Preamble the national advisory Committee on immunization (naCi) provides the public Health agency of Canada (pHaC) with ongoing and timely medical, scientific and public health advice relating to immunization. pHaC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. people administering the vaccine should also be aware of the contents of the relevant product monograph(s). recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. naCi members and liaison members conduct themselves within the context of pHaC's policy on Conflict of interest, including yearly declaration of potential conflict of interest.# Table of Contents

# Summary table of information Contained in this naCi
Statement                             i introduction                                                                      ii methods                                                                        iii epidemiology of pneumococcal disease in Canada                                      iV Vaccine                                                                        V Summary                                                                       Vi Recommendations                                                               Vii Surveillance and Research Priorities                                                 tables                                                                           list of abbreviations                                                                References                                                                       

# Summary Table of Information Contained in this NACI Statement
The following table highlights key information for immunization providers. Please refer to the remainder of the statement for details.

# I. Introduction
this statement will supplement previous conjugate pneumococcal statements  and provide information regarding a newly authorized indication for the use of the 13-valent conjugate vaccine against pneumococcal disease, prevnar 13 (pneu-C-13): as of January 2012, pneu-C-13 has been authorized for use in adults aged 50 years and older for the prevention of invasive pneumococcal disease (ipd), including sepsis, meningitis, bacteremia, and pneumonia (with or without empyema) with bacteremia. as new data becomes available on the use of pneu-C-13 in adults, naCi will review these data and provide new guidance as required. the 23-valent polysaccharide vaccine (pneu-p-23) will not be discussed at length in this statement. recommendations for its use remain unchanged. www.phac-aspc.gc.ca/publicat/ cig-gci/index-eng.php this statement will:
- update the epidemiology of pneumococcal disease in Canada relevant to the introduction of pneu-C-13;
- provide a review of the literature on the use of conjugate pneumococcal vaccines in adult populations (pneu-C-7 and pneu-C-13 when available); and
- provide recommendations for the use of the 13-valent conjugate vaccine in adults (pneu-C-13), and on the use of pneu-p-23 related to the use of pneu-C-13. although pneu-C-13 was authorized for use in adults aged 50 years and over, we will be considering adults (all age groups) with high-risk conditions for ipd and the healthy 65 years and older age group because of the burden of illness that led to the recommendation of pneu-p-23 use in this age group.

# II. Methods
naCi reviewed 4 such considerations as the burden of disease and the target population, safety, immunogenicity, efficacy, effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall immunization strategy. Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence were prepared using naCi's methodological hierarchy (tables 6 and 7), and proposed recommendations for vaccine use were developed. the Working Group chair presented the evidence and proposed recommendations to naCi. Following thorough review of the evidence and consultation at naCi meetings, the committee voted on specific recommendations. the description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text of this statement. pHaC maintains documentation of these processes throughout knowledge synthesis and recommendation development.

# III. Epidemiology of pneumococcal disease in Canada
III.1 DISEASE DESCRIPTION invasive pneumococcal disease (ipd) is a serious illness caused by the bacterium Streptococcus pneumoniae. there are currently 92 serotypes recognized worldwide, 15 of which cause the majority of disease. S. pneumoniae can be spread from an infected person to another person by droplets from the nose or mouth, by sneezing or coughing. infections caused by S. pneumoniae are a major cause of morbidity and mortality worldwide. it is estimated that approximately one million children die of pneumococcal disease each year; the majority of which are young children in developing countries. in developed countries, a large burden of disease also exists among elderly persons.
Children and adults often are asymptomatically colonized with S. pneumoniae in their upper respiratory and nasopharynx. ipd is a severe form of infection that occurs when the bacterium invades normally sterile sites, such as the bloodstream and central nervous system. the symptoms or clinical manifestations depend on the site of infection. invasive disease may lead to several syndromes including bacteremia, meningitis, and/or pneumonia (with or without empyema) with bacteremia.
Certain conditions predispose to complications of pneumococcal infections, including sickle-cell disease, other haemoglobinopathies, chronic renal failure, chronic liver disease, immunosuppression, anatomic or functional asplenia, cerebrospinal fluid leaks, diabetes mellitus and HiV infection. older individuals, especially those over 65 years of age, are also at increased risk for pneumococcal disease. 5 epidemiological data were collected from two sources of Canadian pneumococcal surveillance data: the Canadian notifiable disease surveillance system (Cndss) and the national microbiology laboratory (nml).

# III.2 DISEASE DISTRIbuTION
since ipd became nationally notifiable in Canada in 2000, the number of reported cases and incidence rates have increased but have been stable over the past 5 years at an incidence rate of 10 cases per 100,000 population (Figure 1). the increase in incidence rates from 2001 to 2004 was likely-at least partially-secondary to a reporting bias, where an increase in ipd case reporting occurred as the passive surveillance system was better understood and known.

# III.3 gEOgRAPHICAL DISTRIbuTION
-n average, ontario and Quebec have the highest number of reported cases, which is expected given the large provincial population. However, the incidence rate per 100,000 population in the territories is high with high variability from year to year, most likely due to the small population size (Figure 2, tables 1 and 2). of note, the high incidence rate in british Columbia (bC), alberta (ab), saskatchewan (sK) and manitoba (mb) was thought to be due to large outbreaks of serotype 5 in these provinces from 2006 to 2008. there was no outbreak explaining the higher incidence rates in Quebec.   the pneu-C-7 vaccine was introduced in all provincial and territorial pediatric vaccination programs by 2006 and pneu-C-13 by 2011. Figure 3 shows the mean incidence of invasive pneumococcal disease by province and territory (p/t), both pre and post implementation of the pneu-C-7 vaccine.

