VAXNEUVANCE: Package Insert and Label Information

VAXNEUVANCE- streptococcus pneumoniae type 1 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 3 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 4 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 5 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 6a capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 6b capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 7f capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 9v capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 14 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 18c capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 19a capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 19f capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 22f capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 23f capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 33f capsular polysaccharide diphtheria crm197 protein conjugate antigen and corynebacterium diphtheriae crm197 protein injection, suspension
Merck Sharp & Dohme LLC

1 INDICATIONS AND USAGE

​ VAXNEUVANCE™ is indicated for active immunization 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 in individuals 6 weeks of age and older.

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

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:

Table 1: Catch-Up Vaccination Schedule for Individuals Initiating Vaccination at 7 Months Through 17 Years of Age

​ Age at First Dose	​ Total Number of 0.5 mL Doses
* The first 2 doses are given at least 4 weeks apart; third dose given after the one-year birthday, separated from the second dose by at least 2 months. † Two doses at least 2 months apart.
7 through 11 months of age	3*
12 through 23 months of age	2†
2 years through 17 years of age	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.

3 DOSAGE FORMS AND STRENGTHS

VAXNEUVANCE is a suspension for intramuscular injection supplied in a 0.5 mL single-dose prefilled syringe.

4 CONTRAINDICATIONS

Do not administer VAXNEUVANCE to individuals with a severe allergic reaction (e.g., anaphylaxis) to any component of VAXNEUVANCE or to diphtheria toxoid. [See Description (11).]

5 WARNINGS AND PRECAUTIONS

​ 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 ADVERSE REACTIONS

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.

Table 2: Percentage of US Participants with Solicited Local Adverse Reactions in Infants at 2, 4, 6 and 12 through 15 Months of Age After Vaccination (Study 8)*

Dose	Dose 1		Dose 2		Dose 3		Dose 4
	VAXNEUVANCE (%)N=598	Prevnar 13 (%)N=600	VAXNEUVANCE (%)N=584	Prevnar 13 (%)N=570	VAXNEUVANCE (%)N=559	Prevnar 13 (%)N=540	VAXNEUVANCE (%)N=532	Prevnar 13 (%)N=507
N=Number of participants vaccinated, including those with missing solicited adverse event data. The percentage of participants with missing solicited adverse event data, provided as a range across the 4-dose series, was 0.8% to 3.9%.
* Study 8 (NCT03893448) was a randomized, double-blind, active comparator-controlled clinical study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination following each dose. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † Solicited on Day 1 through Day 14 postvaccination following each dose. ‡ Mild: awareness of symptoms, but easily tolerated; moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities.
Local Reactions †
Pain ‡
Any	40.3	39.5	32.0	28.8	30.8	26.9	25.9	25.0
Mild	24.1	23.2	18.7	14.7	17.9	16.7	16.9	16.4
Moderate	14.7	15.2	12.5	13.3	12.3	10.0	8.8	8.7
Severe	1.5	1.2	0.9	0.7	0.5	0.2	0.2	0.0
Induration
Any	14.0	12.7	13.2	16.1	15.4	16.3	13.7	14.6
≤2.5 cm	11.0	10.0	9.1	11.4	10.7	11.5	7.5	8.5
2.6-7.6 cm	2.8	5.4	4.1	4.7	4.7	4.8	6.2	6.1
>7.6 cm	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0
Erythema
Any	13.7	14.7	16.4	22.5	20.4	23.9	21.4	24.1
≤2.5 cm	11.0	10.8	12.7	16.7	15.4	17.4	14.7	16.8
2.6-7.6 cm	2.3	3.5	3.8	5.6	4.8	6.5	6.8	7.1
>7.6 cm	0.3	0.2	0.0	0.2	0.2	0.0	0.0	0.2
Swelling
Any	12.9	12.7	13.2	11.4	13.4	10.4	11.3	10.8
≤2.5 cm	9.5	7.2	8.2	6.5	8.6	5.7	5.8	7.3
2.6-7.6 cm	3.2	5.3	4.8	4.6	4.8	4.4	5.5	3.4
>7.6 cm	0.0	0.2	0.2	0.0	0.0	0.0	0.0	0.0

