efficacy of PCV-13 in adults 65 years, with substantive reductions seen in community acquired pneumonia, non-bacteremic pneumonia, and IPD caused by PCV-13 serotypes (see Future Research section) (128). 19

32 However, despite the benefits of conjugate vaccines, they are more costly and cover a lower proportion of serotypes causing IPD than does the polysaccharide vaccine. Given the expected large indirect benefit to adults from vaccinating infants, the pertinent issue of which, if any, adults should be vaccinated with conjugate pneumococcal vaccine remains an important and unsettled question. Structures and Governance of Immunization in Canada 1 The National Immunization Strategy provides the basis for coordination and collaboration between federal, provincial, and territorial partners in planning, delivering, and evaluating immunization services in Canada. At the federal level, the National Advisory Committee on Immunization (NACI), which is Canada s national immunization technical advisory group, provides scientific advice and makes evidence-based recommendations for the use of specific vaccines authorized for use in Canada (129). NACI is composed of specialists who have multidisciplinary expertise in fields related to immunization practices and considers burden of disease, vaccine characteristics, and other factors to provide advice related to the use and monitoring/evaluation of vaccines and adverse events. The Canadian Immunization Committee (CIC), which reports to F/P/T Deputy Ministers of Health through the Pan-Canadian Public Health Network, provides recommendations on the implementation of the National Immunization Strategy and on issues affecting immunization and immunization programs (130). This national process for immunization program planning is intended to minimize duplication of effort and to move towards harmonization of immunization schedules across the country. The 1 The information in this section is drawn heavily from the Canadian Immunization Guide, the authoritative Canadian immunization resource authored by the National Advisory Committee on Immunization. 20

33 biologics and genetic therapies directorate of Health Canada is responsible for regulating vaccines under the Food and Drugs Act and Regulations. Together, Health Canada and the Public Health Agency of Canada (PHAC) monitor vaccine safety and effectiveness throughout the vaccine lifecycle. At the provincial level, the provincial and territorial governmental responsibility for the administration and delivery of health services includes immunization, and each jurisdiction has its own processes and mechanisms for setting priorities, targets, and implementing programs. Provincial and territorial governments are also responsible for purchasing vaccines (sometimes independently, but typically as part of a bulk purchasing program coordinated by Public Works and Government Services Canada) for publically funded programs, immunization information systems and surveillance, and professional education and engagement (130). Provincial governments adapt NACI and CIC recommendations based on their regional situations to determine vaccine policy, coverage goals, and vaccine schedules. In Alberta, the ministry of health (Alberta Health) has developed an Alberta Immunization Strategy ( ), which is currently being refreshed. The Alberta government receives advice from the Alberta Advisory Committee on Immunization (AACI). Finally, Alberta Health Services is responsible for the administration and delivery of publicly funded immunization programs. Literature Review A search of the existing literature was carried out on April 4, 2014 to identify published literature relevant to the research question on the indirect protection provided by conjugate pneumococcal vaccines to adults with underlying comorbidities. The paradigm of evidencebased medicine provides an explicit framework for the formulation of well-built, focused clinical questions through the specification of four elements of a clinical query: Problem/Population, 21

34 Intervention, Comparison, and Outcome (PICO) (131). A search question based on the study objective was developed using the PICO framework: what was the (indirect) effect of conjugate pneumococcal vaccine introduction (I) on the occurrence of invasive pneumococcal disease (O) in adults with underlying comorbidities (P) [compared with no intervention (C)]. A MEDLINE and Embase search (Databases: Embase 1974 to 2014 April 11, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present) was performed using the MeSH search terms listed below. The search was restricted to articles with human subjects in the English language with publication year 2000-current. Age of study population was not restricted as some studies that report primarily on child populations also present findings in adult groups. MEDLINE Search Strategy AND (P) Population Terms (Combined with OR) Comorbidity; immunocompromised host; chronic disease AND (I) Intervention Terms (Combined with OR) Pneumococcal vaccines; conjugate vaccines; bacterial vaccines AND (C) Comparison Terms N/A AND 22

35 (O) Outcome Terms (combined with OR): Pneumonia, bacterial; pneumonia, pneumococcal; meningitis, pneumococcal; pneumococcal infections; sepsis; bacteremia; shock, septic; Streptococcus pneumoniae The MEDLINE/Embase search returned 535 references. The titles and abstracts were screened by the writer for relevance to the primary research question of the proposed study. Five papers were found to be directly relevant, with an additional two results providing relevant contextual information. A further manual query of the PubMed database on April 14, 2014 did not reveal any further studies of consequence. The results of the identified studies, none of which were conducted with Canadian populations, are described below (see Table 2 for summary). The hypothesized knowledge gap regarding the extent of indirect protection provided by conjugate pneumococcal vaccines to adults with underlying comorbidities, and specifically in a Canadian context, was confirmed by the literature review. The first identified paper reported on changes in IPD in older adults (50+ years of age) after conjugate pneumococcal vaccine was introduced in the United States in 2000 (34). Using data from population-based surveillance (ABCs) covering eight geographic areas, Lexau et al. (2005) found that after introduction of the PCV-7 childhood program, there was an increase in the proportion of IPD cases with any polysaccharide vaccine-indicating (including immunocompromising) condition (62.3% in to 72% in ) and with HIV (1.7% in to 5.6% in ). Significantly higher proportions of cases were reported to have received recent immunosuppressive therapy, have diabetes, or have chronic obstructive 23

36 pulmonary disease. The proportion of IPD cases with heart disease or renal disease remained unchanged. The second relevant study, which used population-based surveillance data from a single US metropolitan site (Atlanta, GA), supported the findings of Lexau and colleagues. Albrich et al. (2007) also reported that a statistically significantly greater proportion of adult IPD patients (40+ years of age) had comorbidities after the implementation of the routine childhood conjugate pneumococcal vaccine program (64). Specifically, the proportion of those with IPD having AIDS, diabetes mellitus, liver cirrhosis/failure, and/or asthma increased in the four-year period following vaccine introduction. The proportion of IPD cases with HIV infection remained unchanged after vaccination program introduction. Population estimates for comorbid conditions were not reported in the study, and the authors speculated that increases in population prevalence of asthma and diabetes mellitus over the study duration may have been partially responsible for the reported findings. A third US study by Muhammad et al. (2012), assessed IPD incidence among adults with and without PPV-23 indications using population and laboratory-based data (ABCs) and National Health Interview Survey estimates of denominator populations with PPV-23 indications (63). The authors found that despite an overall decline in IPD rates among adults, those with underlying comorbid conditions continued to be at increased risk of IPD; the proportion of adult IPD cases with PPV-23 indications increased from 51% to 61% after PCV-7 introduction, and the incidence of IPD after PCV-7 program onset among adults with polysaccharide vaccineindicating conditions differed substantially from those without polysaccharide indicating conditions (34.9 vs. 8.8 cases per 100,000 population, respectively). 24

37 A study from Great Britain, which investigated the risk of invasive pneumococcal disease outcomes among several clinical risk groups, produced divergent results. Similar to the US studies, Van Hoek et al. (2012) found that the odds of hospitalization or death due to IPD were substantially greater for those with polysaccharide vaccine-indicating conditions (132). However, they reported that the indirect protective effects due to the introduction of PCV-7 were similar in patient groups with and without comorbid conditions. Specifically, the overall proportion of IPD cases with polysaccharide vaccine-indicating conditions observed was similar before and after onset of PCV-7 childhood vaccination program (56% and 58%, respectively). After PCV-7 was introduced into the national immunization program in the Netherlands, van Deursen et al. (2012) compared the incidence of IPD before ( ) and after ( ) conjugate vaccine program onset (133). They reported declines in overall IPD incidence in young children and older adults and a trend toward increasing non-pcv-7 disease in all age groups. The proportion of immunocompromised persons increased significantly (from 18 to 22% of IPD cases). Mortality was found to be lower in the conjugate vaccine era, a finding thought to be largely due to the lower mortality rate of non-pcv-7 serotypes which had become more predominant. Finally, two studies were identified that reported on the changes in IPD epidemiology in adults after PCV program onset but did not directly address the study question. Regev-Yochay and colleagues (2014) provided information about the indirect effects on adults in Israel after introduction of PCV-7 (July 2009) and PCV-13 (Nov 2010) using data from nation-wide active laboratory-based surveillance (134). From July 2009 to June 2011, the proportion of PCV-7 type IPD cases decreased from 27.5% to 13.1%, while non-pcv-13 type IPD cases increased from 32.7% to 40.2%, most significantly in immunocompromised patients. Similarly, Lujan et al. 25

38 (2013) conducted a study of hospitalized IPD patients in two Spanish hospitals to determine which underlying conditions were associated with specific pneumococcal serotypes (135). Nonvaccine serotypes were found more frequently in adults with immunocompromising conditions. 26

39 Table 2. Literature review results: summary of changes in proportion of IPD cases with comorbid conditions Author (Year) Country (PCV onset) IPD cases (N) a Timeframe Age Groups Comorbid Conditions Pre- PCV % Post- PCV % P-value Lexau (2005) Albrich (2007) USA (2000) USA (2000) 9, Any 62.3% 72.0% P< , Any 85.9% 88.5% P= Any - - P=0.004 b Muhammad (2012) Van Hoek (2012) USA (2000) Great Britain (2006) 35, Any 51% 61% P< , Any 56% 58% NS Van Deursen (2012) Netherlands (2006) 1, All ages Any 67% 69% NS Immune Compromise 18% 22% P=0.013 Note: NS = not significant at p < 0.05; a all IPD cases in study population (in some cases includes pediatric patients); b the proportions of comorbid conditions for this sub-group were not presented in referenced article. 27

40 Study Purpose There is a need to determine the optimal methods of providing protection for vulnerable adults from disease caused by Streptococcus pneumoniae in the conjugate pneumococcal vaccine era. The purpose of the present study was to inform provincial and national immunization policy by determining if there are adult groups in Canada who have received relatively less (indirect) protection from childhood PCV programs, and may benefit from direct immunization with pneumococcal conjugate vaccine. The broad objective of this research was to determine how the epidemiology of IPD in adults has changed after introduction of PCV-7 and PCV-13 in Calgary, Alberta, Canada and to document the burden of IPD that is borne by adults with underlying comorbidities. More specifically, the objective of this project was to determine, using data from the CASPER surveillance program, if the proportion of adult IPD cases with underlying comorbidities has changed after introduction of PCV-7 and PCV-13. It was hypothesized that the introduction of PCV-7 and PCV-13 childhood immunization programs will have been associated with an increase in the proportion of IPD cases having underlying immunocompromising and immunocompetent comorbidities. 28