# III.4 AgE DISTRIbuTION
data on ipd by age group shows that up until 2005, children < age of 5 were most affected (Figure 4). the pneu-C-7 vaccine was introduced in all provincial and territorial vaccination programs by 2006, and national data suggests that the introduction of pneu-C-7 led to a decreased incidence rate among <5 year olds. although, an increase in ipd incidence rate was observed from 2006 to 2008, the incidence rate was still below rates observed before vaccine introduction. a steady increase in the incidence rate among adults aged 60 years and older has occurred since 2006.  incidence rates of ipd among adults seem to increase with age, with those aged 60 years and over most affected (Figure 5). incidence rates among older individuals has increased over time in almost all age groups, most markedly among those aged 40 to 59 and 60+.   national laboratory surveillance of ipd serotypes in Canada is currently accomplished through a voluntary, passive system where isolates are submitted to the national microbiology laboratory (nml) for diagnostic reference services. this passive surveillance system is limited by reporting differences between jurisdictions; variability in sample sizes amongst the smaller jurisdictions that result in small counts representing large relative proportions; and the availability of bacterial isolates submitted for testing.
based on isolates submitted by the provinces and territories to the nml, as well as supplemental serotyping information provided to nml by the laboratoire de sante publique du Quebec (lspQ) and the toronto invasive bacterial disease network (tibdn), the most predominant serotypes in Canada in 2011 were 19a, 7F, 3 (all three contained in pneu-C-13 and pneu-p-23 but not in pneu-C-7), 22F (contained in pneu-p-23) and 6C (not a vaccine serotype), together accounting for 51% (n=1252) of ipd isolates tested in Canada (Figure 6). serotype 19a, continues to be the most predominant serotype in 2011 among isolates from the <2 (23%, n=38), 2-4 (41%, n=59), 50-64 (16%, n=108) and 65 (14%, n=126) year olds, whereas 7F continues to be predominant in the 5-14 (28%, n=39) and 15-49 (21%, n=134) year old age groups. serotype 3 is relatively prevalent in the 2-4; 50-64 and 65 year olds, representing 11% (n=16), 8% (n=57) and 11% (n=99) of the age group isolates respectively. serotype 22F tends to be relatively prevalent in the older age groups 15-49 (7%, n=46), 50-64 (6%, n=43) and 65 (10%, n=90) year olds; whereas serotype 6C is prevalent in the 65 year olds representing 7% (n=60) of the isolates tested. the proportion of pneu-C-13 serotypes has decreased from 2010 to 2011 in the <2 year-old age group accounting for 63% (n=118) in 2010 to 43% (n=70) in 2011. pneu-p-23 serotypes have remained relatively constant in all age groups over the two years (Figures 7 to 9).  Figure 6. Regional distribution of S. pneumoniae serotypes in Canada, 2011 prevnar13 , a conjugated pneumococcal vaccine, is a sterile solution of polysaccharide capsular antigen of 13 serotypes of Streptococcus pneumoniae (1, 3, 4, 5, 6a, 6b, 7F, 9V, 14, 18C, 19a, 19F and 23F). the polysaccharides are conjugated individually to a diphtheria Crm 197 protein carrier prior to compounding to a multivalent vaccine. the Crm 197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. each 0.5ml dose of vaccine contains 4.4 mcg of the 6b polysaccharide, and 2.2 mcg each of the remaining polysaccharides.
0 50 N T 4 5 4 2 3 8 3 7 3 5 F 3 5 B 3 5 A 3 4 3 3 B 3 3 A 3 1 2 9 2 8 A 2 7 2 5 A 2 4 F 2 4 B 2 3 B 2 3 A 2 2 A 2 1 1 9 C 1 9 B 1 8 F 1 6 F 1 5 F 1 5 C 1 5 A 1 3 1 1 B 1 0 F 1 0 B 9 L 7 C 7 A 6 D 6 C 3 3 F 2 2 F 2 0 1 7 F 1 5 B 1 2 F 1 1 A 1 0 A 9 N 8 1 9 A 6 A 3 7 F 5 1 2 3 F 1 9 F 1 8 C 1 4 9 V 6 B
pneu-C-13 is the same as pneu-C-7 with the exception of the additional six serotypes, a modification of the conjugation for serotype 19F to improve stability, the addition of 0.02% polysorbate (tween) 80 (an excipient), and the addition of a succinate buffer. the syringe stopper is latex free. pneu-C-13 is marketed in a single dose, prefilled syringe containing 0.5ml of vaccine.

# IV.2 EFFICACY -DIRECT AND INDIRECT (TAbLE 1)
Please refer to Tables 1 for a detailed description of studies there are currently no efficacy data available for pneu-C-13 for any adult indication. it is anticipated that efficacy data on pneu-C-13 for the prevention of community-acquired pneumonia in adults aged 65 years and over will be available in the next few years. a thorough literature review did not reveal efficacy studies using pneu-C-7 or -10 in healthy adults. one vaccine efficacy study done in HiV-seropositive adults was found and is summarized below. pneu-C-7 has a good vaccine efficacy in HiV-positive participants. French et al. randomized 439 HiV-positive patients from malawi, who had recovered from a documented ipd, to receive either 2 doses of pneu-C-7 or placebo. the endpoint was a new episode of ipd from one of the vaccine serotype and 6a, which was chosen because of potential cross-protection. the adjusted vaccine efficacy of 2 doses of pneu-C-7 compared to placebo was 69% (95%Ci 16 -89). 9

