Immunogenicity, Safety, and Antibody Persistence at 3, 5 and 10 Years Postvaccination in

Transcription

1 CVI Accepts, published online ahead of print on 24 December 2014 Clin. Vaccine Immunol. doi: /cvi Copyright 2014, American Society for Microbiology. All Rights Reserved Immunogenicity, Safety, and Antibody Persistence at 3, 5 and 10 Years Postvaccination in Year-Old Adolescents Randomized to Booster Immunization with a Combined Tetanus, Diphtheria, 5-Component Acellular Pertussis, and Inactivated Poliomyelitis Vaccine (Tdap-IPV; Adacel-Polio ) Administered with a Hepatitis B Vaccine (HepB; RECOMBIVAX HB ) Concurrently or 1 Month Apart Running Title: Adacel-Polio plus HepB booster in adolescents Joanne Embree a, Barbara Law a1, Tim Voloshen b, Antigona Tomovici c# a University of Manitoba, Winnipeg, MB, Canada b Sanofi Pasteur, Swiftwater, PA, USA c Sanofi Pasteur, Toronto, ONT, Canada Corresponding Author: Antigona Tomovici, Sanofi Pasteur, 1755 Steeles Avenue West, Toronto, ONT, M2R 3T4, Canada; TEL: ; FAX: ; (miggi.tomovici@sanofipasteur.com) 1 Current affiliation: Public Health Agency of Canada, Ottawa, Canada 1

2 Abstract An understanding of antibody persistence elicited by combined tetanus, diphtheria, 5-component acellular pertussis and inactivated poliovirus vaccine (Tdap-IPV) after adolescent vaccination is important to optimize booster dosing intervals. Our objectives were to compare safety and immunogenicity in adolescents of Tdap-IPV coadministered with HepB to sequential administration and evaluate humoral immunity 3, 5, and 10 years after Tdap-IPV vaccination. This phase II randomized, controlled, open-label study enrolled to 14-year-old adolescents with up to 10 years postvaccination follow-up. Group 1 (n=145) received Tdap-IPV followed by a HepB dose one month later; Group 2 (n=135) received both vaccines simultaneously. No consistent increases in solicited reactions or unsolicited adverse events occurred with coadministration. All vaccinees attained seroprotective antibody levels at 0.01 IU/mL for diphtheria and tetanus; 1:8 dilution for poliovirus (serotypes 1, 2, 3); and 10 miu/ml for hepatitis B at 1 month postvaccination. Clinically relevant immunologic interactions did not occur with coadministration. For pertussis, all participants achieved seropositivity levels ( lower limit of quantitation) and 72.7% 95.8% had 4-fold increases in pertussis antibodies 1 month post-vaccination. At 10 years postvaccination, remaining participants (62.8% of the original cohort) maintained seroprotective levels of 0.01 IU/mL for diphtheria and tetanus, 1:8 for all 3 poliovirus serotypes, and 74.1% 98.2% maintained pertussis seropositivity levels depending on the antigen tested. There were no differences between groups. These results support coadministration of Tdap-IPV and HepB to adolescents and suggest that vaccination with Tdap-IPV can offer protection for 10 years after adolescent booster vaccination. 2

3 40 41 Keywords: combination vaccines; adolescent booster; safety; immunogenicity; antibody persistence; long-term follow-up 42 3

4 INTRODUCTION Despite widespread childhood immunization with pertussis vaccines, recurrence of pertussis has been reported among adolescents and young adults with periodic outbreaks in several countries, suggesting early waning of immunity (1-8). In these outbreaks, high rates of pertussis infection were observed among infants aged <1 year, and the incidence in adolescents aged years was also increased. In addition to pertussis morbidity in infected adolescents and adults, these patients constitute a major source of transmission to infants, especially those <6 months of age who are at highest risk of serious disease and death (3, 9). Thus, pertussis immunization of adults and adolescents is recommended for both personal protection and to reduce exposure of vulnerable infants (10, 11). Current recommendations for adolescent vaccination in some European countries and most Canadian provinces include combined tetanus, diphtheria, and acellular pertussis (Tdap) and hepatitis B (HepB) vaccines (12). In Canada, the incidence of reported pertussis decreased in all age groups after the National Advisory Committee on Immunization (NACI) recommended inclusion of a tetanus-diphtheria-acellular pertussis (Tdap) booster to adolescents years of age (12). Long-term antibody persistence information after adolescence Tdap vaccination has become available in recent years (13-20). In general, antibody levels are highest 1 month postvaccination and decrease over time (13-15, 17); by 10 years postvaccination, antibody concentrations return to levels comparable or approaching those observed before vaccination (19). One strategy for improved health care for adolescents and young adults is vaccination programs targeted at vaccine-preventable illnesses that they are at high risk of acquiring. 4

