2.1 Dosage

Each dose of VAXNEUVANCE is 0.5 mL.

2.2 Administration

Hold the prefilled syringe horizontally and shake vigorously immediately prior to use to obtain an opalescent suspension. Do not use the vaccine if it cannot be resuspended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed.

2.3 Vaccination Schedule

Children

Administer VAXNEUVANCE as a 4-dose series at 2, 4, 6 and 12 through 15 months of age (and at least 2 months after the third dose). The first dose may be given as early as 6 weeks of age.

The 4-dose series initiated with a lower valency pneumococcal conjugate vaccine can be completed with VAXNEUVANCE [see Clinical Studies (14.1)].

Adults

Administer VAXNEUVANCE as a single dose in adults 18 years of age and older.

2.4 Catch-Up Vaccination Schedule in Children and Adolescents

Children 7 months through 17 years of age who have never received a pneumococcal conjugate vaccine may receive VAXNEUVANCE according to the schedule in Table 1:

Children and Adolescents Previously Vaccinated with a Pneumococcal Conjugate Vaccine

Administer a single dose of VAXNEUVANCE to children and adolescents 2 years through 17 years of age who have received an incomplete series of another pneumococcal conjugate vaccine. At least 2 months should elapse between receipt of the last dose of another pneumococcal conjugate vaccine and administration of VAXNEUVANCE.

5.1 Management of Allergic Reactions

Appropriate medical treatment to manage allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration of VAXNEUVANCE.

5.2 Altered Immunocompetence

Some individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to VAXNEUVANCE. [See Use in Specific Populations (8.6).]

5.3 Apnea in Premature Infants

Apnea following intramuscular vaccination has been observed in some infants born prematurely. A decision about when to administer VAXNEUVANCE to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The most commonly reported solicited adverse reactions in children vaccinated with a 4-dose series at 2, 4, 6, and 12 through 15 months of age, provided as a range across the series, were: irritability (57.3% to 63.4%), somnolence (24.2% to 47.5%), injection-site pain (25.9% to 40.3%), fever ≥38.0°C (13.3% to 20.4%), decreased appetite (14.1% to 19.0%), injection-site induration (13.2% to 15.4%), injection-site erythema (13.7% to 21.4%) and injection-site swelling (11.3% to 13.4%).

The most commonly reported solicited adverse reactions in children and adolescents 2 through 17 years of age vaccinated with a single dose were: injection-site pain (54.8%), myalgia (23.7%), injection-site swelling (20.9%), injection-site erythema (19.2%), fatigue (15.8%), headache (11.9%) and injection-site induration (6.8%).

The most commonly reported solicited adverse reactions in adults 18 through 49 years of age were: injection-site pain (75.8%), fatigue (34.3%), myalgia (28.8%), headache (26.5%), injection-site swelling (21.7%), injection-site erythema (15.1%) and arthralgia (12.7%).

The most commonly reported solicited adverse reactions in adults 50 years of age and older were: injection-site pain (66.8%), myalgia (26.9%), fatigue (21.5%), headache (18.9%), injection-site swelling (15.4%), injection-site erythema (10.9%) and arthralgia (7.7%).

Clinical Trials Experience in Children 6 Weeks Through 17 Years of Age

Safety Assessment in Children Receiving a 4-Dose Series

The safety of VAXNEUVANCE in healthy infants (6 weeks through 11 months of age) and children (12 months through 15 months of age) was assessed in 4 randomized, double-blind clinical studies (Studies 8-11 (NCT03893448, NCT03620162, NCT03692871 and NCT02987972)) conducted in the Americas, Europe, and Asia Pacific. These studies included 3,349 participants who received at least one dose of a 4-dose series of VAXNEUVANCE, 1,814 participants who received at least one dose of a 4-dose series of Prevnar 13 [Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)], and 538 participants who received VAXNEUVANCE to complete a 4-dose series of pneumococcal conjugate vaccine initiated with Prevnar 13. In the United States (including Puerto Rico), 2,827 participants received at least one dose of either VAXNEUVANCE or Prevnar 13 and 2,409 participants completed a 4-dose series of either vaccine. Overall, the median age of the participants was 9.0 weeks (6-12 weeks) and 48.6% were female. The racial distribution was as follows: 57.1% were White, 26.4% were Asian, 9.5% were Multi-racial, 4.7% were Black or African American, and 18.8% were of Hispanic or Latino ethnicity. There were no meaningful differences in demographic characteristics across the vaccination groups.

