Public health level recommendations on the use of pneumococcal vaccines in adults, including the use of 15-valent and 20-valent conjugate vaccines

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Organization: Public Health Agency of Canada

Date published: 2023-02-24

Cat.: HP5-153/1-2023E-PDF

ISBN: 978-0-660-47229-4

Pub.: 220712

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)

Summary of information contained in this NACI Statement
I. Introduction
- I.1 Guidance objective
- I.2 Background on pneumococcal vaccines, immunization programs and recommendations in Canada
II. Methods
III. Epidemiology
IV. Vaccine
V. Vaccination of Specific Populations
- V.1. Immunization in Pregnancy and Breastfeeding
- V.2. Immunization of Immunocompromised persons
VI. Ethics, Equity, Feasibility and Acceptability Considerations
VII. Economics
VIII. Recommendations
- VIII.1 Recommendations for Public Health Program Level Decision-Making
IX. Research priorities
X. Surveillance issues
XI. Characteristics of included studies
List of Abbreviations
Acknowledgments
Appendix A: Tables
- Evidence synthesis tables
- Epidemiology tables
References

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 NACI’s 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 PHAC’s 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 (see Table 1).

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.

Table 1. Medical conditions and other biological and/or social risk factors resulting in high risk of IPD
Non-immunocompromising conditions	Immunocompromising conditions ^{Table 1 Footnote a}	Other risk factors
Chronic cerebrospinal fluid (CSF) leak 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 ^{Table 1 Footnote a} Chronic liver disease, including hepatic cirrhosis due to any cause ^{Table 1 Footnote a} Chronic lung disease, including asthma requiring medical care in the preceding 12 months	Sickle cell disease, congenital or acquired asplenia, or splenic dysfunction ^{Table 1 Footnote b} 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) ^{Table 1 Footnote c} Malignant neoplasms, including leukemia and lymphoma Nephrotic syndrome Solid organ or islet transplant (candidate or recipient)	Individuals who smoke who use illicit drugs with alcohol use disorder who are experiencing homelessness who live in communities or settings ^{Table 1 Footnote d} experiencing sustained high IPD rates.
Table 1 Footnote a Conditions considered to result in the highest risk of IPD Return to footnote a referrer Table 1 Footnote b 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 Return to footnote b referrer Table 1 Footnote c Hematopoietic Stem Cell Transplant (HSCT) recipients have specific pneumococcal vaccination recommendations Return to footnote c referrer Table 1 Footnote d Can include long-term care facilities Return to footnote d referrer

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) (Table 1)
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 Pneumococcal Vaccine Chapter of the Canadian Immunization Guide.

PNEU-C-13 in series with PNEU-P-23 was recommended by NACI in 2013 ^{Footnote 1} 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 Table 1 in the Pneumococcal Vaccine Chapter of the Canadian Immunization Guide.

PNEU-C-13 was also recommended by NACI in 2016 ^{Footnote 2} and 2018 ^{Footnote 3} 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:

Knowledge synthesis: retrieval and summary of individual studies, assessment of the risk of bias (RoB) of included studies (summarized in the Summary of evidence tables in Appendix A).
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.
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 NACI’s process and procedures 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 ^{Footnote 4} ^{Footnote 5} ^{Footnote 6}. An assessment using the Evidence to Decision (EtD) framework was prepared for each question, and proposed recommendations for vaccine use were developed ^{Footnote 7}. 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 Notifiable Diseases Online 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 ^{Footnote 8}. 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 ^{Footnote 9}, 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 ^{Footnote 10}. 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 ^{Footnote 11} ^{Footnote 12}.

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 (Table 1).

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 Appendix A, Table 6).

In the absence of disease endpoint and mortality data, immunogenicity (opsonophagocytic [OPA] geometric mean titer [GMT] 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 (Appendix A, Table 8) for each study was assessed using the Cochrane Risk of Bias Tool ^{Footnote 13}. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework (Appendix A, Table 5) 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 [p<0.10] 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 (Appendix A, Table 5), 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 [QALY], incremental cost per disability-adjusted life year [DALY], 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 (Figure 1). 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.