# IV.3 EFFECTIVENESS (TAbLE 1)
there is currently no data on the effectiveness of pneu-C-13 use in adults. the only vaccine effectiveness (Ve) studies that exist were done in HiV-seropositive adults and in the elderly with pneu-p-23 and are summarized below.
HIV-seropositive adults even with appropriate healthcare and treatment, ipd continues to be a significant disease in HiV-seropositive adults. siemieniuk et al. recently published a Canadian study describing 68 cases of ipd among 1946 HiV-positive adults in southern alberta between 2000 and 2010. the crude incidence rate, in this study, was 342/100,000 personyears. overall, 429 (22%) patients had never received a pneu-p-23. among those vaccinated, 34% received at least 2 doses of pneu-p-23. pneu-p-23 vaccination was associated with a decrease in ipd incidence for vaccine serotypes (720 vs. 189/100,000 person-years before vaccination and after vaccination respectively; p<0.0001) and for all serotypes (768 vs. 244/100,000 person-years; p<0.001). Viral load at time of vaccination, adjusted for Cd4 count, was an independent predictor of ipd. Compared to patients who had received pneu-p-23 at least once every 5 years, patients who had received less often than every 5 years had an adjusted or of 2.3 in their risk of ipd (95%Ci 1.0-5.4), illustrating the limited duration of pneu-p-23 effectiveness in this population, as shown in other publications. 10 although 78% of the population was vaccinated, 74% of ipd cases were caused by pneu-p-23 serotypes, broken down as follows: 66% of serotypes isolated from people previously immunized were caused by pneu-p-23 serotypes compared to 86% of serotypes isolated from people who had not been previously immunized.
previous studies have shown the sub-optimal effectiveness of pneu-p-23 in HiV patients in various contexts. breiman et al. reported an adjusted vaccine effectiveness of pneu-p-23 of 49% (95%Ci 12-70), using a case-control design. in their study, race played an important role in vaccine effectiveness: the adjusted Ve was 74% (95%Ci 8 -93%) in Whites and 8% (95% -112 -60%) in blacks. 11 Hung et al., in a prospective observational study of 507 HiV-positive patients (305 vaccinated and 203 not vaccinated with pneu-p-23), reported an adjusted or (aor) for pneumococcal bacteremia of 0.22 (95%Ci 0.02-2.56), giving a Ve of 78% (95%Ci -156 -98) and an aor for all pneumococcal disease of 0.09 (95%Ci 0.01 -0.74) for a Ve of 91% (95%Ci 26 -99). 12 French et al. had randomized 1392 HiV-infected adults in uganda to receive either pneu-p-23 (n=697) or placebo and reported that the hazard ratio (Hr) for a first ipd episode was 1.48 (95%Ci 0.7 -3.3); the Hr for an ipd due to vaccine-specific serotypes was 2.14 (95%Ci 0.86 -5.31), for all-cause pneumonia Hr=2.02 (95%Ci 1.19 -3.45), and for all pneumococcal events Hr = 1.46 (95%Ci 0.73 -2.91). the authors therefore concluded that pneu-p-23 was ineffective in preventing pneumococcal disease in HiV-positive individuals. 13

# Elderly population
Vila-Corcoles et al. studied pneu-p-23 Ve in adults aged 65 years and older in a prospective cohort study (n = 4986 unvaccinated and n = 6255 vaccinated before study entry). the adjusted Ve for the prevention of hospitalization for pneumonia was 19% (95%Ci -30 -49%). the Ve for all-cause pneumonia was 15% (95%Ci -31 -44%), the Ve for death from pneumonia was 72% (95%Ci 20 -91%), and Ve for all-cause mortality was 33% (95%Ci 17 -46%). 14 in a second study where 11,241 adults aged 65 years and over were followed after receipt of pneu-p-23, Vila-Corcoles et al.
showed that the adjusted Ve for ipd due to vaccine-related serotypes was 39% (95%Ci -176 -87%). the Ve for the prevention of pneumococcal pneumonia was 45% (95%Ci 12 -66%), the Ve for the prevention of hospitalization for pneumonia was 26% (95%Ci 8 -41%), and the Ve for the prevention of overall pneumonia was 21% (95%Ci 2-36%). once stratified for influenza vaccination status, the authors reported a pneu-p-23 Ve in decreasing the risk of hospitalization for pneumonia in influenza non-vaccinated individuals of 35% (95%Ci 1 -57%). 15 mooney et al. also looked at pneu-p-23 Ve in adults aged 65 years and over in scotland, using a retrospective cohort design, for the prevention of ipd. the adjusted Ve (excluding high risk patients) was 61.7% (95%Ci 45.1 -73.2%), giving a number needed to vaccinate of 5,206 (95%Ci 4388 -7122). the adjusted Ve for adults aged 65 -74 years, excluding high-risk patients, was 54.4% (95%Ci 20.1 -74%) and it was 68.8% (95%Ci 52.0 -79.8%) in adults aged 75 years and older. 16 melegaro et al. published a meta-analysis of pneu-p-23 Ve. pooled estimates of Ve against pneumococcal pneumonia using random effects model, excluding high-risk groups, gave an estimate of 16% (95%Ci -50 -50%); when high-risk groups were included, Ve was -20% (95%Ci -92 -25%). the pooled Ve estimate against ipd in the general elderly population was 65% (95%Ci -42 -92%); Ve in high-risk groups was 20% (95%Ci -187 -78%). 17 this meta-analysis showed that pneu-p-23 had a very limited Ve in the elderly population.
IV.4 IMMuNOgENICITY (TAbLE 1) the following at-risk groups were reviewed separately: transplant recipients (solid organ and hematopoietic stem cells), HiV seropositive subjects, and the elderly population (aged 65 years and over).