41 METHODS Data Collection Data for this thesis were collected by Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) program. CASPER is an ongoing prospective populationbased active surveillance network that collects data on all patients with invasive pneumococcal disease identified by Calgary Laboratory Services (CLS). CLS serves the entire Calgary Zone, which is composed of the city of Calgary and surrounding communities in southern Alberta. The CASPER case definition for IPD is as follows: acute illness with a positive culture of S. pneumoniae from a sterile site (e.g. blood, cerebrospinal fluid, pleural fluid) in a resident of the CASPER surveillance area. The process for case follow-up begins with laboratory confirmation of diagnosis by CLS, after which the CASPER team is notified and subsequently contacts the patient to request participation in the study. If the patient consents to participation, an in-person interview and chart review are conducted using standardized questionnaire and case report forms. However, if a patient dies before participating in an interview, a chart review alone is conducted and an autopsy report is requested from the Medical Examiner. In this circumstance, an interview with the patient s next of kin is done if possible. If consent is not obtained, basic demographic information is recorded from the Alberta Health Notifiable Disease Report (NDR) and laboratory forms. Variables collected and recorded in the CASPER database include demographic information, exposures and medical history, living arrangements, clinical presentation and course of illness, hospital admission and discharge/outcome circumstances, clinical investigations and (antibiotic and non-antibiotic) treatments. 29

42 IPD episodes were considered distinct when they occurred more than 30 days apart. To avoid counting any case in duplicate, when more than one isolate was collected from a patient during an episode of IPD, only a single isolate was used for analysis. If a non-blood sterile site isolate was identified in addition to pneumococcal bacteremia, the non-blood isolate was given precedence. As well, isolates from the central nervous system (CSF) were prioritized over those from other sites because meningitis is considered to be a more severe manifestation of IPD than non-meningeal disease. S. pneumoniae serotyping was performed on all IPD isolates by the Provincial Laboratory for Public Health (ProvLab) using the Quellung reaction method (136). Study Population The study population consisted of all adult IPD cases (18 years of age and older) captured by the CASPER prospective population-based surveillance system from January 1, 2000 to December 31, Patients with either community-acquired or hospital-acquired IPD whose home address postal code is within the boundaries of the CASPER surveillance system were included. The boundaries of CASPER surveillance area were initially limited to the city of Calgary and immediately neighboring municipalities, but were expanded in 2010 to capture the entire population of the Calgary Zone (Figure 1). The Calgary Zone was created following the reorganization of health services in Alberta under one centralized health authority (Alberta Health Services) and has identical boundaries to those of the immediately preceding version of the Calgary Health Region (see Appendix 1 for included municipalities). 30

43 Figure 1. Alberta Health Services Zone map Study Design Although the health condition of interest in the study was the occurrence of invasive pneumococcal disease (IPD), the lack of accurate information on the frequency of underlying comorbid conditions in the general population (non-cases) did not allow for use of the conceptual study design shown in Figure 2, in which the presence of underlying comorbidities is a covariate, potentially altering the association between indirect protection provided by PCV vaccines (exposure) and IPD incidence (outcome). Therefore, the study used an indirect cohort methodology, in which the study population was restricted to IPD cases and the presence of 31

44 underlying comorbidities served as the study outcome variables (Figure 3). Because infected persons are not being compared with uninfected persons, the results are less likely to be affected by bias resulting from factors that are related both to vaccination status (in this case, exposure to indirect protection from the vaccine) and risk of infection. This approach has been validated previously; several studies that used both this indirect methodology and conventional methods to assess polysaccharide vaccine efficacy produced very similar results (110, 111, 137). Indirect protection (PCV time period) IPD incidence Population: Calgary Zone Adults Underlying comorbidities (and other risk factors) Figure 2. Conceptual study design Indirect protection (PCV time period) Underlying comorbidities Population: Calgary Zone Adult IPD Cases Other covariates Figure 3. Employed study design 32

45 Exposures The primary study predictor (exposure) variable was the time period of disease onset relative to the introduction of the PCV-7 conjugate vaccine program in mid-2002 and the introduction of the PCV-13 vaccine program in mid The exposure variable had four levels and was a proxy for a case s potential to have received indirect protection from the childhood conjugate vaccine programs (Table 3). Table 3. Study exposure variable Reference Category Index Categories PCV Time Period (4 levels) Pre-PCV Early Post PCV-7 Late Post PCV-7 Early Post PCV-13 The period prior to PCV-7 introduction (January 1, 2000 to June 30, 2002) served as the pre-pcv reference category and three time periods following the onset of the routine childhood PCV program in Alberta (July 1, 2002 to end of study) served as the post-pcv index categories as follows. The time period closely following introduction of PCV-7 vaccine (July 1, 2002 to June 30, 2005) served as the early post-pcv-7 period index category, while the time period from 3 years following introduction of PCV-7 vaccine to the introduction of PCV-13 (July 1, 2005 June 30, 2010) served as the late post-pcv-7 period index category. The partitioning of the post PCV-7 period into two divisions was done to account for previously observed change in indirect response several years after vaccine introduction (8). Finally, the time period following introduction of PCV-13 vaccine (July 1, 2010 to December 30, 2011) served as the (early) post- PCV-13 period index category (Figure 4). 33

46 Pre-PCV Early Post-PCV-7 Late Post-PCV-7 Post PCV-13 Jan 1, June 30, 2002 July 1, June 30, 2005 July 1, June 30, 2010 July 1, Dec 31, 2011 Figure 4. Categories for time period of disease onset relative to the introduction of routine childhood conjugate vaccine programs in Alberta Outcomes The primary study outcome was the presence of an underlying comorbidity at the time of IPD diagnosis, operationalized as a medical condition, trait, or health behaviour that increases the risk of IPD, and for which the National Advisory Committee on Immunization (NACI) has recommended the PPV-23 vaccine 2. As described in more detail in the Data Analysis section, underlying comorbidities were studied both as a single group and also clustered to separately assess the occurrence of immunocompromising conditions and immunocompetent conditions (Table 4). As well, specific comorbid conditions demonstrated to increase the risk of developing invasive pneumococcal disease (see Comorbidities section) were assessed individually. 2 The NACI indications for PPV-23 were used to approximate the comprehensive range of factors that increase the risk of developing IPD and/or experiencing more severe disease. The current indications for conjugate vaccine are more restrictive. 34

47 Table 4. Study outcome variables Reference Category Index Categories Underlying Comorbidities (3 levels) No comorbid conditions Immunocompetent conditions o Chronic heart disease o Chronic lung disease o Diabetes mellitus o Chronic liver disease o Chronic CSF leak o Cochlear implant o Current tobacco use o Alcoholism o Illicit drug use o Homelessness Immunocompromising conditions o HIV/AIDS o Chronic renal disease o Cancer o Bone marrow or solid organ transplant o Sickle cell, asplenia, or other hemoglobinopathy o Immunocompromising medication use o Congenital immune deficiencies 35

48 The study outcome variables were derived from existing data fields in the CASPER database based on the indications for adult use of the polysaccharide pneumococcal vaccine as specified in the Canadian Immunization Guide (20). IPD risk groups identified by the (American) Advisory Committee on Immunization Practices (ACIP) were reviewed and were used in several cases to provide further specificity to study outcome definitions. The underlying comorbidities selected for inclusion in the study are defined in Table 5 below. Table 5. Outcome variables definitions Condition Definition Chronic heart disease Atherosclerosis, history of myocardial infarction, congestive heart failure, and cardiomyopathies (excluded hypertension) Chronic lung disease COPD (emphysema and chronic bronchitis) or asthma associated with regular corticosteroid use (defined as regular prednisone use with dose 20mg/day) Diabetes mellitus Insulin and non-insulin dependent diabetes Chronic liver disease Chronic CSF leak Including cirrhosis due to any cause and hepatitis C diagnosis Chronic cerebral spinal fluid (CSF) leak Cochlear implant Cochlear implant Smoker Alcoholism Current smoker (as identified by chart review and patient interview) Alcoholism (as identified by chart review and patient interview) Illicit drug use Illicit drug use (as identified by chart review) 36

49 Homelessness HIV/AIDS Homeless housing status (as identified by chart review and patient interview) HIV/AIDS Chronic renal disease Chronic renal failure or nephrotic syndrome Cancer Transplants Hemoglobinopathies Immunocompromising medication use Congenital immune deficiencies Malignant neoplasms first diagnosed or recurring in 5 years before IPD infection History of solid organ or hematopoietic stem cell transplant Asplenia (functional or anatomic), Sickle cell disease, or other hemoglobinopathy Immunosuppressive therapy including regular use of corticosteroid therapy, chemotherapy, or biological modifiers Congenital immunodeficiencies involving any part of the immune system Covariates Potential confounders/modifiers of the study associations (covariates) were selected based on suspected clinical relevance and review of the literature (see Background). These included patient age/age group (18-49, 50-64, 65-79, 80+), gender, Aboriginal status, clinical (invasive) site, and conjugate vaccine group (PCV-7 serotypes, the six additional PCV-13 serotypes, and non-pcv serotypes) (Table 6). Individual serotypes and dichotomous variables for PCV-7, PCV- 13, and PPV-23 groups were also assessed in the descriptive analysis. Smoking, alcoholism, illicit drug use, and homelessness, which could have appropriately been considered covariates, are NACI PPV-23 indications, and were classified as immunocompetent comorbidities (outcomes) for the purposes of this study. 37

50 Table 6. Study covariates Reference Category Index Categories Age Group (4 levels) Self-reported Gender Female Male (2 levels) PCV Group (3 levels) Non-PCV PCV-7 (4,6B,9V,14,18C,19F,23F) PCV-13 additional (1,5,7F,3,6A,19A) Clinical Site (4 levels) Bacteremia and Uncomplicated pneumonia other clinical Complicated pneumonia sites Meningitis Self-reported Aboriginal Status (2 levels) Non-aboriginal Aboriginal Note: Presence of complicated pneumonia (empyema) was defined by abnormal radiographic evidence and/or positive pleural fluid culture Community Prevalence Data To compare the prevalence of comorbidities in the study population with that of the general Alberta (Calgary Zone) population, data were obtained from the Canadian Community Health Survey - Alberta section and Alberta Health s Interactive Health Data Application. CASPER surveillance catchment area population estimates were obtained from the Health Systems Analysis Unit, Data Integration, Measurement & Reporting Program, Alberta Health Services. Data Analysis Data was extracted from the CASPER database (FileMaker Pro 10.0 v1, Filemaker Inc., Santa Clara, CA), and transferred to STATA/IC, version 12.0 (STATA Corporation, College Station, TX), for statistical analysis. Data analysis consisted of descriptive, univariable, and multivariable analyses, as described in the following sections. 38

51 Descriptive Analysis Incidence was defined as the number of IPD cases divided by the total source population of the CASPER catchment area at the time of assessment. Incidence rates for age group and vaccine group were calculated by year of the study and/or PCV vaccine period; mid-period populations were used for PCV period incidence rate denominators. Characteristics of the CASPER IPD cases for the study period were described. Frequencies and proportions of patient (age and age group, gender, Aboriginal status, homelessness) and disease (clinical site, vaccine groups, and individual serotypes) characteristics, and of overall, immunocompetent, immunocompromising comorbidities were reported for the entire study duration and for each PCV period and/or study year. The frequencies of individual comorbidities were also summarized and odds ratios for their occurrence in each of the post-pcv periods relative to the pre-pcv period were calculated. Community population comorbidities rates were obtained and compared with CASPER comorbidity proportions to identify secular trends that could confound the study findings. Omnibus tests for differences in study variables over PCV periods, followed by a priori comparisons of the pre-pcv period with each of the three post PCV periods, were carried out. An alpha of 0.05 was used to define statistical significance for t-tests (two groups with continuous/numerical outcome variables), analysis of variance (greater than two groups with continuous outcome variables i.e. age variable), or Pearson s chi-square tests (dichotomous outcome variables) performed. Error bars on all charts represent 95% confidence intervals. Throughout the analysis section, relevant summaries with serotypes 5 and 8 removed were provided to illustrate the counterfactual IPD epidemiology over the study period in the absence of community outbreaks (36). 39