5 Coadministration of Tdap combination vaccine with HepB vaccine in early adolescence would facilitate more cost-effective adolescent vaccination strategies. It would also help attain immunization target levels by decreasing the number of health care visits needed to complete vaccination schedules. Long-term humoral immunity follow-up assessments may help select optimal dosing intervals for future booster vaccinations after adolescence. The objective of this study was to determine the safety and immunogenicity of Tdap-IPV followed by a dose of HepB vaccine one month later compared with Tdap-IPV and HepB vaccine administered concurrently in adolescents years of age and evaluate humoral immunity at 3, 5, and 10 years after Tdap-IPV vaccination. Downloaded from on November 10, 2018 by guest 5

6 MATERIALS AND METHODS Study design. This was a phase II, open-label, randomized, controlled study conducted at the University of Manitoba, with vaccinations conducted between January 1999 and May The study was approved by the University of Manitoba Ethics Committee; signed, witnessed informed consent was obtained from parents or legal guardians of the participants prior to the first study intervention. Randomization was performed by the trial statistician and staff who were not involved in the clinical aspects of the trial. Assignment to Group 1 or Group 2 was performed in a 1:1 ratio via telephone at the time of consent. Group 1 received Tdap-IPV followed by HepB approximately 1 month later. Group 2 received Tdap-IPV and HepB concurrently. The second and third doses of HepB were given 1 month and 6 months after the initial HepB vaccination in both groups. All participants kept daily diaries and were assessed for safety for 2 weeks by the study team. For immunogenicity, participants had blood draws immediately before vaccination, 1 month after Tdap-IPV (with or without HepB) vaccination, and 1 month after the last HepB dose for hepatitis B antibody levels. All participants were contacted and asked to return for additional blood draws and subsequent Tdap-IPV serology testing at 3, 5, and 10 years in 2002, 2004, and 2009 respectively. Hep B serology was not performed at the subsequent time points. Follow-up was designed as an open-label, long-term assessment of persistence of Tdap-IPV vaccine-elicited antibodies. Participants. At study entry, participants were years of age and in good health based on reported medical history. Exclusion criteria included immunodeficiency, immunosuppression or receipt of high-dose steroids; any substantial underlying chronic disease, including malignancy; known impairment of neurologic function or seizure disorder of any 6

7 etiology; known or suspected allergy to any vaccine components in the study; receipt of any pertussis, diphtheria, tetanus, or poliomyelitis containing vaccines or HepB vaccine within the previous 5 years; history of physician-diagnosed or laboratory-confirmed pertussis disease within the previous 2 years; receipt of blood products or immunoglobulin within the previous 3 months; receipt of any vaccine within 2 weeks of any study vaccine administration; or daily use of nonsteroidal anti-inflammatory drugs (NSAIDS). To ensure the follow-up populations were representative of the original study participants in terms of immunogenicity, baseline immunogenicity measurements with respect to prevaccination and 1 month postvaccination were assessed for all vaccine antigens for participants at each follow-up period. For the long-term follow-up, participants who were diagnosed with pertussis or received any Td or Tdap vaccine after study vaccine were excluded from analysis. Vaccines. Both vaccines required intramuscular administration with a needle no shorter than 25 mm (1 inch). A single 0.5-mL dose of the Tdap vaccine with inactivated poliomyelitis vaccine (Tdap-IPV; Adacel-Polio ) contained tetanus (5 Lf) and diphtheria (2 Lf) toxoids adsorbed combined with acellular component pertussis (2.5 µg pertussis toxoid [PT], 5 µg filamentous hemagglutinin [FHA], 3 µg pertactin [PRN], 5 µg fimbriae 2+3 [FIM]) and inactivated poliomyelitis vaccine (poliovirus types 1, 2, 3 at 40 D, 8 D and 32 D antigen units respectively) grown in Vero cells (21). This vaccine also contained 1.3 mg aluminum phosphate, 0.6% 2-phenoxyethanol, and polysorbate 80 as excipients. A single dose of the recombinant HepB vaccine (RECOMBIVAX HB ) contained 5μg hepatitis B virus surface antigen (HBsAg) (22). The vaccines administered in the study were Tdap-IPV manufactured by Sanofi Pasteur Limited (Lot ) and Hep B vaccine manufactured by Merck & Co. Inc (Lot C004370). 7

8 Serological assays. Serological assays were performed by Sanofi Pasteur. The Global Clinical Immunology Laboratory (GCI, USA) performed diphtheria and tetanus assays on the 5- year samples and all assays on the 10-years samples. The Clinical Immunology Platform Canada (CIP-CA) performed all baseline, 1-month, and 3-year postvaccination assays and pertussis assays of the 5-year samples. All assays were determined to be concordant between laboratories or adjustment factors were used to make the data concordant. Prevaccination and 1 month postvaccination sera were assayed in parallel; follow-up sera were assayed separately shortly after collection at the 3, 5, and 10-year sampling times. Antitetanus antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and expressed as International Units (IU)/mL. Diphtheria antibody responses were measured by microneutralization assay and expressed as IU/mL. Antibody titers to poliovirus serotypes 1, 2, and 3 were measured by microneutralization assay and expressed as the inverse serum dilution able to neutralize 50% of the challenge virus. Antibody levels to PT, FHA, PRN, and FIM were measured by ELISA and expressed in ELISA units (EU)/mL. Because there are no universally accepted correlates of pertussis protection, seropositivity was evaluated by determining by the proportion of participants with antibody levels the lower limit of quantitation (LLOQ) (23). For assays performed at CIP-CA, LLOQs were 5 EU/mL for PT, 3 EU/mL for FHA, 3 EU/mL for PRN, and 17 EU/mL for FIM; for the assays performed at GCI, LLOQs were 4 EU/mL for PT, PRN, and FIM and 3 EU/mL for FHA; seropositivity results are expressed using the relevant laboratory s LLOQ. Antibodies to HBsAg were measured by radioimmunoassay only as part of the original study and expressed as miu/ml. Safety Endpoints. Safety endpoints and related periods of follow-up postvaccination were as follows: rates of solicited injection site reactions (pain, erythema, swelling, axillary 8

9 lymph node swelling) and solicited systemic reactions (fever, chills, headache, generalized bodyache and/or muscle weakness, tiredness and/or decreased energy, nausea, vomiting, diarrhea, and sore and/or swollen joints) at 0 24 hours, hours, and 3 14 days; rates of immediate reactions within 30 minutes; unsolicited adverse events (AEs) as spontaneously reported within 14 days after Tdap-IPV injection; and serious adverse events (SAEs) at any time during the study through 30 days after the last vaccination. The intensity of solicited local and systemic reactions was classified as mild, moderate and severe based on magnitude (mild < 10 mm; moderate mm and severe >35 mm of redness or swelling) and degree of interference with daily activities for systemic AEs. Orally measured fever was classified as mild (38.0 ºC 38.9 ºC), moderate (39.0 ºC 39.9 ºC), or severe ( 40 ºC). Moderate and severe AEs were grouped together in the analysis. Immunogenicity Endpoints. Immunogenicity was measured by the proportion of participants achieving seroprotective levels of antibodies 0.01 IU/mL and 0.1 IU/mL for diphtheria and tetanus, and 1:8 dilution for poliovirus. For pertussis, rates of 4-fold increase in antibody levels were calculated 1 month postvaccination. To examine immunologic interactions between Tdap-IPV and HepB, geometric mean titers (GMTs) of antibodies and corresponding seroprotection rates achieved for each Tdap-IPV antigen (not shown for pertussis) were compared. For HepB vaccine, immunogenicity was measured by the proportion of participants attaining 10 miu/ml, the seroprotective hepatitis B antibody level. Immunogenicity endpoints for all Tdap-IPV antigens were also evaluated at 3, 5, and 10 years postvaccination, as described above. Pertussis antibody levels were assessed against LLOQ where antibody levels LLOQ were considered seropositive. 9

10 Statistical analysis. A sample size of 140 participants per treatment arm was calculated to provide 90% power at a two-sided significance level of 5% to detect a difference in treatment arms of 15% and allow for a 10% drop-out rate. The intended sample size was determined based on antibody responses to pertussis antigens in prior studies using the two-sided equivalence approach for the difference in two proportions (24). No formal hypothesis was tested and no statistical testing was performed in this study. Safety endpoints were summarized as the number and percentage of participants with a solicited reaction or unsolicited AE tabulated by intensity and study group. Differences between groups in response rates with 90% confidence intervals (CIs) were calculated for each AE at each time point. The solicited AEs were considered clinically equivalent if the confidence interval on the difference in the rates between groups was within the interval of 15% to +15%. For immunogenicity endpoints, continuous variables were presented by summary statistics (mean, standard deviation [SD], GMTs with 95% CI) and categorical variables by frequency distributions (counts and percentages). Differences in anti-diphtheria, anti-tetanus, and antipoliovirus seroprotection rates, and pertussis 4-fold increases were calculated with 90% CIs (data not shown). For pertussis in the long-term follow-up, seropositivity ( LLOQ) was presented by descriptive statistics. All participants who received study vaccine and had 1 valid postvaccination safety or immunogenicity evaluation were included in the intent-to-treat (ITT) analysis set and analyzed for safety and immunogenicity. All participants without a protocol deviation were included in the per-protocol (PP) analysis set for immunogenicity analyses. 10

11 RESULTS Participants. Healthy participants (N=280) were randomized to Group 1 (n=145) or Group 2 (n=135). Nine participants terminated the study before completion (Figure 1). The groups were balanced for age (mean 12.4 years for both Groups) and sex distribution (52.1% female in Group 1; 44.7% female in Group 2). Of the 277 participants available for immunogenicity assessments in the original study, 274 (98.9%) provided serum samples at 1 month, 224 (80.9%) at 3 years, 225 (81.2%) at 5 years, and 174 (62.8%) at 10 years postvaccination. The participants who contributed samples in the long-term follow-up were representative of the original study with respect to age, sex, and baseline vaccine antigen immune responses (data not shown). The first participant visit occurred on January 9, 1999 and the last participant visit following vaccination was May 27, First and last participant visits, respectively, were January 23, 2002 and October 14, 2002 for the 3-year sampling; February 18, 2004 and October 20, 2004 for the 5-year sampling; and March 24, 2009 and June 4, 2009 for the 10-year sampling. Safety results. Overall, the rates of AEs were comparable between groups. No vaccination-related SAEs were reported and no safety concerns were identified. No consistent increases in solicited reactions or unsolicited AEs were reported when Tdap-IPV and HepB with coadministration. Solicited reactions. Most solicited local reactions at the Tdap-IPV injection site were mild and occurred within 0 24 hours postvaccination (Table 1). Pain was the most frequently reported local reaction at 0 24 hours and was reported by almost all participants. In the hour interval, reports of pain at the Tdap-IPV injection site were higher in Group 1 (58.3%) than Group 2 (50.8%). By 3 14 days, the frequency of pain reports had diminished equally in both 11

12 groups. A similar trend was observed for redness and swelling. Axillary lymph node swelling was most frequently reported within hours. Overall, the local AE rates at the Tdap-IPV injection site were comparable between groups. Solicited systemic reactions were mostly mild and more commonly reported in both groups in the first 24 hours (Table 2). The most frequent reports in the first 24 hours were for bodyache/muscle weakness and tiredness. At hours, the frequency of systemic AE reports decreased in both groups (ranging from 0 for vomiting to a maximum of 23.5% for headaches and tiredness in Group 2). At 3 14 days, there was an apparent increase in the rate of headache, diarrhea, nausea, and vomiting reports (ranging from 2.3% for vomiting in Group 2 to 40.3% for headaches in Group 1). These events were equally distributed between groups and were not considered to be directly related to the vaccination. Fever reports were rare in both groups: 3 in each group within 0 24 hours; 4 in Group 1 and 2 in Group 2 within hours. Rates of solicited systemic reactions were numerically similar in both groups. Unsolicited AEs. Unsolicited AEs were reported by approximately 60% of participants, with comparable reporting at 61.8% in Group 1 and 58.3% in Group 2. Most unsolicited AEs were mild, with onset in the first days after vaccination and were reported as unrelated to study vaccine. These reports were not coded; however, the most common AEs reported were cold symptoms/flu-like syndrome followed by stomach ache. Unsolicited AEs reported as definitely related to vaccination were also equally distributed between Group 1 and 2 (8 per group). Serious Adverse Events. Four SAEs were reported; all required hospitalization and none was considered to be vaccination-related. One participant from each group experienced a fracture (at 7 days postvaccination for one participant and 29 days postvaccination for the other [third HepB dose)]. In addition, a Group 2 participant experienced appendicitis at 11 days after the 12

13 first dose of HepB and Tdap-IPV, and a diabetic Group 2 participant experienced viral gastroenteritis and unstable glycaemia 3 months after the second dose of HepB. Immunogenicity. Seroprotection/seroresponse. At 1 month postvaccination, seroprotection rates against diphtheria, tetanus, and poliomyelitis were comparable between groups (Tables 3 and 4); all reached seroprotective antibody levels of 0.01 IU/mL for diphtheria and tetanus, 1:8 for poliovirus types 1, 2, and 3, and ( 10 miu/ml) for hepatitis B. All participants achieved levels of 0.1 IU/mL for tetanus. For diphtheria, 98.6% of Group 1 participants and 100% of Group 2 participants achieved seroprotective levels of 0.1 IU/mL. Pertussis antibody seroresponses 1 month after Tdap-IPV vaccination were comparable between Groups 1 and 2 as measured by 4-fold increases: PT (Group 1=88.7% versus Group 2=86.4%), FHA (76.6% versus 72.7%), FIM (88.7% versus 90.8%), and PRN (95.8% versus 87.9%). No clinically relevant interference was observed with Tdap-IPV and HepB coadministration. Antibody geometric mean titers. Although high prevaccination tetanus, diphtheria, and poliovirus antibody levels were observed, GMTs rose after vaccination indicating a booster response (Table 5). Tetanus and diphtheria GMTs at 1 month after Tdap-IPV vaccination were comparable whether the vaccine was given alone or with a dose of HepB. Poliovirus GMTs achieved were high (Table 5). Antibody persistence. Long-term antibody persistence was evaluated from blood samples taken 3, 5, and 10 years after Tdap-IPV vaccination. Immunogenicity profiles were comparable between groups for all endpoints and at all time points. For diphtheria, tetanus, and poliomyelitis, seroprotection rates remained high for up to 10 years postvaccination (Tables 3 and 4). At 10 years, 100% of participants had anti-diphtheria antibody levels of 0.01 IU/mL, while 85.9% 13

14 (Group 1=88.4%; Group 2=82.9%) maintained levels 0.1 IU/mL, adequate for long-term protection (25). For tetanus, 100% of participants maintained levels 0.01 IU/mL at 10 years, while 98.7% (Group 1=100%; Group 2=97.1%) maintained levels 0.1 IU/mL. All participants maintained poliovirus seroprotective levels 1:8 for all 3 poliovirus types at all postvaccination time periods. After substantial increases at 1 month after vaccination, anti-diphtheria, anti-tetanus and anti-poliovirus GMTs declined during the first 3 years (Table 5). At 10 years, diphtheria and tetanus GMTs had returned to prevaccination levels. Anti-poliovirus GMT levels declined over time, but remained above prevaccination levels for all 3 poliovirus types (Table 5). Antipertussis GMTs declined over time, with the largest decrease occurring in the first years postvaccination (Figure 2). Pertussis seropositivity was defined as LLOQ for follow-up time points, and at 1 month postvaccination, 100% of participants had detectable antibodies for each pertussis antigen (Table 6). Antibodies persisted at levels higher than prevaccination at 5 years, but returned to those levels after 10 years for PT and FHA (Figure 2). Anti-PRN and anti-fim antibody levels at 10 years were still above prevaccination levels. PT had the lowest percentage of participants with detectable antibodies after 10 years (74.1%); the other three antigens were higher (96.5% 98.2%). Results for immunogenicity outcomes were similar between the ITT and PP populations. 14

15 DISCUSSION Tdap-IPV is approved in numerous countries around the world as a booster vaccine in persons 3 years of age and older. This study examined coadministration of Tdap-IPV with HepB in adolescents and the persistence of Tdap-IPV antibodies for up to 10 years. The solicited AE rates were generally comparable to those observed in adolescents and adults who were vaccinated with a single dose of a Tdap or Tdap-Polio vaccine (26). AE rates were comparable between study groups. There were no consistent increases in rates of solicited reactions or unsolicited AEs when Tdap-IPV and HepB were coadministered at separate injection sites, except for pain reports at hours postvaccination. One month after the Tdap-IPV vaccination, immune responses to all antigens were robust. Long-term immunogenicity results from this study are consistent with results from a pooled analysis of 10-year immunogenicity data from three clinical trials conducted in adolescents and adults (19). In that analysis, 99.3% of adolescents had protective levels of antibodies against diphtheria and tetanus and seropositivity to 1 or more pertussis antigens 10 years after their booster dose of Tdap. Adolescents in one of the studies included in the pooled analysis also received HepB vaccine, which did not appear to affect immunogenicity of diphtheria, tetanus, and pertussis, similar to the results presented here. While pertussis protective levels have not yet been clearly defined, previous publications have defined minimal long-term protective levels as greater than the LLOQ value (14, 27). For all pertussis antigens at 1 month postvaccination, all participants achieved antibody levels that were LLOQ; at 10 years postvaccination, between 74.1% and 98.2% of participants (2 groups combined) maintained detectable antibody levels. Further, all vaccinees maintained seroprotective levels for diphtheria, tetanus and all 3 poliovirus serotypes at 10 years after Tdap- 15

16 IPV administration. Thus, the long-term antibody profile suggests seroprotection against diphtheria, tetanus and poliomyelitis is maintained for at least 10 years after booster adolescent vaccination. The study had some limitations. The study was powered to evaluate immunogenicity and rare AEs or SAEs may not have been detected. Safety was assessed for 14 days after each vaccination (except for SAEs, which were collected at any time through 30 days after the last vaccination), but was not collected throughout the 10-year follow-up. Only 62.8% of participants could be assessed at the 10-year follow-up and not all participants could be assessed at all timepoints. The determination of prior exposure to pertussis disease or pertussis vaccination was based on participants recall only and was not verified from medical records. When given alone or concurrently with HepB, the results demonstrated that Tdap-IPV is safe and immunogenic in 11- to 14-year-old adolescents. Clinically relevant immunologic interactions did not occur when Tdap-IPV and HepB were given concurrently, which provides evidence for a recommendation that the vaccines can be administered simultaneously. This strategy would eliminate the need for an additional medical visit and facilitate cost-effective vaccination. This approach would also improve the ability of immunization programs to meet target goals for vaccine coverage. 16

17 ACKNOWLEDGMENTS We thank the Study Investigators and the staff at University of Manitoba. Robert Lersch of Sanofi Pasteur reviewed and edited the manuscript FUNDING AND ROLE OF THE SPONSOR: This study was funded by Sanofi Pasteur, which also contributed to study design, data collection, analysis and interpretation, review of manuscript and decision to publish. AUTHOR DISCLOSURES: J. Embree and B. Law had no conflicts of interest to declare. T.Voloshen and A.Tomovici are employees of Sanofi Pasteur. AUTHOR CONTRIBUTIONS: J.Embree and B. Law participated in study design and data acquisition. T.Voloshen and A.Tomovici participated in study design, and acquisition and interpretation of data. All authors helped write, edit or review the manuscript. 17

18 335 REFERENCES Centers for Disease Control and Prevention (CDC) Notifiable Diseases and Mortality Tables. MMWR Morb. Mortal. Wkly. Rep. 59: Sin MA, Zenke R, Ronckendorf R, Littmann M, Jorgensen P, Hellenbrand W Pertussis outbreak in primary and secondary schools in Ludwigslust, Germany demonstrating the role of waning immunity. Pediatr. Infect. Dis. J. 28: Edwards KM Overview of pertussis: focus on epidemiology, sources of infection, and long term protection after infant vaccination. Pediatr. Infect. Dis. J. 24:S World Health Organization Pertussis vaccines: WHO position paper. Wkly. Epidemiol. Rec. 40: Poolman JT, Hallander H, Halperin SA Pertussis vaccines: where to now? Expert Rev. Vaccines. 10: Wood N, McIntyre P Pertussis: review of epidemiology, diagnosis, management and prevention. Paediatr. Respir. Rev. 9: Centers for Disease Control and Prevention (CDC) Pertussis Epidemic Washington, MMWR Morb. Mortal. Wkly. Rep. 61:

19 Centers for Disease Control and Prevention (CDC) Notifiable diseases and mortality tables. MMWR Morb. Mortal. Wkly. Rep. 61:ND635-ND Kowalzik F, Barbosa AP, Fernandes VR, Carvalho PR, Avila-Aguero ML, Goh DY, Goh A, de Miguel JG, Moraga F, Roca J, Campins M, Huang M, Quian J, Riley N, Beck D, Verstraeten T Prospective multinational study of pertussis infection in hospitalized infants and their household contacts. Pediatr. Infect. Dis. J. 26: de Greeff SC, Mooi FR, Westerhof A, Verbakel JM, Peeters MF, Heuvelman CJ, Notermans DW, Elvers LH, Schellekens JF, de Melker HE Pertussis disease burden in the household: how to protect young infants. Clin. Infect. Dis. 50: Coudeville L, van Rie A, Andre P Adult pertussis vaccination strategies and their impact on pertussis in the United States: evaluation of routine and targeted (cocoon) strategies. Epidemiol. Infect. 136: National Advisory Committee on Immunization (NACI) Statement on alternate adolescent schedule for hepatitis B vaccine (ACS-5). An Advisory Committee Statement (ACS). Can. Commun. Dis. Rep. 26: McIntyre PB, Turnbull FM, Egan AM, Burgess MA, Wolter JM, Schuerman LM High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine. Vaccine. 23:

20 Edelman KJ, He Q, Makinen JP, Haanpera MS, Tran Minh NN, Schuerman L, Wolter J, Mertsola JA Pertussis-specific cell-mediated and humoral immunity in adolescents 3 years after booster immunization with acellular pertussis vaccine. Clin. Infect. Dis. 39: Barreto L, Guasparini R, Meekison W, Noya F, Young L, Mills E Humoral immunity 5 years after booster immunization with an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine. Vaccine. 25: Mertsola J, Van Der Meeren O, He Q, Linko-Parvinen A, Ramakrishnan G, Mannermaa L, Soila M, Pulkkinen M, Jacquet JM Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. Clin. Infect. Dis. 51: McIntyre PB, Burgess MA, Egan A, Schuerman L, Hoet B Booster vaccination of adults with reduced-antigen-content diphtheria, Tetanus and pertussis vaccine: immunogenicity 5 years post-vaccination. Vaccine. 27: Booy R, Van der Meeren O, Ng SP, Celzo F, Ramakrishnan G, Jacquet JM A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (Boostrix) is immunogenic and well tolerated in adults. Vaccine. 29: Tomovici A, Barreto L, Zickler P, Meekison W, Noya F, Voloshen T, Lavigne P Humoral immunity 10 years after booster immunization with an adolescent and adult formulation 20

21 combined tetanus, diphtheria, and 5-component acellular pertussis vaccine. Vaccine. 30: Bailleux F, Coudeville L, Kolenc-Saban A, Bevilacqua J, Barreto L, Andre P Predicted long-term persistence of pertussis antibodies in adolescents after an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine, based on mathematical modeling and 5-year observed data. Vaccine. 26: Adacel -Polio Product Monograph. Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed combined with inactivated poliomyelitis vaccine Sanofi Pasteur Ltd., Toronto, Ontario, Canada. 22. Recombivax HB Product Monograph. Hepatitis B vaccine (recombinant) Merck Canada Inc., Kirkland, Quebec, Canada. 23. World Health Organization, Department of Immunization, Vaccines and Biologicals The Immunological Basis for Immunization Series. Module 4: Pertussis - Update World Health Organization, Geneva, Switzerland 24. Farrington C, Manning G Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat.Med. 9:

22 World Health Organization, Department of Immunization, Vaccines and Biologicals The Immunological Basis for Immunization Series. Module 2: Diphtheria - Update World Health Organization, Geneva, Switzerland Halperin SA, Smith B, Russell M, Scheifele D, Mills E, Hasselback P, Pim C, Meekison W, Parker R, Lavigne P, Barreto L Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults. Pediatr. Infect. Dis. J. 19: Storsaeter J, Hallander HO, Gustafsson L, Olin P Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine. 16:

23 Table 1. Summary of local adverse events reported at 0-24 hours and hours postvaccination (ITT analysis set) Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity 0-24 hours postvaccination Redness Swelling Pain n (%) 36 (25.0) 9 (6.3) 31 (21.5) 22 (15.3) 138 (95.8) 55 (38.2) n (%) 30 (22.7) 12 (9.1) 27 (20.5) 23 (17.4) 126 (95.5) 52 (39.4) % (95% CI) -2.3 (-10.7, 6.2) 2.8 (-2.4, 8.1) -1.1 (-9.1, 7.0) 2.1 (-5.2, 9.5) -0.4 (-4.4, 3.7) 1.2 (-8.5, 10.9) Downloaded from Lymph node swelling hours postvaccination Redness Swelling 7 (4.9) 1 (0.7) 22 (15.3) 4 (2.8) 18 (12.5) 10 (6.9) 3 (2.3) 2 (1.5) 19 (14.4) 9 (6.8) 17 (12.9) 14 (10.6) -2.6 (-6.2, 1.1) 0.8 (-1.3, 2.9) -0.9 (-7.9, 6.2) 4.0 (-0.2, 8.3) 0.4 (-6.2, 7.0) 3.7 (-2.0, 9.3) on November 10, 2018 by guest Pain 84 (58.3) 67 (50.8) -7.6 (-17.4, 2.3) 7 (4.9) 10 (7.6) 2.7 (-2.1, 7.5) 23