# Transplant Recipients
A) Solid Organ Transplant (SOT) Recipients: Kumar et al. published a randomized, placebocontrolled trial (rCt) of 130 participants who had undergone a liver transplant at least 3 months before study enrolment and, if previously vaccinated with pneu-p-23, had received this vaccine at least 5 years prior to study enrolment. sixty-five participants were randomized to receive a placebo followed by pneu-p-23 eight weeks later or pneu-C-7 followed by pneu-p-23 eight weeks later. there was no difference in the proportion of participants who had previously been vaccinated with pneu-p-23 (8% in placebo vs. 14% in pneu-C-7, p=0.17), who were receiving prednisone (p=0.09), or had previously received anti-thymocyte globulin therapy (p=0.06). there was no difference in the proportion of liver transplant recipients who responded to at least 1 serotype at 16 weeks (85.7% vs. 91.2% for placebo and pneu-C-7, respectively) or in the mean number of serotypes with a response (3.72.3 vs. 4.42.2 for placebo and pneu-C-7, respectively). there was no difference in the serotype-specific geometric mean titers (Gmt -antibody level) at 16 weeks after the first vaccine dose or in the opsonophagocytic activity (opa -considered the best functional measure, as it represents the host's primary defense mechanism against pneumococcal infections18) when comparing placebo and pneu-C-7, each followed by pneu-p-23. 19 Kumar et al. also published a double-blinded rCt of 60 participants who had undergone a renal transplant 3 months to 3 years before the study. splenectomized patients or those who had received pneu-p-23 in the last 5 years were excluded. the majority of participants were still receiving cyclosporine, corticosteroids, or mycophenolate mofetil (mmF) at the time of vaccination. thirty participants in each group were randomized to receive either pneu-p-23 or pneu-C-7. baseline characteristics in both groups were similar. there was no significant difference in the serotype-specific Gmt mean fold-increase at eight weeks compared to baseline for the two study groups for 5 of 7 serotypes (4, 6b, 14, 18C, 19F). Gmt increase was higher after pneu-C-7 compared to pneu-p-23 for serotype 23F and had a trend towards better response for serotype 9 (p=0.09). the proportion of participants who responded (elisa titers at least 2-fold increase compared to baseline with absolute titer of at least 1 g/ml) to at least 1 serotype was not statistically significantly different in both groups (73.3% vs. 53.3% for pneu-C-7 and pneu-p-23, respectively; p=0.11). the median number of serotypes with a response was 2.5 (pneu-C-7) and 1.0 (pneu-p-23) p=0.069. there was no difference between groups for opa titers-fold increase: an opa response to any serotype was present in 80% of participants after pneu-C-7 and in 83.3% of participants after pneu-p-23. 20 a follow-up 3 years later (pneu-C-7
-r pneu-p-23 showed that there was no difference in the proportion of participants who maintained a serotype-specific response at 3 years for all 7 serotypes. the overall Gmt at 3 years declined significantly for 6 of 7 serotypes compared to the eight-week titers, except for serotype 19F (not different). However, the 3-year titers were significantly greater than pre-vaccination titers for all serotypes except 14 in both groups. the rate of decline in Gmt was similar in both groups. 21 tobudic et al. 22 completed a randomized single blind controlled study to investigate the use of pneu-C-7 or pneu-p-23 as priming doses to a pneu-p-23 boost one year later in adult renal transplant recipients. transplantation had occurred at least 6 months prior to study enrollment. exclusion criteria included splenectomy, pneumococcal vaccine within the preceding 5 years, treatment for allograft rejection, iViG within the previous 6 weeks and an acute febrile illness within 2 weeks of study enrollment. a total of 80 participants were randomized to receive either pneu-C-7 or pneu-p-23 followed by a booster dose of pneu-p-23 1 year later. immunogenicity results were compared after the second dose of pneumococcal vaccine in both groups, but were also compared to immunogenicity results obtained after the initial dose of pneu-p-23 received upon enrolment. outcomes measures were a 2-fold increase in the antibody concentration from baseline and an absolute post vaccination value of > 1g/ml. after the initial dose, in the pneu-C-7 group, 77.1% of subjects had a response to at least one serotype as compared to 93.1% in the pneu-p-23 group (p=0.046). one year later, after a second vaccination with pneu-p-23, the response to at least one serotype was 87.5% in the pneu-C-7/pneu-p-23 group and 87.1% in the pneu-p-23/pneu-p-23 group. the median number of serotypes with a response was not statistically different between the two groups. based on these findings, the authors concluded that a single dose of pneu-p-23 should continue to be the standard of care in adult renal transplant recipients.

# b) Hematopoietic Stem Cell Transplant (HSCT)
Cordonnier et al. published a multicenter rCt where 158 allogeneic HsCt recipients were randomized to receive either pneu-C-7 at 3, 4, and 5 months post-HsCt followed by pneu-p-23 (early group; n=75) at 12 months post-HsCt or pneu-C-7 at 9, 10, and 11 months post-HsCt followed by pneu-p-23 at 18 months post-HsCt (late group; n=83). baseline characteristics were similar in both groups but differed significantly in the proportion of participants with antibody titers  0.15 g/ml to all 7 serotypes prior to pneu-C-7 vaccination (44% in early group vs. 9% in late group; p<0.001). one month after the 3rd dose of pneu-C-7, 79 and 82% of participants had an antibody titer  0.15 g/ml to all 7 serotypes and 56 vs. 54% had a response to all 7 serotypes (Gmt0.5g/ml) in the early and late group, respectively. at 24 months post-HsCt, 59% vs. 83% (p=0.013) of participants had an antibody titer  0.15 g/ml to all 7 serotypes and 34% vs. 55% had a response to all 7 serotypes (Gmt0.5g/ml) in the early and late group, respectively. one month after the 3rd dose of pneu-C-7, Gmts were not different for any of the serotypes in both groups. However, at 24 months post-HsCt, Gmts were significantly lower for all serotypes except 23F in the early vaccination group. 23 molrine et al. studied immunization of donors in a rCt of allogeneic HsCt recipients. donors were immunized or not with pneu-C-7 10 days prior to harvest and transplantation. all recipients received pneu-C-7 at 3, 6, and 12 months post-HsCt. donors for 30 HsCt recipients were immunized; donors for 35 were unimmunized, and 31 recipients were not evaluable (21 died in the peri-transplantation period, 5 were excluded prior to transplantation, 2 were excluded because of protocol violation, and 3 relapsed). there was no difference in the proportion of recipients who had a Gmt  0.5 g/ml at 3, 12, and 13 months post-HsCt when comparing both groups. differences between Gmts were significantly higher at 6 and 12 months post transplant for serotypes 6b, 9V, 18C, 19F, and 23F when the donor was immunized. although difficult to interpret, the authors compared Gmt concentrations after pneu-C-7 in their study with results from a previous study of allogeneic HsCt participants who had received pneu-p-23 at 12 months post transplant. Gmt concentrations were significantly higher for the 7 common serotypes after pneu-C-7 than after pneu-p-23. 24 Kumar et al. randomized 64 donor-recipient allogeneic HsCt pairs (32 pairs in each group) so that each pair received either pneu-p-23 or pneu-C-7: donors were vaccinated at least 2 weeks prior to harvesting and HsCt recipients received 1 dose at 6 months post-HsCt. both groups (donors and recipients) were similar in terms of baseline characteristics. donors' Gmts -2 weeks after vaccination -were not different between both groups. at 6 months post-HsCt, Gmts were similar for all 7 serotypes, except for 6b (higher after pneu-C-7). at 12 months post-HsCt, Gmts were higher after pneu-C-7 for serotypes 14 and 18C. a response to at least 1 serotype ( 0.35 g/ml) occurred in 38.1% and 0% of HsCt recipients after pneu-C-7 and pneu-p-23 at 6 months post-HsCt, respectively (p=0.003). at 12 months post-HsCt, the proportion of respondents was 90.8% vs. 55.6% in the pneu-C-7 vs. pneu-p-23 groups, respectively (p=0.02). 25