52 Multivariable Analysis Two pre-planned logistic regression models (one binomial and one multinomial) were developed to assess the influence of the study exposure on the study s categorical outcome variable under the concurrent influence of the study covariates. The two levels of the binomial model outcome variable were: no comorbidity vs. any comorbidity, while the three levels of multinomial model outcome variable were: no comorbidity vs. immunocompetent comorbidity and immunocompromising comorbidity. The initial models were developed based on informed plausible relations (i.e. clinical meaningfulness), capturing the potential for study covariates to confound or modify the primary study relationship. The only effect measure modification term included in the initial models was PCV group by PCV period, the justification being that certain serotypes (i.e. non-pcv-13 group) have been shown to be more frequent in IPD cases with underlying comorbidities, and there is robust evidence that the relative burden caused by PCV groups has changed after PCV childhood program introduction (138). Backward elimination was used to produce final parsimonious models that explained maximum variability in study outcomes (139). Nested regression models were compared with likelihood ratio tests (p 0.05). Potential confounding was assessed through the degree of change observed in measures of association after removal of model terms, with a 10% change signifying a confounded association. Unadjusted and adjusted odds ratios (binomial model) or relative risk ratios (multinomial model) were reported with 95% confidence intervals and p- values. Model term definitions E = PCV period A = Age group 40

53 G = Gender S = PCV group C = Clinical site N = Aboriginal status Note: E, A, G, S, C, N are all categorical variables; Ei = indicator which equals 1 if the value of the observation is i and equals 0 otherwise. A categorical age group variable was retained rather than a continuous age variable as the association between age and the probability of having an underlying comorbidity is not linear; a sensitivity analysis using a smoothed age variable as per the STATA lowess function did not lead to divergent study results. Initial Binomial Model The binomial model assessed the probability of any comorbidity (PC) compared to the probability of no comorbidity (PN). The initial model, consisting of terms representing all levels of study predictor variables and the interaction term for PCV group x PCV period, is shown below. The interpretations of the coefficients in the initial binomial model can be found in Appendix 2. log(pc/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 4A1+ 5A2+ 6A3) + 7G + ( 8S1+ 9S2) + ( 10C+ 11C+ 12C)+ 13N + ( 14E1S1+ 15E1S2 + 16E2S1+ 17E2S2+ 18E3S1 + 19E3S2) Initial Multinomial Models The multinomial models assessed the probability of: 1) immunocompetent comorbidity (PCP) compared to no comorbidity (PN) 2) immunocompromising comorbidity (PCR) compared to no comorbidity (PN) 41

54 The initial models, consisting of terms representing all levels of study predictor variables and the interaction term for PCV group x PCV period, are shown here 3. log(pcp/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 4A1+ 5A2+ 6A3) + 7G + ( 8S1+ 9S2) + ( 10C+ 11C+ 12C) + 13N + ( 14E1S1+ 15E1S2 + 16E2S1+ 17E2S2+ 18E3S1 + 19E3S2) log(pcr/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 4A1+ 5A2+ 6A3) + 7G + ( 8S1+ 9S2) + ( 10C+ 11C+ 12C) + 13N + ( 14E1S1+ 15E1S2 + 16E2S1+ 17E2S2+ 18E3S1 + 19E3S2) The interpretations of the coefficients in the initial multinomial models can be found in Appendix 2. Ethics CASPER projects have pre-existing ethics approval from the Conjoint Health Research Ethics Board (CHREB) of the University of Calgary. Ethics approval for this project was sought as a CASPER sub-study, with the addition of the author to the current study approval letter. Written informed consent was obtained for all patient interviews. 3 As the comparisons in the two models above are between different levels of the outcome variable, the equivalent coefficients from each model represent different quantities. 42

55 RESULTS Descriptive Analysis Study Population From , there were 1153 episodes of laboratory confirmed IPD in Calgary and area adults. There were 35 instances in which an individual had more than one episode of IPD (greater than 30 days apart). Fourteen patients refused participation; these and any other patients without complete information were included in descriptive analyses where relevant data was present cases had sufficient information for inclusion in the multivariable analysis. Over the entire study period, a majority of cases were male, had uncomplicated pneumonia, and were infected with serotypes included in either the conjugate or polysaccharide vaccines (Table 7). Table 7. Characteristics of Adult CASPER IPD cases ( ) Characteristic N (% total) Study Population Cases with complete information (98.1%) Age Group (years) (42%) 330 (29%) 200 (17%) 128 (11%) Gender Female Male 492 (43%) 661 (57%) 43

56 Aboriginal No Yes 1,057 (92%) 96 (8%) Homeless No Yes 941 (81%) 212 (18%) Clinical Site Bacteremia (or other foci) Uncomplicated pneumonia Complicated pneumonia Meningitis 137 (11.9%) 852 (74.0%) 113 (9.8%) 51 (4.4%) Vaccine Groups 4 PCV-7 PCV-13 PPV (24.7%) 640 (56.4%) 951 (83.9%) IPD Incidence The overall incidence of adult IPD decreased by 37% over the duration of the study, from 11.2 (pre-pcv period) to 7.0 (post PCV-13 period) cases per 100,000 population. There were community IPD outbreaks in 2005 to 2007, which increased the incidence in the late post PCV-7 period (Table 8) (36). This outbreak-induced variance in disease occurrence, which was no 4 Note: vaccine groups here are not mutually exclusive categories 44

57 longer seen after removal of the responsible serotypes (serotype 5 and serotype 8), complicates numerous study associations and trends and is addressed recurrently in subsequent sections. IPD incidence in all adult age groups was lower in 2011 than in 2000 (Table 9). Table 8. CASPER IPD case frequency and incidence over study period Time Period Pre-PCV (Jan 1, June 30, 2002) Early Post PCV-7 (July 1, June 30, 2005) Late Post PCV-7 (July 1, June 30, 2010) Early Post PCV-13 (July 1, Dec 31, 2011) Time Period Duration Number of Cases Incidence (per 100,000 population) All serotypes Excluding serotypes 5 & years years years years

58 Table 9. Overall IPD incidence per 100,000 population by age group over study year Age Group All Both initial IPD incidence and degree of decline over the study period increased with greater patient age. Consequently, the largest disease reduction observed was the 68% decrease in overall IPD incidence (from 66.6 to 21.5 cases per 100,000 population) in the 80+ age group from the pre-pcv period to the post PCV-13 period (Figure 5). 46

59 Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV IPD Incidence per 100,000 Population Age Group (Years) Figure 5. Overall IPD incidence per 100,000 population by age group over PCV period The reduction in overall IPD incidence during the study was a consequence of the extensive decline in conjugate vaccine type disease. PCV-13 type disease fell from 8.2 (2000) to 4.2 (2011) cases per 100,000 population, and PCV-7 type disease decreased from 6.6 (2000) to 1.4 (2011) cases per 100,000 population. Similarly, the reduction seen in polysaccharide vaccine (PPV-23) type disease, from 9.6 (2000) to 6.4 (2011) cases per 100,000 population, was due to decreases in IPD caused by serotypes also present in the conjugate vaccines (i.e. incidence of non PCV-13 serotypes included in PPV-23 did not decline: 1.8 cases per 100,000 in 2000 and 2.7 cases per 100,000 in 2011). Non-PCV serotype and non-vaccine (PPV-23 or PCV-13) serotype disease remained relatively constant throughout the duration of the study, with ~3-4 and ~1-2 cases, respectively, per 100,000 population reported most years (Table 10). 47

60 Table 10. IPD incidence per 100,000 population by vaccine group over study year Vaccine Group All PPV PCV PCV Non-PCV Non-Vaccine As seen in Figure 6, the decrease in PCV-13 type disease incidence was again most dramatic in the 80+ age group, with a 92% decrease (from 43.7 to 3.6 cases per 100,000 population) observed from the pre-pcv to the early post PCV-13 period. 48

61 Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV IPD Incidence per 100,000 Population Age Group (Years) Figure 6. PCV-13 IPD incidence per 100,000 population by age group over study period The outbreaks of serotype 5 and 8 disease in the late post PCV-7 period were responsible for a substantial proportion of observed disease activity. Serotype 5 is a PCV-13 (but not PCV-7) serotype, and both serotype 5 and 8 are included in PPV-23. The influence of the outbreaks on overall and vaccine group-specific incidence trends can be seen by comparing Figure 7 (all serotypes) and Figure 8 (outbreak serotypes removed) 5. When serotypes 5 and 8 are excluded, a consistent progressive decline is seen for overall, PCV-7, and PCV-13 incidence over PCV period, as the transitory increases in overall, PCV-13, and non-pcv type disease incidence in the late post PCV-7 period are no longer observed. 5 Note that in Figure 7 and Figure 8, groups are not mutually exclusive. Therefore, comparisons are only relevant for each vaccine group over time period and not between vaccine types. 49

62 20 18 IPD Incidence per 100,000 Population Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All IPD PCV13 type PCV7 Type Non-PCV type Figure 7. IPD incidence per 100,000 population by vaccine group over PCV period IPD Incidence per 100,000 Population Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All IPD PCV13 type PCV7 Type Non-vaccine type Figure 8. IPD incidence per 100,000 population by vaccine group over PCV period (excluding serotypes 5 and 8) 50

63 Patient Characteristics Age The mean age of the study population was 55.0 (SD = 17.7), with a range from 18.5 (bounded at 18 years by the study inclusion criteria) to 97.8 years of age. Despite the increased IPD risk in older adults, the largest proportion of cases occurred in the year age group (Table 11). Table 11. Frequency of IPD cases by age group over study year Total Total ,153 51

64 The age distributions of 1) all adult IPD cases, and 2) cases excluding serotypes responsible for the community IPD outbreaks over the duration of the study is presented in Figure 9, again demonstrating the large number of cases occurring in those too young to be considered at high-risk for IPD because of older age Age (years) All Cases Excluding serotypes 5 and 8 Figure 9. Age distribution of adult CASPER IPD cases with and without outbreak serotypes ( ) The mean age of IPD cases in the late post PCV-7 period (53.0 years) was considerably lower than that of the other PCV periods (average 56.9 years); however, removal of serotypes 5 and 8, which, as mentioned, were implicated in community IPD outbreaks from 2005 to 2007, resulted in a relatively consistent mean age throughout the entire study period (p=0.71) (Figure 10). 52

65 Age (years) Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All Serotypes No Serotype 5 or 8 Figure 10. Mean age over PCV period for all serotypes and non-outbreak serotypes The distribution of IPD cases by age group over study year is presented in Figure 11 below. As with the statistics for mean age, the proportions of age groups in each year and study period were relatively constant, with the exceptions of a greater occurrence of cases in the year age group in 2006 and 2007 and somewhat fewer cases in the year age group in

66 100% 90% 80% Proportion of IPD Cases 70% 60% 50% 40% 30% 20% 10% 0% Figure 11. Proportion of IPD cases by age group over study year Gender Overall, 57.3% of cases (n=661) were male and 42.7% (n=492) were female. In the majority of study years (8 of 12), there were a greater number of male IPD cases than female cases (Figure 12). Similar to the age variable data, an increase in the proportion of male IPD cases in the post PCV-7 period occurred during the outbreak-related upsurges in serotypes 5 and 8 (Figure 13). Although this change in gender differential between PCV periods was not statistically significant (p=0.12), removal of serotypes 5 and 8 from the analysis further limited variability in the gender variable over study period (p=0.79). 54

67 Proportion Male Figure 12. Proportion of IPD cases of male gender over study year Proportion Male Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All Serotypes No Serotype 5 or 8 Figure 13. Proportion of IPD cases of male gender over PCV period for all serotypes and non-outbreak serotypes 55

68 Aboriginal Status Over the course of the study, 8.3% of IPD cases (n=96) were classified as Aboriginals. As shown in Table 12, a large number of Aboriginal IPD cases (n=48) were of serotypes 5 and 8, with a substantial proportion occurring in the late post PCV-7 period. After exclusion of these serotypes, the proportion of IPD cases in the post PCV-7 period classified as Aboriginal remained elevated but did not significantly differ from the other PCV periods (p=0.06). Table 12. Frequency and proportion of IPD cases with Aboriginal status over study year All Serotypes Excluding Serotypes 5 and 8 Frequency Proportion Frequency Proportion % 2 2.7% % 4 4.9% % 2 3.0% % 6 7.1% % 4 6.0% % 3 4.1% % % % 7 9.3% % % % 0 0.0% % 3 6.0% % 0 0.0% Total % % 56

69 Homelessness There were 212 cases (18.4%) of IPD in individuals classified as homeless (Table 13). Substantially more cases of serotype 5 and serotype 8 IPD were seen in the homeless population from 2006 and 2007 (p<0.001) (Figure 14). The statistical significance of the increase in homeless IPD cases in the late post PCV-7 period persisted after removal of the outbreak serotypes (p=0.001). Table 13. Frequency and proportion of IPD cases with homeless status over study year All Serotypes Excluding Serotypes 5 and 8 Frequency Proportion Frequency Proportion % 3 4.0% % 8 9.8% % 4 6.0% % 6 7.1% % 5 7.5% % 4 5.4% % % % % % % % % % 3 6.0% % % Total % % 57

70 Prooportion of Cases Figure 14. Proportion of IPD cases classified as homeless over study year Disease Characteristics Clinical Site Uncomplicated pneumonia was the dominant clinical manifestation of IPD, comprising at least 60% of cases in all study periods (Figure 15). Much less common were primary diagnoses of bacteremia (11.9%), complicated pneumonia (9.8%) and meningitis (4.4%). A greater proportion of pneumonia cases in the post PCV-13 period were classified as complicated pneumonia than in any of the previous periods (17.4%), but this difference was not statistically significant (p=0.12). Similarly, although the number of cases was quite small (resulting in very wide confidence intervals for the point estimates), the proportion of meningitis cases was higher in the post PCV-13 period (6.0%) than any other portion of the study (p=0.85) (Figure 16). For both complicated pneumonia and meningitis, the relative increases seen were primarily due to a decline in the absolute frequency of uncomplicated pneumonia rather than an increase in the occurrence of those more severe clinical manifestations. 58

71 Proportion of IPD Cases % 4.28% 4.17% 6.03% 7.84% 10.12% 8.85% 17.24% 78.92% 73.54% 74.65% 62.07% 8.82% 12.06% 12.33% 14.66% Pre-PCV Early PCV7 Late PCV7 PCV13 Bacteremia or other Foci Uncomp. Pneumonia Comp. Pneumonia Meningitis Figure 15. Proportion of IPD cases by clinical site over PCV period Proportion Meningitis Pre-PCV Early PCV7 Late PCV7 PCV13 Figure 16. Proportion of IPD cases classified as meningitis over PCV period Serotype Frequencies Serotype information was available for 1133 of the 1153 cases. The majority of IPD cases were of polysaccharide (83.9%) and conjugate (56.4%) vaccine serotype (Table 14). The 59

72 proportion of PCV-7 serotype IPD decreased from over half (52.5%) of all cases in the pre-pcv period to 13.8% in the post PCV-13 period (p<0.001). In contrast, non-pcv serotypes increased over the study from 31.8% (pre-pcv) to 52.6% (post PCV-13) of IPD cases (Figure 17). Table 14. Frequency of pneumococcal vaccine serotypes Vaccine Frequency % Total Cases Group PCV % PCV % PPV % Note: Serotype information not available for 20 IPD cases Proportion of IPD Cases Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 PCV-7 PCV-13 Additional Non-PCV Figure 17. Proportion of IPD cases by PCV group over PCV period 60

73 Similarly, PCV-13 additional serotypes increased from 15.7% (pre-pcv) to 33.6% (post PCV-13), with an intervening peak at 61.1% of cases in 2007 during the community-based outbreaks (Figure 18). The increases in the proportion of IPD seen for PCV-13 additional and non-pcv type disease were largely explained by the decline in PCV-7 type disease. There was an increase in absolute frequency of non-pcv and PCV-13 additional type disease; the number of PCV-13 additional type IPD cases for (n=82) was higher than in (n=44) and the frequency of non-vaccine type IPD for (n=33) was also greater than in (n=20). However, as the population of the CASPER surveillance area increased substantially over the study, the incidence rates for these disease groups was largely unchanged Proportion of IPD Cases PCV-7 PCV-13 Additional PPV-23 Non-PCV Figure 18. Proportion of IPD cases by vaccine group over study year 61

74 For the entire study duration, the most common serotypes causing disease were serotype 5 at 15.5% (n=176), serotype 8 at 8.2% (n=93), serotype 3 at 7.7% (n=87), serotype 4 at 7.6% (n=86), and serotype 22F at 6.7% (n=76) (Table 15). Serotype 19A disease, which was not reported in the CASPER database during the two surveillance years prior to conjugate vaccine introduction, was responsible for 41 cases of disease from Meningitis cases were caused by a variety of serotypes. The most common were serotype 4 at 13.8% (n=7), serotype 8 and 23F at 7.8% each (n=4), and 3 and 19A at 5.9% each (n=3). Table 15. IPD cases by individual serotype over study year Serotype Total PCV-7 serotypes B V C F F PCV-13 serotypes A F PCV-13 serotypes include all those in PCV-7 plus serotypes 1, 3, 5, 6A, 7F, 19A 62

75 19A PPV-23 serotypes N A A F B F F F Non-vaccine serotypes 7C A L F B C F A A C F B PPV-23 serotypes include all those in PCV-13 (except 6A) plus 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F 63

76 A A B A A A B C F The most common serotypes causing IPD in the last three years of the study were serotypes 19A at 12.2% (n=27), serotypes 3 and 7F at 10.0% each (n=22), serotype 22F at 8.6% (n=19), serotype 8 at 7.7% (n=17), and serotype 4 at 5.9% (n=13) (Figure 19). As such, the majority of disease in this latter part of the study was caused by PCV-13 additional (19A, 3, 7F) and non-pcv (22F and 8, along with 9N, 33F, 23F) serotypes; only one PCV-7 serotype (serotype 4) continued to cause a substantial amount of disease. 64

77 Frequency A 3 7F 22F 8 4 9N 33F 23F 6A 15B 17F 23B 31 NF 12F 15A 5 11A 14 19F 15C B 6B NV 10A 18C 35A 9A 9V NA NT Serotype Figure 19. Frequency of serotypes causing IPD cases in For adults with immunocompromising comorbidities, serotypes 19A at 15.7% (n=11) and 22F at 11.4% (n=8) were responsible for a great proportion of disease in the last three years of the study, after having been much less common in the earlier years of the study timeframe. Multiple other serotypes made smaller contributions to the burden of disease in adults with underlying immunocompromising comorbidities in (Figure 20). 65

78 Frequency A 22F 3 33F 15B 7F 17F A 20 23B 23F 6A 9N NF 10A 14 15C 19F A 35B 6B NA Serotype Figure 20. Frequency of serotypes causing IPD cases in adults with immunocompromising comorbidities in Comorbidity Frequencies The majority of IPD cases had some type of underlying comorbidity (84.6%) ( 66

79 Table 16). Immunocompetent conditions were far more prevalent (n=876) than immunocompromising conditions (n=326), largely due to the inclusion of current smokers (50.3%) and alcoholics (27.6%). 67

80 Table 16. CASPER cases characteristics and community population estimates Characteristic CASPER N (% total) Population Estimates 8 (% total) Age Group (years) Gender Female Male Vaccine Groups 9 PCV-7 PCV-13 PPV-23 Clinical Site Bacteremia (or other foci) Uncomplicated pneumonia Complicated pneumonia Meningitis 495 (42%) 330 (29%) 200 (17%) 128 (11%) 492 (43%) 661 (57%) 280 (24.7%) 640 (56.4%) 951 (83.9%) 137 (11.9%) 852 (74.0%) 113 (9.8%) 51 (4.4%) (67%) (21%) (9%) (3%) (51%) (49%) N/A N/A 8 Alberta adult population estimates were obtained from the Alberta Health Services Health Systems Analysis Unit, Data Integration, Measurement & Reporting Program; comorbidity estimates were obtained from the Canadian Community Health Survey - Alberta section and Alberta Health s Interactive Health Data Application (see page 75) 9 Vaccine groups presented here are not mutually exclusive categories 68

81 Any Underlying Comorbidity Immunocompetent Conditions Current smoker Alcoholism Chronic lung disease Illicit drug use Chronic heart disease Chronic liver disease Diabetes mellitus Chronic CSF leak Cochlear implant 975 (84.6%) N/A 876 (76.0%) N/A 580 (50.3%) ( %) 318 (27.6%) ( %) 209 (18.1%) (Asthma: 8.1%) (COPD: ~1.5%) 207 (18.0%) 197 (17.1%) (IHD: ~2.0%) 171 (14.8%) 126 (10.9%) ( %) 1 (0.1%) 0 (0.0%) Immunocompromising Conditions 326 (28.3%) N/A Immunocompromising medications Cancer HIV Chronic renal disease Transplants Sickle cell/asplenia Congenital Immunodeficiences 180 (15.6%) 127 (11.0%) 51 (4.4%) 49 (4.2%) 22 (1.9%) 19 (1.6%) 5 (0.4%) ( %) (~0.2%) Note: 227 IPD cases had both an immunocompetent and an immunocompromising comorbidity 69

82 Overall Comorbidities The proportion of IPD cases with any underlying comorbidity was highest in the late post PCV-7 and early post PCV-13 periods at 86-87% (Table 17). Table 17. Proportion of IPD cases with any underlying comorbidity over PCV period for all serotypes and without outbreak serotypes PCV Period Proportion (95% CI): All Serotypes Proportion (95% CI): Excluding Serotypes 5 and 8 Pre-PCV 0.82 (0.77 to 0.87) 0.81 (0.76 to 0.87) Early Post-PCV (0.74 to 0.84) 0.79 (0.73 to 0.84) Late Post-PCV (0.84 to 0.90) 0.84 (0.80 to 0.88) Early Post-PCV (0.81 to 0.93) 0.87 (0.81 to 0.94) There was a statistically significant difference in the proportion of IPD cases having any underlying comorbidity across PCV periods (p = 0.038). However, none of the post-pcv period proportions were significantly different than that of the pre-pcv period and the largest observed difference in proportions was between the early and late post PCV-7 periods (Figure 21). With serotypes 5 and 8 removed from the analysis, there was no significant difference in proportion of overall underlying comorbidities between PCV periods (p = 0.195). 70

83 Proportion with Comorbidity Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All Serotypes No Serotypes 5 and 8 Figure 21. Proportion of IPD cases with any underlying comorbidity over PCV period Immunocompetent Comorbidities Similarly, there was a global significant difference in the proportion of IPD cases with an underlying immunocompetent comorbidity across study periods (p= 0.007). Again, there were no significant differences from the pre-pcv period to any of the post-pcv periods. The proportion with an immunocompetent comorbidity was again highest in the late post PCV-7 period (0.80) and lowest in the early post PCV-7 period (0.69) (Table 18). The demonstrated statistical significance of the differences in proportions did not persist with removal of serotype 5 and serotype 8 cases from the analysis (p=0.39) (Figure 22). 71

84 Table 18. Proportion of IPD cases with an immunocompetent underlying comorbidity over PCV period for all serotypes and without outbreak serotypes PCV Period Proportion (95% CI): All Serotypes Proportion (95% CI): Excluding Serotypes 5 and 8 Pre-PCV 0.75 (0.69 to 0.81) 0.74 (0.67 to 0.80) Early Post-PCV (0.64 to 0.75) 0.67 (0.61 to 0.73) Late Post-PCV (0.77 to 0.83) 0.73 (0.69 to 0.78) Early Post-PCV (0.63 to 0.80) 0.72 (0.63 to 0.81) Proportion with Immunocompetnet CMC Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All Serotypes No Serotypes 5 and 8 Figure 22. Proportion of IPD cases with an underlying immunocompetent comorbidity over PCV period Immunocompromising Comorbidities The proportion of IPD cases with an underlying immunocompromising comorbidity ranged from 0.25 to 0.36 over the study periods (Table 19). Although there were no significant differences across PCV periods, either for all serotypes (p= 0.093) or without serotypes 5 and 8 72

85 (p=0.206), a trend was seen toward a greater proportion of IPD cases having an immunocompromising comorbidity over time (i.e. high proportion in more recent PCV periods). (Figure 23). Table 19. Proportion of IPD cases with an immunocompromising underlying comorbidity over PCV period for all serotypes and without outbreak serotypes PCV Period Proportion (95% CI): All Serotypes Proportion (95% CI): Excluding Serotypes 5 and 8 Pre-PCV 0.25 (0.19 to 0.31) 0.27 (0.20 to 0.33) Early Post-PCV (0.25 to 0.36) 0.34 (0.27 to 0.40) Late Post-PCV (0.23 to 0.30) 0.34 (0.29 to 0.38) Early Post-PCV (0.27 to 0.45) 0.38 (0.28 to 0.47) Proportion with Immunocompromising. CMC Pre-PCV Early Post-PCV7 Late Post-PCV7 Early Post-PCV13 All Serotypes No Serotypes 5 and 8 Figure 23. Proportion of IPD cases with an underlying immunocompromising comorbidity over PCV period 73

86 Individual comorbidities The odds ratios for IPD cases having individual underlying comorbidities in each of the post-pcv periods (relative to the pre-pcv period) are provided in Table 20 and Table 21 below. For immunocompetent comorbidities, the odds of smoking (1.63; 95% CI ), alcoholism (2.28; 95% CI ), IDU (6.46; 95% CI ) and chronic liver disease (2.89; 95% CI ) were significantly higher, and the odds of chronic heart disease was significantly lower (0.49; 95% CI ), during the late post PCV-7 period. The odds of illicit drug use was also significantly higher (2.32; 95% CI ) in early post PCV-7 period and it was the only immunocompetent condition with odds ratios greater than one for all post-pcv periods. Table 20. Odds ratios a for immunocompetent comorbidities for the post PCV periods Condition Early Post PCV-7 Late Post PCV-7 Post PCV-13 Current Smoker 0.94 ( ) 1.63 ( )* 0.97 ( ) Alcoholism 0.91 ( ) 2.28 ( )* 0.78 ( ) IDU 2.32 ( )* 6.46 ( )* 1.84 ( ) Chronic heart 0.81 ( ) 0.49 ( )* 1.20 ( ) Chronic lung 0.73 ( ) 0.72 ( ) 0.87 ( ) Diabetes 0.71 ( ) 0.75 ( ) 0.97 ( ) Chronic liver 1.73 ( ) 2.89 ( )* 0.87 ( ) Note: CSF leak and cochlear implant case frequencies were too low for inclusion in analysis a Relative to the odds of having an immunocompetent comorbidity in the pre-pcv period *p <

87 For immunocompromising comorbidities, the odds of a transplant history were strikingly higher in the early post PCV-7 (8.21; 95% CI ) and post PCV-13 (11.07; 95% CI ) periods (but not in the late post PCV-7 period), the odds of immunosuppressive medication use were higher in the post-pcv-13 period (3.00; 95% CI ), and the odds of HIV (3.23; 95% CI ) was higher only in the late post PCV-7 period. The only immunocompromising conditions with odds ratios greater than one for all post PCV periods were history of transplant and immunocompromising medication use. It should be noted that the number of cases for individual comorbidities was quite low, resulting in quite wide confidence intervals for many of the individual comorbidity variable estimates. Table 21. Odds ratios a for immunocompromising comorbidities in the post PCV periods Condition Early Post PCV-7 Late Post PCV-7 Post PCV-13 Chronic renal 0.87 ( ) 0.94 ( ) 1.18 ( ) Sickle Cell/ 0.33 ( ) 0.35 ( ) 0.75 ( ) Asplenia Transplants 8.21 ( )* 1.78 ( ) ( )* Congenital 0.79 ( ) 0.71 ( ) 1.77 ( ) immunodef. Immunosupp ( ) 1.31 ( ) 3.00 ( )* medications HIV 2.24 ( ) 3.23 ( )* 0.43 ( ) Cancer 1.28 ( ) 0.61 ( ) 0.14 ( ) a Relative to the odds of having an immunocompromising comorbidity in the pre-pcv period *p <

88 Community Comorbidity Prevalence 10 The population prevalence of representative underlying chronic conditions was either consistent or increased somewhat in the general population over the study period. From the Alberta Interactive Health Data Application (IHDA), which contains information on health status and determinants of health from various data sources including physician claims and hospital discharge abstracts, the prevalence of diabetes mellitus increased from 3.07% in 2000 to 5.08% in 2011, the prevalence of ischemic heart disease rose from 1.66% in 2000 to 2.58% in 2011, and the prevalence of chronic obstructive pulmonary disease increased marginally from 1.30% in 2002 to 1.63% in 2011 in the Calgary Zone. From self-report data in the Alberta section of the Canadian Community Health Survey (CCHS) 11, the prevalence of asthma was unchanged over the study period, from 8.12% in 2001 to 8.19% in The prevalence of self-reported current daily smoking decreased from 20.69% in 2001 to 12.81% in 2011, while the prevalence of self-reported heavy binge drinking (five or more drinks at least once per month) increased from 16.04% in 2001 to 20.65% in The prevalence of self-reported cancer increased from 1.85% in 2001 to 2.32% in Finally, the rate of newly diagnosed HIV in Alberta increased from 194 cases per 100,000 population in 2000 to 218 cases per 100,000 population in The community comorbidity prevalence data are summarized and contrasted with CASPER case characteristics in Table The data reported here are descriptive in nature and no statistical testing was carried out on the observed changes. 76

89 Multivariable Analysis All Comorbidities (Binomial Model) 1131 of 1153 cases had complete information for all covariates necessary for inclusion in the regression analyses. The final binomial logistic model, with the inclusion of terms for the covariates PCV group (S) and clinical site (C), is shown below. The three coefficients for study exposure (E) levels provide the change in log odds of having any underlying comorbidity for each of the respective PCV period index categories. Exponentiation of these coefficients provides odds ratios for each of the index categories relative to the pre-pcv reference category. log(pc/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 8S1+ 9S2) + ( 10C1+ 11C2+ 12C3) 1E1 log odds of having any underlying comorbidity in the early post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group and clinical site. 2E2 log odds of having any underlying comorbidity in the late post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group and clinical site. 3E3 log odds of having any underlying comorbidity in the post-pcv13 period relative to the pre-pcv period, after adjustment for PCV group and clinical site. There were no significant differences in the odds of having an underlying comorbidity between the pre-pcv period and any of the post-pcv periods. The adjusted odds of having an underlying comorbidity in the early post-pcv7 period were 0.77 (95% CI: ) of those in the pre-pcv period. Similarly, the adjusted odds of having an underlying comorbidity in the late post-pcv7 period were 1.21 (95% CI: ) times those of the pre-pcv period. Finally, the adjusted odds of having an underlying comorbidity in the post PCV13 period were 1.03 (95% CI: ) times those of the pre-pcv period. These unadjusted and adjusted odds ratios are summarized in Table 22 below. 77

90 Table 22. Unadjusted and adjusted odds ratios of any underlying comorbidity by PCV period PCV Period Pre-PCV ORunadjusted (95%CI) P-value ORadjusted (95%CI) Reference category P-value Early Post PCV ( ) ( ) 0.31 Late Post PCV ( ) ( ) 0.44 Post PCV ( ) ( ) 0.92 There were no substantive differences between the reported odds ratios for each the individual PCV periods). Because the estimates from the individual strata did not differ, the three post-pcv periods were collapsed into a single global post-pcv index category. This simplified model and the interpretation for the coefficient representing the log odds of any underlying comorbidity for the global post-pcv period is: log(pc/pn) = 0 + 1E + 8S + ( 10C1+ 11C2+ 12C3) 1E log odds of having any underlying comorbidity in the global post-pcv period relative to the pre-pcv period, after adjustment for PCV group and clinical site. The adjusted odds of having an underlying comorbidity in the post-pcv period was 1.14 (95% CI: ) times that of the pre-pcv period (Table 23). This overall summary statistic provided by the binomial logistic regression analysis indicates that there was no difference in the odds of an IPD case having any underlying comorbidity before and after PCV introduction. 78

91 Table 23. Unadjusted and adjusted odds ratios of any underlying comorbidity for global post PCV period PCV Period Pre-PCV ORunadjusted (95%CI) P-value ORadjusted (95%CI) Reference category P-value Post PCV (global) 1.22 ( ) ( ) 0.53 Comorbidities by Type (Multinomial Model) The final multinomial model ended up being adjusted only for PCV group (S) as none of the other covariates sufficiently altered the study association to justify retention in the model. As well, there was no significant effect modification by PCV group, and the interaction term for PCV period by PCV group was removed from the model. The two outcome levels of the multinomial model, representing the relative risk ratios of having an underlying immunocompetent comorbidity and immunocompromising comorbidity, are presented separately in the following sections. Immunocompetent Comorbidities The final model for the multinomial immunocompetent outcome level assessed the probability of an immunocompetent comorbidity (PCP) compared to no comorbidity (PN) for each of the post-pcv periods relative to the pre-pcv period. log(pcp/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 8S1+ 9S2) 1E1 log risk ratio of having an immunocompetent underlying comorbidity in the early post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group. 2E2 log risk ratio of having an immunocompetent underlying comorbidity in the late post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group. 79

92 3E3 log risk ratio of having an immunocompetent underlying comorbidity in the post-pcv13 period relative to the pre-pcv period, after adjustment for PCV group. There were no significant differences in the relative risks ratios 12 for having an underlying immunocompetent comorbidity between pre-pcv period and any of the post-pcv periods. The adjusted relative risk of having an immunocompetent underlying comorbidity in the early post-pcv7 period was 0.67 (95% CI: ) of that in the pre-pcv period. The adjusted relative risk of having an underlying comorbidity in the late post-pcv7 period was 1.20 (95% CI: ) times that of the pre-pcv period. Finally, the adjusted relative risk of having an underlying comorbidity in the post PCV13 period was 0.97 (95% CI: ) of that in the pre-pcv period. These unadjusted and adjusted relative risk ratios are summarized in Table 24 below. Table 24. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity by PCV period PCV Period Pre-PCV RRRunadjusted (95%CI) P-value (95%CI) Reference category RRRadjusted P-value Early Post PCV ( ) ( ) 0.13 Late Post PCV ( ) ( ) 0.48 Post PCV ( ) ( ) 0.93 As with overall comorbidities, there were no meaningful differences between the reported relative risk ratios for each the individual PCV periods, and the three post-pcv periods were 12 Note: the relative risk ratios produced by the multinomial model can be interpreted similarly to odds ratios (for the index category of relevance relative to the reference category of having no comorbidity). 80

93 collapsed into a single global post-pcv index category. Again, this simplified model and the interpretation for the coefficient representing the relative risk of an immunocompetent underlying comorbidity for the global post-pcv period are below. log(pcp/pn) = 0 + 1E + 8S 1E log risk ratio of having an immunocompetent underlying comorbidity in the global post-pcv period relative to the pre-pcv period, after adjustment for PCV group. There was no difference between the relative risk of an IPD case having an immunocompetent underlying comorbidity before and after PCV introduction as the adjusted relative risk of having an immunocompetent underlying comorbidity in the global post-pcv period was 1.10 (95% CI: ) times that of the pre-pcv period (Table 25). Table 25. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity for global post PCV period PCV Period Pre-PCV RRRunadjusted (95%CI) P-value (95%CI) Reference category RRRadjusted P-value Post PCV (global) 1.16 ( ) ( ) 0.66 Immunocompromising Comorbidities The final model for the multinomial immunocompromising outcome level assessed the probability of an immunocompromising comorbidity (PCR) compared to no comorbidity (PN) for each of the post-pcv periods relative to the pre-pcv period. log(pcr/pn) = 0 + ( 1E1+ 2E2+ 3E3) + ( 8S1+ 9S2) 81

94 1E1 log risk ratio of having an immunocompromising underlying comorbidity in the early post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group. 2E2 log risk ratio of having an immunocompromising underlying comorbidity in the late post-pcv7 period relative to the pre-pcv period, after adjustment for PCV group. 3E3 log risk ratio of having an immunocompromising underlying comorbidity in the post-pcv13 period relative to the pre-pcv period, after adjustment for PCV group. There were also no significant differences in the relative risk ratios for having an underlying immunocompromising comorbidity between the pre-pcv period and any of the post- PCV periods. The adjusted relative risk of having an immunocompromising underlying comorbidity in the early post PCV-7 period was 1.01 (95% CI: ) times that of the pre- PCV period. The adjusted relative risk of having an underlying comorbidity in the late post- PCV7 period was 1.36 (95% CI: ) times that of the pre-pcv period. Finally, the adjusted relative risk of having an underlying comorbidity in the post PCV-13 period was 1.69 (95% CI: ) times that of the pre-pcv period. The unadjusted and adjusted relative risk ratios are summarized in (Table 26) below. Table 26. Unadjusted and adjusted relative risk ratios of an immunocompromising underlying comorbidity by PCV period PCV Period Pre-PCV RRRunadjusted (95%CI) P-value (95%CI) Reference category RRRadjusted P-value Early Post PCV ( ) ( ) 0.98 Late Post PCV ( ) ( ) 0.27 Post PCV ( ) ( )

95 As can be seen in Figure 24 below, the potential trend towards an increase in the proportion of IPD cases with an immunocompromising condition over time appears to be largely due to non-pcv serotype disease. 0.7 Proportion IPD with ICompromising CMC Pre-PCV Early Post-PCV7 Late Post PCV7 Early Post-PCV13 PCV-7 PCV-13 additional Non-PCV Figure 24. Proportion of IPD cases with an underlying immunocompromising comorbidity by PCV group over PCV period Finally, a sensitivity analysis was carried out for the multinomial regression with exclusion of serotype 5 and serotype 8 IPD cases; 247 cases were removed, leaving 884 observations included in this analysis. As seen in Table 27 and Table 28, the results were very similar to the full analysis, again demonstrating no change in the relative risk ratios for immunocompetent conditions and perhaps a trend towards a (non-significant) increase in the proportion of cases with underlying immunocompromising comorbidities. 83

96 Table 27. Unadjusted and adjusted relative risk ratios of an immunocompetent underlying comorbidity by PCV period (excluding serotype 5 and serotype 8) PCV Period Pre-PCV RRRunadjusted (95%CI) P-value (95%CI) Reference category RRRadjusted P-value Early Post PCV ( ) ( ) 0.14 Late Post PCV ( ) ( ) 0.68 Post PCV ( ) ( ) 0.66 Table 28. Unadjusted and adjusted relative risk ratios of an immunocompromising underlying comorbidity by PCV period (excluding serotype 5 and serotype 8) PCV Period Pre-PCV RRRunadjusted (95%CI) P-value (95%CI) Reference category RRRadjusted P-value Early Post PCV ( ) ( ) 0.88 Late Post PCV ( ) ( ) 0.55 Post PCV ( ) ( )

97 DISCUSSION Summary of Results In this population-based study from Calgary, Alberta, overall IPD incidence in all adult age groups declined from 2000 to 2011, with substantial reductions seen in conjugate vaccinetype IPD, particularly in the and 80+ age groups. Some increase in the proportion of disease caused by non-pcv serotypes was observed, most notably for those with underlying immunocompromising conditions. There was no evidence of a broad shift in demographics of adult IPD cases or an increase in disease severity in the conjugate vaccine era. As a whole, these results support the hypothesis that conjugate pneumococcal vaccine use in universal childhood immunization programs has led to a reduction of community transmission of vaccine serotypes, and provided considerable indirect protection from IPD to adult populations in Alberta, Canada. However, adults with underlying comorbidities continue to be make up a much higher proportion of IPD cases than their healthy counterparts, with over 8 of 10 IPD cases in the study population having a history of some type of comorbid condition or high risk trait/behaviour. Differing from the recent trends observed in the United States, the proportion of adult cases in this study with immunocompetent conditions was unchanged over the study duration. However, although not statistically significant, the proportion of adults with immunocompromising comorbidities did increase with each successive PCV period, resulting in an 11% rise from the pre-pcv to the post PCV-13 period. In this patient group, serotypes 19A (a PCV-13 serotype) and 22F (a non-pcv serotype) were the leading causes of recent cases of IPD, responsible for over a quarter of disease in the last three study years. There was also an increase in the representation of patients with several individual comorbidities in the conjugate vaccine era, most notably those with a history of bone marrow or solid organ transplant and those with a 85

98 history of immunocompromising medication or illicit drug use. The proportion of IPD cases with several other individual comorbidities that have increased in other studies, including HIV, were elevated in only some of the post-pcv study periods, but the low frequencies of occurrence for these conditions limit the inferences that may be drawn from these mixed results. Interpretation of Results Epidemiologic Trends The introduction of PCV programs did not lead to substantial change in the demographic composition of CASPER IPD cases. During the community outbreaks in , IPD cases were younger, more likely to be male, Aboriginal, homeless, and to have used illicit drugs; a complete description of the characteristics of the vulnerable outbreak populations has been published elsewhere (36). However, after exclusion of serotypes associated with the community outbreaks, there were no significant changes in the age and gender distribution of the Calgary Zone study population over the study period. There was some evidence of a temporary increase in IPD occurrence in homeless and Aboriginal cases due to non-outbreak serotypes during the late post PCV-7 period. The reasons for this are not clear. The near-significant increase in non-outbreak serotype disease in Aboriginals may relate to the variability in the under-reporting of (urban off-reserve) Aboriginal status or may be a true increase in case occurrence during this timeframe. Several factors may have contributed to the parallel observation in homeless IPD cases, including the fluctuation of the size of the homeless population in Calgary, varying degrees of information (misclassification) bias due to inconsistent data collection and coding of homeless status, and/or a true increase in disease activity in this vulnerable group. 86

99 A greater proportion of IPD cases in the post PCV-13 period were of more severe clinical manifestation, as complicated pneumonia and meningitis cases made up a greater share of disease occurrence (mortality was not assessed in this study). However, the absolute frequency of these clinical syndromes did not rise; the relative increase was due to a decline in the occurrence of IPD cases with uncomplicated pneumonia. The reasons for these changes in clinical syndromes are not well understood, but may relate to differing propensities of serotypes to cause disease at different clinical sites. However, in the present study there were no obvious explanations for the observed changes as the proportion of disease caused by vaccine serotypes was similar for each of the clinical manifestations of IPD in the post PCV-13 period and there were no individual serotypes implicated in cases of more severe disease. Notably, in the PCV-13 period all cases of meningitis and complicated pneumonia had some kind of underlying comorbidity and all cases of meningitis had an immunocompromising condition. Indirect Protection The indirect (herd) effects of pneumococcal conjugate vaccine use are an important aspect of the public health impact of these immunization programs. When conjugate vaccines have been introduced into routine childhood schedules, most jurisdictions have seen declines in IPD caused by vaccine serotypes in populations not eligible for the vaccine (older children, adolescents, and adults). However, the degree of impact on overall IPD incidence in these age groups when considering all serotypes has been more equivocal. In cases where an overall reduction in IPD was not reported, possible explanations have included a low baseline disease occurrence due to vaccine serotypes, or co-occurring outbreaks of disease caused by non-vaccine serotypes (32, 69, 134, 140). The latter factor has complicated assessment of pneumococcal disease trends in Calgary and area. Earlier reports from the CASPER surveillance program 87

