Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines
Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing, and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
 In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
 The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included. 
 This statement contains NACIs independent advice and recommendations, which 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 PHACs Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Summary of information contained in this NACI Statement
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.

#  1. What
 Pneumococcal disease in adults includes invasive pneumococcal disease (IPD), an acute and serious communicable disease with manifestations such as meningitis, bacteremia and bacteremic pneumonia and empyema, as well as non-invasive pneumococcal disease such as community acquired pneumonia and acute otitis media in children. It is caused by the *Streptococcus pneumoniae- bacterium. Of the more than 100 serotypes of this bacterium, a small number cause the majority of disease. Bacteremic pneumococcal pneumonia is the most common presentation of IPD among adults.
 Based on immunogenicity data relative to previously authorized pneumococcal conjugate vaccines (PNEU-C) and pneumococcal polysaccharide vaccines (PNEU-P), Health Canada has recently authorized two new PNEU-C vaccines:
- PNEU-C-15 (15-valent) is authorised for infants, children, and adolescents from 6 weeks through 17 years of age and adults 18 years of age and older with an indication for prevention of IPD caused by 15 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).
- PNEU-C-20 (20-valent) is authorized for adults 18 years of age and older with an indication for prevention of pneumonia and IPD caused by 20 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F).
No efficacy data are currently available for either PNEU-C-15 or PNEU-C-20.

#  2. Who
 IPD is most common in the very young, the elderly, and groups with medical conditions and/or other risk factors that place them at high risk of IPD (). 
 NACI recommends the use of PNEU-C-20, or PNEU-C-15 followed by pneumococcal polysaccharide vaccine, 23-valent pneumococcal polysaccharide vaccine (PNEU-P-23), in adults at a higher risk of invasive pneumococcal disease. 
- All adults 65 years of age and older should receive a single dose of PNEU-C-20.
- Adults who are 50 to 64 years of age and living with underlying medical conditions and/or other risk factors that place them at high risk of IPD should receive a single dose of PNEU-C-20.
- Adults who are 18 years of age and older living with immunocompromising conditions (IC) should also receive a single dose of PNEU-C-20.
- PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative if PNEU-C-20 is not available.
Additional details including immunization of adults who received a hematopoietic stem cell transplant, as well as intervals between previous pneumococcal vaccines and PNEU-C-15/PNEU-C-20 are discussed in Section VII.
- Chronic neurologic condition that may impair clearance of oral secretions
- Cochlear implants, including children and adults who are to receive implants
- Chronic heart disease
- Diabetes mellitus
- Chronic kidney disease  
- Chronic liver disease, including hepatic cirrhosis due to any cause  
- Chronic lung disease, including asthma requiring medical care in the preceding 12 months
- 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
- Immunocompromising therapy, including use of long-term corticosteroids, chemotherapy, radiation therapy, and post-organ transplant therapy
- HIV infection
- Hematopoietic stem cell transplant (recipient) 
- Malignant neoplasms, including leukemia and lymphoma
- Nephrotic syndrome
- Solid organ or islet transplant (candidate or recipient)
- who use illicit drugs
- with alcohol use disorder
- who are experiencing homelessness
- who live in communities or settings   experiencing sustained high IPD rates.
Conditions considered to result in the highest risk of IPD
Generally, asplenia (functional or anatomic), sickle cell disease and other hemoglobinopathies are not considered immunocompromising conditions, but for the purposes of pneumococcal vaccine recommendations, they are included in this category
Hematopoietic Stem Cell Transplant (HSCT) recipients have specific pneumococcal vaccination recommendations
Can include long-term care facilities

# 3. How
 PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe. Both PNEU-C-15 and PNEU-C-20 are to be administered intramuscularly. A standard schedule for immunization is one 0.5ml dose. Contraindications to administration of either PNEU-C-15 or PNEU-C-20 include hypersensitivity (e.g., anaphylaxis) to the vaccine or any of its components. Pneumococcal vaccines may be administered concurrently with other vaccines, except for a different formulation of pneumococcal vaccine (e.g., concurrent use of conjugate and polysaccharide).

#  4. Why
 Pneumococcal infection can cause severe infections and can lead to significant mortality and morbidity with lifelong complications. The most effective way to prevent these infections is through immunization. 
I. Introduction

# I.1 Guidance objective
The need for this National Advisory Committee on Immunization (NACI) Statement on the use of pneumococcal vaccines was triggered by the approvals of two additional pneumococcal conjugate vaccines for adults 18 years of age and older, a 15-valent vaccine, PNEU-C-15 (VaxneuvanceTM) on November 16, 2021, and a 20-valent vaccine, PNEU-C-20 (Prevnar 20TM) on May 9, 2022. The primary objective of this statement is to review the evidence on the efficacy, effectiveness, immunogenicity, safety, and cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines and provide recommendations for their use in consideration of the disease burden in Canada among adults for whom pneumococcal vaccination is currently recommended: 
- immunocompetent adults aged 65 and older
- immunocompetent adults at higher risk of pneumococcal disease (PD) ()
- immunocompetent adults residing in long term care facilities (LTCF)
- immunocompromised adults, including hematopoietic stem cell transplant recipients

# I.2 Background on pneumococcal vaccines, immunization programs and recommendations for adults in Canada
For prevention of IPD in adults, two vaccines are currently available in routine, publicly funded programs: PNEU-P-23 and PNEU-C-13. Conjugate vaccines induce formation of long-term memory cells, provide longer duration of protection, and provide ability for boosting by involving T cells in the immune response to the vaccine, in a way that polysaccharide vaccines do not. 
 PNEU-P-23 was previously recommended by NACI for the routine immunization against IPD of all adults 65 years of age and older. PNEU-P-23 was also recommended for adults 18 to 64 years old who are residents of LTCF, smokers or persons with an alcohol use disorder, and persons experiencing homelessness as well for those living with both immunocompromising and non-immunocompromising underlying medical conditions that put them at higher risk of IPD. A complete list of underlying medical conditions that increase the risk of IPD along with dose and schedule is available in the . 
 PNEU-C-13 in series with PNEU-P-23 was recommended by NACI in 2013  for adults 18 years of age and older with immunocompromising conditions resulting in high risk of IPD. For a complete list of immunosuppressing conditions that increase the risk of IPD, please refer to . 
 PNEU-C-13 was also recommended by NACI in 2016  and 2018  on an individual basis for immunocompetent adults aged 65 years and older who wish to protect themselves against the 13 serotypes included in the vaccine for prevention of community-acquired pneumonia (CAP) and IPD. PNEU-C-13 was not recommended for publicly funded routine immunization programs due to cost-effectiveness. 
II. Methods
In brief, the stages in the preparation of a NACI advisory committee statement are:
1. Knowledge synthesis: retrieval and summary of individual studies, assessment of the risk of bias (RoB) of included studies (summarized in the ).
2. Summary of evidence: benefits (immunogenicity) and potential harms (safety), considering the certainty of the synthesized evidence and, where applicable, the magnitude of effects observed across the studies.
3. Use of the evidence to inform recommendations.
NACI also uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance. NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. 
 Further information on  is available elsewhere.
 For this statement, NACI reviewed evidence pertaining to the burden of IPD in the target population(s), the safety, immunogenicity, efficacy, and effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall adult pneumococcal vaccine immunization strategy. The knowledge synthesis was performed by NACI Secretariat and reviewed by the Pneumococcal Working Group. Following critical appraisal of individual studies, summary tables with ratings of the certainty of the evidence using GRADE methodology were prepared   . An assessment using the Evidence to Decision (EtD) framework was prepared for each question, and proposed recommendations for vaccine use were developed . NACI reviewed the available evidence on May 19, 2022, July 4, 2022, and Sept 12, 2022. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described.

