2.1 Preparation for Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vaccine if either of these conditions exist. Shake vigorously to obtain a homogeneous, turbid, white suspension before administration. Do not use if resuspension does not occur with vigorous shaking.

For the prefilled syringes, attach a sterile needle and administer intramuscularly.

For the vials, use a sterile needle and sterile syringe to withdraw the 0.5-mL dose and administer intramuscularly. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated.

2.2 Administration, Dose, and Schedule

BOOSTRIX is administered as a 0.5-mL intramuscular injection into the deltoid muscle of the upper arm.

Active Booster Immunization

An initial dose of BOOSTRIX is administered 5 years or more after the last dose of the Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) series or 5 years or more after a dose of Tetanus and Diphtheria Toxoids Adsorbed (Td).

BOOSTRIX may be administered as an additional dose 9 years or more after the initial dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap).

BOOSTRIX may be administered for tetanus prophylaxis for wound management. For management of a tetanus-prone wound, a dose of BOOSTRIX may be administered if at least 5 years have elapsed since previous receipt of a tetanus toxoid-containing vaccine.

Immunization During the Third Trimester of Pregnancy

To prevent pertussis in infants younger than 2 months of age, administer BOOSTRIX to pregnant individuals during the third trimester of pregnancy.

2.3 Additional Dosing Information

The use of BOOSTRIX as a primary series or to complete the primary series for diphtheria, tetanus, or pertussis has not been established.

4.1 Severe Allergic Reaction

Do not administer BOOSTRIX to individuals with a known history of severe allergic reaction (e.g., anaphylaxis) to any component of BOOSTRIX or after a previous dose of any tetanus toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine [see Description (11)].

4.2 Encephalopathy

Encephalopathy within 7 days of administration of a previous dose of a pertussis antigen-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis antigen-containing vaccine, including BOOSTRIX.

5.1 Management of Acute Allergic Reactions

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

5.2 Guillain-Barré Syndrome and Brachial Neuritis

If Guillain-Barré syndrome occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the risk of Guillain-Barré syndrome may be increased following a subsequent dose of tetanus toxoid-containing vaccine, including BOOSTRIX. A review by the Institute of Medicine (IOM) found evidence for a causal relationship between receipt of tetanus toxoid and both Guillain-Barré syndrome and brachial neuritis.1

5.3 Progressive or Unstable Neurologic Disorders

Progressive or unstable neurologic conditions (e.g., cerebrovascular events, acute encephalopathic conditions) are reasons to defer vaccination with a pertussis-containing vaccine, including BOOSTRIX. It is not known whether administration of BOOSTRIX to persons with an unstable or progressive neurologic disorder might hasten manifestations of the disorder or affect the prognosis. Administration of BOOSTRIX to persons with an unstable or progressive neurologic disorder may result in diagnostic confusion between manifestations of the underlying illness and possible adverse effects of vaccination.

5.4 Arthus-Type Hypersensitivity

Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoid-containing vaccine usually have a high serum tetanus antitoxin level and should not receive BOOSTRIX or other tetanus toxoid-containing vaccines unless at least 10 years have elapsed since the last dose of tetanus toxoid-containing vaccine.

5.5 Altered Immunocompetence

As with any vaccine, if administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained.

5.6 Syncope

Syncope (fainting) may occur in association with administration of injectable vaccines, including BOOSTRIX. Procedures should be in place to avoid injury from fainting.

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 with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Table 1 provides an overview of the studies that evaluated the safety of BOOSTRIX in various populations.

In these studies, subjects were monitored for solicited adverse events using standardized diary cards during the 4 days (Days 0 to 3), 7 days (Days 0 to 6), 8 days (Days 0 to 7), or 15 days (Days 0 to 14) following vaccination. Unsolicited adverse events were monitored for the 30-day period following vaccination (Days 0 to 29) or for the 31-day period following vaccination (Days 0 to 30).

Serious adverse events were monitored for 6 months post-vaccination in the initial-dose studies (NCT00109330, NCT00263679, NCT00346073, NCT00835237), for the 31-day (Days 0 to 30) period post-vaccination in the revaccination (NCT01738477, NCT00489970), and the concomitant-vaccine administration studies with MCV4 and TIV (NCT00282295, NCT00385255), for up to 12 months (Day 0 up to study end) post-vaccination in the concomitant administration study with SHINGRIX (NCT02052596), and from vaccination through 2 months after delivery in the study of pregnant individuals (NCT02377349).