Table 3: Percentage of US Participants with Solicited Systemic Adverse Reactions in Infants at 2, 4, 6 and 12 through 15 Months of Age After Vaccination (Study 8)*

Dose	Dose 1		Dose 2		Dose 3		Dose 4
	VAXNEUVANCE (%)N=598	Prevnar 13 (%)N=600	VAXNEUVANCE (%)N=584	Prevnar 13 (%)N=570	VAXNEUVANCE (%)N=559	Prevnar 13 (%)N=540	VAXNEUVANCE (%)N=532	Prevnar 13 (%)N=507
Following Doses 1-3, rectal temperature measurements were provided for 76.7% to 77.6% of participants and axillary temperature measurements were provided for 22.4% to 23.3% of participants, provided as a range across the doses. Following Dose 4, rectal temperature measurements were provided for 70.6% of participants and axillary temperature measurements were provided for 29.4% of participants. N=Number of participants vaccinated, including those with missing solicited adverse event data. The percentage of participants with missing solicited adverse event data, provided as a range across the 4-dose series, was 0.8% to 3.9%.
* Study 8 (NCT03893448) was a randomized, double-blind, active comparator-controlled clinical study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination following each dose. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † Solicited on Day 1 through Day 14 postvaccination following each dose. ‡ Mild: awareness of symptoms, but easily tolerated; moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities. § Solicited on Day 1 through Day 7 postvaccination following each dose. ¶ Percentages reflect the number of participants with temperature data.
Systemic Reactions †
Irritability ‡
Any	63.4	67.3	57.4	58.1	59.0	55.4	57.3	56.6
Mild	27.3	29.3	23.6	21.9	30.2	28.9	28.0	26.6
Moderate	31.4	33.0	30.0	33.2	25.0	24.4	26.7	27.4
Severe	4.7	5.0	3.6	3.0	3.8	2.0	2.6	2.6
Somnolence ‡
Any	47.5	52.7	35.6	39.3	31.1	30.2	24.2	29.6
Mild	24.2	29.5	20.2	18.8	19.1	16.3	13.9	17.0
Moderate	21.6	21.8	14.6	19.6	11.4	12.8	10.0	11.8
Severe	1.7	1.3	0.9	0.9	0.5	1.1	0.4	0.8
Decreased appetite ‡
Any	18.2	19.0	19.0	16.0	14.1	17.8	17.5	16.4
Mild	11.0	11.2	12.0	8.2	7.5	11.1	9.2	10.7
Moderate	6.7	7.2	7.0	7.4	6.3	6.5	7.9	5.5
Severe	0.5	0.7	0.0	0.4	0.4	0.2	0.4	0.2
Urticaria ‡
Any	1.2	0.8	1.5	1.4	1.1	1.9	3.4	2.6
Mild	0.8	0.5	1.4	0.7	1.1	1.5	1.7	1.2
Moderate	0.2	0.2	0.2	0.7	0.0	0.2	1.5	1.2
Severe	0.2	0.2	0.0	0.0	0.0	0.2	0.2	0.2
Fever §¶
≥38.0°C	18.4	16.4	20.4	21.7	20.0	20.0	13.3	14.0
≥38.0°C to <39.0°C	17.3	15.7	18.5	18.1	17.2	17.2	12.1	13.2
≥39.0°C to <40.0°C	1.0	0.7	1.6	3.4	2.4	2.5	0.8	0.8
≥40.0°C	0.0	0.0	0.4	0.2	0.4	0.2	0.4	0.0

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.

Table 4: Percentage of Participants with Fever in Infants at 2, 4, 6 and 12 through 15 Months of Age After Vaccination (Studies 8-10)*