**Figure 1: Annual incidence rate of IPD by age group reported to Canadian Notifiable Disease Surveillance System, 2001-2019**

Year	Age group	Incidence rate (per 100,000 population)
2001	Under 5 years	29.5
5 to 17 years	2.2
18 to 49 years	2.7
50 to 64 years	5.9
65 years and older	13.2
2002	Under 5 years	39.1
5 to 17 years	2.2
18 to 49 years	3.2
50 to 64 years	7.5
65 years and older	19.2
2003	Under 5 years	41.8
5 to 17 years	2.4
18 to 49 years	4.4
50 to 64 years	10.0
65 years and older	22.9
2004	Under 5 years	34.0
5 to 17 years	2.2
18 to 49 years	4.6
50 to 64 years	11.9
65 years and older	25.5
2005	Under 5 years	22.7
5 to 17 years	2.9
18 to 49 years	4.9
50 to 64 years	11.4
65 years and older	23.9
2006	Under 5 years	15.7
5 to 17 years	2.6
18 to 49 years	6.4
50 to 64 years	10.5
65 years and older	24.0
2007	Under 5 years	19.8
5 to 17 years	2.5
18 to 49 years	6.9
50 to 64 years	13.3
65 years and older	25.1
2008	Under 5 years	20.2
5 to 17 years	2.4
18 to 49 years	5.5
50 to 64 years	12.8
65 years and older	26.2
2009	Under 5 years	20.9
5 to 17 years	2.9
18 to 49 years	5.3
50 to 64 years	12.5
65 years and older	26.7
2010	Under 5 years	17.9
5 to 17 years	2.5
18 to 49 years	4.9
50 to 64 years	13.1
65 years and older	27.3
2011	Under 5 years	17.0
5 to 17 years	3.2
18 to 49 years	4.8
50 to 64 years	12.9
65 years and older	25.5
2012	Under 5 years	14.4
5 to 17 years	3.1
18 to 49 years	4.9
50 to 64 years	13.4
65 years and older	26.8
2013	Under 5 years	12.5
5 to 17 years	2.3
18 to 49 years	4.3
50 to 64 years	12.1
65 years and older	25.4
2014	Under 5 years	12.7
5 to 17 years	2.3
18 to 49 years	4.1
50 to 64 years	12.0
65 years and older	25.1
2015	Under 5 years	10.9
5 to 17 years	2.4
18 to 49 years	4.2
50 to 64 years	12.4
65 years and older	24.2
2016	Under 5 years	12.4
5 to 17 years	2.3
18 to 49 years	4.5
50 to 64 years	12.6
65 years and older	23.3
2017	Under 5 years	12.3
5 to 17 years	2.2
18 to 49 years	4.4
50 to 64 years	12.8
65 years and older	24.7
2018	Under 5 years	12.3
5 to 17 years	2.2
18 to 49 years	5.2
50 to 64 years	15.6
65 years and older	26.6
2019	Under 5 years	11.9
5 to 17 years	2.1
18 to 49 years	5.2
50 to 64 years	13.6
65 years and older	23.8

IPD incidence is directly proportional to age in persons 50 years of age and older (Figure 2). 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.

**Figure 2. Annual incidence rate of IPD in Canadian adults 50 years of age and older, reported to Canadian Notifiable Disease Surveillance System, 2001-2019**

Year	Age group	Incidence rate (per 100,000 population)
2011	50 to 64 years	12.9
65 to 74 years	18.3
75 to 84 years	27.6
85 years and older	49.8
2012	50 to 64 years	13.4
65 to 74 years	19.9
75 to 84 years	28.8
85 years and older	50.8
2013	50 to 64 years	12.1
65 to 74 years	19.3
75 to 84 years	26.9
85 years and older	47.6
2014	50 to 64 years	12.0
65 to 74 years	19.5
75 to 84 years	26.6
85 years and older	45.7
2015	50 to 64 years	12.4
65 to 74 years	18.3
75 to 84 years	27.5
85 years and older	41.8
2016	50 to 64 years	12.6
65 to 74 years	19.5
75 to 84 years	23.4
85 years and older	39.5
2017	50 to 64 years	12.8
65 to 74 years	19.9
75 to 84 years	26.3
85 years and older	41.8
2018	50 to 64 years	15.6
65 to 74 years	21.8
75 to 84 years	27.2
85 years and older	45.8
2019	50 to 64 years	13.6
65 to 74 years	19.7
75 to 84 years	25.2
85 years and older	39.1

The Toronto Invasive Bacterial Diseases Network (TIBDN) ^{Footnote 14}, 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 (Figure 3) ^{Footnote 15}.

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 ^{Footnote 15}.

**Figure 3. Annual incidence rate of IPD in northern Canada, ICS 2001-2021, and rest of Canada, 2001-2019, CNDSS**

Year	Northern Canada Crude incidence (per 100,000 population)	Rest of Canada Crude incidence (per 100,000 population)
2001	37.95	5.58
2002	25.78	7.24
2003	21.02	8.66
2004	23.39	9.19
2005	16.12	8.94
2006	18.78	8.92
2007	31.07	9.94
2008	23.12	9.67
2009	30.23	9.83
2010	20.51	9.90
2011	22.74	9.69
2012	16.61	9.92
2013	18.32	9.14
2014	25.71	9.00
2015	17.30	9.04
2016	16.49	9.19
2017	14.46	9.59
2018	28.49	10.96
2019	21.72	10.08

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 (Figure 4). Serotypes 3 and 22F were identified as the most common causes of IPD overall and in older adults based on isolates submitted to NML (Figure 4).

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 (Figure 5). 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 Appendix A, Tables 21-23.

**Figure 4. Proportion of isolates of invasive *S. pneumoniae* for all ages and adults 65 years and older in Canada, by serotype, 2016 to 2020, combined total**

Serotype (n by age group)	All ages (n=15234)	≥65 years (n=5860)
*1 (5,1)‡**	0.0%	0.0%
*3 (1638,653)**	10.8%	11.1%
*4 (1120,194)**	7.4%	3.3%
*6A (51,31)**	0.3%	0.5%
*6B (46,32)**	0.3%	0.5%
*7F (509,83)**	3.3%	1.4%
*9V (157,44)**	1.0%	0.8%
*14 (75,32)**	0.5%	0.5%
*18C (45,13)**	0.3%	0.2%
*19A (767,275)**	5.0%	4.7%
*19F (333,125)**	2.2%	2.1%
*23F (12,2)**	0.1%	0.0%
22F (1346,624)**	8.8%	10.6%
33F (500,183)**	3.3%	3.1%
8^ (865,239)	5.7%	4.1%
10A^ (304,117)	2.0%	2.0%
11A^ (473,227)	3.1%	3.9%
12F^ (654,129)	4.3%	2.2%
15B/C^ (519,178)	3.4%	3.0%
2~ (5,1)	0.0%	0.0%
9N~ (933,361)	6.1%	6.2%
17F~ (156,73)	1.0%	1.2%
20~ (542,135)	3.6%	2.3%
6C (298,172)	2.0%	2.9%
7C (198,106)	1.3%	1.8%
15A (641,381)	4.2%	6.5%
16F (384,191)	2.5%	3.3%
23A (574,301)	3.8%	5.1%
23B (482,198)	3.2%	3.4%
31 (235,124)	1.5%	2.1%
34 (144,73)	0.9%	1.2%
35B (348,194)	2.3%	3.3%
35F (248,128)	1.6%	2.2%
38 (192,92)	1.3%	1.6%
Other (435,148)	2.9%	2.5%

Figure 5 shows the proportion of IPD isolates by year among all isolates tested and older adults. In 2020, the proportion of isolates with PNEU-C-20/non-PNEU-C-13 (i.e., serotypes 8, 10A, 11A, 12F, 15B/C, 22F and 33F) among all IPD cases accounted for 30.4% and among IPD cases in adults 65 years old or older, for 28.4%. The proportion of IPD isolated covered by each vaccine among younger adults 18 to 49 and 50 to 64 years of age is shown in Appendix A, Figure 6.

**Figure 5. Proportion of IPD isolates from 2016 to 2020 by vaccine, for all ages and adults 65 years of age and older**

Age Group	Year	PNEU-C-13 (%, N)	PNEU-C-15/ non-PNEU-C-13 (%, N)	PNEU-C-20/ non-PNEU-C-15 (%, N)	PNEU-P-23/ non-PNEU-C-20 (%, N)	NVT (%, N)	Total
All Ages	2016	32.9%	(938)	12.6%	(360)	18.4%	(526)	8.8%	(251)	27.3%	(780)	(2855)
2017	32.2%	(1054)	11.9%	(390)	17.7%	(578)	11.3%	(371)	26.8%	(877)	(3270)
2018	33.0%	(1099)	11.7%	(388)	19.1%	(634)	10.7%	(357)	25.5%	(850)	(3328)
2019	32.6%	(1198)	13.8%	(507)	17.3%	(637)	11.5%	(423)	24.7%	(908)	(3673)
2020	36.4%	(767)	9.5%	(201)	20.9%	(440)	11.1%	(234)	22.1%	(466)	(2108)
≥65 years	2016	29.1%	(307)	12.7%	(134)	16.8%	(177)	7.2%	(76)	34.2%	(360)	(1054)
2017	26.5%	(355)	12.7%	(171)	15.9%	(213)	10.4%	(139)	34.6%	(464)	(1342)
2018	28.8%	(367)	14.2%	(181)	15.1%	(192)	9.9%	(126)	32.0%	(408)	(1274)
2019	29.3%	(431)	15.4%	(226)	13.5%	(199)	10.1%	(149)	31.7%	(467)	(1472)
2020	27.4%	(197)	13.2%	(95)	15.2%	(109)	11.1%	(80)	33.0%	(237)	(718)

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 ^{Footnote 16}. 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 ^{Footnote 17} 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) ^{Footnote 18} program, an active surveillance program in Calgary, found that between 2000 to 2013, IPD incidence rate among adults with underlying comorbidities decreased by 37% [from 11.8 cases/100,000/year before the introduction of pneumococcal conjugate vaccines (2000-2001) to 7.4 cases/100,000/year in the post-PNEU-C-13 period (2010-2013)].

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 ^{Footnote 19}. The most recent survey conducted over the 2020-2021 influenza season showed that about 55% of adults 65 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 (Table 2).

PNEU-C-13 (Prevnar®13) ^{Footnote 20} 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®) ^{Footnote 21} 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) ^{Footnote 22} 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 (Pneumovax®23) ^{Footnote 23} 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.

Table 2: Comparison of vaccines authorized for use in adults in Canada
	PREVNAR® 13 (PNEU-C-13)	VAXNEUVANCE® (PNEU-C-15)	PREVNAR 20TM (PNEU-C-20)	PNEUMOVAX 23® (PNEU-P-23)
Manufacturer	Pfizer	Merck	Pfizer	Merck
Date of initial authorization in Canada	December 21, 2009	November 16, 2021	May 9, 2022	December 23, 1983
Type of vaccine	Conjugate vaccine	Conjugate vaccine	Conjugate vaccine	Polysaccharide vaccine
Composition	2.2 mcg of each saccharide for S. pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F, 4.4 mcg of saccharide for serotype 6B, 34 mcg of CRM197 carrier protein, 4.25 mg of sodium chloride, 100 mcg of polysorbate 80, 295 mcg of succinic acid and 125 mcg of aluminum as aluminum phosphate adjuvant and water for injection	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, 125 mcg of aluminum (as aluminum phosphate adjuvant), 1.55mg of L-histidine, 1 mg of polysorbate 20, 4.50 mg of sodium chloride and water for injection	Approximately 2.2 mcg of each of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F saccharides, 4.4 mcg of 6B saccharide, 51 mcg of CRM197 carrier protein, 100 mcg of polysorbate 80, 295 mcg of succinic acid, 4.4 mg of sodium chloride and 125 mcg of aluminum as aluminum phosphate adjuvant and water for injection	25 mcg of capsular polysaccharides from each of S. pneumoniae serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F, sodium chloride 0.9 % w/w, phenol 0.25% w/w and water for injection to volume
Schedule for immunocompetent adults	1-dose schedule	1-dose schedule	1-dose schedule	1-dose schedule
Route of administration	Intramuscular injection	Intramuscular injection	Intramuscular injection	Intramuscular or subcutaneous injection
Indications for adults	Indicated for active immunization of adults 18 years of age and older for prevention of pneumonia and invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F	Indicated for active immunization of adults 18 years of age of older for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F	Indicated for active immunization of adults 18 years of age and older for the prevention of pneumonia and invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F	Indicated for active immunization of adults 18 years of age and older for prevention of pneumococcal disease caused by pneumococcal types included in the vaccine (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F)
Contraindications	Known hypersensitivity to any component of the vaccine, including diphtheria toxoid	History of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or any diphtheria toxoid-containing vaccine	Known hypersensitivity to the active substance or to any component of the vaccine, including diphtheria toxoid	Known hypersensitivity (e.g., anaphylaxis) to any component of the vaccine
Precautions	Individuals with immunocompromising conditions (limited data; may have reduced immune response) Pregnancy (limited data) Breastfeeding (limited data)	Individuals with immunocompromising conditions (may have reduced immune response) Pregnancy (limited data) Breastfeeding (no data)	Individuals with immunocompromising conditions (no data) Pregnancy (limited data) Breastfeeding (limited data)	Pregnancy (no data) Breastfeeding (no data)
Storage Requirements	Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Store in original package	Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Do not freeze. Protect from light. Administer as soon as possible after being removed from the refrigerator	Single-dose prefilled syringe. Refrigerate at 2°C to 8°C. Store syringes horizontally in the refrigerator. Do not freeze. Administer as soon as possible after being removed from the refrigerator	Multi-dose vial. Refrigerate at 2°C to 8°C. Discard opened vial after 48 hours

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 ^{Footnote 24} ^{Footnote 25}. 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 ^{Footnote 24} 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 ^{Footnote 25} 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 ^{Footnote 26} ^{Footnote 27} and five Phase 3 trials ^{Footnote 28} ^{Footnote 29} ^{Footnote 30} ^{Footnote 31} ^{Footnote 32}. Three studies evaluated medically stable, vaccine-naïve 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 (Table 5). Immunogenicity assessments were at a low RoB (Appendix A, Table 8).

Summary of PNEU-C-15 immunogenicity evidence

In immunocompetent pneumococcal vaccine-naïve 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 (Appendix A Tables 9). 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 9 and 10).

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 comparisons among age groups and age subgroup data for seroresponse are reported in Appendix A, Tables 9 and 10. Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (Appendix A, Table 12), and adults with immunocompromising conditions (Appendix A, Table 14).

In pneumococcal vaccine-naïve 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 (Appendix A, Table 11). 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 (Appendix A, Table 15).

Non-inferiority for shared serotypes was not evaluated in the comparison with PNEU-C-13 for adults with previous PNEU-P-23 vaccination (Appendix A, Table 12), as well as people with chronic medical conditions (CMC) 18 to 64 years of age (Appendix A, Table 13) and with immunocompromising conditions (Appendix A, Table 14).

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 ^{Footnote 33} and two Phase 3 trials ^{Footnote 34} ^{Footnote 35}. Two trials evaluated vaccine-naïve 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 (Appendix A, Table 8).

Summary of PNEU-C-20 immunogenicity evidence

Non-inferiority criteria were met following the administration of PNEU-C-20 in vaccine-naïve populations over age 60. However, there was an observed lower proportion of seroresponders compared to PNEU-C-13 for shared serotypes (Appendix A, Table 16). 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 17 and 18). 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 ^{Footnote 29}, 6 months ^{Footnote 30} and 1 year ^{Footnote 31} 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 ^{Footnote 33}. 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 ^{Footnote 36}.

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 ^{Footnote 21}.

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 ^{Footnote 22}.

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 2°C to 8°C. 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 ^{Footnote 21}.

PNEU-C-20 should be refrigerated at 2°C to 8°C. 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 ^{Footnote 22}.

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 ^{Footnote 37}. However, lower pneumococcal OPA GMTs were reported when pneumococcal vaccines were co-administered with QIV compared with when pneumococcal vaccines were given alone ^{Footnote 32} ^{Footnote 37} ^{Footnote 38}. 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 ^{Footnote 39}.

IV.9 Vaccine Safety

Summary of PNEU-C-15 study characteristics

Safety of PNEU-C-15 was evaluated in two Phase 2 trials ^{Footnote 26} ^{Footnote 27} and five Phase 3 trials ^{Footnote 28} ^{Footnote 29} ^{Footnote 30} ^{Footnote 31} ^{Footnote 32}. 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-naïve 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 9, 10 and 13 to 15). 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 14 and 15).

There was little to no difference in SAEs for PNEU-C-15 administered concomitantly with QIV for vaccine-naïve adults (Appendix A, Table 11). 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 ^{Footnote 33} and two Phase 3 trials ^{Footnote 34} ^{Footnote 35}. Data were available for pneumococcal vaccine-naïve 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-naïve 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 (Appendix A, Table 16).

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 (Appendix A, Table 18). 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 (Appendix A, Table 17).

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 ^{Footnote 40}.

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 NACI’s 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 United Nations Declaration on the Rights of Indigenous Peoples.

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) ^{Footnote 41}. 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 Appendix A for a more detailed explanation of strength of NACI recommendations (Table 19) and the GRADE assessment of the body of evidence (Table 6).

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 3 and 4 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

NACI recommends that pneumococcal conjugate vaccine PNEU-C-20 should be offered to pneumococcal vaccine naïve 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).