# II.1 Burden of IPD
IPD has been nationally notifiable in Canada to the Canadian Notifiable Disease Surveillance System (CNDSS) since 2000, with all provincial and territorial jurisdictions reporting cases meeting the national case definition. Cases not captured by CNDSS may include those that do not get medical attention, those where clinical measures were applied with no specimen being taken. Information such as serotype, antimicrobial susceptibility, vaccine coverage as well as other enhanced epidemiological patient information are not reported through the CNDSS. 
 The national surveillance line list data used to assess the burden of IPD among different age groups were available from the CNDSS for six provinces (BC, AB, SK, ON, QC, and PEI) and from the International Circumpolar Surveillance (ICS) program for the three territories (YK, NU, and NT). Some provinces (MB, NS, NL, NB) were not included in the national surveillance line list as they provided aggregate data with broad age group intervals which could not be broken down to compare the IPD burden in different age groups among older adults in Canada. All cases were presumed to meet the national case definition of IPD. More information about the CNDSS data is provided on the  website.
 Northern regions of Canada captured in the ICS system include Nunavut, Northwest Territories, Yukon, Northern Labrador, and Northern Quebec. The incidence of IPD in these regions was compared to IPD incidence from all other PTs using aggregate CNDSS data.
 The National Microbiology Laboratory (NML) collaborates with provincial and territorial public health laboratories to conduct passive, laboratory-based surveillance of IPD in Canada . All IPD isolates from the provincial/territorial public health laboratories are serotyped by the NML, although specimen collection may be limited by variable regional standards, the preliminary nature of some data and the availability of bacterial isolates for testing. Serotype data may also be biased toward over representing more virulent serotypes for which medical treatment is sought and clinical specimens taken. Despite these limitations, the passive national surveillance program from 2015  2019, including additional data submitted by the provincial reference laboratories of Alberta and Quebec, provided timely reporting of serotype distributions, and accounted for 80 to 98% of all IPD cases reported to CNDSS. In 2020 , a total of 2,067 isolates were reported to the NML, representing 94.3% of the 2,193 reported by all PTs to the CNDSS (preliminary 2020 data).
 For vaccine serotype groupings, serotype 6C was included with PNEU-C-13 serotypes due to cross protection with 6A . Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them *in vivo- during infection, making it difficult to precisely differentiate between the two types  .

# II.2 Literature Review of PNEU-C-15 and PNEU-C-20 studies
The policy question addressed in this statement is: What is the efficacy, effectiveness, and safety of PNEU-C-15 and PNEU-C-20, administered in series with or without PNEU-P-23, when used with the objective to reduce the risk of IPD in adults.
Population: Adults 50 years of age or older without IPD risk factors; adults 18 years or older with IPD risk factors ().
Intervention: PNEU-C-15 or PNEU-C-20, alone and in series with PNEU-P-23 (depending on the population group of interest).
Comparator: Currently recommended age and risk factor-appropriate pneumococcal vaccine schedule.
Outcomes: Death due to vaccine preventable serotype *S. pneumoniae*, IPD due to vaccine preventable pneumococcal serotype, IPD due to any pneumococcal serotype (vaccine preventable and not vaccine preventable), pneumococcal community-acquired pneumonia (pCAP) due to a vaccine preventable serotype, serious adverse events (SAEs), severe systemic adverse events (AEs), and mild/moderate systemic AEs following vaccination. Outcomes were accompanied by definitions and are summarized in the appendix (see ). 
 In the absence of disease endpoint and mortality data, immunogenicity (opsonophagocytic  geometric mean titer  ratios and percentage of seroresponders defined as greater or equal to a 4-fold increase in OPA GMT ratio from before vaccination to after vaccination) was evaluated.
 Safety and immunogenicity data for PNEU-C-15 and PNEU-C-20 in adults from key clinical trials, published studies, and supplementary data obtained from manufacturers were reviewed. Data were extracted from eligible studies related to the study design, population, intervention, comparator, and outcomes of interest. The RoB () for each study was assessed using the Cochrane Risk of Bias Tool . The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework () was used to assess the certainty in evidence. 
 Meta-analytic techniques were used to synthesize adverse event data; statistical heterogeneity was considered using a combination of factors (direction of estimates, overlapping confidence intervals, and the Cochran Q  and I-squared statistics). For I-squared statistics, a rough guide of low (0-25%), moderate (25-50%), substantial (50-75%), and considerable (75-100%) was used. For binary outcomes and where event rates were low (using 1% as a rough guide), the Peto Odds Ratio was used; otherwise, the Risk Ratio was used. Where possible to do so, relative effect measures were used to calculate risk differences, aligning with the GRADE approach. For immunogenicity, narrative syntheses were used, and heterogeneity was determined according to the direction of effect, using the magnitude of the estimates. The focus for GMT ratios was the study investigators demonstration of non-inferiority for shared serotypes between vaccines. For the percentage of seroresponders, point estimates were used to gauge the direction of effect based on those magnitudes. It is important to note, however, that no immunologic correlates of protection have been established for PD.
 For the GRADE certainty of evidence assessments (), control group data from studies were used to estimate baseline risk. The use of surrogate measures was the main consideration for indirectness. The review information sizes of 400 people with events for binary data, at least 4,000 people analyzed for small event rates, and 800 people for continuous data were used to inform imprecision when confidence intervals were not importantly wide. Planned subgroup analyses was not undertaken for the age-based recommendation owing to the nature of the data and insufficient number of studies. Sensitivity analyses were undertaken to restrict analyses to studies at a low RoB, where applicable, to see if the results changed appreciably. Too few studies were located to perform a test for small study effects.
 Modifications to scope and process during conduct of the review: (a) an evaluation for the 75 years and older age group was added for the age-based recommendation; (b) expansion of eligibility to include additional vaccines administered concurrently with pneumococcal vaccines; and (c) full verification of data extraction, RoB assessments, and GRADE assessments were reduced to partial verification or single person review to facilitate a rapid review of the evidence.

# II.3 Literature review of PNEU-C-15 and PNEU-C-20 cost-effectiveness
A systematic review of the cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines for preventing IPD was conducted. The search included economic evaluations conducted in adults aged 18 years or older, comparing currently used vaccines to prevent IPD to PNEU-C-15 or PNEU-C-20. The components of the research question are summarized as:
- Population: Adults aged 18 years or older
- Intervention: PNEU-C-15 or PNEU-C-20 (alone or in series with other pneumococcal vaccines)
- Comparator: Current pneumococcal vaccines (PNEU-C-7, PNEU-C-10, PNEU-C-13, PNEU-P-23)
- Outcomes: Measures of cost-effectiveness (incremental cost per quality-adjusted life year , incremental cost per disability-adjusted life year , and cost per life year, etc.)
Additional details of the economic literature review are provided in a supplementary economic evidence appendix. 

# II.4 NACI Cost-utility analysis and multi-model comparison
A model-based cost-utility analysis was conducted from health system and societal perspectives. A Markov cohort model was developed to compare the benefits (in QALYs) and costs (in 2022 Canadian dollars) associated with using PNEU-C-15 or PNEU-C-20, either alone or in series with PNEU-P-23, compared to PNEU-P-23 alone. Vaccination was evaluated at ages 50, 65, or 75. The Northern Canadian Territories were assessed separately from the rest of Canada to account for higher PD incidence in the north. The primary outcome was the incremental cost-effectiveness ratio (ICER). The analysis used a lifetime time horizon and 1.5% discount rate. Scenario and sensitivity analyses were conducted to examine the impact of uncertainties in model parameters and assumptions.
 To evaluate the robustness of the cost-utility model, a multi-model comparison was conducted using two additional cost-utility models developed by the manufacturers of PNEU-C-15 and PNEU-C-20 with different structures and assumptions. Wherever possible, all models were modified to use the same input parameters. ICERs for a single base case were compared across models.
 Additional details of the cost-utility analysis and multi-model comparison are provided in a supplementary economic evidence appendix.
III. Epidemiology

# III.1 IPD burden in Canada
Based on the data from CNDSS, the incidence rate of IPD in children under 5 years of age decreased from 41.8 cases to 15.7 cases per 100,000 population between 2003 and 2006. Following a few years of increasing incidence, IPD incidence rates in children under 5 years have remained relatively steady at around 12 cases per 100,000 population since 2012 (). Children aged 5 to17 years consistently had the lowest IPD incidence rate, remaining below 5 cases per 100,000 population during the 2001-2019 study period. Canadians aged 18 to 49, 50 to 64 and 65 years and older showed similar trends with increased IPD incidence from 2001 to 2004, probably due to improvements in diagnosis and reporting, followed by relatively stable incidence rates in the subsequent 15 years. The incidence rate in adults 65 year of age and older was reported to be consistently higher by approximately 10 to 15 cases per 100,000 population than in adults aged 50 to 64 years old (e.g., in 2019, it was reported at 25 cases and 14 cases per 100,000 population, respectively). Adults aged 18 to 49 years consistently had the second lowest IPD incidence rates compared to other age groups, maintaining an incidence around 5 cases per 100,000 population from 2001-2019.
Text Description
IPD incidence is directly proportional to age in persons 50 years of age and older (). From 2011-2019, IPD incidence rates were highest in the oldest age group (85 years and older). In the other age groups, the incidence rates fluctuated slightly but remained relatively steady from 2011-2019. In Canadians aged 85 years and over, however, the incidence decreased from 50 to 40 cases per 100,000 population between 2011 and 2016. After 2016, incidence rates fluctuated ranging from 39 to 46 cases per 100,000 population, with a mean of 42 cases per 100,000 population. Incidence rates in the other age groups were approximately: 12 to 13 cases per 100,000 population in the 50 to 64 year-old age group; 19-20 cases per 100,000 population in the 65 to 74 year-old age group; and 26-28 cases per 100,000 population in the 75-84 year-old age group.
Text Description
The Toronto Invasive Bacterial Diseases Network (TIBDN) , an active surveillance program in Metropolitan Toronto and the Peel region, found that between 2012/2013 and 2018/2019, the incidence of IPD in adults aged 15 to 64 years increased significantly from 3.7 to 5.4 cases/100,000/year. During this same period, the incidence of IPD in adults aged 65 years and older decreased from 22.8 to 18.7 cases/100,000/year; however, this change was not significant. TIBDN also found that from 2018/2019 to 2020, IPD incidence in adults aged 15 to 64 years decreased from 5.4 to 2.6 cases/100,00/year, and IPD incidence in adults 65 years and older decreased from 18.7 to 8.7 cases/100,000/year. 