Dose	Dose 1		Dose 2		Dose 3		Dose 4
	VAXNEUVANCE (%)N=2,995	Prevnar 13 (%)N=1,458	VAXNEUVANCE (%)N=2,902	Prevnar 13 (%)N=1,394	VAXNEUVANCE (%)N=2,865	Prevnar 13 (%)N=1,344	VAXNEUVANCE (%)N=2,772	Prevnar 13 (%)N=1,287
Following Doses 1-3, rectal temperature measurements were provided for 53.2% to 54.9% of participants and axillary temperature measurements were provided for 45.1% to 46.8% of participants, provided as a range across the doses. Following Dose 4, rectal temperature measurements were provided for 47.0% of participants and axillary temperature measurements were provided for 53.0% of participants. N=Number of participants with temperature data.
* Studies 8-10 (NCT03893448, NCT03620162 and NCT03692871) were randomized, double-blind, active comparator-controlled clinical studies. Licensed pediatric vaccines were administered concomitantly according to the study design or local recommended schedule. † Solicited on Day 1 through Day 7 postvaccination following each dose.
Fever †
≥38.0°C	15.2	12.6	19.2	18.3	17.1	16.4	15.2	13.0
≥38.0°C to <39.0°C	14.4	11.7	17.1	15.8	14.6	14.7	12.7	11.4
≥39.0°C to <40.0°C	0.7	0.9	2.0	2.2	2.3	1.6	1.9	1.4
≥40.0°C	0.0	0.0	0.1	0.3	0.2	0.1	0.5	0.2

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.

Table 5: Percentage of Participants with Solicited Local and Systemic Adverse Reactions in Children and Adolescents 2 Years Through 17 Years of Age Using a Catch Up Vaccination Schedule (Study 12)*

	VAXNEUVANCE (%)N=177	Prevnar 13 (%)N=175
The percentage of participants 2 to <3 years of age with rectal temperature measurements was 5.0% and with axillary temperature measurements was 95.0%.The percentage of participants ≥3 to 17 years of age with oral temperature measurements was 65.4% and with axillary temperature measurements was 34.6%.N=Number of participants vaccinated.
* Study 12 (NCT03885934) was a randomized, double-blind, active comparator-controlled clinical study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination following each dose. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † For all participants, reactions were solicited on Day 1 through Day 14 postvaccination following each dose. ‡ Different systemic adverse events were solicited for participants 2 to <3 years of age than for participants ≥3 to 17 years of age. For participants <3 years of age (VAXNEUVANCE N=32, Prevnar 13 N=28), decreased appetite, irritability, somnolence, and urticaria were solicited from Day 1 through Day 14 following vaccination. For participants ≥3 to 17 years of age, fatigue, headache, myalgia, arthralgia and urticaria were solicited from Day 1 through Day 14 following vaccination; no events of arthralgia were reported in VAXNEUVANCE recipients. § Moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities. ¶ Solicited on Day 1 through Day 7 postvaccination following each dose. # Percentages reflect the number of participants with temperature data.
Local Reactions †
Pain ‡
Any	54.8	56.6
Moderate	27.7	22.9
Severe	4.5	1.7
Swelling
Any	20.9	24.0
2.6-7.6 cm	10.2	12.0
>7.6 cm	0.0	0.6
Erythema
Any	19.2	21.1
2.6-7.6 cm	6.2	7.4
>7.6 cm	1.1	0.6
Induration
Any	6.8	14.9
2.6-7.6 cm	3.4	5.7
>7.6 cm	0.0	0.0
Systemic Reactions † ‡
Myalgia §
Any	23.7	16.6
Moderate	14.7	6.9
Severe	0.6	0.6
Fatigue §
Any	15.8	17.1
Moderate	6.2	5.7
Severe	2.8	0.6
Headache §
Any	11.9	13.7
Moderate	6.2	8.6
Severe	0.6	0.6
Somnolence §
Any	2.8	2.9
Moderate	1.7	1.1
Severe	0.0	0.6
Irritability §
Any	2.8	4.0
Moderate	0.6	0.6
Severe	0.0	0.0
Decreased appetite §
Any	2.3	2.9
Moderate	0.6	1.7
Severe	0.0	0.0
Urticaria §
Any	1.1	1.1
Moderate	0.0	0.0
Severe	0.0	0.0
Fever ¶#
≥38.0°C	4.0	1.7
≥38.0°C to <39.0°C	2.8	1.7
≥39.0°C to <40.0°C	1.1	0.0
≥40.0°C	0.0	0.0

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.