# HIV-seropositive participants
Feikin et al. randomized 90 HiV-positive patients (Cd4 of at least 200 cells/l) to receive 2 doses of a combination of placebo, pneu-C-7, and pneu-p-23. there were 67 evaluable participants. participants receiving pneu-C-7 tended to have an improved response compared to pneu-p-23 for 3 of 5 serotypes tested (23F, 4, 9V). However, the 2nd dose of vaccine did not add any additional benefit: after the 2nd dose geometric mean concentrations (GmC) were equivalent for participants who had received pneu-C-7/ pneu-C-7 or pneu-C-7/pneu-p-23. opa titers were significantly better after pneu-C-7 compared to pneu-p-23 for the 5 serotypes tested. again, the 2nd dose did not further increase opa titers. 26 penaranda et al. randomized 220 HiV-positive patients (Cd4: 200-500 cells/l, viral load <5 log copies/ml) to receive either pneu-C-7/pneu-p-23 or pneu-p-23 (n=110 in each group). the baseline characteristics were similar in both groups with a high proportion of patients on highly active antiretroviral therapy (Haart) (98 and 91%). there was no statistical difference in the proportion of responders at 8 weeks, based on igG 2-fold increase with a minimum level of 1 g/ml, and no difference in igG avidity. 27 Crum-Cianflone et al. randomized 131 HiV-positive participants to be revaccinated with pneu-C-7 and 73 to pneu-p-23, 3-8 years after their previous dose of pneu-p-23. twenty-five HiV-negative participants who were previously unvaccinated received pneu-C-7. the median Cd4 count was 533 and 513 cells/mm3 in the pneu-C-7 and the pneu-p-23 group, respectively. participants in the pneu-C-7 group were more likely to be on Haart (84.7% vs. 56%). the proportion of subjects with a 2-fold increase in their igG titers at day 60 for 2 of 4 serotypes (4, 9V, 14, 19F) was higher in the group revaccinated with pneu-C-7 (57%), compared to pneu-p-23 (36%); p=0.004. the proportion of respondent in HiV-negative participants was 88%. in HiV-infected participants, the adjusted or (adjusted for Cd4 count, age, ethnicity, prior pneumonia, Haart at baseline, and HiV viral load) for response to 2 of 4 serotypes, when comparing pneu-C-7 and pneu-p-23 was 2.6 (95%Ci 1.4-5.0). 28 lesprit et al. randomized 212 HiV-positive patients with Cd4 counts between 200-500 cells/l to receive either pneu-C-7/ pneu-p-23 (n=106) or pneu-p-23 alone. baseline igG titers and characteristics were similar in both groups. Four weeks after the last vaccine dose, igG titers were similar in both groups except for an improved response after pneu-C-7/ pneu-p-23 for serotypes 18C and 23F. at week 24, igG titers were higher in the pneu-C-7/pneu-p-23 group for 4 of 7 serotypes. there was a higher proportion of subjects with a response (2-fold increase in igG levels and a minimum level of 1 mg/l) to 5 of 7 serotypes in the prime-boost arm: with a 59% response vs. 40% in the pneu-p-23 alone; p=0.005. the same was found at 24 weeks: 30% vs. 10% responded to 5 of 7 serotypes in the prime-boost and pneu-p-23 group, respectively (p=0.003). 29 Elderly population two multicenter studies looked at the immunogenicity of the concomitant administration of the trivalent influenza vaccine (tiV) with pneu-C-13 in healthy participants, previously not immunized with any pneumococcal vaccine, aged 50-59 years (u.s. study) 30 and 65 years and over (european study) 31. these studies compared the administration of pneu-C-13/ tiV followed 1 month later by placebo vs. tiV/placebo followed 1 month later by pneu-C-13. no comparison was made with pneu-p-23. schwarz et al. reported 13 serotypes GmCs between 1.08 (serotype 3) and 11.93 (19a) g/ml in the concomitant group and between 1.15 (3) and 17.10 (19a) g/ml when pneu-C-13 was administered alone, with GmC ratios (concomitant/pneu-C-13 alone) < 1.0 -all reaching the pre-determined non-inferiority criterion except for serotype 19F. response to tiV was similar in both groups.31 similarly, Frenck et al. reported GmCs between 1.15 (serotype 3) and 16.80 (19a) g/ml in concomitant group and between 1.46 (3) and 18.84 (19a) g/ml when pneu-C-13 was administered alone. opa Gmts were between 61 (serotype 3) and 2421 (6b) in the concomitant group and between 78 (3) and 3215 (6b) when pneu-C-13 was administered alone. in this study, although GmC ratios were all <1, all serotypes reached the non-inferiority criterion. However, for opa Gmt ratios, all were also <1; and 5 of 13 serotypes (1, 5, 7F, 9V, and 19F) did not met the non-inferiority criterion (lower bound of 95% Ci <0.5). 30 Jackson et al randomized healthy adults aged 70 to 79 years, who had received pneu-p-23 at or after their 65th birthday (at least 5 years before the study) to receive either a dose of pneu-p-23 or pneu-C-7 at doses of 0.5, 1, or 2 ml. post vaccination titers were significantly higher with the 2-ml dose compared to 0.5-ml dose for 3 of 7 serotypes (6b, 9V, 23F) and significantly higher with the 1-ml and 2-ml dose, compared to 0.5 ml for serotypes 18C and 19. one year after vaccination, GmC for all serotypes were similar to pre-vaccine titers, regardless of vaccine and dose administered. there was no significant difference in GmC between pneu-C-7 (0.5 ml) and pneu-p-23; however, once adjusted for baseline GmC, 2 serotypes met criteria for superior immunogenicity in the pneu-C-7 group. opa Gmts were significantly higher after pneu-C-7 (0.5 ml) compared to pneu-p-23 for serotypes 9V and 23F. However, there was no significant difference in opa Gmts 1 year after the vaccine. 32 de roux et al. randomized 219 adults aged 70 years and over to receive either pneu-C-7 (n=110) or pneu-p-23 (n=109) as their first dose, followed one year later with either pneu-C-7 or pneu-p-23 for participants who had received pneu-C-7 as their first vaccine dose, or pneu-C-7 if the first dose was pneu-p-23. serotype specific igG titers were significantly higher one month after a single dose of pneu-C-7 compared with pneu-p-23. titers were significantly lower in the group who received pneu-p-23 followed 1 year later by pneu-C-7 when measured one month after pneu-C-7 compared to the group that received a single dose of pneu-C-7. there was no added benefit in a second dose of pneu-C-7 one year after a primary pneu-C-7 dose. opa Gmts followed the same trends as igG titers. 33 miernyk et al. randomized alaskan natives aged 55-70 years, who were not previously vaccinated against pneumococcus, to receive either pneu-p-23 (n=28), pneu-C-7 followed 2 months later by pneu-p-23 (n=29), or pneu-C-7 followed 6 months later by pneu-p-23 (n=29). baseline characteristics of all groups were similar. there was a significant increase in GmCs to all vaccine serotypes compared to baseline among the 3 groups (pneu-p-23  and pneu-C-7 and the increase was similar for the 3 groups except for serotype 1 (higher after pneu-p-23). two months after the final dose, there was no difference in GmCs for all serotypes among the 3 groups. opa titers 1 month after the 1st dose and 2 months after the final dose were similar for the 3 groups. 34 Goldblatt et al. randomized patients aged 50 to 80 years who were not vaccinated against pneumococcus in the previous 5 years to receive either pneu-C-7 and pneu-C-7
6 months later (n = 133); pneu-C-7 and pneu-p-23 6 months later (n = 171), pneu-p-23 (n = 159), or pneu-C-7 (n = 136). one month after pneu-C-7 or pneu-p-23, serotypes 4, 9, and 23F had higher GmCs after pneu-C-7; however, one year after vaccination, there was no significant difference between the 2 groups for 6 of 7 serotypes (23F had higher GmC after pneu-p-7). one month after the 2nd dose, there was no difference in GmCs for 6 of 7 serotypes (19F had higher GmC after pneu-C-7/pneu-p-23 compared with pneu-C-7/pneu-C-7). one year after pneu-C-7/pneu-C-7 vs. pneu-p-23, the proportion of subjects with serotypespecific antibody concentrations > 1g/ml was not different. 35 schenkein et al. randomized 45 adults aged < 45 years and 58 adults aged 65 years and over to receive pneu-p-23. there was no difference in GmC found between the younger and the older age groups. However, there was a significantly higher antibody potency (opsonization titers) for all serotypes in the younger age group. 36 musher et al. randomized adults who were either previously vaccinated (no minimal interval between previous dose of pneu-p-23 and study enrolment) or not vaccinated with pneu-p-23, aged 50-65 years and 65 years and over, to receive pneu-p-23 or placebo. they reported that, for all serotypes, except 8 and 14 in the 65 years and over and 14 in the 50-65 years, there was no significant difference in igG titers between groups who were vaccinated for the first time and the group that was being revaccinated, when measured at 30 and 60 days. 37