## III.1.2 IPD incidence in Northern Canada
The age-standardized incidence rate in Northern Canada, based on the data submitted to ICS, was significantly higher (25.8 cases per 100,000 population, 95% CI: 23.5 to 28.1%) than the rest of Canada (9.1 cases per 100,000 population, 95% CI: 9.1 to 9.2%) between 2001 and 2019 () . 
 In northern Canada, the IPD incidence rate in Indigenous Canadians was significantly higher at 31.3 cases per 100,000 population per year compared with non-Indigenous Canadians at 7.0 cases per 100,000 population per year (p<0.0001) for the same time period . 
Text Description
The incidence rate of IPD was consistently and significantly higher in Northern Canada when compared to the rest of Canada, with an exception of the year 2017, which was the minimum IPD incidence rate in Northern Canada at around 15 cases per 100,000 population. In this year, the incidence was still higher in Northern Canada but not significantly. The maximum overall IPD incidence rate Northern Canada occurred in 2001 with 38 cases per 100,000 population. The incidence rate subsequently decreased to 16 cases per 100,000 population in 2005 following the introduction of pediatric pneumococcal immunization in Canada. Since 2005, the IPD incidence rate fluctuated yet remained relatively stable, and was most recently calculated as 23 cases per 100,000 population in 2021. IPD cases have remained slightly elevated from 2018 to 2021 when compared to 2015 to 2017.

# III.2 Distribution of IPD Serotypes in Canada, 2016  2020
Distribution of IPD Serotypes in Canada, 2016  2020 
 From 2016 to 2020, a combined 15,234 isolates of *S. pneumoniae- causing invasive disease were characterized by the NML with 34% of these being identified from adults 65 years of age or older. The majority of IPD cases were caused by vaccine-contained serotypes (). Serotypes 3 and 22F were identified as the most common causes of IPD overall and in older adults based on isolates submitted to NML (). 
 Overall, the proportion of IPD isolates covered by each vaccine (PNEU-C-13, PNEU-C-15/non-PNEU-C-13, PNEU-C-20/non-PNEU-C-15 and PNEU-P-23/non-PNEU-C-20) have remained relatively stable since 2016 (). In 2020, among adults 65 years old or older, 27.4% of circulating serotypes were covered by PNEU-C-13, 40.6% were covered by PNEU-C-15, 55.8% were covered by PNEU-C-20 and 66.9% were covered by PNEU-P-23. Circulating serotypes not covered by any pneumococcal vaccine amounted to 33.1%. 
 Serotype distribution for IPD among adults are summarized in . 
\- Component of PNEU-C-13; \*\- Component of PNEU-C-15; ^ Component of PNEU-C-20; ~ Component of PNEU-P-23;  Number of isolates for all ages and adults 65 years and older, respectively (2016-2020, combined total).
Text Description
\*Vaccine serotypes include PNEU-C-13 (1, 3, 4, 5, 6A/C, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F); PNEU-C-15 (all PNEU-C-13 plus 22F and 33F); PNEU-C-20 (All PNEU-C-15 plus 8, 10A, 11A, 12F, 15B/C) and PNEU-P-23 (PNEU-C-20 serotype except 6A, plus 2, 9N, 17F, 20); NVT = all serotypes not included in PNEU-C-13, PNEU-C-15, PNEU-C-20 and PNEU-P-23. Serotype 6C included in PNEU-C-13 Serotypes due to cross protection with 6A. Serotypes 15B and 15C were grouped together as 15B/C because of reported reversible switching between them in vivo during infection, making it difficult to precisely differentiate between the two types.
Text Description
 non-PNEU-C-13
 non-PNEU-C-15
 non-PNEU-C-20
Distribution of IPD serotypes in Northern Canada 
IPD distribution in Northern Canada was assessed using data from all five Arctic regions captured in the ICS system. Overall, there were 159 isolates of invasive *S. pneumoniae- characterized between 2016 and 2020: 26% of *S. pneumoniae- isolates were PNEU-C-13 serotypes, 14% were PNEU-C-15/non-PNEU-C-13 serotypes, 23% were PNEU-C-20/non-PNEU-C-15 serotypes, 20% were PNEU-P-23/non-PNEU-C-20 serotypes, and 16% were NVT serotypes. However, trends were difficult to ascertain due to the small number of cases and relatively smaller population in the North.

# III.3 Burden of Pneumococcal community acquired pneumonia in Canada
Using CIRN SOS Network data from 13 hospitals across five provinces, Leblanc et al. (2022) reported on CAP incidence in hospitalized adults from 2010 to 2017 . During this period, 14.2% (1264/8912) of all-cause CAP was found to be caused by *S. pneumoniae- with 64.1% (811/1264) being non-bacteremic, and 35.9% (455/1264) being bacteremic. Among pCAP cases in adults, 49.8% occurred in those over 65 years of age, 31.3% in those 50 to 64 years of age and 19.0% in those 16-49 years of age. Among all pCAP cases, 89.1% had one or more co-morbidity, and 28.6% had an immunocompromising condition. Of all *S. pneumoniae- CAP cases captured during the study period, the serotype distribution showed serotypes 3, 7F, 9N, 11A, 19A, and 22F as common. 
Data from the 2018 to 2019 Discharge Abstract Database (Canadian Institute for Health Information 2022) reported inpatient CAP cases per 100,000 with pneumonia as a significant diagnosis (excluding pneumonia due to influenza). These data showed that for adults 75 years of age and older, there were 5,104 cases/100,000 population in Northern Canada and 2,846 cases/100,000 population across the rest of Canada; for adults 60 to 74, there were 1,777/100,000 population cases in Northern Canada and 871/100,000 population across the rest of Canada; and for adults 50 to 64 years, there were 569 cases/100,000 population in Northern Canada and 348 cases/100,000 population across the rest of Canada.   

# III.4 High Risk Groups
The TIBDN  found that, in their population, IPD incidence among individuals aged 15 to 64 years with chronic underlying illness increased significantly from 7.3 cases/100,000/year in 2012 to 11.0 cases/100,000/year in 2019. During the same time period, the IPD incidence among adults aged 65 years and older decreased in those with underlying illness mainly because IPD cases due to PNEU-C-13 contained serotypes decreased from 10.0 to 4.6 cases/100,000/year in people with an underlying chronic illness, and from 27.0 to 16.0 cases/100,000/year in people with immunocompromising conditions. 
 The Calgary Area *Streptococcus pneumonia- Epidemiology Research (CASPER)  program, an active surveillance program in Calgary, found that between 2000 to 2013, IPD incidence rate among adults with underlying comorbidities decreased by 37% . 