Initial-Dose Studies

In clinical studies, 4,949 adolescents (aged 10 to 18 years) and 4,076 adults (aged 19 years and older) were vaccinated with a single dose of BOOSTRIX. Of these adolescents, 1,341 were vaccinated with BOOSTRIX in a coadministration study with meningococcal conjugate vaccine [see Clinical Studies (14.5)]. Of these adults, 1,104 were aged 65 years and older [see Clinical Studies (14.2)]. A total of 860 adults aged 19 years and older received concomitant vaccination with BOOSTRIX and influenza vaccines in a coadministration study [see Clinical Studies (14.6)].

Solicited Adverse Events in the U.S. Adolescent Study: Table 2 presents the solicited local adverse reactions and general adverse events within 15 days of vaccination with BOOSTRIX or Td vaccine for the total vaccinated cohort.

The primary safety endpoint was the incidence of Grade 3 pain (spontaneously painful and/or prevented normal activity) at the injection site within 15 days of vaccination. Grade 3 pain was reported in 4.6% of those who received BOOSTRIX compared with 4.0% of those who received the Td vaccine. The difference in rate of Grade 3 pain was within the pre-defined clinical limit for non-inferiority (upper limit of the 95% Confidence Interval [CI] for the difference [BOOSTRIX minus Td] ≤4%).

Unsolicited Adverse Events in the U.S. Adolescent Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (25.4% and 24.5% for BOOSTRIX and Td vaccine, respectively).

Solicited Adverse Events in the German Adolescent Study: BOOSTRIX was administered to 319 children aged 10 to 12 years previously vaccinated with 5 doses of acellular pertussis antigen-containing vaccines; 193 of these subjects received 5 doses of INFANRIX (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). Table 3 presents the rates of solicited local adverse reactions and fever within 15 days of vaccination for those subjects who had previously been vaccinated with 5 doses of INFANRIX. No cases of whole arm swelling were reported. Two individuals (2/193) reported large injection site swelling (range: 110 to 200 mm diameter), in 1 case associated with Grade 3 pain. Neither individual sought medical attention. These episodes were reported to resolve without sequelae within 5 days.

Solicited Adverse Events in the U.S. Adult (Aged 19 to 64 Years) Study: Table 4 presents solicited local adverse reactions and general adverse events within 15 days of vaccination with BOOSTRIX or the comparator Tdap vaccine for the total vaccinated cohort.

Unsolicited Adverse Events in the U.S. Adult (Aged 19 to 64 Years) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.8% and 22.2% for BOOSTRIX and Tdap vaccine, respectively).

Solicited Adverse Events in the U.S. Elderly (Aged 65 Years and Older) Study: Table 5 presents solicited local adverse reactions and general adverse events within 4 days of vaccination with BOOSTRIX or the comparator Td vaccine for the total vaccinated cohort.

Unsolicited Adverse Events in the U.S. Elderly (Aged 65 Years and Older) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.1% and 14.4% for BOOSTRIX and Td vaccine, respectively).

Serious Adverse Events (SAEs): In the U.S. and German adolescent safety studies, no serious adverse events were reported to occur within 31 days of vaccination. During the 6-month extended safety evaluation period, no serious adverse events that were of potential autoimmune origin or new onset and chronic in nature were reported to occur. In non-U.S. adolescent studies in which serious adverse events were monitored for up to 37 days, 1 subject was diagnosed with insulin-dependent diabetes 20 days following administration of BOOSTRIX. No other serious adverse events of potential autoimmune origin or that were new onset and chronic in nature were reported to occur in these studies. In the U.S. adult (aged 19 to 64 years) study, serious adverse events were reported to occur during the entire study period (0-6 months) by 1.4% and 1.7% of subjects who received BOOSTRIX and the comparator Tdap vaccine, respectively. During the 6-month extended safety evaluation period, no serious adverse events of a neuroinflammatory nature or with information suggesting an autoimmune etiology were reported in subjects who received BOOSTRIX. In the U.S. elderly (aged 65 years and older) study, serious adverse events were reported to occur by 0.7% and 0.9% of subjects who received BOOSTRIX and the comparator Td vaccine, respectively, during the 31-day period after vaccination. Serious adverse events were reported to occur by 4.2% and 2.2% of subjects who received BOOSTRIX and the comparator Td vaccine, respectively, during the 6-month period after vaccination.