# IV.5 VACCINE ADMINISTRATION AND SCHEDuLE
the dose of pneu-C-13 for adults is 0.5 ml administered im once, followed 8 weeks later by pneu-p-23 for patients at high-risk of ipd. HsCt recipients should receive a priming series composed of 3 doses of pneu-C-13 given at least 4 weeks apart. the exact timing of the series initiation should be assessed on a case-by-case basis and discussed with hemato-oncologists. the literature shows that this priming series can be started between 3 and 9 months after HsCt. this primary series should be boosted with one dose of pneu-p-23 given 6 to 12 months later.

# IV.6 SEROLOgICAL TESTINg
there is no indication for routine pre-or post-immunization serology.

# IV.7 STORAgE REQuIREMENTS
the vaccine should be refrigerated, with the temperature maintained between 2oC to 8oC. Vaccine, which has been frozen, should be discarded. in cases of temporary breaks in the cold chain, pneu-C-13 has been shown to be stable at temperatures up to 40oC for up to 4 days. 38 However, practitioners should adhere to usual provincial procedures for deciding on vaccine viability following breaks in the cold chain.

# IV.8 SIMuLTANEOuS ADMINISTRATION WITH OTHER VACCINES
pneu-C-13 has only been administered concomitantly with tiV in the adult population 30,31 and seemed to provide a similar response to tiV, whether pneu-C-13 was given concomitantly or alone. pneu-C-13 serotype specific titers were not different when given alone or concomitantly in most instances. one study showed a decrease in opa Gmts when pneu-C-13 was given with tiV but the clinical implications for these findings are unclear.
pneu-C-13 has been studied when given concomitantly with a number of vaccine antigens used in a childhood schedule in Canada with no adverse effect on immunogenicity or safety profile. these antigens include: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis b, meningococcal serogroup C, measles, mumps, rubella and varicella. 39 as with general guidance given for all vaccines, pneu-C-13 should be administered at a different site than concomitantly administered vaccines, using a different needle and syringe.