In Studies 8 and 9, Pentacel (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate [Tetanus Toxoid Conjugate] Vaccine) (DTaP-IPV-Hib vaccine) for US participants or a non-US-licensed DTaP-IPV-Hib vaccine for non-US participants was administered concomitantly with VAXNEUVANCE at 2, 4 and 6 months of age. RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) and RECOMBIVAX HB (Hepatitis B Vaccine [Recombinant]) were also administered concomitantly at 2, 4, and 6 months of age. M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live), VAQTA (Hepatitis A Vaccine, Inactivated), VARIVAX (Varicella Virus Vaccine Live), and Hiberix (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]) were administered concomitantly with VAXNEUVANCE at 12 through 15 months of age. Study 9 also evaluated the use of VAXNEUVANCE to complete a pneumococcal conjugate vaccine series initiated with Prevnar 13.

Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination. Study investigators reviewed the VRC with the participant or participant’s legal guardian 15 days postvaccination to ensure consistency with protocol definitions. The analyses presented in Tables 2-3 below reflect the information based on the final assessment by the study investigators. Injection-site adverse events and systemic adverse events were solicited on Day 1 through Day 14 postvaccination. Body temperature was solicited on Day 1 through Day 7 postvaccination via rectal or axillary measurement. Unsolicited adverse events were monitored using the VRC through 14 days postvaccination. The duration of the safety follow-up period for serious adverse events following the last study vaccination was 1 month in Study 11 and 6 months in Studies 8-10.

Solicited Adverse Reactions in Children Receiving a 4-Dose Series

Study 8 was a multicenter, double-blind, active comparator-controlled study that assessed the safety of VAXNEUVANCE when administered as a 4-dose series in children (N=858 received VAXNEUVANCE and N=855 received Prevnar 13). The percentage of US participants with solicited adverse reactions that occurred within 14 days following administration of VAXNEUVANCE or Prevnar 13 are shown in Tables 2-3. Solicited adverse reactions following administration of VAXNEUVANCE lasted a median of 1 day with 90.6% of reactions lasting ≤3 days.

Across Studies 8-10 (excluding participants in Study 9 who received VAXNEUVANCE to complete a pneumococcal conjugate vaccine series initiated with Prevnar 13), the percentage of participants with fever that occurred within 7 days following administration of VAXNEUVANCE or Prevnar 13 is shown in Table 4.

Unsolicited Adverse Reactions in Children Receiving a 4-Dose Series

Across Studies 8-11 (excluding participants in Study 9 who received VAXNEUVANCE to complete a pneumococcal conjugate vaccine series initiated with Prevnar 13), injection-site urticaria within 14 days following each dose of VAXNEUVANCE occurred in up to 0.6% of children. Participants in these studies may have received either US-licensed or non-US licensed concomitant vaccines according to the local recommended schedule.

Serious Adverse Events in Children Receiving a 4-Dose Series

Among children who received VAXNEUVANCE (N=3,349) or Prevnar 13 (N=1,814) across Studies 8-11 (excluding participants in Study 9 who received VAXNEUVANCE to complete a pneumococcal conjugate vaccine series initiated with Prevnar 13), serious adverse events up to 6 months following vaccination with the 4-dose series were reported by 9.6% of VAXNEUVANCE recipients and by 8.9% of Prevnar 13 recipients. Participants in these studies may have received either US-licensed or non-US licensed concomitant vaccines according to the local recommended schedule.

Up to 30 days following completion of Doses 1 through 3, serious adverse events were reported by 4.8% of VAXNEUVANCE recipients and by 5.0% of Prevnar 13 recipients. An adverse reaction of febrile seizure was reported in a 9 week old female (Study 11) one day after receiving VAXNEUVANCE (Dose 1) and recommended infant vaccines. Up to 30 days following Dose 4, serious adverse events were reported by 1.0% of VAXNEUVANCE recipients and by 0.7% of Prevnar 13 recipients.

There were no notable patterns or numerical imbalances between vaccination groups for specific categories of serious adverse events that would suggest a causal relationship to VAXNEUVANCE.