Revaccination Studies

U.S. Revaccination Studies in Adults: In 2 clinical studies, 974 adults (aged 20 years and older) were vaccinated with a dose of BOOSTRIX [see Clinical Studies (14.4)].

Solicited Adverse Events in the U.S. Revaccination Studies: Table 6 presents solicited local adverse reactions and general adverse events within 4 days of vaccination with BOOSTRIX for the total vaccinated cohort in both studies.

Concomitant Vaccination with Meningococcal Conjugate Vaccine in Adolescents

Table 7 presents the percentages of subjects experiencing local reactions at the injection site for BOOSTRIX and solicited general events following BOOSTRIX. The incidence of unsolicited adverse events reported in the 31 days after any vaccination was similar following each dose of BOOSTRIX in all cohorts.

Concomitant Vaccination with SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) in Adults ≥50 Years

Table 8 presents the percentage of subjects experiencing local reactions at the injection site for BOOSTRIX and SHINGRIX, respectively, and solicited general events following BOOSTRIX and SHINGRIX vaccination when administered concomitantly or separately. The incidence of unsolicited adverse events within the 30-day post‑vaccination period was similar in the concomitant administration and the separate administration control groups.

Vaccination During Pregnancy

Safety of non-U.S. formulation BOOSTRIX (0.5 mg aluminum/per dose) during the third trimester of pregnancy was evaluated in study NCT02377349. The safety data with the non-U.S. formulation are relevant because the non-U.S. formulation of BOOSTRIX contains the same antigens and in the same quantities as BOOSTRIX. However, the non-U.S. formulation contains more aluminum per dose (see Table 1).

In the randomized, controlled study NCT02377349, 687 pregnant individuals received the non-U.S. formulation of BOOSTRIX or placebo during the third trimester (341 non-U.S. formulation of BOOSTRIX, 346 placebo [saline]). The placebo recipients received the non-U.S. formulation of BOOSTRIX postpartum. The rates of reported solicited adverse reactions following receipt of the non-U.S. formulation of BOOSTRIX administered during pregnancy were consistent with the rates following receipt of the non-U.S. formulation of BOOSTRIX administered to study participants postpartum. For further information about pregnancy outcomes [see Use in Specific Populations (8.1)].

6.2 Postmarketing Experience

In addition to reports in clinical trials for BOOSTRIX, the following adverse events have been identified in persons aged 10 years and older during postapproval use of BOOSTRIX worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Blood and Lymphatic System Disorders

Lymphadenitis, lymphadenopathy.

Immune System Disorders

Allergic reactions, including anaphylactic and anaphylactoid reactions.

Cardiac Disorders

Myocarditis.

General Disorders and Administration Site Conditions

Extensive swelling of the injected limb, injection site induration, injection site inflammation, injection site mass, injection site pruritus, injection site nodule, injection site warmth, injection site reaction.

Musculoskeletal and Connective Tissue Disorders

Arthralgia, back pain, myalgia.

Nervous System Disorders

Convulsions (with and without fever), encephalitis, facial palsy, loss of consciousness, paresthesia, syncope.

Skin and Subcutaneous Tissue Disorders

Angioedema, exanthem, Henoch-Schönlein purpura, rash, urticaria.

7.1 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to BOOSTRIX.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BOOSTRIX during pregnancy. Healthcare providers are encouraged to register women by calling 1-888-452-9622 or visiting http://pregnancyregistry.gsk.com/boostrix.html.

Risk Summary

All pregnancies have a 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.

In a randomized, controlled clinical study (NCT02377349), in which the non-U.S. formulation of BOOSTRIX was administered during the third trimester of pregnancy, there were no identified vaccine-related adverse effects on pregnancy or on the fetus/newborn child (see Data).

Available data from the pregnancy registry and from spontaneous and postmarketing reports suggest that the rates of major birth defects and miscarriage in women who received BOOSTRIX within 28 days prior to conception or during pregnancy are consistent with estimated background rates (see Data).

A developmental toxicity study was performed in female rats administered INFANRIX prior to mating and BOOSTRIX during gestation, 0.1 mL at each occasion (a single human dose is 0.5 mL). In a second study, female rats were administered 0.2 mL of BOOSTRIX prior to mating and during the gestation and lactation period. In a third study, female New Zealand White rabbits were given 0.5 mL (full human dose) of BOOSTRIX (non-U.S. formulation) prior to mating and during gestation. These studies revealed no evidence of harm to the fetus due to BOOSTRIX (see Data).