# III.5 Summary of Pneumococcal Immunization Coverage in Canada
The Vaccine Coverage and Effectiveness Monitoring program at PHAC collects pneumococcal vaccination coverage information among Canadians as part of the seasonal influenza vaccination coverage survey . The most recent survey conducted over the 2020-2021 influenza season showed that about 55% of adults65 years of age and over reported receiving a pneumococcal vaccine in adulthood. The coverage was higher for females (60%) than males (40%). Overall, 26% of adults 18 to 64 years old with underlying medical conditions reported receiving pneumococcal vaccination. The survey did not differentiate between the two different pneumococcal vaccines recommended for adults. 
IV. Vaccine

# IV.1 Preparations authorized for use in Canada
Four preparations of pneumococcal vaccine are currently authorized for use in adults in Canada ().
 PNEU-C-13 (Prevnar13)  is a sterile solution of polysaccharide capsular antigen of 13 serotypes of *S. pneumoniae- (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F). The antigens are individually conjugated to a diphtheria, *Corynebacterium diphtheriae- (CRM197), protein carrier. The CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-13 is available as a 0.5mL single dose, prefilled syringe. 
 PNEU-C-15 (Vaxneuvance)  is a sterile suspension of purified capsular polysaccharides from 15 serotypes of *S. pneumoniae- (PCV13 serotypes plus serotypes 22F and 33F). The antigens are individually conjugated to diphtheria CRM197 protein carrier. This CRM197 protein carrier is adsorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 32 mcg of total pneumococcal polysaccharide (2.0 mcg each of polysaccharide Serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B) conjugated to 30 mcg of CRM197 carrier protein. PNEU-C-15 is available as a 0.5mL single-dose prefilled syringe. 
 PNEU-C-20 (Prevnar 20TM)  is a sterile saccharide suspension of the capsular antigens of 20 serotypes of *S. pneumoniae- (PCV13 serotypes + serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F). The antigens are individually conjugated to non-toxic diphtheria CRM197 protein. This CRM197 protein carrier is absorbed on aluminum phosphate as an adjuvant. Each dose of vaccine contains 4.4 mcg of the 6B polysaccharide, and 2.2 mcg each of the remaining polysaccharides. PNEU-C-20 is supplied as a 0.5mL single dose prefilled syringe.
 PNEU-P-23 (Pneumovax23)  is a sterile solution of 23 highly purified capsular polysaccharides (PCV13 serotypes with the exception of 6A, plus serotypes 2, 9N,17F, and 20). PNEU-P-23 is available as a single-dose vial containing 0.5 ml of liquid vaccine and a 0.5mL single dose prefilled syringe.
 aluminum (as aluminum phosphate adjuvant),
 1.55mg of L-histidine, 1 mg of polysorbate 20,
 4.50 mg of sodium chloride and water for
- Pregnancy (limited data)
- Breastfeeding (limited data)
- Pregnancy (limited data)
- Breastfeeding (no data)
- Pregnancy (limited data)
- Breastfeeding (limited data)
- Breastfeeding (no data)

# IV.2 Efficacy and effectiveness
There are currently no efficacy or effectiveness data available for PNEU-C-15 or PNEU-C-20 for any adult indication. 
 Recently reported systematic reviews continue to support the effectiveness of PNEU-C-13 against IPD and pneumococcal pneumonia among adults 65 and older  . Two observational studies included in the systematic review by Childs et al found a PNEU-C-13 vaccine effectiveness against pneumonia caused by vaccine-contained serotypes in the range of 38 to 68%. Three observational studies from the systematic review by Farrar et al found a PNEU-C-13 effectiveness against IPD caused by vaccine-contained serotypes in the range of 59 to 68%. 
 A recent systematic review  reported a pooled PNEU-P-23 effectiveness against IPD caused by vaccine-contained serotypes in adults 65 years of age and older to be 38%. Another systematic review  found a limited protection against pneumonia caused by vaccine-contained serotypes (pooled effectiveness of 18% from 3 observational studies with PNEU-P-23 given to adults 65 years and older less than 5 years before illness onset). 

# IV.3 Immunogenicity

## IV.3.1  Measures of Immunogenicity
OPA assays were used to assess immune response for PNEU-C-15 and PNEU-C-20. While no specific threshold of OPA titer has been identified that correlates with protection against IPD or pneumonia in adults, OPA responses have been used as an established surrogate of protection to infer efficacy when comparing to an efficacious vaccine.
 Previously, OPA responses were used as a surrogate marker of vaccine efficacy for IPD and pneumonia in the approval of PNEU-C-13 in adults. 

## IV.3.2 Immunogenicity of PNEU-C-15
Summary of PNEU-C-15 study characteristics
 Immunogenicity of PNEU-C-15 was evaluated in two Phase 2 trials   and five Phase 3 trials     . Three studies evaluated medically stable, vaccine-naive adults 50 years of age or older and one study focused on previously vaccinated adults 65 years of age and older. Data for adults 18 years of age and older with medical risk factors for PD were available in two studies (one as a study population subset analysis). One study evaluated adults with HIV. Most studies had participants of a majority white race and with gender balance (). Immunogenicity assessments were at a low RoB ().
Summary of PNEU-C-15 immunogenicity evidence 
 In immunocompetent pneumococcal vaccine-naive adults 65 years of age and older, for shared serotypes, PNEU-C-15 demonstrated overall similar immune responses, including for serotype3, compared to PNEU-C-13 (). All analyses for serotypes not covered by PNEU-C-13 showed numerically higher responses with PNEU-C-15. However, seroresponses varied for the shared serotypes. Results from studies comparing PNEU-C-15 to PNEU-P-23 showed similar results, although seroresponse was higher with serotype3 with PNEU-C-15 (Appendix A, Tables  and ). 
 While no studies evaluated non-inferiority for other age groups (50 to 64 years; 65 to 74 years; 75 years of age and older) observational comparisonsamong age groups and age subgroup data for seroresponse are reported in Appendix A, Tables  and . Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (), and adults with immunocompromising conditions (). 
 In pneumococcal vaccine-naive adults over the age of 65, PNEU-C-15 administered concurrently with quadrivalent seasonal influenza vaccine, seroresponses were found to be similar for serotype 3 but numerically lower for the other shared serotypes (). In adults who subsequently received PNEU-P-23 following the receipt of PNEU-P-15, there was an observed numerically lower proportion of seroresponders with serotype 3, PNEU-C-15 unique serotypes, as well as some shared serotypes when compared to seroresponse rates following previous PNEU-C-13 vaccination in series with PNEU-P-23 for some shared serotypes (). 
 Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (), as well as people with chronic medical conditions (CMC) 18 to 64 years of age () and with immunocompromising conditions (). 

## IV.3.3. Immunogenicity of PNEU-C-20
Summary of PNEU-C-20 study characteristics 
 Immunogenicity of PNEU-C-20 was evaluated in one Phase 2 trial3  and two Phase 3 trials  . Two trials evaluated vaccine-naive healthy adults, as well as adults with underlying CMCs. Of these studies, one recruited participants 60 to 64 years of age while the other enrolled participants 18 years of age or older into three age cohorts (i.e., 18 to 49, 50 to 59, 60 years and older). One study evaluated immune responses in previously PNEU-P-23 vaccinated adults 65 years of age or older. Studies were assessed to be at low RoB (). 
Summary of PNEU-C-20 immunogenicity evidence 
 Non-inferiority criteria were met following the administration of PNEU-C-20 in vaccine-naive populations over age 60. However, there was an observed lower proportion of seroresponders compared to PNEU-C-13 for shared serotypes (). While PNEU-C-20 was not directly compared to PNEU-C-13 or PNEU-P-23, individuals previously vaccinated with PNEU-P-23, PNEU-C-13 or both, showed robust immune responses following PNEU-C-20 vaccination (Appendix A, Tables  and ). PNEU-C-20 was not evaluated in adults with immunocompromising conditions.

# IV.4  Persistence of Immune Response
Persistence of PNEU-C- 15 immune response 
 Persistence of PNEU-C-15 immune response was observed 8 weeks , 6 months  and 1 year  following the sequential administration of PNEU-P-23 in adults 18 years of age or older living with immunocompromising conditions, in adults 18 to 49 living with CMCs and in healthy adults 65 years of age or older. In general, OPA GMTs at 8 weeks, 6 months and 1 year were lower than at day 30 post PNEU-C-15 vaccination but higher than at baseline. PNEU-C-15 elicited an immune response that was comparable to PNEU-C-13 at 30 days and 8 weeks, 6 months, and 12 months post- vaccination for the 13 shared serotypes and higher than PNEU-C-13 for the 2 serotypes 22F and 33F unique to PNEU-C-15. 
 Persistence of PNEU-C-20 immune response 
 Persistence of PNEU-C-20 immune response was observed at 12 months in healthy adults aged 60 through 64 years with no history of pneumococcal vaccination . OPA GMTs at 12 months declined compared with those at 30 days after vaccination but remained elevated above baseline. The same pattern of antibody decline in the 12 months after vaccination has previously been observed with PNEU-C-13. However, vaccine effectiveness against pneumonia caused by serotypes in the vaccine did not decline through 4 years of follow-up . 

# IV.5 Vaccine Administration and Schedule
PNEU-C-15 and PNEU-C-20 are supplied in a single-dose, prefilled syringe. 
 A 0.5mL dose of PNEU-C-15 should be administered intramuscularly. The standard schedule for immunization is one dose. The need for a booster dose or re-immunization is not indicated. Please see the product monograph for additional details .
 A 0.5mL dose of PNEU-C-20 should be administered intramuscularly. The standard schedule for healthy adults is one dose. Please see the product monograph for additional details .