Safety of VAXNEUVANCE When Used to Complete a 4-Dose Pneumococcal Conjugate Vaccine Series Initiated with Prevnar 13

The safety profile observed when VAXNEUVANCE was used to complete a 4-dose pneumococcal conjugate vaccine series initiated with Prevnar 13 was similar to the safety profile following a complete 4-dose regimen of either VAXNEUVANCE or Prevnar 13 [see Clinical Studies (14.1)].

Safety Assessment in Infants and Children Receiving Catch-Up Vaccination

The safety of VAXNEUVANCE in healthy infants and children 7 months through 17 years of age was assessed in a double-blind, multi-regional, clinical study (Study 12, NCT03885934). Participants were randomized to receive 1 to 3 doses of VAXNEUVANCE (N=303) or Prevnar 13 (N=303), depending on age at enrollment. All infants and children less than 2 years of age were pneumococcal vaccine-naïve. Among 352 children 2 through 17 years of age, 42.9% had a history of previous vaccination with a lower valency pneumococcal conjugate vaccine. Among participants 7 through 11 months of age, the median age was 8.0 months, 48.4% were female, 82.8% were Asian, 17.2% were White and none were of Hispanic or Latino ethnicity. Among participants 12 through 23 months of age, the median age was 18.0 months, 54.0% were female, 83.3% were Asian, 16.7% were White and 0.8% were of Hispanic or Latino ethnicity. Among participants 2 through 17 years of age, the median age was 4.0 years, 47.7% were female, 66.8% were White, 33.0% were Asian, and none were of Hispanic or Latino ethnicity. The safety assessment was consistent with that used in Studies 8-11, as described above with the exception that in children 3 years of age and older, oral or axillary temperature measurements were obtained. The duration of the safety follow-up period for serious adverse events following the last dose of vaccine within each age cohort was 6 months.

Solicited Adverse Reactions in Children Receiving Catch-Up Vaccination

Among participants 7 through 11 months of age who received 3 doses of VAXNEUVANCE (N=64) or Prevnar 13 (N=64), the percentage of participants reporting solicited local and systemic adverse reactions that occurred within 14 days following any dose (VAXNEUVANCE participants vs. Prevnar 13 participants) were: fever ≥38.0°C (21.9% vs. 14.1%), irritability (32.8% vs. 43.8%), injection-site erythema (28.1% vs. 34.4%), somnolence (21.9% vs. 15.6%), injection-site swelling (18.8% vs. 15.6%), injection-site pain (18.8% vs. 7.8%), injection-site induration (17.2% vs. 14.1%), decreased appetite (15.6% vs. 18.8%) and urticaria (1.6% vs. 4.7%).

Among participants 12 through 23 months of age who received 2 doses of VAXNEUVANCE (N=62) or Prevnar 13 (N=64), the percentage of participants reporting solicited local and systemic adverse reactions that occurred within 14 days following any dose (VAXNEUVANCE participants vs. Prevnar 13 participants) were: fever ≥38.0°C (11.3% vs. 9.4%), irritability (35.5% vs. 21.9%), injection-site pain (33.9% vs. 23.4%), somnolence (24.2% vs. 17.2%), decreased appetite (22.6% vs. 18.8%), injection-site erythema (21.0% vs. 21.9%), injection-site swelling (14.5% vs. 12.5%) and injection-site induration (8.1% vs. 9.4%).

In children 2 through 17 years of age, the percentage of participants with solicited adverse reactions that occurred within 14 days following administration of a single dose of VAXNEUVANCE or Prevnar 13 is shown in Table 5.

Clinical Trials Experience in Adults

Safety Assessment in Clinical Studies

The safety of VAXNEUVANCE was assessed in 7 randomized, double-blind clinical studies conducted in the Americas, Europe and Asia Pacific, in which 5,630 adults 18 years of age and older received VAXNEUVANCE and 1,808 adults received Prevnar 13. In Studies 1-3 (NCT03950622, NCT03950856, and NCT03480763), a total of 3,032 adults 50 years of age and older with no history of pneumococcal vaccination received VAXNEUVANCE and 1,154 participants received Prevnar 13. In Study 4 (NCT03547167), adults 18 through 49 years of age with no history of pneumococcal vaccination, including individuals with increased risk of developing pneumococcal disease, received VAXNEUVANCE (N=1,134) or Prevnar 13 (N=378), followed by PNEUMOVAX 23 six months later. In Study 5 (NCT02573181), adults 65 years of age and older previously vaccinated with PNEUMOVAX 23 (at least 1 year prior to study entry) received VAXNEUVANCE (N=127) or Prevnar 13 (N=126). In Study 6 (NCT03615482), adults 50 years of age and older received VAXNEUVANCE concomitantly with a seasonal inactivated quadrivalent influenza vaccine (Fluarix Quadrivalent; QIV) (Group 1, N=600) or nonconcomitantly 30 days after QIV (Group 2, N=585). In this study population, 20.9% of individuals had a history of prior vaccination with PNEUMOVAX 23. In Study 7 (NCT03480802), HIV-infected adults 18 years of age and older received VAXNEUVANCE (N=152) or Prevnar 13 (N=150), followed by PNEUMOVAX 23 two months later.