# IV.9 ADVERSE EVENTS

# IV.10 CONTRAINDICATIONS AND PRECAuTIONS
pneu-C-13 is contraindicated in any individual with a history of anaphylaxis to any component of the vaccine, including diphtheria toxoid.
V. Summary the evidence reviewed show improved immune response of pneumococcal conjugate vaccines compared to pneu-p-23 for adults who have undergone a HsCt; the evidence for sot is not as compelling. pneu-p-23 Ve in HiV-positive subjects is low -at best -but most often not protective, whereas pneu-C-7 has shown better protection. there is no efficacy or effectiveness study on the use of pneumococcal conjugate vaccines in the elderly and results from immunogenicity studies that compared the use of pneu-C-7 and pneu-p-23 showed similar antibody titers one year after vaccination for the seven common serotypes. there is currently no published immunogenicity study comparing the use of pneu-C-13 and pneu-p-23 in the elderly population and no established correlates of protection to allow for the interpretation of immunogenicity results in this population.

# VI. Recommendations
please note that provinces and territories must consider economic factors and other local programmatic/operational factors when considering inclusion of the following recommendations in publicly funded immunization programs.
As new data become available, these recommendations will be reviewed and updated.
naCi concludes that there is good evidence to recommend the use of pneu-C-13 for HsCt recipients given the improved immunogenicity of pneumococcal conjugate vaccines compared to pneu-p-23 in HsCt recipients. HsCt recipients should receive a primary series of 3 doses of pneu-C-13 starting 3-9 months after transplant, after discussion with transplant specialists. the primary series (3 doses) should be administered at least 4 weeks apart, followed by a booster dose of pneu-p-23 12 to 18 months post transplant (6 to 12 months after the last dose of pneu-C-13). (naCi recommendation a)
naCi concludes that there is good evidence to recommend the use of pneu-C-13 for HiV-positive patients given the improved efficacy and effectiveness of pneumococcal conjugate vaccine (pneu-C-7) in HiV-positive subjects.
HiV-positive subjects should receive one dose of pneu-C-13 followed 8 weeks later by one dose of pneu-p-23. there is currently no evidence that a pneu-C-13 booster dose adds any benefit. (naCi recommendation a) most published studies excluded participants who had received a dose of pneu-p-23 in the 5 years preceding study enrolment. therefore data on the minimal interval between a previous pneu-p-23 dose and pneu-C-13 is unknown. However, given the potential for decrease in antibody titers following pneu-p-23, severity of ipd in immunocompromised individuals, and benefits from pneu-C-13 in this patient population, naCi recommends to administer pneu-C-13 at least one year after any previous dose of pneu-p-23. (experts' opinions)
re-immunization with one lifetime booster dose of pneu-p-23 is recommended for those at highest risk of ipd, i.e. HiV-positive individuals. HiV-positive patients who previously received pneu-p-23 and who require an additional dose of pneu-p-23 should therefore receive it no sooner than 8 weeks after pneu-C-13 and no sooner than 5 years after the most recent dose of pneu-p-23. (experts' opinion)
naCi concludes that there is currently fair evidence to recommend the use of pneu-C-13 for subjects with other immunocompromising conditions including:
- asplenia (anatomical or functional)
- sickle cell disease or other hemoglobinopathies
- Congenital immunodeficiencies involving any part of the immune system, including b-lymphocyte (humoral) immunity, t-lymphocyte (cell) mediated immunity, complement system (properdin, or factor d deficiencies), or phagocytic functions
- immunosuppressive therapy including use of long term corticosteroids, chemotherapy, radiation therapy, postorgan-transplant therapy, biologic and non-biologic immunosuppressive therapies for rheumatologic and other inflammatory diseases.
- malignant neoplasms including leukemia and lymphoma
- solid organ or islet cell transplant (candidate or recipient).
these immunocompromised patients should receive one dose of pneu-C-13 followed 8 weeks later by one dose of pneu-p-23. there is currently no evidence that a pneu-C-13 booster dose adds any benefit. (naCi recommendation b) published studies excluded participants who had received a dose of pneu-p-23 in the 5 years preceding study enrolment. therefore data on the minimal interval between a previous pneu-p-23 dose and pneu-C-13 is unknown. However, given the potential for decrease in antibody titers following pneu-p-23, severity of ipd in immunocompromised individuals, and benefits from pneu-C-13 in this patient population, naCi recommends to administer pneu-C-13 at least one year after any previous dose of pneu-p-23. (experts' opinions)
re-immunization with one lifetime booster dose of pneu-p-23 is recommended for those at highest risk of ipd, i.e. those with functional or anatomic asplenia or sickle cell disease; and immunosuppression related to disease or therapy, including solid organ transplant recipients. individuals from these high-risk categories who have previously received pneu-p-23 and who require an additional dose of pneu-p-23 should therefore receive it no sooner than 8 weeks after pneu-C-13 and no sooner than 5 years after the most recent dose of pneu-p-23. (experts' opinion) there are currently no available studies for all of the abovementioned conditions. However, based on data from solid organ transplants recipients, the recommendation has been generalized to other immunosuppressed individuals.

# Recommendation #4:
naCi concludes that there is currently insufficient evidence to recommend the use of pneu-C-13 in patients with chronic conditions without immunosuppression (listed below). However, other factors may influence decisionmaking. recommendations for vaccination with pneu-p-23 have not changed. (naCi recommendation i) patients with chronic conditions without immunosuppression include:
- Chronic CsF leak
- Cochlear implants
- Chronic neurologic condition that may impair clearance of oral secretions
- Chronic cardiac or pulmonary disease
- diabetes mellitus
- Chronic kidney disease, including nephrotic syndrome
- Chronic liver disease (including hepatitis b and C, and hepatic cirrhosis due to any cause)
naCi concludes that there is currently insufficient evidence to recommend the use of pneu-C-13 in healthy adults aged 65 years and over. However, other factors may influence decision-making. recommendations for vaccination with pneu-p-23 have not changed. (naCi recommendation i) naCi considers that the following critical information is currently missing to allow for a recommendation of pneu-C-13 use in healthy adults aged 65 and over:
- efficacy or effectiveness data -in comparison to placebo and ideally pneu-p-23 -on the ability of pneu-C-13 to prevent ipd in this population 2. efficacy or effectiveness data -in comparison to placebo and ideally pneu-p-23 -on the ability of pneu-C-13 to prevent community-acquired pneumonia in this population 3. Correlates of protection that would allow for the interpretation of immunogenicity data that are currently available for pneu-C-13 4. the indirect protection provided by the infant and childhood pneu-C-13 program on ipd and serotypes causing ipd in the adult population.