# IV.6 Serological Testing
Serological testing is not recommended before or after receiving pneumococcal vaccine.

# IV.7 Storage Requirements
PNEU-C-15 should be refrigerated at 2C to 8C. The vaccine should not be frozen. Protect the vaccine from light. The prefilled syringes should be administered as soon as possible after being removed from the refrigerator .
PNEU-C-20 should be refrigerated at 2C to 8C. The pre-filled syringes should be stored horizontally in the refrigerator to minimize the re-dispersion time. The vaccine should be discarded if it has been frozen. The vaccine should be administered as soon as possible after being removed from the refrigerator .

# IV.8 Concurrent Administration with Other Vaccines
PNEU-C-15 and PNEU-C-20 can be concurrently administered with quadrivalent inactivated influenza vaccine (QIV) in adults, as concurrent administration has been demonstrated to be immunogenic and safe . However, lower pneumococcal OPA GMTs were reported when pneumococcal vaccines were co-administered with QIV compared with when pneumococcal vaccines were given alone   . No data are available on co-administration of PNEU-C-15 or PNEU-C-20 with other adult vaccines. Preliminary data on the co-administration of PNEU-C-20 and the Pfizer-BioNTech Comirnaty mRNA COVID-19 vaccine showed no significant interference in the immune response . 

# IV.9 Vaccine Safety
Summary of PNEU-C-15 study characteristics
 Safety of PNEU-C-15 was evaluated in two Phase 2 trials   and five Phase 3 trials     . Data on local and systemic AEs were solicited through electronic vaccine report cards for two weeks after each dose, as well as follow up for serious events for 6 months. Reported outcomes included SAEs, vaccine-related SAEs, as well as mild/moderate and severe systemic AEs (i.e., fever, fatigue, headache, muscle, and joint pain). Safety data was reported for pneumococcal vaccine-naive individuals, concurrent administration with season influenza vaccine, and for specific populations of interest including adults aged 18 to 64 years with chronic medical or immunocompromising conditions, and previously vaccinated adults aged 65 years or older. Six studies were at low RoB for all domains. In one study the reasons for missing data were not reported in the assessment of SAEs and vaccine-related SAEs, which is challenging.
 Summary of PNEU-C-15 Safety
 There was little to no difference reported in clinical trials between PNEU-C-15 and PNEU-P-23 or PNEU-C-13 for all mild/moderate and severe systemic AEs occurring within 14 days of vaccination as well as reported SAEs up to six months after vaccination in all evaluated populations (Appendix A, Tables ,  and  to ). Results were similar following sequential administration of PNEU-P-23 after PNEU-C-15 or PNEU-C-13 in adults 65 years of age or older with an immunocompromising condition (Appendix A, Tables  and ). 
 There was little to no difference in SAEs for PNEU-C-15 administered concomitantly with QIV for vaccine-naive adults (). Results were similar with respect to severe fatigue, joint and muscle pain up to 14 days after vaccination. There was no difference between groups for severe and mild/moderate systemic AEs.
 Summary of PNEU-C-20 study characteristics 
 The safety of PNEU-C-20 was primarily evaluated for GRADE in one Phase 2 trial  and two Phase 3 trials  . Data were available for pneumococcal vaccine-naive adults 18 years of age and older, and previously vaccinated adults 65 years of age and older. The full safety evaluation included 6 pre-licensure clinical trials, with safety data collection including solicited local reactions within 10 days of vaccination and systemic events within 7 days. Unsolicited events were collected for 1 month after vaccination and SAEs and newly diagnosed CMCs within 6 months after vaccination. 
 Safety of PNEU-C-20 
 There was little to no difference between PNEU-C-20 and PNEU-C-13 in SAEs up to one month post-vaccination for vaccine-naive adults aged 60 years or older. Results showed no difference for all mild/moderate and severe systemic AEs up to seven days post-vaccination. Certainty of evidence varied across assessments ranging from moderate to high ().
For adults 65 years of age and older previously vaccinated with PNEU-P-23 one to five years prior, SAEs up to six months and systemic AEs 7 days after vaccination were similar between PNEU-C-20 and PNEU-C-13 (). Findings were similar when PNEU-C-20 and PNEU-P-23 were compared among those previously vaccinated with PNEU-13 at least six months prior ().

# IV.10 Contraindications and Precautions
PNEU-C-15 and PNEU-C-20 are contraindicated in individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine. Administration of vaccine should be postponed in persons suffering from acute severe febrile illness. 
V. Vaccination of Specific Populations

# V.1. Immunization in Pregnancy and Breastfeeding
There are no adequate and well-controlled studies of PNEU-C-15 and PNEU-C-20 in individuals who are pregnant or breastfeeding. 

# V.2. Immunization of Immunocompromised persons
Individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to the vaccine. 
VI. Ethics, Equity, Feasibility and Acceptability Considerations
NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance .
 NACI evaluated the following ethical considerations when making its recommendations: promoting well-being and minimizing risk of harm, maintaining trust, respect for persons and fostering autonomy, and promoting justice and equity. NACI took into account the available evidence from the clinical studies of PNEU-C-15 and PNEU-C-20 along with the real-world evidence on the effectiveness and safety of currently available pneumococcal vaccines PNEU-C-13 and PNEU-P-23, as well as data on the burden of illness of PD and evolving serotype distribution, and risk factors in particular for IPD. 
 Achieving coverage of 80% of adults 65 years old or older vaccinated with a pneumococcal vaccine, as well as reducing overall burden of disease by 5% by 2025, is one of the goals of the Canadian national immunization strategy. However, vaccine uptake in adults 65 years of age or older is well below the target, with approximately 55% reporting receiving a pneumococcal vaccine in Canada. Uptake is even lower among younger adults 18 to 64 years of age with underlying medical conditions that predispose them to PD at approximately 26%). A survey conducted in Quebec in 2020 reported that lack of awareness that the pneumococcal vaccine is needed or recommended is the most frequent reason for not being vaccinated.
 The new higher-valent pneumococcal conjugate vaccines offer an opportunity to protect individuals against additional serotypes and further reduce the burden of disease in adults. PNEU-C-20 covers more than 90% of serotypes included in PNEU-P-23, with the additional benefits of conjugate vaccines. Thus, PNEU-C-20 may be offered in programs as a single dose without a subsequent dose of PNEU-P-23, unlike PNEU-C-15 which is recommended to be administered in series with PNEU-P-23 to optimize protection. A single dose vaccine schedule minimizes complexity and cost in a vaccine program and can facilitate vaccination of populations that are otherwise difficult to reach to complete a series requiring more than one dose. 
 Among factors that may contribute to health inequity as described in NACIs EFFA framework, pre-existing disease, social factors, place of residence, and age are important to consider with pneumococcal recommendations. Pneumococcal disease burden increases with age and adults with pre-existing conditions are at greater risk. Therefore, by providing age-based and risk-based recommendations as well as inclusion of settings of higher disease burden, inequity may be reduced.
 First Nations, Metis, or Inuit communities in Canada have a younger age distribution compared to the general Canadian population but have also been observed to have increased risk for severe PD due to a variety of intersecting factors including underlying medical conditions and potential decreased access to health care. Therefore, age-based recommendations may need to be modified to offer effective protection to individuals in these communities. Autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the . 
VII. Economics
A systematic review, de novo model-based economic evaluation, and a multi-model comparison were used as economic evidence to support decision-making for the use of PNEU-C-15 and PNEU-C-20. 
 Full details of these analysis, including assumptions and limitations, are provided in a supplementary appendix.
 A review of the peer-reviewed and grey literature identified four cost-utility studies of PNEU-C-15 and PNEU-C-20 compared to current vaccination recommendations for adults in the United States (that are PNEU-P-23 plus optional PNEU-C-13 under shared clinical decision-making for adults aged 65 years or older; PNEU-P-23 at diagnosis of CMCs if under age 65 years; and PNEU-C-13 in series with PNEU-P-23 at diagnosis of immunocompromising condition if under age 65 years) . The studies generally found that PNEU-C-20 use in older adults was associated with increased QALYs, and with lower ICERs when the vaccine was used in adults aged 65 years and older compared to programs in adults aged 50 years and older. ICER estimates for PNEU-C-15 use in series with PNEU-P-23 at age 65 showed variability across studies. The estimated impact of adding risk-based programs for younger adults with IC/CMC to an age-based strategy depended on the vaccine product, with lower ICERs reported for PNEU-C-20 than for PNEU-C-15 in series with PNEU-P-23. 
 A cost-utility model developed by NACI was used to evaluate the cost-effectiveness of different age-based recommendations for PNEU-C-15 and PNEU-C-20 vaccines (used alone or in series with PNEU-P-23) in the Canadian population compared to current recommendations. Results are presented for the health system perspective. The base-case analysis, supported by scenario analyses, indicated that PNEU-C-20 used alone is likely a cost-effective strategy at age 65 or 75, with ICERs ranging from $6,500 to $17,400 per QALY gained. The ICERs for PNEU-C-20 at age 50 were higher than for ages 65 or 75. In sequential analysis that compared all possible vaccination strategies, PNEU-C-15 was dominated (more costly and less effective) or subject to extended dominance (i.e., would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20. PNEU-C-20 plus PNEU-P-23 at age 65 or age 75 had ICERs ranging from 80,000 to $113,500 per QALY gained. Findings were sensitive to the assumed vaccine prices for PNEU-C-15 and PNEU-C-20 (see supplementary appendix). Analysis of populations in Northern Canada showed similar trends as the rest of Canada.
In a multi-model comparison, three cost-utility models with harmonized parameter values and using the same health system perspective and discount rate, showed qualitatively consistent results despite differing model structures and assumptions. The comparison supported the finding that, based on currently available data, PNEU-C-20 used alone ($4,100-106,000 per QALY gained) could be a cost-effective strategy for use in the adult Canadian population, depending on the cost-effectiveness threshold used. All models estimated PNEU-C-15 or PNEU-C-15 in series with PNEU-P-23 to be dominated (more costly and less effective) or subject to extended dominance (would never be the optimal option regardless of the cost-effectiveness threshold) by PNEU-C-20.
VIII. Recommendations
Following the review of available evidence summarized above, NACI makes the following recommendations for public health level decision-making. Considerations in the management options table should also be reviewed in order to inform decision making. 
 A *strong recommendation- applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. 
 A *discretionary recommendation- may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. 
 Please see  for a more detailed explanation of strength of NACI recommendations () and the GRADE assessment of the body of evidence (). 
 NACI will continue to carefully monitor the scientific developments related to pneumococcal vaccination in adults and will update recommendations as evidence evolves.