The clinical studies included adults with stable underlying medical conditions (e.g., diabetes mellitus, renal disorders, chronic heart disease, chronic liver disease, chronic lung disease including asthma) and/or behavioral risk factors (e.g., smoking, increased alcohol use) that are known to increase the risk of pneumococcal disease. Overall, the mean age of the participants was 58 years and 54.6% were female. The racial distribution was as follows: 72.3% were White, 9.9% were Asian, 8.1% were American Indian or Alaska Native, 7.4% were Black or African American, and 18.1% were of Hispanic or Latino ethnicity.

In all studies, safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination. Study investigators reviewed the VRC with the participants 15 days postvaccination to ensure consistency with protocol definitions. The analyses presented in Tables 1-3 below reflect the information based on the final assessment by the study investigators. Oral body temperature and injection-site adverse reactions were solicited on Day 1 through Day 5 postvaccination. Systemic adverse reactions were solicited on Day 1 through Day 14 postvaccination. Unsolicited adverse events were reported on Day 1 through Day 14 postvaccination.

The duration of the safety follow-up period for serious adverse events postvaccination with VAXNEUVANCE was 1 month in Study 5; 2 months in Study 7; 6 months in Studies 1, 2, 4 and 6; and 12 months in Study 3.

Solicited Adverse Reactions

The percentage of participants with solicited adverse reactions that occurred within 5 or 14 days following administration of VAXNEUVANCE or Prevnar 13 in 3 studies are shown in Tables 6-8. The majority of solicited adverse reactions lasted ≤3 days.

Unsolicited Adverse Reactions

Across all studies, injection-site pruritus was reported to occur in up to 2.8% of adults vaccinated with VAXNEUVANCE.

Serious Adverse Events

Across all studies, among participants 18 years of age and older who received VAXNEUVANCE (excluding those who received QIV concomitantly; N=5,030) or Prevnar 13 (N=1,808), serious adverse events within 30 days postvaccination were reported by 0.4% of VAXNEUVANCE recipients and by 0.7% of Prevnar 13 recipients. In a subset of these studies, among those who received VAXNEUVANCE (N=4,751) and Prevnar 13 (N=1,532), serious adverse events within 6 months postvaccination were reported by 2.5% of VAXNEUVANCE recipients and by 2.4% of Prevnar 13 recipients.

There were no notable patterns or numerical imbalances between vaccination groups for specific categories of serious adverse events that would suggest a causal relationship to VAXNEUVANCE.

Safety with Concomitant Influenza Vaccine Administration

The safety profile was similar when VAXNEUVANCE was administered with or without inactivated quadrivalent influenza vaccine.

8.1 Pregnancy

Risk Summary

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

There are no adequate and well-controlled studies of VAXNEUVANCE in pregnant women. Available data on VAXNEUVANCE administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

Developmental toxicity studies have been performed in female rats administered a human dose of VAXNEUVANCE on four occasions; twice prior to mating, once during gestation and once during lactation. These studies revealed no evidence of harm to the fetus due to VAXNEUVANCE [see Animal Data below].

Data

Animal Data

Developmental toxicity studies have been performed in female rats. In these studies, female rats received a human dose of VAXNEUVANCE by intramuscular injection on day 28 and day 7 prior to mating, and on gestation day 6 and on lactation day 7. No vaccine related fetal malformations or variations were observed. No adverse effect on pup weight up to post-natal day 21 was noted.

8.2 Lactation

Risk Summary

Human data are not available to assess the impact of VAXNEUVANCE on milk production, its presence in breast milk, or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VAXNEUVANCE and any potential adverse effects on the breastfed child from VAXNEUVANCE or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

The safety and effectiveness of VAXNEUVANCE have been established in individuals 6 weeks through 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. The safety and effectiveness of VAXNEUVANCE in individuals younger than 6 weeks of age have not been established.