100 during and after the community outbreaks did not demonstrate an overall decline in IPD among adults after PCV program introduction (8). However, with more time having now elapsed since the conclusion of the outbreaks, the present results do now reveal a PCV-associated reduction in overall adult disease burden, with a particularly strong effect seen in older adults. The hypothesis that the reduction in the observed IPD incidence decline is due to indirect protection from the routine childhood PCV program is supported by several lines of evidence. The mechanism for the PCV-induced indirect effect is presumed to be a consequence of decreased transmission of vaccine serotypes that are carried in the upper respiratory tracts of children. These study results provide support for this mechanism as the observed decreases in adult disease were overwhelmingly due to less PCV serotype IPD, with little change in incidence seen in IPD incidence for PPV-23 serotypes not included in conjugate vaccines, or those serotypes not included in any vaccine. The increase in proportion of IPD caused by non-vaccine serotypes is consistent with changes in the distribution of colonizing serotypes in children toward organisms with less overall invasive potential; more judicious antibiotic use and stewardship of antibiotics could lead to less selective advantage for conjugate vaccine serotypes, but would not plausibly lead to the degree of disease reductions observed (98). With respect to the polysaccharide vaccine, a single dose of PPV-23 (and a second dose for some groups) has been publically funded in Alberta for all adults 65 years of age and older since It is unlikely that the observed changes were due to enhanced PPV-23 associated protection, because the uptake of the vaccine has remained relatively low in most adult populations (~40-60% in older adults), and the observed serotype distribution changes are not consistent with this hypothesis (141). Finally, the timing and magnitude of the IPD decrease and 88

101 the sustained nature of the effect over time of the IPD decline provide evidence against background temporal fluctuations as an explanation for the observed epidemiology. Replacement Disease Because conjugate vaccines contain a limited number of the 90+ pneumococcal serotypes, the potential reductions in vaccine type carriage may be offset by a concomitant increase in nasopharyngeal carriage of non-vaccine serotypes. Transmission and subsequent disease due to these serotypes may then become more common relative to the pre-vaccine era epidemiology, a phenomenon known as replacement disease. The extent of serotype replacement disease that occurs in a given population is largely determined by the invasiveness of the circulating non-vaccine serotypes (24). However, the degree to which observed increases in nonvaccine serotype disease are due to serotype replacement is difficult to determine. Other factors, such as variability in population immunity, secular trends in pneumococcal disease, and changes in surveillance system characteristics may also contribute to changing patterns of IPD epidemiology that can mimic serotype replacement. In the present study, there was a relative increase in the proportion of IPD cases caused by non-vaccine serotypes, most notably for those with immunocompromising conditions. However, the incidence of IPD caused by non-pcv serotypes did not rise over the course of the study, indicating that there was minimal to no increase in IPD occurrence due to serotype replacement. Non-vaccine serotypes have been shown to be more likely to cause disease in immunocompromised individuals. Many of these serotypes have a lower invasiveness potential and may act more like opportunistic pathogens for those with underlying risk factors (82). In the present study, the non-significant trend toward this finding was primarily due to an increase in IPD caused by serotypes 19A (non PCV-7), 22F (non PCV-13), and 3 (non PCV-7). Individuals 89

102 with HIV or AIDS have been shown to have some of the most dramatic increases in non-vaccine serotypes after conjugate vaccine introduction (142). However, this study was not able to adequately assess this phenomenon; strong efforts have been made to vaccinate the HIV population in Calgary against pneumococcal disease and only one IPD case with HIV was reported during the post PCV-13 period. Although 14 cases of serotype 5 (a non PCV-7 serotype) IPD did occur in the late post PCV-7 period in persons with HIV, the significance of this observation in relation to the effect of the conjugate vaccine program is difficult to assess because it transpired in an outbreak setting. Previous studies have also shown that in some Aboriginal groups environmental, socioeconomic, and/or genetic factors have led to an increased susceptibility to disease caused by non-vaccine serotypes (68, 69). As with HIV/AIDS, although there was an increase in IPD seen in Aboriginal groups during the community outbreaks, only four cases occurred in persons of Aboriginal status in the last three years of the study, not allowing adequate assessment of the phenomenon in this sub-population. In 2011, NACI reported that the most common serotypes causing IPD in Canada were 19A, 7F, and 3, which accounted for 51% of IPD isolates (35). Similarly, these were the most common serotypes seen in the CASPER IPD population in Although these serotypes are included in PCV-13 (but not PCV-7), which has been demonstrated to have good immunogenicity and efficacy, there may not have yet been adequate time for the PCV-13 childhood program to sufficiently alter the circulating strains at the population level and provide protection against these disease serotypes in adults (143). Of particular note is that, as with many other jurisdictions, serotype 19A was the main serotype implicated in residual disease in the conjugate vaccine era (144). This fact is likely due to both an increase in the predominance of the 90

103 existing 19A clone and the emergence of new clones that were previously PCV-7 serotypes but now have adapted to express the 19A capsular serotype (145). Underlying Comorbidities Invasive pneumococcal disease occurs much more frequently in adults with underlying comorbidities than in healthy adults. Compounding this disparity, most of these individuals also have an increased risk of more severe disease and mortality as many of the conditions that increase the risk of developing IPD have also been associated with poorer outcomes (44, 146, 147). Because immunocompromised individuals seem to have an increased susceptibility to non- PCV serotypes that have become more important in the conjugate vaccine era, they now potentially have an even greater disproportionate risk of developing IPD and its more severe consequences (34). In the present study, the vast majority (>80%) of IPD cases had some type of condition, trait, or behaviour that NACI considers high risk and recommends immunization with polysaccharide pneumococcal vaccine. It is difficult to compare the overall IPD burden associated with underlying comorbidities with other jurisdictions because studies to date have included differing combinations of conditions into their classification schemes, with estimates of underlying comorbidities ranging from ~60% to 85%. The inclusion of alcohol use and smoking variables into the immunocompetent comorbidities category in this study elevated the proportion of cases with an immunocompetent comorbidity substantially. However, smoking and alcoholism have been shown to be independent risk factors for IPD and inclusion of all NACI vaccine-indicating conditions was consistent with the purpose of this study to inform population immunization policy development. Although there was the potential for this design decision to have masked an underlying increase in the proportion of the remainder of immunocompetent 91

104 comorbidities (as the proportion of smokers did not change significantly over the course of the study), assessment of trends in individual immunocompetent comorbidities provided reassurance that this was not the case (i.e. the majority of odds ratios for individual immunocompetent comorbidities did not provide evidence for increases in comorbidities from pre- to any of the post-pcv periods). An increase in the prevalence of these chronic medical conditions and risk behaviours in the general population could contribute to an increased representation of adults with underlying comorbidities among IPD cases. One notable distinction between the North American findings is that the proportion of cases with diabetes mellitus has increased substantially in the United States, doubling from 10% to 20% in the last decade (63). That the documented population prevalence in Alberta rose only 2 percentage points over a similar time period, and the proportion of IPD cases with diabetes did not rise over the study duration, is likely relevant to the divergence in results between the two North American jurisdictions. An increase in the share of disease in adults with immunocompromising conditions in the conjugate vaccine era has been reported in most prior studies addressing indirect protection in adults (see Literature Review). In this study, although there was not a significant increase relative to the pre-pcv period, there was a progressively greater proportion of immunocompromised IPD cases in each subsequent PCV period. The estimates for the post PCV-13 period were not statistically significant, but the confidence intervals were highly asymmetric toward a positive association, suggesting that with additional data a significant difference may be observed; with the current sample size, the study had only a ~50% power to detect the observed difference in proportions of immunocompromising comorbidities between the pre-pcv and the post PCV-13 periods (0.25 vs 0.36). The addition of 2012 (and potentially 92

105 2013) data for publication of these results will provide further statistical precision, as based on an average of 80 cases per year, there would be an estimated 63% (2012 only) or 70% (2012 and 2013) power to detect a 10% difference in proportions between these groups. Relevance and Implications Establishing accurate estimates of burden of disease is essential in determining the merits and drawbacks of the available IPD prevention options in order to meet the dual goals of population health: protecting/improving the health of all people and the reduction of inequities in health. Once a successful immunization program has reduced overall disease in the target population, there are likely to be specific sub-groups that remain (or become) at relatively higher risk of disease than the general population. The identification and prioritization of such high-risk groups facilitates the use of effective targeted immunization strategies, and in some cases, there may be an ethical obligation to attempt to reduce health gaps through targeted immunization if the differences are considered to be unfair, preventable, and/or socially constructed. However, the opportunity costs of resource allocation to address such inequities must also be balanced against investment in other health priorities. The analytical framework developed by Erickson, De Wals, and Farand for immunization programs in Canada provides criteria (including burden of disease, vaccine characteristics and immunization strategy, cost-effectiveness, acceptability, feasibility, and evaluability of program, research questions, equity, ethical, legal and political considerations) to guide such decision making (148). The population effects of childhood pneumococcal vaccine programs and the degree of indirection protection from IPD for adults with comorbidities reported in the international body of literature have been heterogeneous. While nearly all studies have shown a reduction in conjugate vaccine serotype disease, and most have shown some increase in the proportion of IPD 93

106 cases with immunocompromising conditions, reports have been mixed on both the degree of serotype replacement and change in representation of immunocompetent persons with comorbid conditions seen after PCV introduction. Therefore, local evidence that is generalizable to the Albertan and Canadian context is important for setting pneumococcal immunization strategies and priorities. The present study makes a contribution to the literature supporting such decision making through determination of change in share of IPD borne by adults with underlying comorbidities in the conjugate vaccine era in Calgary, Alberta. PCV-13 was licensed for use in children in Canada in 2010 and for adults 50 years of age in 2011, with NACI recommending that all adults with immunocompromising conditions receive a single dose of PCV-13 in addition to previous recommendations pertaining to PPV-23 (35). Therefore, currently adults in Canada may benefit from both the herd effects of the childhood PCV program, and if they are eligible, direct vaccination with PCV-13 and/or PPV-23. However, there remains significant debate about the role of conjugate vaccines in high-risk adults relative to strategies employing polysaccharide vaccination. On one hand, far-reaching indirect protection has already reduced the potential benefits of direct PCV immunization for adults. Further, it is likely that the indirect benefits of the 13- valent vaccine may not have fully manifested, because along with non-vaccine serotypes, those serotypes found in the PCV-13 (but not PCV-7) were still predominant causes of disease in the later years of this study. If the experience with PCV-7 is paralleled by an eventual similar decline in PCV-13 serotype disease, continued efforts to enhance polysaccharide vaccine coverage, which is cheaper and currently protects against nearly 80% of serotypes causing disease, may be of greater benefit to most adults. 94

107 Conversely, the incidence of IPD remains high in persons for whom PPV-23 has long been recommended, because of low coverage, its limited effectiveness in persons with high-risk conditions, and relatively short duration of protection. It is also important to note that PCV-13 serotypes still caused 47% of IPD cases in the last study period; as long as a substantial burden of pneumococcal disease caused by PCV serotypes persists for adults from high risk groups, direct vaccination with conjugate vaccine is likely to continue to have a relevant role because of its greater immunogenicity (149). Dosing Schedules The number and timing of conjugate vaccine doses that will provide optimum individual and population protection from pneumococcal disease has been unclear, leading to varied childhood vaccine schedules in use. Four doses of conjugate vaccine were initially thought necessary for optimal immune response to conjugate vaccines, and the Alberta childhood program began with a 4-dose (3+1) dose schedule, in which infants were recommended to receive a primary series of doses at 2, 4, and 6 months of age and a booster dose at 12 months. However, two doses of PCV-7 given at a 2 month interval with a booster at 12 months was subsequently shown to induce an immune response comparable to a standard 3-dose-plus-booster schedule (150, 151). As of July 2010, there was a program change to a 2+1 schedule in Alberta, with the elimination of the 6-month dose (except for high risk children). Because the data for this study were primarily collected when the 3+1 schedule was implemented, the generalizability of the study findings with respect to the degree of indirect protection provided by the 2+1 childhood program in Alberta is somewhat uncertain. Reports from Quebec, which was the first jurisdiction to employ a 3-dose (2+1) schedule, suggest that the indirect benefits for adults may be more 95