# VIII.1 Recommendations for Public Health Program Level Decision-Making
In considering NACI recommendations for publicly funded immunization programs and for the purposes of publicly funded program implementation, provinces and territories may take into account other local operational factors (e.g., current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to Management Options Tables  and  below for a summary of the considerations for using different products (e.g., with respect to cost-effectiveness and feasibility).
For adults not previously vaccinated with a pneumococcal vaccine, or adults whose vaccination status is unknown 
1. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to pneumococcal vaccine naive adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 49 years of age living with immunocompromising conditions. (Strong NACI recommendation).
Summary of evidence and rationale 
- Conjugate vaccines induce memory, provide longer duration of protection, and provide ability for boosting by involving T cells in a way that polysaccharide vaccines cannot. The more durable protection offered by conjugate vaccines may result in fewer cases of PD, even though they protect against fewer serotypes than polysaccharide vaccine.
- In immunocompetent adults 65 years of age and older, PNEU-C-20 has been demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13, although immune responses were noted to be lower following PNEU-C-20, and superior immune responses compared to PNEU-C-23 for shared serotypes.
- No PNEU-C-20 studies in immunocompromised adults have been conducted. Among persons with ICs for PD, PNEU-C-20 is expected to be similarly efficacious as PNEU-C-13 against disease attributable to the 13 matched serotypes.
- PNEU-C-20 has a comparable safety profile to PNEU-C-13 in adults.
- Immunization of older adults with PNEU-C-20 vaccine is expected to be cost-effective, based on the current burden of IPD and assumptions regarding pricing of the PNEU-C-15, PNEU-C-20, and PNEU-P-23.
- Individuals at increasing age and/or with certain underlying medical conditions (both non-immunocompromising and immunocompromising) and other risk factors are at higher risk of IPD (see ). Adults 65 years of age and older have the highest incidence rate of IPD compared to other adult age groups, followed by adults 50 to 64 years of age. However, the benefit of vaccinating adults 50 to 64 with underlying medical conditions or other risk factors that place them at higher risk for IPD are anticipated to be greater than vaccinating all adults in this age group.
- Age-based recommendations may need to be modified for communities with younger age distributions. In First Nations, Metis, or Inuit communities, autonomous decisions should be made by Indigenous Peoples with the support of healthcare and public health partners in accordance with the .
- Current uptake of pneumococcal vaccines among older adults and adults living with underlying medical conditions, both non-immunocompromising and immunocompromising, is well below national goals.
- Program feasibility and vaccine acceptability and uptake may be superior with single dose PNEU-C-20 as compared to a PNEU-C-15 + PNEU-P-23 strategy, the latter of which would require coordination of two doses of different vaccine products.
2. NACI recommends that PNEU-C-15 followed by PNEU-P-23 may be offered as an alternative to PNEU-C-20 to pneumococcal vaccine naive adults or adults whose vaccination status is unknown and who are 65 years of age and older, or who are 50 to 64 years of age living with risk factors placing them at higher risk of pneumococcal disease, or who are 18 to 64 years of age living with immunocompromising conditions. (Discretionary NACI recommendation)
Summary of evidence and rationale 
- In immunocompetent adults 65 years of age and older, PNEU-C-15 has demonstrated to produce a similar (non-inferior) immune response compared to PNEU-C-13 for shared serotypes.
- In adults with underlying medical conditions, including ICs, PNEU-C-15 has shown comparable immune responses to PNEU-C-13 for 13 shared serotypes.
- An interval between PNEU-C-15 and PNEU-P-23 of 1 year is recommended for adults 65 years of age and older and adults 50 to 64 years of age living with risk factors for PD to provide expanded protection to 8 additional serotypes not in PNEU-C-15.
- An interval between PNEU-C-15 and PNEU-P-23 of 8 weeks is recommended for adults 18 to 64 years of age living with ICs to provide expanded protection to additional serotypes not in PNEU-C-15 allowing for quicker completion of series in vulnerable population. A longer interval may result in less blunting of immune responses and could be considered if risk of pneumococcal infection if low.
- Although PNEU-C-15 is not expected to yield the same population-level epidemiological benefits as PNEU-C-20 and requires a second dose with PNEU-P-23, it is anticipated to improve disease outcomes compared to offering PNEU-P-23 alone.
- Although PNEU-C-20 dominated PNEU-C-15 + PNEU-P-23 in cost-effectiveness analyses, the results were sensitive to vaccine price. A large enough differential in vaccine price between PNEU-C-20 and PNEU-C-15 + PNEU-P-23 would result in similar cost-effectiveness (i.e., PNEU-C-15 + PNEU-P-23 would no longer be dominated).
For adults previously vaccinated with a pneumococcal vaccine
3. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 65 years of age and older who have been immunized previously with PNEU-P-23 alone, or PNEU-C-13 and PNEU-P-23 in series, if it has been at least 5 years from the last dose ofa previous pneumococcal vaccine (PNEU-P-23 or PNEU-C-13).(Strong NACI recommendation)
Summary of evidence and rationale 
- Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-P-23 alone or together with PNEU-C-13; however, the data were non-comparative to PNEU-C-13.
- PNEU-C-20 has shown little to no difference in safety profiles to PNEU-C-13 in adults 65 years of age and older previously vaccinated.
- An interval of 5 years between PNEU-P-23 and PNEU-C-20 takes advantage of the estimated effectiveness duration of PNEU-P-23 and the boosting anticipated with PNEU-C-20; it also maximizes the total duration of protection against pneumococcal infection.
- There may be benefit to offering PNEU-C-15 to adults 65 years of age and older who have received PNEU-P-23 alone if PNEU-C-20 is not available. For adults 65 years of age and older who are also at the highest risk of IPD, an additional dose of PNEU-P-23 may be offered one year later.  There is limited benefit to giving PNEU-C-15 to individuals who received PNEU-C-13 as it will only offer protection against two additional serotypes.
4. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 may be offered to adults 65 years of age and older who have been immunized previously with PNEU-C-13 alone, if it has been 1 year from the last dose of PNEU-C-13. (Discretionary NACI recommendation)
Summary of evidence and rationale 
- Robust immune responses were reported for PNEU-C-20 in adults previously vaccinated with PNEU-C-13 only; however, the data were non-comparative to PNEU-C-13.
- An interval of 1 year between PNEU-C-13 and PNEU-C 20 is to expand serotype coverage offered by PNEU-C-13 in a time-effective manner.
- A shorter interval of 8 weeks might be considered to align with immunization clinics and/or programs.
- The additional benefit of offering PNEU-C-15 is limited as PNEU-C-15 will only offer protection against two additional serotypes. However, PNEU-C-15 in series with PNEU-P-23 or PNEU-P-23 alone can be considered if PNEU-C-20 is unavailable or inaccessible.
For hematopoietic stem cell transplant recipients 
5. NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to adults 18 years old or older who received a hematopoietic stem cell transplant (HSCT) after consultation with transplant specialist. A primary series of 3 doses of PNEU-C-20 starting 3 to 9 months after transplant should be administered at least 4 weeks apart, followed by a booster dose of PNEU-C-20 12 to 18 months post-transplant (6 to 12 months after the last dose of PNEU-C-20). (Strong NACI recommendation)
Summary of evidence and rationale