8.5 Geriatric Use

Of the 4,389 individuals aged 50 years and older who received VAXNEUVANCE, 2,478 (56.5%) were 65 years and older, and 479 (10.9%) were 75 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Overall, there were no clinically meaningful differences in the safety profile or immune responses observed in older individuals (65 to 74 years and 75 years of age and older) when compared to younger individuals.

8.6 Individuals at Increased Risk for Pneumococcal Disease

Infants Born Prematurely

The safety and immunogenicity of VAXNEUVANCE were evaluated in preterm infants (<37 weeks gestation at birth) who were randomized to receive a complete 4-dose series of either VAXNEUVANCE (N=142) or Prevnar 13 (N=144) within Study 8, Study 9, and Study 10. Participants in these studies may have received either US-licensed or non-US licensed concomitant vaccines according to the local recommended schedule. In descriptive analyses, serotype-specific immunoglobulin G (IgG) and opsonophagocytic activity (OPA) responses at 30 days postdose 3, predose 4 and at 30 days postdose 4 were numerically similar between vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes. The safety profile of VAXNEUVANCE was similar to the safety profile of Prevnar 13. In addition, the immune responses and safety profile in preterm infants receiving a 4-dose series of VAXNEUVANCE were similar to those observed in term infants in these studies. The effectiveness of VAXNEUVANCE in infants born prematurely has not been established.

Children with Sickle Cell Disease

In a double-blind, descriptive study (Study 13, NCT03731182), the safety and immunogenicity of VAXNEUVANCE were evaluated in children 5 through 17 years of age with sickle cell disease. Participants were randomized 2:1 to receive a single dose of VAXNEUVANCE (N=70) or Prevnar 13 (N=34). Immune responses were assessed by serotype-specific IgG GMCs and OPA GMTs at 30 days postvaccination for all 15 serotypes contained in VAXNEUVANCE. For all vaccine serotypes included in VAXNEUVANCE, serotype-specific IgG GMCs and OPA GMTs were higher following vaccination compared to pre-vaccination. IgG GMCs and OPA GMTs were numerically similar between the two vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for serotypes 22F and 33F. The safety profile of VAXNEUVANCE was similar to the safety profile of Prevnar 13. The effectiveness of VAXNEUVANCE in children with sickle cell disease has not been established.

Individuals with HIV Infection

Children with HIV Infection

In a double-blind, descriptive study (Study 14, NCT03921424), the safety and immunogenicity of VAXNEUVANCE were evaluated in HIV-infected children 6 through 17 years of age, with CD4+ T-cell count ≥200 cells per microliter and plasma HIV RNA value <50,000 copies/mL. Participants were randomized to receive a single dose of VAXNEUVANCE (N=203) or Prevnar 13 (N=204), followed by PNEUMOVAX 23 two months later. For all vaccine serotypes included in VAXNEUVANCE, serotype-specific IgG GMCs and OPA GMTs were higher following vaccination compared to pre-vaccination. Serotype-specific IgG GMCs and OPA GMTs were numerically similar for the 13 shared serotypes and higher for the 2 unique serotypes (22F and 33F) at 30 days following vaccination with VAXNEUVANCE or Prevnar 13 and were numerically similar for all 15 serotypes contained in VAXNEUVANCE at 30 days following subsequent vaccination with PNEUMOVAX 23. The safety profile of VAXNEUVANCE was similar to the safety profile of Prevnar 13. The effectiveness of VAXNEUVANCE in HIV-infected children has not been established.

Adults with HIV Infection

In a double-blind, descriptive study (Study 7), the safety and immunogenicity of VAXNEUVANCE were evaluated in pneumococcal vaccine-naïve HIV-infected adults 18 years of age and older, with CD4+ T-cell count ≥50 cells per microliter and plasma HIV RNA value <50,000 copies/mL. Participants were randomized to receive VAXNEUVANCE (N=152) or Prevnar 13 (N=150), followed by PNEUMOVAX 23 two months later [see Adverse Reactions (6.1)]. Anti-pneumococcal opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) were higher after administration of VAXNEUVANCE, compared to pre-vaccination, for the 15 serotypes contained in VAXNEUVANCE. After sequential administration with PNEUMOVAX 23, OPA GMTs observed at 30 days after PNEUMOVAX 23 vaccination were numerically similar between the two vaccination groups for all 15 serotypes contained in VAXNEUVANCE. The safety profile of VAXNEUVANCE was similar to the safety profile of Prevnar 13. The effectiveness of VAXNEUVANCE in HIV-infected adults has not been established.