Data

Human Data: Safety data from a randomized (1:1), controlled clinical study (NCT02377349) (341 non-U.S. formulation of BOOSTRIX, 346 placebo pregnancy outcomes) in which the non-U.S. formulation of BOOSTRIX was administered to pregnant women during the third trimester did not reveal any vaccine-related adverse effects on pregnancy or on the fetus/newborn child. Safety data from prospective clinical studies on the use of BOOSTRIX during the first and second trimester of pregnancy are not available.

An assessment of data from the U.S. pregnancy exposure registry over approximately 17 years (2005-2022) included 1,523 prospective reports of exposure to BOOSTRIX within 28 days prior to conception or during pregnancy. Among the 256 reports with known pregnancy outcomes, 19 women were exposed to BOOSTRIX in the first trimester with no major birth defects reported and 3 spontaneous abortions with no apparent birth defect; 28 women were exposed to BOOSTRIX in the second trimester, and 199 women were exposed to BOOSTRIX in the third trimester with no major birth defects reported; 10 women were exposed to BOOSTRIX at an unknown timing in pregnancy with no major birth defects reported.

An assessment of U.S. spontaneous reports and postmarketing data included 810 prospective reports of exposure to BOOSTRIX during pregnancy since May 2005 through 31 August 2022. Among the 138 reports with known pregnancy outcomes, 17 women were exposed to BOOSTRIX in the first trimester with no major birth defects reported and 2 spontaneous abortions with no apparent birth defect; 26 women were exposed to BOOSTRIX in the second trimester, and 92 women were exposed to BOOSTRIX in the third trimester with no major birth defects reported; 3 women were exposed to BOOSTRIX at an unknown timing in pregnancy with no major birth defects reported.

Animal Data: Developmental toxicity studies were performed in female rats and New Zealand White rabbits. In one study, female rats were administered 0.1 mL of INFANRIX (a single human dose is 0.5 mL) by intramuscular injection 30 days prior to mating and 0.1 mL of BOOSTRIX (a single human dose is 0.5 mL) by intramuscular injection on Gestation Days 6, 8, 11, and 15. The antigens in INFANRIX are the same as those in BOOSTRIX, but INFANRIX is formulated with higher quantities of these antigens. In a second study, female rats were administered 0.2 mL of BOOSTRIX by intramuscular injection 28 days and 14 days prior to mating, on Gestation Days 3, 8, 11, and 15, and on Lactation Day 7. In these studies, no adverse effects on embryo-fetal or pre-weaning development up to Postnatal Day 25 were observed; there were no fetal malformations or variations observed. In a third study, female New Zealand White rabbits were administered 0.5 mL (full human dose) of BOOSTRIX (non-U.S. formulation) by intramuscular injection on Premating Days -28 and -14 and on Gestation Days 3, 8, 11, 15, and 24. In this study, no adverse effects on embryo-fetal development related to BOOSTRIX were observed; postnatal development was not evaluated.

8.2 Lactation

Risk Summary

It is not known whether the vaccine components of BOOSTRIX are excreted in human milk. Data are not available to assess the effect of administration of BOOSTRIX on breastfed infants or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BOOSTRIX and any potential adverse effects on the breastfed child from BOOSTRIX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

BOOSTRIX is not indicated for use in children aged younger than 10 years. Safety and effectiveness of BOOSTRIX in this age group have not been established.

8.5 Geriatric Use

In the initial-dose clinical trials, 1,104 subjects aged 65 years and older received BOOSTRIX; of these subjects, 299 were aged 75 years and older. Adverse events following BOOSTRIX were similar in frequency to those reported with the comparator Td vaccine [see Adverse Reactions (6.1)].

A revaccination study of BOOSTRIX in adults aged 28 to 73 years [see Clinical Studies (14.4)] did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

Active Immunization

Tetanus is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2 A level ≥0.1 IU/mL by ELISA has been considered as protective.

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL, measured by neutralization assays, is the lowest level giving some degree of protection; a level of 0.1 IU/mL by ELISA is regarded as protective. Diphtheria antitoxin levels ≥1.0 IU/mL by ELISA have been associated with long-term protection.3

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

Passive Immunization to Prevent Pertussis in Infants

Antibodies to pertussis antigens from individuals vaccinated during the third trimester of pregnancy are transferred transplacentally to prevent pertussis in infants younger than 2 months of age.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

BOOSTRIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rabbits and rats with BOOSTRIX had no effect on fertility. [See Use in Specific Populations (8.1).]

14.1 Effectiveness of BOOSTRIX, INFANRIX, and PEDIARIX

Effectiveness of BOOSTRIX

The effectiveness of the tetanus and diphtheria toxoid components of BOOSTRIX is based on the immunogenicity of the individual antigens compared with U.S.-licensed vaccines using established serologic correlates of protection. The effectiveness of the pertussis components of BOOSTRIX was evaluated by comparison of the immune response of adolescents and adults following an initial dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of INFANRIX or by comparison of the immune response of adults following an additional dose of BOOSTRIX to the immune response of infants following a 3-dose primary series of PEDIARIX. In addition, the ability of BOOSTRIX to induce a booster response to each of the antigens was evaluated.

Efficacy of INFANRIX against Pertussis

The efficacy of a 3-dose primary series of INFANRIX in infants has been assessed in 2 clinical studies: A prospective efficacy trial conducted in Germany employing a household contact study design and a double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy sponsored by the National Institutes of Health (NIH) (for details see INFANRIX prescribing information). In the household contact study, the protective efficacy of INFANRIX in infants against WHO-defined pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was calculated to be 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%) (for details see INFANRIX prescribing information).

Immune Responses to Pertussis Antigens of PEDIARIX Compared with INFANRIX

The diphtheria, tetanus, and pertussis components in PEDIARIX are the same as those in INFANRIX. The effectiveness of the pertussis component of PEDIARIX was determined in clinical trials by comparison to antibody responses to INFANRIX (for details see PEDIARIX prescribing information).

Immune Responses to Pertussis Antigens of BOOSTRIX Compared with INFANRIX or PEDIARIX

Although a serologic correlate of protection for pertussis has not been established, serological data from a subset of infants immunized with a 3-dose primary series of INFANRIX in the German household contact study were compared with the sera of adolescents and adults immunized with an initial dose of BOOSTRIX [see Clinical Studies (14.2)]. Serological data from infants immunized with a 3-dose primary series of PEDIARIX in an additional pediatric study were compared with the sera of adults immunized with an additional dose of BOOSTRIX [see Clinical Studies (14.4)]. The GMCs to each of the pertussis antigens 1 month following a dose of BOOSTRIX were compared with the GMCs of infants following INFANRIX administered at 3, 4, and 5 months of age or were compared with the GMCs of infants following PEDIARIX administered at 2, 4, and 6 months of age. The majority of subjects in the study of INFANRIX had only anti-PT serology data.

14.2 Immunological Evaluation following an Initial Dose of BOOSTRIX

Adolescents (Aged 10 to 18 years)

In a multicenter, randomized, observer-blinded, controlled study conducted in the United States (NCT00109330), the immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration of a single dose of vaccine to adolescent subjects (aged 10 to 18 years). Of the subjects enrolled in this study, approximately 76% were aged 10 to 14 years and 24% were aged 15 to 18 years. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either DTwP or a combination of DTwP and DTaP in childhood. The racial/ethnic demographics were as follows: White 85.8%, Black 5.7%, Hispanic 5.6%, Oriental 0.8%, and other 2.1%.

Response to Tetanus and Diphtheria Toxoids: The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with Td vaccine are shown in Table 9. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) and booster response rates were comparable between BOOSTRIX and the comparator Td vaccine.

Response to Pertussis Antigens: The booster response rates of adolescents to the pertussis antigens are shown in Table 10. For each of the pertussis antigens the lower limit of the 2-sided 95% CI for the percentage of subjects with a booster response exceeded the pre-defined lower limit of 80% for demonstration of an acceptable booster response.

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 11 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). Anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adolescents 1 month after a single dose of BOOSTRIX were non-inferior to those infants following a primary vaccination series with INFANRIX.

Adults (Aged 19 to 64 Years)

A multicenter, randomized, observer-blinded study, conducted in the United States (NCT00346073), evaluated the immunogenicity of BOOSTRIX compared with the licensed comparator Tdap vaccine (Sanofi Pasteur). Vaccines were administered as a single dose to subjects (N = 2,284) who had not received a tetanus-diphtheria booster within 5 years. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration. Approximately 33% of subjects were aged 19 to 29 years, 33% were aged 30 to 49 years, and 34% were aged 50 to 64 years. Among subjects in the combined vaccine groups, 62% were female; 84% of subjects were White, 8% Black, 1% Asian, and 7% were of other racial/ethnic groups.

Response to Tetanus and Diphtheria Toxoids: The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with the comparator Tdap vaccine are shown in Table 12. One month after a single dose, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between BOOSTRIX and the comparator Tdap vaccine.

Response to Pertussis Antigens: Booster response rates to the pertussis antigens are shown in Table 13. For the FHA and PRN antigens, the lower limit of the 95% CI for the booster responses exceeded the pre-defined limit of 80% demonstrating an acceptable booster response following BOOSTRIX. The PT antigen booster response lower limit of the 95% CI (74.9%) did not exceed the pre-defined limit of 80%.

The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 14 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). Anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adults 1 month after a single dose of BOOSTRIX were non-inferior to those infants following a primary vaccination series with INFANRIX.

Elderly (Aged 65 Years and Older)

The U.S. elderly (aged 65 years and older) study, a randomized, observer-blinded study (NCT00835237), evaluated the immunogenicity of BOOSTRIX (n = 887) compared with a U.S.-licensed comparator Td vaccine (n = 445) (Sanofi Pasteur). Vaccines were administered as a single dose to subjects who had not received a tetanus-diphtheria booster within 5 years. Among all vaccine recipients, the mean age was approximately 72 years; 54% were female and 95% were White. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after administration.

Response to Tetanus and Diphtheria Toxoids: Immune responses to tetanus and diphtheria toxoids were measured 1 month after administration of a single dose of BOOSTRIX or a comparator Td vaccine. Anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL) were comparable between BOOSTRIX and the comparator Td vaccine (Table 15).

Response to Pertussis Antigens: The GMCs to each of the pertussis antigens 1 month following a single dose of BOOSTRIX were compared with the GMCs of a subset of infants following a 3-dose primary series of INFANRIX in the German household contact study [see Clinical Studies (14.1)]. Table 16 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least 1 pertussis antigen). Anti-PT, anti-FHA, and anti-PRN antibody concentrations in the elderly 1 month after a single dose of BOOSTRIX were non-inferior to those of infants following a primary vaccination series with INFANRIX.

14.3 Study in Pregnant Women

The effectiveness of BOOSTRIX immunization during the third trimester of pregnancy to prevent pertussis among infants younger than 2 months of age was based on a re-analysis within a Bayesian meta-analysis framework of the BOOSTRIX-relevant data from an observational case-control study of Tdap vaccine effectiveness.4 In this re-analysis, a conditional logistic regression model controlling for age, maternal education, and family size was fit to data from 108 cases (including 4 cases whose mothers received BOOSTRIX during the third trimester) and 183 controls (including 18 whose mothers received BOOSTRIX during the third trimester) matched by age group (<2 weeks old, ≥2 weeks old) and birth hospital. This yielded a preliminary vaccine effectiveness estimate of 78.0% (95% CI: -38.0, 96.5) for vaccination during the third trimester of pregnancy. This preliminary effectiveness estimate was updated using a Bayesian meta-analysis with an informative prior constructed from four observational studies that provided estimates of the vaccine effectiveness of the non-U.S. formulation of BOOSTRIX against pertussis in infants whose mothers were immunized during pregnancy.5, 6, 7, 8 To account for potential publication bias, this informative prior was downweighted by combining it with an uninformative prior. When the informative prior has 20% weight, the Bayesian update resulted in estimates of effectiveness of vaccination during the third trimester of pregnancy of 81.5% (95% credible interval:12.9, 94.5). When the informative prior has 90% weight, the Bayesian update resulted in estimates of effectiveness of vaccination during the third trimester of pregnancy of 83.4% (95% credible interval: 55.7, 92.5). The vaccine effectiveness point estimates were consistent, regardless of the weight applied to the informative prior.

14.4 Immune Responses to Vaccination in Infants Born to Mothers Who Received BOOSTRIX During Pregnancy

Data are not available on immune responses to US licensed vaccines administered on the US schedule among infants born to mothers who received BOOSTRIX during pregnancy.

In infants whose mothers received BOOSTRIX (non-US formulation) during the third trimester of pregnancy, antibody responses to a non-US licensed DTaP-containing vaccine were diminished for anti-PT, anti-FHA and anti-PRN following the primary series (NCT 02422264), and for anti-PT and anti-FHA following a booster dose (NCT 02853929) compared to infants who received the same vaccine but whose mothers received placebo during pregnancy. Whether the diminished immune responses observed in vaccinated infants whose mothers received BOOSTRIX (non-US formulation) during pregnancy result in diminished effectiveness of pertussis vaccination in infants is unknown.

14.5 Immunological Evaluation following Revaccination with BOOSTRIX

Adults (Aged 20 to 29 Years)

A multicenter, open-label, controlled study conducted in the United States evaluated the immunogenicity of BOOSTRIX in adults aged 20 to 29 years who received an initial dose of BOOSTRIX (n = 128) or the comparator Td vaccine (MassBiologics) (n = 37) in the U.S. adolescent (aged 10 to 18 years) study (NCT01738477). BOOSTRIX was administered to all subjects 10 years after initial vaccination. The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after vaccine administration. Among all vaccine recipients, the mean age was 23.5 years; 45.5% were female, and 87.9% were White.

Response to Tetanus and Diphtheria Toxoids: The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX are shown in Table 17. One month after vaccination, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between groups.

Response to Pertussis Antigens: The GMCs to each of the pertussis antigens 1 month following revaccination with BOOSTRIX in subjects who had received an initial dose of BOOSTRIX 10 years earlier were compared with the GMCs of infants following a 3-dose primary series of PEDIARIX [see Clinical Studies (14.1)]. Table 18 presents the results for the ATP cohort for immunogenicity in both studies. Anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adults 1 month after revaccination with BOOSTRIX were non-inferior to those of infants following a primary vaccination series with PEDIARIX.

Adults (Aged 28 to 73 Years)

A multicenter, open-label, controlled study conducted in the United States evaluated the immunogenicity of BOOSTRIX in adults aged 28 to 73 years who received an initial dose of BOOSTRIX (n = 309) or the licensed comparator Tdap vaccine (Sanofi Pasteur) (n = 138) in the U.S. adult (aged 19 to 64 years) study (NCT00489970). BOOSTRIX was administered to all subjects 9 years after initial vaccination. A control group of newly enrolled adult subjects received an initial dose of BOOSTRIX (n = 362). The immune responses to each of the antigens contained in BOOSTRIX were evaluated in sera obtained approximately 1 month after vaccine administration. Of the subjects enrolled in this study, the mean age was 52.1 years; 62.6% were female, and 86.6% were White.

Response to Tetanus and Diphtheria Toxoids: The antibody responses to the tetanus and diphtheria toxoids of BOOSTRIX are shown in Table 19. One month after vaccination, anti-tetanus and anti-diphtheria seroprotective rates (≥0.1 IU/mL by ELISA) were comparable between groups.

Response to Pertussis Antigens: The GMCs to each of the pertussis antigens 1 month following a dose of BOOSTRIX in subjects who had received an initial dose of BOOSTRIX or the licensed comparator Tdap vaccine (Sanofi Pasteur) 9 years earlier were compared with the GMCs of infants following a 3-dose primary series of PEDIARIX [see Clinical Studies (14.1)]. Table 20 presents the results for the ATP cohort for immunogenicity in both studies. Anti-PT, anti-FHA, and anti-PRN antibody concentrations observed in adults 1 month after a dose of BOOSTRIX were non-inferior to those of infants following a primary vaccination series with PEDIARIX.

Compared with the Control Group, non-inferiority of booster response rates to the pertussis antigens following a dose of BOOSTRIX in subjects who had received an initial dose of BOOSTRIX or another licensed Tdap vaccine (Sanofi Pasteur) was achieved for the PT antigen [BOOSTRIX minus Control Group] and the FHA antigen [Tdap minus Control Group], respectively (Table 21). Non-inferiority was not achieved for FHA and PRN booster response rates [BOOSTRIX minus Control Group] or for PT and PRN booster response rates [Tdap minus Control Group].