- No studies assessing immunogenicity and safety of PNEU-C-20 in HSCT recipients were available; however, PNEU-C-20 is expected to have similar immunogenicity and safety profiles to PNEU-C-13 in this population.
- The recommended timing of PNEU-C-20 for HSCT recipients should be determined in consultation with the recipients transplant specialist.
- PNEU-C-15 may be considered if PNEU-C-20 is unavailable or inaccessible to ensure these individuals will receive the needed protection.
Considerations for continued PNEU-C-13 and PNEU-P-23 use and other risk groups 
- NACI supports the continued use of PNEU-C-13 and PNEU-P-23 in adults only when PNEU-C-15 and/or PNEU-C-20 are unavailable or inaccessible.
- At this time, there are no public health level recommendations on the use of PNEU-C-15 or PNEU-C-20 for adults 18 to 49 years of age with non-immunocompromising risk factors that place them at high risk of IPD as additional analyses on the cost-effectiveness of conjugate PNEU-C-15 and PNEU-C-20 in this population are needed. PNEU-C-15 or PNEU-C-20 may be considered at clinical discretion for these adults.
Management options 
Options for the vaccine schedule, vaccine type (VT), age cohort and risk group are available, and the decision on which option is preferable may depend on one or more considerations outlined below.
PNEU-C-13 - Efficacy/Effectiveness data not yet available
- Immunogenicity (based on OPA GMTs and % seroresponse) non-inferior to PNEU-C-13 for shared serotypes however immune responses numerically lower
- Safety profile of PNEU-C-20 consistent with safety of PNEU-C-13, for both vaccine naive and vaccine experienced
- Cost-utility analysis estimates that PNEU-C-20 use is likely a cost-effective strategy, regardless of age or region.
- Simplified recommendation with a single vaccine is expected to increase acceptability for both recipients and vaccine program implementation, thus the potential to prevent more disease
- PNEU-C-15 and PNEU-C-20 contain different serotypes, which can have different impacts on IPD rates based on local serotype epidemiology
Unknowns- Speed of serotype replacement
- Extent of serotype replacement
- Impact on disease burden in adults when higher valent pneumococcal conjugate vaccines become available for use in pediatric vaccine programs
Duration of protection- Waning protection from pneumococcal conjugate vaccines appears to occur at a slower rate compared to pneumococcal polysaccharide vaccines
Unknowns- VE and duration of protection of PNEU-C-15 and PNEU-C-20
Immunogenicity- Both PNEU-C-15 and PNEU-C-20 are immunogenic compared to PNEU-C-13
- PNEU-C-20 appears to have lower immune response compared to PNEU-C-13 for shared serotypes
- PNEU-C-15 appears to have higher immune response compared to PNEU-C-13 for shared serotype 3
Unknowns- Correlates of protection
Safety- Both vaccines are safe in immunocompetent individuals
Economics
 Based on a cost utility analysis: - PNEU-C-20 was cost-effective compared to current recommendations in adults 65 years of age and older
- When PNEU-C-20 is available, PNEU-C-15 is more costly and less effective than giving PNEU-C-20 alone.
- If PNEU-C-20 is not available, PNEU-C-15 in series with PNEU-P-23 is more cost-effective than PNEU-C-15 alone
 Unknowns- Cost-effectiveness in other high-risk populations
Feasibility/Acceptability- PNEU-C-15 should be offered in series with PNEU-P-23 to optimize protection against more serotypes. This would make it a 2-product series, compared to PNEU-C-20, which is 1 dose only. Consideration to improve adherence and acceptability of the 2nd dose, as well as additional operational costs for the administration of the 2nd dose would be required.
Unknowns- It is unknown what the adherence to the complete 2-product vaccination schedule with PNEU-C-15 and PNEU-P-23 will be
- Efficacy/effectiveness data not yet available
- Immunogenicity (based on OPA GMTs and % seroresponse) showed non-inferiority for shared serotypes with PNEU-C-13 and mixed results in the proportion of seroresponders compared with PNEU-C-13
- Safety profile of PNEU-C-15 consistent with safety of PNEU-C-13, for both vaccine naive and vaccine experienced
- Administration costs of combined program with PNEU-P-23 higher than single dose PNEU-C-20 program regardless of age, region.
- To the extent that second doses are missed, effectiveness in preventing pneumococcal disease reduced
- PNEU-P-23 may be less effective for shared serotypes than PNEU-P-20, especially in the longer term
- Mixed schedule would require the coordination of two doses and products
- Efficacy and effectiveness data available
- PNEU-C-13 effective against IPD in adults 65 years and older
- Findings from observational studies support efficacy against vaccine type pneumonia and IPD
- Mixed schedule would require the coordination of two doses and products
- Acceptability of pneumococcal vaccination in adults at risk is below national target
Feasibility/Acceptability- PNEU-C-13 has the lowest serotype coverage of any of the authorized pneumococcal vaccines
- Some effectiveness data available, although limited and uncertain
- PNEU-P-23 may be preferred if the willingness to pay per QALY gained is lower than commonly used cost-effectiveness thresholds.
- Pooled analysis from 8 observational studies show that PNEU-P-23 is effective against IPD in adults 65 years and older.
- Pooled vaccine effectiveness against VT pneumonia from recent observational studies suggest PNEU-P-23 provides limited protection against VT pneumonia within 5 years of vaccination.
- Acceptability of PNEU-P-23 have been below national vaccination target for adults 65 years old or older and for adults 18 years old and older living with underlying medical conditions
Feasibility/Acceptability - PNEU-P-23 has the highest serotype coverage of any of the authorized pneumococcal vaccines.
- Waning protection occurring faster (within 5 years of vaccination) compared to conjugate vaccines due to its T cell independent mode of action.
- The risk of IPD associated with some medical conditions is unrelated to age
- There are no cost-effectiveness analyses for PNEU-C15 or PNEU-C-20 available for this group
- The incidence of CAP similarly increased with increasing age from 348/100,000 population (50 to -64 years) 871/100,000 (65 to -74 years) and 2846/100,000 (75 years and older). 20% of those estimated to be pneumococcal.
- PNEU-C-15 showed comparable immune responses to PNEU-C-13 for shared serotypes across all age groups. Immune responses did trend lower with increasing age
- PNEU-C-20 showed robust immune responses across all age groups
- Both PNEU-C-15 and PNEU-C-20 have comparable safety profile to PNEU-C-13/PNEU-P-23
- At age 65, the most efficient strategies (using PNEU-C-20) had estimated ICERs ranging from $6,500-80,300 per QALY gained (health system perspective) and $2,200-153,600 per QALY gained (societal perspective)
- At age 50, ICERs for the most efficient options (using PNEU-C-20) were higher than at age 65 with ICERs ranging from $16,300-81,900, depending on the strategy used and the region
- At age 75, ICERs for the most efficient strategies (using PNEU-C-20) were comparable to those at age 65. ICERs were somewhat higher in Northern Canada compared to vaccination at age 65.
- Lower burden of illness compared to older adult age groups and lower vaccine uptake (existing pneumococcal vaccination program) compared to older age groups
- Possible risk of waning protection by the time this cohort is at highest risk of IPD; therefore, will likely require a booster if protection wanes
- Higher ICERs than for the 65 years and older and 75 years and older age groups, but vaccination with PNEU-C-20 still likely to be considered cost-effective under commonly used thresholds
- Longer life expectancy than the 75 years and older age cohort; therefore, benefits of vaccination over a longer period
- Might need a booster
- ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
- Shorter life expectancy, one dose vaccination without the need for booster
- Vaccine uptake might be better compared to younger age groups
- Immunogenicity responses likely lowest in the oldest age groups due to immunosenescence
- ICERs suggest vaccination at this age with PNEU-C-20 would be cost-effective under commonly used thresholds