Individuals with Hematopoietic Stem Cell Transplant

In a double-blind, descriptive study (Study 15, NCT03565900), the safety and immunogenicity of VAXNEUVANCE compared to Prevnar 13 were evaluated in participants who had received an allogeneic hematopoietic stem cell transplant (allo-HSCT) 3 to 6 months prior to enrollment. All participants had a history of stable engraftment and none had severe graft-versus-host disease. In this study, participants were randomized to receive 3 doses of VAXNEUVANCE (N=139) or Prevnar 13 (N=138), administered one month apart. Among those participants 3 through 17 years of age, 8 participants received VAXNEUVANCE and 6 participants received Prevnar 13. The remaining participants were 18 through 74 years of age. Twelve months after allo-HSCT, participants without chronic graft-versus-host disease (cGVHD) received a single dose of PNEUMOVAX 23 (N=164) and those with cGVHD received a fourth consecutive dose of VAXNEUVANCE (N=29) or Prevnar 13 (N=37). IgG GMCs and OPA GMTs were higher after administration of 3 doses of VAXNEUVANCE, compared to pre-vaccination, for the 15 serotypes contained in VAXNEUVANCE. Serotype-specific IgG GMCs and OPA GMTs were numerically similar between the two vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the two unique serotypes (22F and 33F). Similarly, in participants who received VAXNEUVANCE or Prevnar 13 twelve months after allo-HSCT, IgG GMCs and OPA GMTs at 30 days following vaccination were numerically similar between the two vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the two unique serotypes (22F and 33F). In participants who received PNEUMOVAX 23 twelve months after allo-HSCT, IgG GMCs and OPA GMTs at 30 days following vaccination were numerically similar between those who had received either 3 doses of VAXNEUVANCE or Prevnar 13 for all 15 serotypes contained in VAXNEUVANCE. The safety profile of VAXNEUVANCE was similar to the safety profile of Prevnar 13. The effectiveness of VAXNEUVANCE in recipients of allo-HSCT has not been established.

12.1 Mechanism of Action

Protection against invasive disease is conferred mainly by antibodies (Immunoglobulin G [IgG] directed against capsular polysaccharides) and opsonophagocytic activity (OPA) against S. pneumoniae. VAXNEUVANCE induces IgG antibodies and OPA against the serotypes contained in the vaccine.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VAXNEUVANCE has not been evaluated for carcinogenic or mutagenic potential or for impairment of male fertility in animals. VAXNEUVANCE administered to female rats had no effect on fertility [see Use in Specific Populations (8.1)].

14.1 Clinical Trials in Children

Children Receiving a 4-Dose Series

In a double-blind, active comparator-controlled study (Study 8), participants were randomized to receive VAXNEUVANCE (N=860) or Prevnar 13 (N=860) in a 4-dose series; the first 3 doses were administered to infants at 2, 4, and 6 months of age and the fourth dose was administered to children 12 through 15 months of age. Pentacel (US participants) or a non-US-licensed DTaP-IPV-Hib vaccine (non-US participants), RECOMBIVAX HB, and RotaTeq were administered concomitantly with each of the 3 infant doses. VAQTA, M-M-R II, VARIVAX, and Hiberix were administered concomitantly with the fourth dose. [See Adverse Reactions (6.1) and Clinical Studies (14.3).]

Study 8 assessed serotype-specific IgG response rates, IgG geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) geometric mean titers (GMTs), for all 15 serotypes contained in VAXNEUVANCE. At 30 days postdose 3, VAXNEUVANCE was noninferior to Prevnar 13 for the 13 shared serotypes, as assessed by the proportion of participants meeting the serotype-specific IgG threshold value of ≥0.35 mcg/mL (response rate). VAXNEUVANCE was noninferior for the 2 unique vaccine serotypes, as assessed by the IgG response rates for serotypes 22F and 33F compared with the response rate for serotype 6B (the lowest response rate for any of the shared serotypes in Prevnar 13 among US participants, excluding serotype 3) at 30 days postdose 3 (Table 9).