Table 6: Percentage of Participants with Solicited Local and Systemic Adverse Reactions in Pneumococcal Vaccine-Naïve Adults 50 Years of Age and Older (Study 2)*

	VAXNEUVANCE (%)N=2,103	Prevnar 13 (%)N=230
N=Number of participants vaccinated.
* Study 2 (NCT03950856) was a randomized (9:1), double-blind, active comparator-controlled, lot to lot consistency study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † Solicited on Day 1 through Day 5 postvaccination. ‡ Any use of narcotic pain reliever or prevents daily activity. § Solicited on Day 1 through Day 14 postvaccination. ¶ Percentages are based on the number of participants with temperature data.
Local Reactions †
Pain
Any	66.8	52.2
Grade 3‡	0.9	0.0
Erythema
Any	10.9	9.6
>10 cm	0.6	0.4
Swelling
Any	15.4	14.3
>10 cm	0.2	0.0
Systemic Reactions §
Fatigue
Any	21.5	22.2
Grade 3‡	0.7	0.9
Headache
Any	18.9	18.7
Grade 3‡	0.8	0.0
Myalgia
Any	26.9	21.7
Grade 3‡	0.4	0.0
Arthralgia
Any	7.7	5.7
Grade 3‡	0.2	0.0
Fever †¶
≥38.0°C and <38.5°C	0.6	0.4
≥38.5°C and <39.0°C	0.1	0.0
≥39.0°C	0.0	0.0

Table 7: Percentage of Participants with Solicited Local and Systemic Adverse Reactions in Pneumococcal Vaccine-Naïve Adults 18 to 49 Years of Age With or Without Risk Factors for Pneumococcal Disease (Study 4)*

	VAXNEUVANCE (%)N=1,134	Prevnar 13 (%)N=378
N=Number of participants vaccinated.
* Study 4 (NCT03547167) was a randomized (3:1), double-blind, descriptive study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † Solicited on Day 1 through Day 5 postvaccination. ‡ Any use of narcotic pain reliever or prevents daily activity. § Solicited on Day 1 through Day 14 postvaccination. ¶ Percentages are based on the number of participants with temperature data.
Local Reactions †
Pain
Any	75.8	68.8
Grade 3‡	1.1	1.6
Erythema
Any	15.1	14.0
>10 cm	0.5	0.3
Swelling
Any	21.7	22.2
>10 cm	0.4	0.5
Systemic Reactions §
Fatigue
Any	34.3	36.8
Grade 3‡	1.0	0.8
Headache
Any	26.5	24.9
Grade 3‡	0.8	0.5
Myalgia
Any	28.8	26.5
Grade 3‡	0.3	0.5
Arthralgia
Any	12.7	11.6
Grade 3‡	0.4	0.0
Fever †¶
≥38.0°C and <38.5°C	1.0	0.3
≥38.5°C and <39.0°C	0.3	0.0
≥39.0°C	0.2	0.0

Table 8: Percentage of Participants with Solicited Local and Systemic Adverse Reactions in Adults 65 Years of Age and Older with Previous Pneumococcal Vaccination (Study 5)*

	VAXNEUVANCE (%)N=127	Prevnar 13 (%)N=126
N=Number of participants vaccinated.
* Study 5 (NCT02573181) was a randomized, double-blind, descriptive study. Safety was monitored using a Vaccination Report Card (VRC) for up to 14 days postvaccination. The table represents the final assessment by the study investigators upon review of the VRC 15 days postvaccination, to ensure consistency with protocol definitions. † Solicited on Day 1 through Day 5 postvaccination. ‡ Any use of narcotic pain reliever or prevents daily activity. § Solicited on Day 1 through Day 14 postvaccination. ¶ Percentages are based on the number of participants with temperature data.
Local Reactions †
Pain
Any	55.1	44.4
Grade 3‡	0.8	0.0
Erythema
Any	7.9	7.1
>10 cm	0.8	0.0
Swelling
Any	14.2	6.3
>10 cm	0.0	0.0
Systemic Reactions §
Fatigue
Any	18.1	19.0
Grade 3‡	0.0	0.0
Headache
Any	13.4	15.9
Grade 3‡	0.0	0.0
Myalgia
Any	15.7	11.1
Grade 3‡	0.8	0.0
Arthralgia
Any	5.5	8.7
Grade 3‡	0.0	0.0
Fever †¶
≥38.0°C and <38.5°C	1.6	0.0
≥38.5°C and <39.0°C	0.0	0.0
≥39.0°C	0.0	0.0

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.