108 modest due to significant serotype replacement (38). Other jurisdictions in Europe that employed a 3-dose program included England and Wales, which also saw a greater degree of serotype replacement than did Alberta, and Denmark, which did not (125, 152). Again, programmatic and contextual factors other than dosing schedule may limit the utility of these comparisons, emphasizing the importance of continued monitoring of IPD epidemiology. Strengths and Limitations Canada does not currently have a national surveillance system that links epidemiological and serological data for vaccine-preventable diseases, making robust active regional surveillance initiatives such as CASPER valuable in tracking the epidemiology of invasive pneumococcal disease and answering policy-relevant research questions; the consistent surveillance methodology used since shortly after CASPER s inception allows for identification of long term IPD trends. Specifically with respect to this study, consistency in the CASPER surveillance mechanisms for the documentation and coding of underlying comorbidities also allowed for confidence in the observed trends and patterns. The present study employed the serotype distribution method, which relies on the assumption that when an effective vaccine is in use, vaccine serotypes will be less common among vaccinated persons with IPD (and those indirectly protected) than among unvaccinated persons (or those not receiving indirect protection). An advantage of this approach, which was necessitated by the lack of individual comorbidity information in non-cases, is that there is less potential for bias from factors related to both vaccine-related protection and risk of pneumococcal infection (23). There are several important limitations of the study that should be considered when interpreting the findings. First, the CASPER catchment area captures a relatively small number 96

109 of annual IPD cases, and the substantial yearly variation for some study variables complicates the interpretation of changes (or lack thereof) in epidemiology seen after vaccine program onset. Second, the CASPER database doesn t explicitly capture all at-risk conditions for IPD; however, the bias resulting from this omission is likely minimal as the frequency of these conditions relative to those included in the study would be low. Relatedly, there is potential for misclassification bias related to the imprecise coding of some variables or mapping of NACI indications to CASPER variables, particularly for the Aboriginal and homelessness variables. PPV-23 vaccination status was not ascertained for IPD cases, which could undermine the certainty of attribution of the observed changes in epidemiology to the effects of indirect protection. However, as neither the rates of PPV-23 adult immunization nor the incidence of PPV-23 serotype disease changed over the study time frame it is unlikely that this uncontrolled confounding factor played a significant role. Finally, co-infection with influenza, which has been shown to influence disease incidence by enhancing short-term risk of invasion in colonised subjects, was not assessed. If influenza activity in Calgary and area was systematically different after conjugate vaccine introduction, and IPD cases with comorbidities were more likely to have co-infection with influenza, the study results may have been confounded. Future Research Pneumococcal conjugate vaccines have had a dramatic impact on pneumococcal disease in Canada. However, the persistently elevated incidence and case fatality rates in high-risk adults necessitates additional research efforts to inform current strategies and evaluate potential new options. Ongoing surveillance is needed to evaluate changes in clinical presentation, populations at risk, and serotype distribution of IPD. As PCV-13 childhood programs mature, more robust 97

110 evidence on the indirect effects need to be reported to determine if there are diminishing returns in directly vaccinating adult populations with PCV-13. Because S. pneumoniae has demonstrated an ability to adapt, further changes in the prominence of emerging non-vaccine type disease (serotype replacement and antibiotic resistance) should be monitored. In particular, capsular switching that can lead to re-emergence of antibiotic resistance in non PCV-13 serotypes is of particular concern (64). In the Alberta context, the results of this study should be re-evaluated when more post PCV-13 data is available and greater study power is possible (the writer is planning to re-analyze this CASPER data once 2012 and 2013 results are available to improve the statistical power of the study). Generalizability in pneumococcal vaccine studies is limited by a multitude of factors: size of surveillance systems, study methodologies, background IPD incidence rates, prevaccination proportion of disease caused by vaccine serotypes, immunization schedules, and use of catch-up programs. Because the prevalence of comorbidities and serotype distributions vary substantially by jurisdiction, other Canadian regions that have pneumococcal surveillance capacity should attempt to replicate the CASPER findings. The results of the Community-Acquired Pneumonia Trial in Adults (CAPiTA), a randomized placebo-controlled, double-blind trial in the Netherlands, will provide high-level evidence on the efficacy of PCV-13 in adults 65 and over. Preliminary reports are that CAPiTA met both its primary objective, with 45.6% fewer first episodes of vaccine-type community acquired pneumonia (CAP), and secondary objectives, with 45.0% fewer episodes of vaccinetype non-invasive pneumonia, and 75.0% fewer episodes of vaccine-type invasive pneumococcal disease in the PCV-13 group (128). Cost effectiveness studies will also continue to be important in determining the societal benefits of direct vaccination with conjugate vaccine, particularly in 98

111 resource limited locations. Finally, several lines of research are being pursued to improve and expand the immunogenicity of conjugate vaccines, such as development of new components, adjuvants, and novel administration routes (e.g. intranasal). Ongoing research into new pneumococcal immunogens (e.g. whole-cell, DNA and protein antigens) are at various stages of development, with the majority currently employing animal models (24). Knowledge Translation Plan The Canadian Institute for Health Research (CIHR) defines knowledge translation (KT) as the dynamic and iterative process that includes synthesis, dissemination, exchange, and ethically-sound application of knowledge to improve the health of Canadians, provide more effective health services and products and strengthen the health care system (153). Its purpose is to close gaps between knowledge and practice and to facilitate evidence-informed decision making, ideally leading to implementation and positive impacts on health. CIHR defines two types of knowledge translation: integrated KT, in which stakeholders or potential knowledge users are engaged in the entire research process, and end of grant KT, where researchers develop and implement a plan for making knowledge users aware of the knowledge gain during the project. Although several potential knowledge users have been involved with, or were aware of the research from the onset, the present study is an example of end of grant KT. The Public Health Agency of Canada KT Planning Primer and John Lavis Framework for Knowledge Transfer informed the structure of the knowledge translation plan for this project (154, 155). KT Objectives The initial step in the knowledge translation planning process is to define KT goals. The KT objective of this study was to facilitate optimal IPD protection in adult populations by 99

112 informing national and provincial pneumococcal immunization policies through dissemination of research results to key decision makers and the relevant academic community. Target Audiences The potential end users of these research findings are a well-defined body of expert researchers, public health and medical professionals, and policy actors. Specifically, target audiences include national and provincial immunization decision making bodies, Canadian and international academics engaged in pneumococcal vaccine research, and pharmaceutical industry representatives interested in pneumococcal vaccine efficacy (i.e. Pfizer Canada Inc.). Messages The main KT messages arising from this study are: 1) Overall, adults benefited from good indirect protection from the routine childhood immunization programs. After PCV-7 and PCV-13 introduction, overall IPD incidence declined due to reduced disease caused by vaccine-specific serotypes in all adult age groups. Older adults have received the most benefit. 2) However, some adult groups continue to be relatively less protected and could be considered for direct protection through PCV immunization. After introduction of routine childhood programs, an increased proportion of IPD cases occurred in adults with immunocompromising comorbidities. Along with having a much higher baseline risk, this group may have received relatively less indirect IPD protection from childhood vaccine programs. Strategies The scope of the knowledge translation in end-of-grant KT should be restricted to the appropriate level based on the extent to which there are mature findings suitable for 100

113 dissemination (156). Because the information to be shared originates from a single study, it is important to avoid the KT imperative (the perceived need to do everything to encourage everyone to apply their research findings) and potential harms associated with excessive or inappropriate KT strategies (157). This study alone should not be viewed as sufficiently persuasive to independently change practice or policy. Rather, the aim is to position the present findings for appropriate contribution though future synthesis and integration of research on this topic that will occur in academia and in Canadian public health and health services contexts. Thus, the KT strategies will primary be conventional methods of academic diffusion and targeted dissemination. The chosen modalities will include journal publication, conference presentation, and direct connection with other interested audiences as described below. The publication of a manuscript in a peer-reviewed journal serves as the seminal event for end-ofgrant KT, and a prominent public health/medical journal will be targeted for manuscript submission. Augmenting this strategy will be poster or oral presentation at a relevant national conference (i.e. the Canadian Immunization Conference) to directly reach interested stakeholders in these communities. Further, two of the members of this thesis committee (J. Kellner and J. MacDonald) have provincial-level roles in immunization policy making and program planning. Thus, Dr. Kellner and Dr. MacDonald serve as knowledge brokers and may share the findings of this research with the Alberta Advisory Committee on Immunization and the Alberta Health Services Immunization Steering Committee, respectively. Finally, as pharmaceutical industry representatives have demonstrated interest in these findings, timely communication of available results will be provided to Pfizer Canada representatives. 101

114 Opportunities and Barriers for Knowledge Exchange The primary anticipated threat to successful knowledge exchange is failure of publication. To mitigate this risk, the experience of the committee will be drawn upon to select an appropriate journal that balances the often competing issues of journal profile and probability of manuscript acceptance. Secondly, if other studies providing greater quality of evidence that address the same study question become available prior to journal publication, it may limit the value of this work to potential knowledge users. However, because of the unique nature of the CASPER surveillance in Canada, the local, context-specific value of these results in informing policy decisions will make the complete obsolescence of this work unlikely. Resources Because of the modest nature of the KT plan, minimal resources will be required. Funding for conference attendance will be provided by resources from the University of Calgary Public Health & Preventive Medicine program and University of Calgary Postgraduate Medical Education. Impact The measures used to assess success of the knowledge translation strategies outlined here will include successful publication of the manuscript, number of citations in the peer-reviewed literature, and referencing in NACI statements or other pneumococcal vaccine reviews/guidelines. Conclusions Streptococcus pneumoniae continues to be a major cause of morbidity and mortality. Determining the effect of the childhood conjugate pneumococcal vaccine programs on adult IPD burden and how PCV can best be utilized to protect adults are important research priorities, as 102

115 IPD burden has remained high despite advances in medical therapies. This is particularly true for adults with underlying comorbidities, who have consistently been shown to be disproportionately represented among IPD cases. In this study from the population-based CASPER surveillance system, substantive indirect protective effects of childhood PCV immunization programs on IPD for adults in Alberta, Canada were seen and there was some evidence that the proportion of IPD in immunocompromised adults has increased in the conjugate vaccine era. Both indirect protection and direct PCV vaccination should complement PPV-23 in the prevention of IPD in adults with underlying comorbidities as the majority of disease is presently caused by a combination of PCV-13 and non-vaccine serotypes. 103

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