# VII. Surveillance and Research Priorities
the epidemiology of invasive pneumococcal disease is changing in Canada and elsewhere, both due to and independent of the use of pneumococcal vaccines. ongoing changes are expected as pneu-C-13 vaccines are used routinely in childhood vaccination programs. nationwide surveillance systems to detect these changes over time are essential. optimal decisions about the use of pneumococcal vaccines requires ongoing surveillance for serotype-specific rates of invasive pneumococcal disease, and other disease syndromes, serotype-specific estimates of the efficacy of different vaccines, and continuing assessment of the effectiveness and cost-effectiveness of different vaccination schedules over time.
surveillance and research which addresses the following outstanding questions is particularly encouraged:
- What is the efficacy and effectiveness of pneu-C-13 in adults in the prevention of ipd or community-acquired pneumonia, compared to pneu-p-23?
- What is the impact of conjugate pneumococcal vaccines use on ipd in adults aged 65 years and overin particular in terms of serotypes involved?
- What is the serotype-specific efficacy and effectiveness of pneu-C-13?
- What antibody concentrations, or other immunologic markers, correlate best with protection against invasive pneumococcal disease, pneumococcal pneumonia, acute otitis media and nasopharyngeal carriage?
- Will serotype replacement offset the benefits of pneumococcal conjugate vaccine use in children?
- What are the determinants of indirect protection of adults from pediatric vaccines?
- What factors other than immunization influence changes in the incidence of disease due to different serotypes over time?
- does previous vaccination with pneu-p-23 impact the effectiveness of pneu-C-13 in adults?
- is there a need for a booster dose of pneu-C-13 or pneu-p-23 in adults?
Tables Response rate (Gmt  0.5 g/ml to all 7 antibodies at 1 month after 3 rd dose): 56% vs. 54% (p = 0.85, 90 % Ci -13.5 -17)
Response rate (Gmt  0.15g/ml to all 7 pneu-C-7 serotypes at 24 months post-transplantation): 59% vs. 83%; p = 0.013
Response rate (Gmt  0.5 g/ml to all 7 serotypes at 24 months posttransplantation): 34% vs. 55%; p = 0.054 Gmt for all 7 antibodies at 1 month after 3 rd dose of pneu-C-7 were not significantly different between the two groups except for 19F p < 0.001 PNEu-C-7/PNEu-P-23 vs. single dose PNEu-C-7: significantly higher for serotypes 19F and 23 F. no significant difference for serotypes 4, 6b, 9V, 14, 18C.
gMTs of OPA after 1st and 2nd doses:
PNEu-C-7 vs. PNEu-P-23: significantly higher for all serotypes tested; p < 0.01-except 6b and 19F
PNEu-P-23/ PNEu-C-7 vs. single dose PNEu-C-7: significantly lower for all serotypes tested (p < 0.01) except serotype 19F
PNEu-C-7/ PNEu-C-7 vs. single dose PNEu-C-7: no difference for all serotype except 23 F; p < 0.01. For all other serotypes, no significant difference between primary and revaccination groups in both age groups, although marginally higher in the primary vaccination group.
serotype specific igG at day 60: Higher compared to day 30 in older revaccination and older primary vaccination and younger revaccination group for all serotypes; p = ns Higher in younger revaccination group for serotypes 4, 6b, 14, 23F; p = ns serotype-specific igG at 5 years: serotype 3 igG levels returned to baseline in all 4 study groups by year 2.
re-vaccinated patients: For remaining 7 serotypes (except 3), igG levels were similar compared to baseline (p = ns) and at least 2-fold higher than vaccine naive recipients (baseline of primary vaccines)  II-1 evidence from controlled trial(s) without randomization.
II-2 evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
II-3 evidence obtained from multiple time series with or without the intervention. dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
-pinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.
TAbLE 7. Quality (internal validity) Rating of Evidence good a study (including meta-analyses or systematic reviews) that meets all design-specific criteria well.
Fair a study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion but has no known "fatal flaw".
Poor a study (including meta-analyses or systematic reviews) that has at least one design-specific "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.

# TAbLE 8. NACI Recommendation for Immunization -grades
A naCi concludes that there is good evidence to recommend immunization. b naCi concludes that there is fair evidence to recommend immunization.
naCi concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization, however other factors may influence decision-making.
naCi concludes that there is fair evidence to recommend against immunization.
E naCi concludes that there is good evidence to recommend against immunization.
I naCi concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.
Serotype 23F: p < 0.05 0.5 ml -3.4 (1.9-5.9) 2 ml-7.2 (4.3-12.1) post vaccination titers were significantly higher at 1 ml and 2 ml than 0.5 ml for:
Serotype 18C; p < 0.05 0.5 ml-5.0 (3.3-7.7) 1 ml -8.8 (6.5-12.0) 2 ml -8.7 (5.8-13.1)
Serotype 19F; p < 0.05 0.5 ml-3.4 (2.4-4.9 1 ml -6.0 (4.0-8.9) 2 ml -5.6 (4.1-7.8) after 1 year (pre-challenge): GmC by elisa were similar to pre-vaccine, regardless of vaccine given and dose
Adjusted for baseline gMC post-PCV7 vs. PPV23 no significant difference between 0.5 ml pneu-C-7 group and pneu-p-23 group for all serotypes but when adjusted for baseline GmC: 2 serotypes met criteria for superior immunogenicity for pneu-C-7 vs. all study groups showed significant increases in GmCs to all vaccine specific serotypes compared to baseline and were similar in all groups except for: