Capvaxive Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections (as indicated in section 2.1. of the PM Guidance) or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 4.

   Dosage and Administration ............................................................................................. 4

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 4

   4.4. Administration .......................................................................................................... 5

   4.5. Missed Dose ............................................................................................................. 5

4. 5. Overdose ......................................................................................................................... 5
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 5
6. 7.

   Warnings and Precautions ............................................................................................... 6

   General ................................................................................................................................. 6

   Driving and Operating Machinery ......................................................................................... 6

   Hematologic ......................................................................................................................... 6

   Immune ................................................................................................................................ 6

   7.1. Special Populations .................................................................................................. 7

   7.1.1. Pregnancy ........................................................................................................ 7

   7.1.2. Breastfeeding .................................................................................................. 7

   7.1.3. Pediatrics ......................................................................................................... 7

   7.1.4. Geriatrics ......................................................................................................... 7

7. 8.

   Adverse Reactions ........................................................................................................... 7

   8.1. Adverse Reaction Overview ...................................................................................... 7

   8.2. Clinical Trial Adverse Reactions ................................................................................ 8

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................. 15

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 17

   8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics ........................... 17

   8.5. Post-Market Adverse Reactions ............................................................................. 17

8. 9.

   Drug Interactions ........................................................................................................... 17

   9.4. Drug-Drug Interactions ........................................................................................... 17

9. 10.

   Clinical Pharmacology ................................................................................................... 17

   10.1. Mechanism of Action .............................................................................................. 18

10. 11. Storage, Stability, and Disposal ...................................................................................... 18
11. 12. Special Handling Instructions ......................................................................................... 18

Part 2: Scientific Information ................................................................................................ 19

1. 13. Pharmaceutical Information .......................................................................................... 19
2. 14.

   Clinical Trials .................................................................................................................. 20

   14.1. Clinical Trials by Indication ..................................................................................... 20

   Adults 18 years of Age and Older .................................................................................. 20

   Children and Adolescents 2 to Less Than 18 Years of Age at Increased Risk for Pneumococcal Disease due to Certain Medical Conditions ........................................... 29

3. 15. Microbiology ................................................................................................................. 31
4. 16. Non-Clinical Toxicology .................................................................................................. 32

Patient Medication Information ........................................................................................... 33

Part 1: Healthcare Professional Information

1. Indications

CAPVAXIVE® (Pneumococcal 21-valent Conjugate Vaccine) is indicated for active immunization for the prevention of invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes (3, 6A, 6C, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B) in:

• adults 18 years of age and older
• children and adolescents 2 to less than 18 years of age who are at increased risk for pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen.

1.1. Pediatrics

Children less than 2 years old: The safety and effectiveness of CAPVAXIVE® in individuals younger than 2 years of age have not yet been established.

Children and adolescents 2 to less than 18 years old: Based on the data submitted and reviewed by Health Canada, the safety profile and immune responses of CAPVAXIVE® in children and adolescents who are at increased risk for pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen have been established. Therefore, Health Canada has authorized an indication for pediatric use in individuals 2 to less than 18 years of age who are at increased risk for pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen. (see 1. Indications, 8.2.1 Clinical Trial Adverse Reactions – Pediatrics, 14 Clinical Trials).

1.2. Geriatrics

CAPVAXIVE® has been studied in individuals 65 years of age and older (see 7.1.4 Geriatrics, 14 Clinical Trials).

2. Contraindications

CAPVAXIVE® is contraindicated in individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine including diphtheria toxoid (see 6 Dosage Forms, Strengths, Composition and Packaging).

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

Administer a single 0.5 mL dose of CAPVAXIVE® intramuscularly.

Prior vaccination with another Pneumococcal Vaccine

A single dose of CAPVAXIVE® can be given to adults who have been vaccinated with other pneumococcal vaccines at least 1 year prior.

A single dose of CAPVAXIVE® can be given to children and adolescents 2 to less than 18 years of age who are at increased risk for pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen.

4.4. Administration

For intramuscular injection only. Do not inject intravascularly.

Instructions for use:

CAPVAXIVE® should not be diluted or mixed with other vaccines. The full recommended dose of the vaccine should be used.

When CAPVAXIVE® is administered at the same time as another injectable vaccine(s), the vaccines should always be given at different injection sites (see 9.4 Drug-Drug Interactions).

The vaccine is a colorless, clear to opalescent solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. This product should not be used if particulate matter or discoloration is found.

The prefilled syringe is for single use only and should not be used for more than one individual. Attach a needle by twisting in a clockwise direction until the needle fits securely on the syringe. Inject the entire contents of the syringe.

4.5. Missed Dose

Not Applicable. This vaccine is administered as a single dose.

5. Overdose

There have been no reports of administration of higher than the recommended dose of CAPVAXIVE®.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

CAPVAXIVE® is a solution for injection available in 0.5 mL single dose prefilled syringes.

The vaccine is a colorless, clear to opalescent solution.

Available in 1 or 10 prefilled syringes packages.

The tip cap and plunger stopper are latex free.

Table 1: Dosage Forms, Strengths, and Composition

7. Warnings and Precautions

General

As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

As with other vaccines, the administration of CAPVAXIVE® should be postponed in individuals suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

CAPVAXIVE® will only protect against Streptococcus pneumoniae serotypes included in the indication, and will not protect against other microorganisms that cause invasive disease or pneumonia.

As with any vaccine, CAPVAXIVE® may not protect all individuals receiving the vaccine from invasive pneumococcal disease.

Driving and Operating Machinery

CAPVAXIVE® has no or negligible influence on the ability to drive and use machines.

Hematologic

As with all injectable vaccines, the vaccine must be administered with caution to individuals with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration.

Immune

Based on experience with pneumococcal vaccines, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced immune response to CAPVAXIVE®.

7.1. Special Populations

7.1.1. Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see 16 Non-Clinical Toxicology).

Safety during pregnancy has not been established in humans.

7.1.2. Breastfeeding

Safety during lactation has not been established in humans. It is not known whether this vaccine is excreted in human milk.

7.1.3. Pediatrics

The safety and effectiveness of CAPVAXIVE® in children younger than 2 years of age have not been established. Overall, there were no clinically meaningful differences in the safety profile or immune responses observed in children and adolescents 2 to less than 18 years of age who are at increased risk for pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen, when compared to adults 18 years of age and older (see 8 Adverse Reactions and 14 Clinical Trials).

7.1.4. Geriatrics

Across the Phase 3 clinical studies, approximately 34% of individuals were 65 years of age and older. Of the 4,556 individuals who received CAPVAXIVE®, 1,487 (32.6%) were 65 years and older, and 339 (7.4%) were 75 years and older. Overall, there were no clinically meaningful differences in the safety profile or immune responses observed in individuals 65 to 74 years and 75 years of age and older when compared to individuals less than 65 years of age (see 8.2 Clinical Trial Adverse Reactions and 14 Clinical Trials).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of CAPVAXIVE® in adults was assessed in four clinical studies in approximately 6,500 adults ≥ 18 years of age (V116-003, V116-004, V116-005 and V116-006). Across all 4 studies, approximately 4,500 adults received CAPVAXIVE®, approximately 2,000 adults received an active comparator

The most commonly reported (˃10%) solicited adverse reactions in individuals 18 to 49 years of age following vaccination with CAPVAXIVE® were: injection site pain (73.1%), fatigue (36.0%), headache (27.5%), myalgia (16.4%), injection site erythema (13.8%), and injection site swelling (13.3%).

The most commonly reported (˃10%) solicited adverse reactions in individuals 50 years of age and older who received CAPVAXIVE® were: injection site pain (41.2%), fatigue (19.7%), and headache (11.0%).

Across the Phase 3 studies in individuals 18 years of age and older, the majority of local and systemic solicited adverse reactions were mild (based on intensity or size) and of short duration (≤3 days); severe events (defined as an event that prevents normal daily activity or size ˃10 cm) occurred in ≤1.0% of adults (see 8.2 Clinical Trial Adverse Reactions and Table 2, Table 3 and Table 4).

The safety of CAPVAXIVE® was also assessed in populations at increased risk for invasive pneumococcal disease (IPD) (study V116-007 and study V116-008).

The safety of CAPVAXIVE® was assessed in individuals 2 to less than 18 years of age with one or more prespecified chronic medical conditions (diabetes mellitus, chronic heart disease, chronic kidney disease, chronic liver disease, chronic lung disease) known to increase the risk of pneumococcal disease and who have previously completed a primary pneumococcal vaccine regimen (Study V116-013). In Study V116-013, 527 individuals received CAPVAXIVE® and 347 individuals received active comparator vaccine.

The most commonly reported (>10%) solicited adverse reactions in individuals 2 to less than 18 years of who are at increased risk for pneumococcal disease were injection-site pain (67.7%), injection-site erythema (24.3%), fatigue (20.1%), injection-site swelling (18.8%), headache (17.1%), malaise (13.3%), and irritability (11.6%).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety of CAPVAXIVE® in adults was assessed in four clinical studies (V116-003, V116-004, V116-005, and V116-006) conducted across the Americas, Europe, and Asia Pacific, which included approximately 6,500 adults ranging in age from 18 to 97 years of age. Each study included adults with stable underlying medical conditions (see 14 Clinical Trials). Across all 4 studies, approximately 4,500 participants received CAPVAXIVE®, and approximately 2,000 adults received an active comparator.

The safety of CAPVAXIVE® in adults was assessed in two additional studies (V116-007 and V116-008) which enrolled populations at increased risk for invasive pneumococcal disease.

Study V116-007 was conducted across the Americas, Africa, Europe and Asia Pacific among adults ≥18 years of age living with well-managed HIV infection (see 14 Clinical Trials). In this study, 155 adults received CAPVAXIVE® (PCV21) and 157 adults received VAXNEUVANCE® (PCV15) then PNEUMOVAX® 23 (PPSV23) eight weeks later. Among all vaccinated participants, there were 74.7% with CD4+ T-cell count ≥500 cells/µL at screening, and 83.0% with undetectable HIV viral load (<20 copies/mL).

Study V116-008 was conducted across the Americas, Europe, and Asia Pacific among adults 18 to 64 years of age with one or more chronic medical conditions associated with higher risk of IPD (see 14 Clinical Trials). In this study, 386 adults received CAPVAXIVE® and 130 adults received VAXNEUVANCE® then PNEUMOVAX® 23 eight weeks later. Among all vaccinated participants, there were 37.6% with diabetes mellitus only, 19.2% with chronic lung disease only, 16.3% with chronic heart disease only, 6.6% with chronic liver disease only, 4.5% with chronic kidney disease only, and 15.9 % with ≥2 increased-risk conditions.

In all studies, safety was evaluated using an electronic Vaccination Report Card for 30 days postvaccination. Injection site adverse events, systemic adverse events, and body temperature were solicited Day 1 through Day 5 postvaccination. Unsolicited adverse events were reported Day 1 through Day 30 postvaccination. Serious adverse events (SAEs) were reported through 6 months postvaccination with CAPVAXIVE® in all studies.

Solicited Adverse Events

Pneumococcal Vaccine Naïve Adults 18 years of Age and Older

In study V116-003 [NCT05425732], individuals 18 years of age and older who had not previously received a pneumococcal vaccine were enrolled and randomized to receive a single dose of CAPVAXIVE® or Prevnar*20.

A comparable proportion of individuals within each age group (18 to 49 and 50 years of age and older) who received CAPVAXIVE® or Prevnar*20, reported solicited adverse events.

The percentage of individuals with solicited adverse reactions that occurred within 5 days following administration of CAPVAXIVE® or Prevnar*20 in studyV116-003 is shown in Table 2. Pneumococcal vaccine naïve adults 50 years of age and older reported fewer solicited adverse events than adults 18 to 49 years of age, regardless of vaccination group.

Table 2: Individuals with Solicited Local and Systemic Adverse Events Within 5 days Postvaccination in Pneumococcal Vaccine-Naïve Adults 18-49 Years of Age and ≥50 Years of Age – V116-003

In study V116-004 [NCT05464420], individuals 18 to 49 years of age who had not previously received a pneumococcal vaccine were enrolled and randomized to receive a single dose of CAPVAXIVE® or PNEUMOVAX® 23.

A comparable proportion of individuals 18 to 49 years of age who received CAPVAXIVE® or PNEUMOVAX® 23 reported solicited adverse events. The percentage of participants with solicited adverse reactions that occurred within 5 days following administration of CAPVAXIVE® or PNEUMOVAX® 23 in study V116-004 is shown in Table 3.

Table 3: Individuals with Solicited Local and Systemic Adverse Events Within 5 Days Postvaccination in Pneumococcal Vaccine-Naïve Adults 18-49 Years of Age – V116-004

Adults 50 Years of Age and Older Who Previously Received Pneumococcal Vaccines

Study V116-006 [NCT05420961] enrolled individuals 50 years of age and older who had previously received a pneumococcal vaccine at least 1 year prior to enrollment.

Adults who previously received PNEUMOVAX® 23 (double-blind; cohort 1) were randomized to receive a single dose of either CAPVAXIVE® or VAXNEUVANCE®.

Adults who previously received Prevnar*13 (double-blind; cohort 2) were randomized to receive a single dose of either CAPVAXIVE® or PNEUMOVAX® 23.

Adults who previously received other prior pneumococcal vaccines (Prevnar*13 + PNEUMOVAX® 23, VAXNEUVANCE® + PNEUMOVAX® 23, PNEUMOVAX® 23 + Prevnar*13, or VAXNEUVANCE®) were allocated to receive a single dose of CAPVAXIVE® (open-label; cohort 3).

Within Cohort 1 and Cohort 2, a comparable proportion of pneumococcal vaccine experienced individuals who received CAPVAXIVE® or active comparator reported solicited adverse events, regardless of prior pneumococcal vaccines received.

The percentage of participants with solicited adverse reactions that occurred within 5 days following administration of CAPVAXIVE® or a comparator in study V116-006 is shown in Table 4.

Across the 3 cohorts, comparable proportions of individuals who received CAPVAXIVE® reported solicited adverse events, regardless of prior pneumococcal vaccines received.

Table 4: Individuals with Solicited Local and Systemic Adverse Events Within 5 Days Postvaccination in Adults ≥50 Years of Age with Prior Pneumococcal Vaccination – V116-006

Safety with Concomitant Influenza Vaccine Administration in Adults

In study V116-005 [NCT05526716], the safety profile of CAPVAXIVE® when administered concomitantly with quadrivalent inactivated influenza vaccine (QIV) was generally consistent with the safety profile of CAPVAXIVE® in adults 50 years of age and older.

Unsolicited Adverse Events in Adults

Across the Phase 3 clinical studies, there were no notable patterns or imbalances between vaccine groups for unsolicited adverse events assessed to be related to study vaccine by the investigator that occurred within 1-month postvaccination.

Serious Adverse Events in Adults

Across the Phase 3 clinical studies, the proportion of individuals reporting 1 or more SAEs within 6 months postvaccination was comparable between individuals vaccinated with CAPVAXIVE® (1.4%), and individuals vaccinated with an active comparator (2.0%). There were no notable patterns or imbalances between vaccine groups for SAEs. There were 2 SAEs (0.05%; bronchospasm, cellulitis) assessed by the investigator to be related to CAPVAXIVE®.

Additional information in special populations

Adults ≥18 Years of Age Living with HIV infection

In study V116-007 [NCT05393037] among adults living with well-managed HIV infection, the safety profile of CAPVAXIVE® was generally comparable to the safety profile of VAXNEUVANCE® followed by PNEUMOVAX® 23 given eight weeks later. Following vaccination with CAPVAXIVE®, the most frequently reported (>10%) solicited adverse reactions were: injection-site pain (48.4%), fatigue (21.3%), and headache (16.8%). The percentage of individuals with solicited adverse reactions that occurred within 5 days following administration of CAPVAXIVE® followed by placebo or VAXNEUVANCE® followed by PNEUMOVAX® 23 in study V116-007 is shown in Table 5.

Table 5: Individuals with Solicited Local and Systemic Adverse Events Within 5 Days Postvaccination in Pneumococcal vaccine-naïve or pneumococcal vaccine-experienced adults ≥18 years of age living with HIV – V116-007

The proportion of individuals with SAEs were comparable between sequential regimens, and none were assessed by the investigator to be related to CAPVAXIVE® (including one death at Day 128 post-vaccination assessed as unrelated).

Adults 18 to 64 Years of Age with Chronic Medical Conditions

In study V116-008 [NCT05696080] among adults with one or more chronic medical conditions associated with increased risk of invasive pneumococcal disease, the safety profile of CAPVAXIVE® was generally comparable to VAXNEUVANCE® followed by PNEUMOVAX® 23 given eight weeks later. Following vaccination with CAPVAXIVE®, the most frequently reported (>10%) solicited adverse reactions were: injection-site pain (49.5%), fatigue (24.6%), and headache (15.8%). The percentage of individuals with solicited adverse reactions that occurred within 5 days following administration of CAPVAXIVE® followed by placebo or VAXNEUVANCE® followed by PNEUMOVAX® 23 in study V116-008 is shown in Table 6.

Table 6: Individuals With Solicited Local and Systemic Adverse Events Within 5 Days Postvaccination In Pneumococcal vaccine-naïve adults 18 to 64 years of age with increased risk of invasive pneumococcal disease – V116-008

The proportion of individuals with SAEs were comparable between sequential regimens, and none were assessed by the investigator to be related to CAPVAXIVE®.

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

Study V116-013 [NCT06177912] was conducted to evaluate CAPVAXIVE® in children and adolescents 2 to less than 18 years of age with one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease and who have previously completed a primary pneumococcal vaccine regimen. The safety profile of CAPVAXIVE® was generally comparable to PNEUMOVAX® 23 (Table 7). Following vaccination with CAPVAXIVE®, the most frequently reported (>10%) solicited adverse reactions were: injection-site pain (67.7%), injection-site erythema (24.3%), fatigue (20.1%), injection-site swelling (18.8%), headache (17.1%), malaise (13.3%), and irritability (11.6%). There were no notable patterns or imbalances between vaccine groups for unsolicited adverse events assessed to be related to CAPVAXIVE® vaccine by the investigator that occurred within 1-month postvaccination. The proportion of individuals with SAEs were comparable between vaccine groups, and one (0.2%; syncope) was assessed by the investigator to be related to CAPVAXIVE®.

Table 7: Individuals with Solicited Local and Systemic Adverse Events Within 5 Days Postvaccination in Children and Adolescents 2 to Less Than 18 Years of Age with Increased Risk of Pneumococcal Disease – V116-013

8.3. Less Common Clinical Trial Adverse Reactions

No other adverse reactions not listed in the other tables were reported in clinical trials with frequency of ≥1/100.

The list below includes the less common adverse reactions reported in clinical trials with CAPVAXIVE® (Uncommon frequency ≥1/1,000 to < 1/100).

Blood and lymphatic system disorders: Lymphadenopathy

Gastrointestinal disorders: Diarrhea, nausea

General disorders and administration site conditions: Injection-site pruritus, chills

Nervous system disorders: Dizziness

8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics

No other adverse reactions not listed in the other tables were reported in clinical trials with frequency of ≥1/100.

8.5. Post-Market Adverse Reactions

There are no post-marketing data available for CAPVAXIVE®.

9. Drug Interactions

9.4. Drug-Drug Interactions

Use with other vaccines

Adults 18 Years of Age and Older

CAPVAXIVE® can be administered concomitantly with inactivated influenza vaccine (see 8.2 Clinical Trial Adverse Reactions and 14 Clinical Trials). There are no data on the concomitant administration of CAPVAXIVE® with other vaccines.

Children and Adolescents 2 to Less Than 18 Years of Age

There are no data on the concomitant administration of CAPVAXIVE® with other vaccines.

10. Clinical Pharmacology

Therapeutic Class

CAPVAXIVE® is a conjugated polysaccharide vaccine that protects against invasive disease caused by S. pneumoniae.

10.1. Mechanism of Action

Immune responses following pneumococcal vaccination can be determined through the assessments of OPA responses to assess functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing. OPA responses are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. Specific threshold values that correlate with protection in adults have not been defined. There is a positive correlation between OPA responses and anti-capsular IgG responses.

Serotype specific immune responses (OPA and IgG) for the 21 serotypes contained in CAPVAXIVE® and 2 cross-reactive serotypes (15B and 6C) were measured using a validated multiplexed opsonophagocytic assay (MOPA) and pneumococcal electrochemiluminescence (Pn ECL) assay. Serotype 15C represents the immune response to the deOAc15B polysaccharide as the molecular structure for deOAc15B and 15C are similar.

As with any vaccine, CAPVAXIVE® may not protect all vaccine recipients.

1. 11. Storage, Stability, and Disposal

Store refrigerated at 2°C to 8°C.

Do not freeze. Protect from light.

CAPVAXIVE® should be administered as soon as possible after being removed from the refrigerator.

In the event of temporary temperature excursions, stability data indicate that CAPVAXIVE® is stable at temperatures up to 25°C for 96 hours.

12. Special Handling Instructions

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

CAPVAXIVE® (Pneumococcal 21-valent Conjugate Vaccine)

Physicochemical properties: The vaccine is a colorless, clear to opalescent solution.

Product Characteristics:

CAPVAXIVE® (Pneumococcal 21-valent Conjugate Vaccine) is a sterile solution of purified capsular polysaccharides from S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, deOAc15B (de-O-acetylated serotype 15B), 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B individually conjugated to CRM197 carrier protein. CRM197 is a nontoxic mutant of diphtheria toxin (originating from Corynebacterium diphtheriae C7) expressed recombinantly in Pseudomonas fluorescens.

Each of the 21 serotypes is manufactured independently using a common manufacturing platform with slight variations to accommodate for differences in strains, polysaccharides, and process stream properties. The process comprises fermentation and inactivation steps to produce the inactivated pneumococcal bacteria, followed by purification steps to produce the purified polysaccharide powder. The purified polysaccharides are size reduced to a target molecular mass, chemically activated via sodium metaperiodate oxidation, and buffer exchanged by ultrafiltration. Each serotype of activated polysaccharide is then individually conjugated to CRM197 carrier protein via reductive amination. The final vaccine is prepared by blending the 21 conjugates in a final buffer containing histidine, polysorbate 20, and sodium chloride.

14. Clinical Trials

14.1. Clinical Trials by Indication

Adults 18 years of Age and Older

Table 8: Summary of Patient Demographics for Clinical Trials for Pneumococcal Disease Immunogenicity and Safety

Immunogenicity

Clinical Trials Experience in Adults 18 Years of Age and Older

Four Phase 3, clinical studies (V116-003, V116-004, V116-005, and V116-006) conducted across the Americas, Europe, and Asia Pacific evaluated the immunogenicity of CAPVAXIVE® in approximately 6,500 adults 18 years of age and older, approximately 4,500 of whom received CAPVAXIVE®. Of these adults enrolled, approximately 1,000 had received other prior pneumococcal vaccines. Approximately 34% of enrolled adults had chronic medical conditions (e.g., diabetes, renal disorders, chronic heart disease, chronic liver disease, chronic lung disease including asthma, smoking, alcoholism) known to increase the risk of invasive pneumococcal disease.

In each study, immunogenicity was assessed by serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) responses at 1-month postvaccination.

Clinical Trials Conducted in Pneumococcal Vaccine-Naïve Adults

CAPVAXIVE® effectiveness in adults against invasive pneumococcal disease was demonstrated based on comparative immunogenicity to a licensed pneumococcal vaccine (Prevnar*20).

In a double-blind study (V116-003), 2,362 pneumococcal vaccine-naïve adults 50 years of age and older were randomized to receive one single dose of either CAPVAXIVE® or Prevnar*20. The study demonstrated that CAPVAXIVE® was noninferior to Prevnar*20 for the 10 common serotypes as assessed by the GMT ratio (CAPVAXIVE®/Prevnar*20) where the noninferiority statistical criteria were met if the lower bound of the 2-sided 95% Confidence Interval (CI) was greater than 0.5. CAPVAXIVE® was superior to Prevnar*20 for 10 of 11 serotypes unique to CAPVAXIVE® as assessed by the GMT ratio (CAPVAXIVE®/Prevnar*20) where the superiority statistical criterion was met if the lower bound of the 2-sided 95% CI was greater than 2.0 (Table 9). The lower bound of the 2-sided 95% CI for serotype 15C was 1.77.

CAPVAXIVE® was superior to Prevnar*20 for 10 of 11 unique serotypes in CAPVAXIVE® as assessed by the proportion of individuals who achieved a ≥4-fold rise from prevaccination to 1-month postvaccination for OPA responses. The statistical criterion was defined as the lower bound of the 2- sided 95% CI of the difference between CAPVAXIVE® and Prevnar*20 being greater than 10%. For serotype 15C, 83.4% of individuals achieved a ≥4-fold rise in OPA responses from prevaccination to 1-month postvaccination; the lower bound of the 2-sided 95% CI of the difference (CAPVAXIVE® – Prevnar*20) was 5.6% and did not meet the statistical criterion for superiority of ˃10%. The immune response to serotype 15C in the comparator group was likely attributed to cross-reactivity based on the presence of the 15B antigen.

Table 9: Serotype Specific OPA GMTs in Pneumococcal Vaccine Naïve Adults ≥50 Years of Age (V116-003)

Immunobridging in Pneumococcal Vaccine Naïve Adults 18 to 49 Years of Age

In a double-blind study (V116-003), pneumococcal vaccine-naïve individuals 18 to 49 years of age were randomized in a 2:1 ratio to receive CAPVAXIVE® or Prevnar*20.

CAPVAXIVE® successfully immunobridged serotype-specific immune responses to each of the 21 vaccine serotypes in individuals 18 to 49 years of age to individuals 50 to 64 years of age, as the lower bound of the 2-sided 95% CI for the GMT ratio for each serotype was ˃0.5 Table 10).

Table 10: Comparison of Serotype-Specific OPA GMTs in Pneumococcal Vaccine-NaÏve Adults 18-49 Years of Age to 50-64 Years of Age Who Received CAPVAXIVE® (V116-003)

Cross-reactive immune responses to CAPVAXIVE®

CAPVAXIVE® elicited an immune response to serotype 15B (cross reactive to serotype 15C) and serotype 6C (cross reactive to serotype 6A). In study 003, in individuals 50 years of age and older, CAPVAXIVE® met the predefined criterion (lower bound of the 2-sided 95% CI of the proportion of individuals with a ≥4-fold rise in OPA responses is ˃50%) for antibody response to serotype 15B, with lower bound of the 2-sided 95% CI being 61.4%; the antibody response did not meet the criterion for serotype 6C, with the lower bound of the 2-sided 95% CI being 46% vs. 50%. CAPVAXIVE® successfully immunobridged serotype-specific immune response for serotype 15B in individuals 18 to 49 years of age to individuals 50 to 64 years of age, as the lower bound of the 2-sided 95% CI for the GMT ratio was >0.5. For the immune response to serotype 6C in individuals 18 to 49 years of age, as compared to individuals 50 to 64 years of age, the GMT ratio observed was 2.05 (95% CI: 1.52, 2.77).

In a double-blind study (V116-004), 2,162 pneumococcal vaccine naïve adults 18 to 49 years of age were randomized in a 1:1:1:1 ratio to receive 1 of 3 lots of CAPVAXIVE® or PNEUMOVAX® 23. The study demonstrated that all 3 lots were equivalent as the lower and upper limits of the 2sided 95% CI of the serotype specific OPA GMT ratios between any 2 lots were within the equivalence margin (0.5 to 2.0) for all 21 serotypes. Immune responses following vaccination with CAPVAXIVE® were comparable to PNEUMOVAX® 23 for the 12 common serotypes and higher for 9 unique serotypes.

Clinical Trials Conducted in Adults with Prior Pneumococcal Vaccination

V116-006, a descriptive Phase 3 study, enrolled adults ≥50 years of age who were previously vaccinated with other pneumococcal vaccines at least 1 year prior to study entry.

Adults who previously received PNEUMOVAX® 23 (double-blind cohort) were randomized to receive a single dose of either CAPVAXIVE® or VAXNEUVANCE®. CAPVAXIVE® elicited comparable immune responses as compared with VAXNEUVANCE® for the 6 common serotypes, and higher immune responses for the 15 unique serotypes.

Adults who previously received Prevnar*13 (double-blind cohort) were randomized to receive either CAPVAXIVE® or PNEUMOVAX® 23. CAPVAXIVE® elicited comparable immune responses as compared with PNEUMOVAX® 23 for the 12 common serotypes, and higher immune responses for the 9 unique serotypes.

Adults who received other prior pneumococcal vaccines (Prevnar*13 + PNEUMOVAX® 23, VAXNEUVANCE® + PNEUMOVAX® 23, PNEUMOVAX® 23 + Prevnar*13, or VAXNEUVANCE®) were allocated to receive CAPVAXIVE® (open-label cohort). CAPVAXIVE® was demonstrated to be immunogenic for all serotypes included in the vaccine, based on OPA GMTs and the proportion of individuals with ≥4-fold rise in OPA responses from baseline to 1-month postvaccination. The immune responses to CAPVAXIVE® were consistent in adults who have been vaccinated with other pneumococcal vaccines at least 1 year prior.

Concomitant Vaccination

In a double-blind study (V116-005), 1,080 adults 50 years of age and older, with or without a history of prior pneumococcal vaccination, were randomized in a 1:1 ratio. One vaccination group received CAPVAXIVE® and QIV concomitantly, followed by placebo 30 days later (concomitant group). A second vaccination group received QIV and placebo concomitantly, followed by CAPVAXIVE® 30 days later (sequential group).

CAPVAXIVE® administered concomitantly with QIV was non-inferior to CAPVAXIVE® administered sequentially after QIV for 20 of 21 serotypes contained in the vaccine as the lower bound of the 2-sided 95% CI of the GMT ratio (concomitant group/sequential group) was ˃0.5; the lower bound for serotype

23B was 0.44. QIV administered concomitantly with CAPVAXIVE® was non-inferior to QIV administered with placebo as assessed by influenza strain specific- hemagglutination inhibition (HAI) GMTs at 1-month postvaccination for 3 of 4 influenza strains. The lower bound of the 2-sided 95% Cis for HAI GMT ratios (concomitant group/sequential group) was ˃0.67 (the non-inferiority margin) for 3 of 4 influenza strains in QIV; the lower bound was 0.67 for the A/H3N2 influenza strain.

Clinical immunogenicity in Special Populations

Adults ≥18 Years of Age Individuals Living with HIV

In a double-blind study, V116-007, 313 adults living with well-managed HIV infection, with CD4+ T-cells/µL ≥50 and plasma HIV ribonucleic acid (RNA) <50,000 copies/mL, with or without a history of prior pneumococcal vaccination (i.e., ~36% vs ~64%), were randomized in a 1:1 ratio to receive either a sequential regimen of CAPVAXIVE® (PCV21) followed by placebo eight weeks later (CAPVAXIVE® + placebo), or VAXNEUVANCE® (PCV15) followed by PNEUMOVAX® 23 (PPSV23) eight weeks later (VAXNEUVANCE® + PNEUMOVAX® 23).

At screening, among all participants vaccinated, 6.7% had a CD4+ T-cell counts ≥50 to <350 cells/µL, 18.6% had CD4+ T-cell counts ≥350 to <500 cells/µL, and 74.7% had CD4+ T-cell counts ≥500 cells/µL. A majority of study participants were treated with ≥3 drug antiretroviral therapy.

CAPVAXIVE® was immunogenic for all 21 serotypes contained in the vaccine, as assessed by serotype specific OPA GMTs at 1-month postvaccination with CAPVAXIVE®, which elicited immune responses that were generally comparable to VAXNEUVANCE® and PNEUMOVAX® 23 for the 13 common serotypes, and higher for the 8 serotypes unique to CAPVAXIVE® as assessed by OPA GMTs at 1-month postvaccination with CAPVAXIVE® and 1-month postvaccination following VAXNEUVANCE® and 1-month postvaccination following PNEUMOVAX® 23.

Adults 18 to 64 Years of Age with Chronic Medical Conditions

In a double-blind study, V116-008, 518 pneumococcal vaccine naïve adults with one or more prespecified chronic medical conditions known to increase the risk of invasive pneumococcal disease (e.g., diabetes mellitus, chronic lung disease, chronic heart disease) were randomized in a 3:1 ratio to receive either CAPVAXIVE® followed by placebo eight weeks later (CAPVAXIVE® + placebo), or VAXNEUVANCE® followed by PNEUMOVAX® 23 eight weeks later (VAXNEUVANCE® + PNEUMOVAX® 23).

Among all vaccinated participants, 194 (37.6%) had diabetes mellitus only, 84 (16.3%) had chronic heart disease only, 23 (4.5%) had chronic kidney disease only, 34 (6.6%) had chronic liver disease only, 99 (19.2%) had chronic lung disease only, and 82 (15.9%) had ≥2 increased risk conditions.

CAPVAXIVE® was immunogenic for all 21 serotypes contained in the vaccine, as assessed by serotype-specific OPA GMTs at 1-month postvaccination with CAPVAXIVE® which elicited immune responses that were generally comparable to VAXNEUVANCE® and/or PNEUMOVAX® 23 for the 13 common serotypes, and higher for the 8 serotypes unique to CAPVAXIVE® as assessed by OPA GMTs at 1-month postvaccination with CAPVAXIVE® and 1-month postvaccination following VAXNEUVANCE® and 1-month postvaccination following PNEUMOVAX® 23.

Children and Adolescents 2 to Less Than 18 Years of Age at Increased Risk for Pneumococcal Disease due to Certain Medical Conditions

Table 11: Summary of Pediatric Patient Demographics for Clinical Trials for Pneumococcal Disease Immunogenicity and Safety

Immunogenicity

Clinical Trials Experience in individuals 2 to less than 18 years of age at increased risk for Pneumococcal Disease and who have previously completed a primary pneumococcal vaccination regimen.

The purpose of Protocol 013 was to evaluate the safety, tolerability, and immunogenicity of V116 compared to PPSV23 in children and teenagers 2 through 17 years of age at increased risk for Pneumococcal Disease, who had completed routine pneumococcal vaccine as infants/toddlers.

In a double-blind study (V116-013), 882 individuals 2 to less than 18 years of age with one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease and who completed a primary pneumococcal vaccination regimen at least 8 weeks prior to enrollment were randomized in a 3:2 ratio to receive either CAPVAXIVE® or PNEUMOVAX® 23. Among the vaccinated participants (874), 135 (15.4%) had diabetes mellitus, 143 (16.4%) had chronic heart disease, 76 (8.7%) had chronic kidney disease, 60 (6.9%) had chronic liver disease, 499 (57.1%) had chronic lung disease, and 36 (4.1%) had ≥2 increased-risk conditions. Immunogenicity was assessed by OPA GMTs at 1-month postvaccination with either CAPVAXIVE® or PNEUMOVAX® 23.

The study demonstrated that CAPVAXIVE® was non-inferior to PNEUMOVAX® 23 for the 12 common serotypes as assessed by the GMT ratio (CAPVAXIVE®/PNEUMOVAX® 23) where the non-inferiority statistical criteria were met if the lower bounds of the 2-sided 95% CI were >0.5. CAPVAXIVE® was superior to PNEUMOVAX® 23 for the 9 serotypes unique to CAPVAXIVE® as assessed by the GMT ratio (CAPVAXIVE®/PNEUMOVAX® 23) where the superiority statistical criteria were met if the lower bounds of the 2-sided 95% CI were >2.0 (Table 12).

CAPVAXIVE® also elicited immune responses to serotype 15B (cross-reactive to serotype 15C). In a post hoc analysis utilizing the same prespecified non-inferiority criterion that was used for the common serotypes, CAPVAXIVE® was non-inferior to PNEUMOVAX® 23 for serotype 15B.

Table 12: Serotype-Specific OPA GMTs in Children and Adolescents 2 to Less Than 18 Years of Age with Increased Risk of Pneumococcal Disease and who have previously completed a primary pneumococcal vaccination regimen (V116-013) .

15. Microbiology

No microbiological information is required for this vaccine.

16. Non-Clinical Toxicology

General Toxicology: No hazards to humans were revealed in a repeat dose toxicity study in which rats were administered 42 mcg per dose (one-half the full human dose) via intramuscular injection for 2 doses 3 weeks apart. The study also included an evaluation of single dose toxicity and local tolerance.

CAPVAXIVE® has not been evaluated for the potential to cause carcinogenicity or genotoxicity.

Reproductive and Developmental Toxicology:

CAPVAXIVE® was administered to female rats at 42 mcg per dose (one-half the full human dose) via intramuscular injection. There were no effects on mating performance, fertility, or embryonic/fetal survival and no fetal malformations or adverse effects on pre weaning development were observed.