14.6 Concomitant Administration with Meningococcal Conjugate Vaccine

The concomitant use of BOOSTRIX and a tetravalent meningococcal (groups A, C, Y, and W-135) conjugate vaccine (Sanofi Pasteur) was evaluated in a randomized study in healthy adolescents aged 11 to 18 years (NCT00282295). A total of 1,341 adolescents were vaccinated with BOOSTRIX. Of these, 446 subjects received BOOSTRIX administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects received BOOSTRIX followed by meningococcal conjugate vaccine 1 month later, and 449 subjects received meningococcal conjugate vaccine followed by BOOSTRIX 1 month later.

Immune responses to diphtheria and tetanus toxoids (% of subjects with anti-tetanus and anti-diphtheria antibodies ≥1.0 IU/mL by ELISA), pertussis antigens (booster responses and GMCs), and meningococcal antigens (vaccine responses) were measured 1 month (range: 30 to 48 days) after concomitant or separate administration of BOOSTRIX and meningococcal conjugate vaccine. For BOOSTRIX given concomitantly with meningococcal conjugate vaccine compared with BOOSTRIX administered first, non-inferiority was demonstrated for all antigens, with the exception of the anti-PRN GMC. The lower limit of the 95% CI for the GMC ratio was 0.54 for anti-PRN (pre-specified limit ≥0.67). For the anti-PRN booster response, non-inferiority was demonstrated. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to PRN.

There was no evidence that BOOSTRIX interfered with the antibody responses to the meningococcal antigens when measured by rabbit serum bactericidal assays (rSBA) when given concomitantly or sequentially (meningococcal conjugate vaccine followed by BOOSTRIX or BOOSTRIX followed by meningococcal conjugate vaccine).

14.7 Concomitant Administration with FLUARIX (Inactivated Influenza Vaccine)

The concomitant use of BOOSTRIX and FLUARIX was evaluated in a multicenter, open-label, randomized, controlled study (NCT00385255) of 1,497 adults aged 19 to 64 years. In one group, subjects received BOOSTRIX and FLUARIX concurrently (n = 748). The other group received FLUARIX at the first visit, then 1 month later received BOOSTRIX (n = 749). Sera was obtained prior to and 1 month following concomitant or separate administration of BOOSTRIX and/or FLUARIX, as well as 1 month after the separate administration of FLUARIX.

Immune responses following concurrent administration of BOOSTRIX and FLUARIX were non-inferior to separate administration for diphtheria (seroprotection defined as ≥0.1 IU/mL), tetanus (seroprotection defined as ≥0.1 IU/mL and based on concentrations ≥1.0 IU/mL), PT antigen (anti-PT GMC), and influenza antigens (percent of subjects with hemagglutination-inhibition [HI] antibody titer ≥1:40 and ≥4-fold rise in HI titer). Non-inferiority criteria were not met for the anti-pertussis antigens FHA and PRN. The lower limit of the 95% CI of the GMC ratio was 0.64 for anti-FHA and 0.60 for anti-PRN and the pre-specified limit was ≥0.67. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to FHA and PRN.

14.8 Concomitant Administration with SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted)

The concomitant use of BOOSTRIX and SHINGRIX was evaluated in an open-label clinical study (NCT 02052596) of subjects aged 50 years and older. Subjects in Group 1 received BOOSTRIX and the first dose of SHINGRIX at Month 0 and the second dose of SHINGRIX at Month 2 (n = 412; concomitant administration group). Subjects in Group 2 received BOOSTRIX at Month 0, the first dose of SHINGRIX at Month 2, and the second dose of SHINGRIX at Month 4 (n = 418; separate administration control group). The mean age of the subjects was 63 years; 54% were female. The majority of subjects were White (87%), followed by Black (11%), and other racial groups; 2% were of American Hispanic or Latino ethnicity.

The immune responses to BOOSTRIX (anti-D, anti-T, and antibodies to pertussis antigens) were measured 1 month after administration of the single dose of BOOSTRIX. The immune response to SHINGRIX was measured by anti-gE Ab concentrations 1 month after the second dose of SHINGRIX. Concomitant administration showed no evidence for interference in the immune response to the antigen contained in SHINGRIX or the antigens contained in BOOSTRIX, with the exception of one of the pertussis antigens (pertactin), which did not satisfy the noninferiority criterion: the UL of the 95% CI for the adjusted GMC ratio (separate administration control group/concomitant administration group) for anti-pertactin antibody was 1.58 (noninferiority criterion <1.5). The clinical significance of the reduced immune response to pertactin is unknown.