At 30 days postdose 3, serotype-specific IgG GMCs in the VAXNEUVANCE group were noninferior to Prevnar 13 for 12 of the 13 shared serotypes, except for serotype 6A. The IgG response to serotype 6A missed the prespecified noninferiority criterion by a small margin (the lower bound of the 2-sided 95% CI for the GMC ratio [VAXNEUVANCE/Prevnar 13] being 0.48 versus >0.5). VAXNEUVANCE was noninferior to Prevnar 13 for the 2 unique serotypes, as assessed by serotype-specific IgG GMCs for serotypes 22F and 33F compared with the IgG GMCs for serotype 4 (the lowest IgG GMC for any of the shared serotypes in Prevnar 13 among US participants, excluding serotype 3) (Table 10).

At 30 days postdose 4, serotype-specific IgG GMCs for VAXNEUVANCE were noninferior to Prevnar 13 for all 13 shared serotypes (the lower bound of the 2-sided 95% CI for the GMC ratio [VAXNEUVANCE/Prevnar 13] being >0.5) and for the 2 unique serotypes 22F and 33F as assessed by the IgG GMCs for serotypes 22F and 33F compared with the IgG GMCs for serotype 4 (the lowest IgG GMC for any of the shared serotypes in Prevnar 13 among US participants, excluding serotype 3) (Table 11).

Additionally, IgG response rates and IgG GMCs at 30 days postdose 3 and IgG GMCs at 30 days postdose 4 were statistically significantly greater for VAXNEUVANCE compared to Prevnar 13 for serotype 3 and the 2 unique serotypes (22F, 33F).

Serotype-specific OPA GMTs and response rates at 30 days postdose 3 and OPA GMTs at 30 days postdose 4 were descriptively evaluated in a subset of participants in Study 8. Serotype-specific OPA GMTs and response rates were numerically similar across groups for the 13 shared serotypes and higher in the VAXNEUVANCE group for the 2 unique serotypes.

Children Receiving VAXNEUVANCE to Complete a 4-Dose Series Initiated with Prevnar 13

In a double-blind, active comparator-controlled, descriptive study (Study 9), participants were randomized in a 1:1:1:1:1 ratio to one of five vaccination groups. Two vaccination groups received a 4-dose series composed entirely of either VAXNEUVANCE (N=180) or Prevnar 13 (N=179). The remaining 3 study groups received either 1, 2, or 3 doses of Prevnar 13 followed by VAXNEUVANCE to complete the 4-dose series (N=180, 180, and 181, respectively). Participants also received other pediatric vaccines concomitantly [see Adverse Reactions (6.1) and Clinical Studies (14.3)]. Serotype-specific IgG GMCs for the 13 shared serotypes at 30 days postdose 4 were numerically similar for participants completing the vaccination series with VAXNEUVANCE compared to participants who received a complete series with Prevnar 13.

Children and Adolescents Receiving Catch-Up Vaccination

In a double-blind, active comparator-controlled, descriptive study (Study 12), participants were enrolled in three age cohorts (7 through 11 months of age, 12 through 23 months of age, and 2 through 17 years of age) and randomized to receive VAXNEUVANCE (N=303) or Prevnar 13 (N=303). Children in the two youngest age cohorts were pneumococcal vaccine-naïve at enrollment. Children in the oldest age cohort (2 through 17 years of age) were either pneumococcal vaccine-naïve, not fully vaccinated, or had completed a dosing regimen with a lower valency pneumococcal conjugate vaccine (excluding Prevnar 13). Participants who were pneumococcal vaccine-naïve at enrollment received 1 to 3 doses of VAXNEUVANCE or Prevnar 13, depending on age at enrollment and according to the schedule shown in Table 1. All participants 2 through 17 years of age received one dose of VAXNEUVANCE. Catch-up vaccination with VAXNEUVANCE elicited immune responses, as assessed by serotype-specific IgG GMCs at 30 days following the last dose of vaccine, in children 7 months through 17 years of age that were numerically similar to Prevnar 13 for the shared serotypes and higher than Prevnar 13 for the unique serotypes 22F and 33F. Within each age cohort, serotype-specific IgG GMCs at 30 days following the last dose of vaccine were numerically similar between the vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes.