IX. Research priorities
- Estimates/assessments of the PNEU-C-15 and PNEU-C-20 vaccine effectiveness in the general population of individuals 65 years of age and older and in additional populations (e.g., indigenous people, people living with chronic medical, social, and immunocompromising conditions).
- Cost-effectiveness analyses on the use of PNEU-C-15 and PNEU-C-20 in adults 18 to 49 years of age with risk factors that place them at high risk of IPD.
- Assessment of the effects of community immunity and serotype replacement of PNEU-C-15 childhood programs over time on the incidence of IPD, VT IPD, CAP, and VT CAP and on carriage within the Canadian population of individuals 65 years of age and older and in additional populations (e.g., indigenous, people living with chronic medical, social, and immunocompromising conditions).
- Estimates of efficacy and effectiveness of PNEU-C-15 and PNEU-C-20 boosters in immunocompetent adults over 65 years of age.
- Assessment of pneumococcal vaccination programs on the reduction of myocardial infarction and stoke.
X. Surveillance issues
Ongoing surveillance is fundamental to planning, implementation, evaluation, and evidence-based decision-making. (Indicate if the disease to be prevented is reportable nationally.) To support such efforts, NACI encourages surveillance improvements in the following areas:
- Nationally representative data is not currently available on the burden of CAP and VT pCAP in Canada
- National surveillance data on vaccination status are not available for identified cases of IPD and VT IPD in Canada, which limits extension of findings
- National surveillance on pneumococcal vaccine coverage by age and time since vaccine administration (and in the future) and the number of doses received is limited
- Additional risk factors (e.g., comorbidities) are not available for identified cases of IPD and VT IPD, which limits extensions of findings to high-risk groups due to underlying health conditions
- Missing data was present within both the CNDSS and NML datasets.
- Enhanced surveillance that includes high risk individuals and can provide incidence of IPD stratified by risk factors and serotypes for individuals in the greater than 65-year age group.
- Epidemiological studies of non-invasive disease such as CAP or acute otitis media in children caused by *S. pneumoniae*.
XI. Characteristics of included studies
V114-002
Multicenter: 25 sites from across Canada, Denmark, Israel, Norway, Poland, Spain, Sweden, United States. 
Study period: March 2012-February 2013
- PNEU-P-23
- PNEU-C-15 vs
- PNEU-C-13
 PNEU-P-23 (N=231), or PNEU-C-13 (N=230)
Gender (total study): 53% female
Ethnicity (total study): 93% non-Hispanic or non-Latino
 Race (total study): 93% White
 Age (total study):- 50 to 64 years: 34.6%
- 65 to 74 years: 32.6%
- 75 years: 32.9%
 V114-016 
 Multicenter: 22 sites from across United States, the Republic of Korea, Spain, Taiwan. 
Study period: June 2018-December 2016
- PNEU-P-23 vs
- PNEU-C-13 +
- PNEU-P-23
 Gender (total study): 56.8% female
Ethnicity (total study): 87.4% non-Hispanic or non-Latino
 Race (total study): 61.6% White
Median age: 65.0 years
 Age (total study):- 50 to 64 years: 49.9%
- 65 to 74 years: 37.9%
- 75 years: 12.1%
 V114-019 
 Multicenter: 30 sites from across Canada, United States, Japan, Spain, Taiwan. 
Study period: June 2019-March 2020
- PNEU-C-13
 Gender (total study): 57.3% female
Ethnicity (total study): 78.0% non-Hispanic or non-Latino
 Race (total study): 67.7% White
Median age: 66.0 years
 Age (total study):- 50 to 64 years: 30.9%
- 65 to 74 years: 57.6%
- 75 years: 11.5%
 V114-007
 Multicenter: 17 sites in United States
Study period: November 2015-January 2016
- PNEU-C-13
 Total randomized = 253
Gender (whole study): 59.7% female
 Median Age (whole study): 72.0 years
Age distribution: 65-74 years, 70%; 75 years, 30%
 Race (whole study): 94.1% White
Ethnicity (whole study): 84.6% non-Hispanic or non-Latino
Time since PNEU-P-23 vaccination: 1-3 years, 32.4%; >3 years, 67.6%
Authors state groups were similar for gender, age, ethnicity/race, pre-existing conditions, prior therapy, and time interval since 
 V114-017
 Multicentred: 79 sites from 7 countries (United States, Canada, Chile, Poland, Russia, Australia, New Zealand).
Study period: July 2018 to July 2020
- PNEU-P-23 vs
- PNEU-C-13 +
- PNEU-P-23
- PNEU-P-23 (n=1135) or PNEU-C-13+
- PNEU-P-23 (n=380).
Total randomized: 1515. 
 Gender (total study): 52% female
Ethnicity (total study): 87% non-Hispanic or non-Latino
Race (total study): 51% White, 39% Indigenous (US. 39% of participants were from US Center for American Indian Health (CAIH) sites.
Mean age: 36.0 years
 By risk factor (total study):
 No risk factors: 25%
 1 risk factor: 75%
Risk factors included: chronic lung disease including asthma, tobacco use, diabetes mellitus, chronic liver disease, chronic heart disease, and alcohol consumption.
 All subjects with no risk factor and subjects with single risk factor of alcohol consumption were enrolled at CAIH sites.
 V114-018
 Multicenter: 13 sites from across France, Peru, South Africa, Thailand, United States.
Study period: July 2018-January 2020
- PNEU-C-13
- PNEU-C-15+
- PNEU-P-23 vs
- PNEU-C-13+
- PNEU-P-23
 Vaccine series at 8-week interval
- PNEU-P-23 (n=152) or PNEU-C-13+
- PNEU-P-23 (n=150)
 Gender (total study): 21% female
Ethnicity (total study): 68% non-Hispanic or non-Latino
Race (total study): 31% Black, 30% White, 21% more than one race, 18% Asian
Median age: 41y. Of the total study, 72% were 18-49y. Few participants (3.6%) were 65y. 
 By CD4+ T-cell count (cells/L):- 50 to <200: 1.3%
- 200 to <500: 50.3%
V114-021
Multicenter: 45 sites in United States
Study period: September 24, 2018-June 24, 2019
Vs
Total randomized = 1200
Prior vaccination of PNEU-P-23 eligible if received >12 months before first study visit but designed to have at least 50% of participants vaccine-naive. 
Gender (total study): 56.1% female
 Ethnicity (total study): 78.8% non-Hispanic or non-Latino
 Race (total study): 82.5% White
 Median age: 65.0 years
Age (total study):- 50 to 64 years: 49.9%
- 65 to 74 years: 39.4%
- 75 years: 10.7%
Prior vaccination with PNEU-P-23: 20.9%
 Multicenter: 14 sites from across United States
 Study period: NR
 placebo vs
- PNEU-C-13 +
- PNEU-P-23
 (PNEU-C-13 arm) one month after first vaccination
 Gender (total study): 56.0% female
 Ethnicity (total study): 87.4% non-Hispanic or non-Latino
 Race: 75.4% White
 Median age: 62.0 years
 Multicenter: Sites from across United States and Sweden
 Study period: December 2018-December 2019
 PNEU-C-13 followed by 
 PNEU-P-23 (1 month interval).
Participants 60 years of age were randomized to single dose of PNEU-C-20 (N=1514) or PNEU-C-13 (N=1495) followed by single dose saline (PNEU-C-20 arm) or PNEU-P-23 (PNEU-C-13 arm) one month after first vaccination.
Participants 50-59 years randomized to single dose PNEU-C-20 (N=334) or PNEU-C-13 (N=111).
Participants 18-49 years randomized to single dose PNEU-C-20 (N=336) or PNEU-C-13 (N=112).
 Total randomized:- 60 years = 3009,
- 50-59 years = 445,
- 18-49 years = 448
 Gender, % female (by age cohort):- 60 years: 59.3%
- 50-59 years: 59.3%
- 18-49 years: 65.1%
Ethnicity, % non-Hispanic or non-Latino (by age cohort):- 60 years: 87.8%
- 50-59 years: 94.4%
- 18-49 years: 89.9%
Race, % White (by age cohort):- 60 years: 84.5%
- 50-59 years: 82.7%
- 18-49 years: 83.9%
Age (60 year cohort):- 60 to 64 years: 66.2%
- 65 to 69 years: 20.8%
- 70 to 79 years: 11.5%
- 80 years: 2.3%
Multicenter: 33 sites in United States and 8 sites in Sweden.
Study period: February 2019-February 2020
 current PNEU-C-20 vs Prior PNEU-P-23 + 
 current PNEU-C-13
2. Prior PNEU-C-13 vaccination + 
 PNEU-C-20 vs Prior PNEU-C-13 + 
 current PNEU-P-23
PNEU-P-23+
 PNEU-C-20 (N=253) vs PNEU-P-23+
 PNEU-C-13 (N=122) 
PNEU-C-13+
 PNEU-C-20 (N=248) vs PNEU-C-13+
 PNEU-P-23 (N=127)
A third cohort with prior vaccination to both PNEU-P-23 and PNEU-C-13 was not in this review as it was not a randomized comparison.
 Demographics (across relevant group subset):- Gender: range 52.5-56.5% female
- Ethnicity: range 94.0-97.6% non-Hispanic or non-Latino
- Race: range 90.2-93.3% White
- Mean age: range 69.6-70.7 years