14.2 Clinical Trials in Pneumococcal Vaccine-Naïve Adults

Study 1

Study 1 assessed serotype-specific opsonophagocytic activity (OPA) responses for each of the 15 serotypes contained in VAXNEUVANCE at 30 days postvaccination in a double-blind, active comparator-controlled study that enrolled pneumococcal vaccine-naïve participants 50 years of age and older. Participants were randomized to receive either VAXNEUVANCE (N=604) or Prevnar 13 (N=601) at sites in USA, Canada, Spain, Taiwan, and Japan. The mean age of participants was 66 years and 57.3% were female. The racial distribution was as follows: 67.7% were White, 25.1% were Asian, 6.1% were Black or African American and 22.0% were of Hispanic or Latino ethnicity.

Table 12 summarizes the OPA geometric mean antibody titers (GMTs) at 30 days postvaccination for the 15 serotypes contained in VAXNEUVANCE. The study demonstrated that VAXNEUVANCE is noninferior to Prevnar 13 for the 13 shared serotypes and induces statistically significantly greater OPA GMTs compared to Prevnar 13 for shared serotype 3 and for the 2 unique serotypes (22F, 33F).

Study 3

In a double-blind, active comparator-controlled, descriptive study (Study 3), pneumococcal vaccine-naïve adults 50 years of age and older were randomized to receive either VAXNEUVANCE (N=327) or Prevnar 13 (N=325), followed by PNEUMOVAX 23 one year later.

Following vaccination with PNEUMOVAX 23, OPA GMTs were numerically similar between the two vaccination groups for the 15 serotypes in VAXNEUVANCE.

Study 4

In a double-blind, descriptive study (Study 4), adults 18 through 49 years of age, including individuals with increased risk of developing pneumococcal disease, were randomized to receive VAXNEUVANCE (N=1,135) or Prevnar 13 (N=380), followed by PNEUMOVAX 23 six months later [see Adverse Reactions (6.1)]. Among those who received VAXNEUVANCE, 620 participants had one risk factor and 228 participants had two or more risk factors for pneumococcal disease.

Table 13 presents OPA GMTs in the overall study population for each of the 15 serotypes 30 days following vaccination with VAXNEUVANCE or Prevnar 13.

Following vaccination with PNEUMOVAX 23, the OPA GMTs for the 15 serotypes in VAXNEUVANCE were numerically similar among participants who had received VAXNEUVANCE or Prevnar 13 for the first vaccination.

14.3 Concomitant Vaccination

Children

In Study 8, the concomitant administration of Pentacel with each of the 3 infant doses of either VAXNEUVANCE (N=598) or Prevnar 13 (N=601) was evaluated 30 days following the third dose; concomitant administration of single doses of VAQTA, M-M-R II, VARIVAX and Hiberix with the fourth dose of either VAXNEUVANCE or Prevnar 13 was evaluated 30 days following vaccination. There was no evidence that VAXNEUVANCE, as compared to Prevnar 13, interfered with the immune responses to these concomitantly administered vaccines. The immune responses to the antigens in Pentacel following completion of the 4-dose series were not evaluated.

In Study 9, the concomitant administration of RECOMBIVAX HB with either VAXNEUVANCE (N=124) or Prevnar 13 (N=266) was evaluated 30 days following the third dose of pneumococcal conjugate vaccine. Most infants (97.2%) received a birth dose of hepatitis B vaccine, followed by two doses of RECOMBIVAX HB administered concomitantly with VAXNEUVANCE or Prevnar 13. There was no evidence that VAXNEUVANCE, as compared to Prevnar 13, interfered with the immune response to RECOMBIVAX HB.

Adults

In a double-blind, randomized study (Study 6), adults 50 years of age and older were randomized to receive VAXNEUVANCE concomitantly administered with a seasonal inactivated quadrivalent influenza vaccine (Fluarix Quadrivalent; QIV) (Group 1, N=600) or VAXNEUVANCE 30 days after receiving QIV (Group 2, N=600) [see Adverse Reactions (6.1)]. Pneumococcal vaccine serotype OPA GMTs were evaluated 30 days after VAXNEUVANCE and influenza vaccine strain hemagglutinin inhibition assay (HAI) GMTs were evaluated 30 days after QIV. The noninferiority criteria for the comparisons of GMTs [lower limit of the 2-sided 95% confidence interval (CI) of the GMT ratio (Group 1/Group 2) >0.5] were met for the 15 pneumococcal serotypes in VAXNEUVANCE and for the 4 influenza vaccine strains tested.

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Do not freeze. Protect from light.

The tip cap and plunger stopper of the prefilled syringe are not made with natural rubber latex.