24 Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity n (%) n (%) % (95% CI) Lymph node swelling 7 (4.9) 5 (3.8) -1.1 (-5.1, 2.9) (0.7) 1 (0.8) a Group1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. c Difference = Group 2 rate Group 1 rate. ITT, intent-to-treat; CI, confidence interval. 0.1 (-1.6, 1.7) Downloaded from on November 10, 2018 by guest 24

25 423 Table 2. Summary of systemic adverse events (ITT analysis set) Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity n (%) n (%) % (95% CI) 0-24 hours postvaccination Fever Chills Headache Nausea 3 (2.1) 0 25 (17.4) 6 (4.2) 51 (35.4) 10 (6.9) 3 (2.3) 1 (0.8) 21 (15.9) 3 (2.3) 47 (35.6) 8 (6.1) 0.2 (-2.7, 3.1) 0.8 (-0.5, 2.0) -1.5 (-8.8, 5.9) -1.9 (-5.4, 1.6) 0.2 (-9.3, 9.7) -0.9 (-5.8, 4.0) Downloaded from Vomiting Diarrhea Bodyache/muscle weakness 20 (13.9) 5 (3.5) 2 (1.4) 1 (0.7) 3 (2.1) 0 59 (41.0) 22 (16.7) 4 (3.0) (5.3) 1 (0.8) 50 (37.9) 2.8 (-4.4, 9.9) -0.4 (-4.0, 3.1) -1.4 (-3.0, 0.2) -0.7 (-1.8, 0.4) 3.2 (-0.5, 7.0) 0.8 (-0.5, 2.0) -3.1 (-12.8, 6.6) on November 10, 2018 by guest 12 (8.3) 17 (12.9) 4.5 (-1.6, 10.7) Tiredness 58 (40.3) 53 (40.2) -0.1 (-9.8, 9.6) 7 (4.9) 12 (9.1) 4.2 (-0.8, 9.3) 25

26 Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity n (%) n (%) % (95% CI) Sore joints 26 (18.1) 27 (20.5) 2.4 (-5.4, 10.2) hours postvaccination Fever Chills Headache 6 (4.2) 4 (2.8) 0 11 (7.6) 1 (0.7) 30 (20.8) 2 (1.4) 6 (4.5) 2 (1.5) 0 9 (6.8) 0 31 (23.5) 1 (0.8) 0.4 (-3.7, 4.4) -1.3 (-4.1, 1.6) NA -0.8 (-6.0, 4.3) -0.7 (-1.8, 0.4) 2.7 (-5.6, 10.9) -0.6 (-2.7, 1.4) Downloaded from Nausea Vomiting Diarrhea Bodyache/muscle weakness 9 (6.3) 1 (0.7) (4.9) 0 15 (11.4) 2 (1.5) (3.0) (-0.5, 10.8) 0.8 (-1.3, 2.9) NA NA -1.8 (-5.7, 2.0) NA on November 10, 2018 by guest 24 (16.7) 23 (17.4) 0.8 (-6.7, 8.2) 4 (2.8) 2 (1.5) -1.3 (-4.1, 1.6) 26

27 Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity n (%) n (%) % (95% CI) Tiredness 31 (21.5) 31 (23.5) 2.0 (-6.3, 10.3) Sore joints 3-14 days postvaccination Fever Chills 3 (2.1) 15 (10.4) 6 (4.2) 3 (2.1) 1 (0.7) 26 (18.1) 3 (2.1) 3 (2.3) 14 (10.6) 0 7 (5.3) 0 17 (12.9) 2 (1.5) 0.2 (-2.7, 3.1) 0.2 (-5.9, 6.3) -4.2 (-6.9, -1.4) 3.2 (-0.5, 7.0) -0.7 (-1.8, 0.4) -5.2 (-12.3, 2.0) -0.6 (-3.2, 2.1) Downloaded from Headache Nausea Vomiting Diarrhea 58 (40.3) 18 (12.5) 30 (20.8) 13 (9.0) 6 (4.2) 1 (0.7) 52 (39.4) 12 (9.1) 17 (12.9) 5 (3.8) 3 (2.3) 1 (0.8) -0.9 (-10.6, 8.8) -3.4 (-9.5, 2.7) -8.0 (-15.3, -0.6) -5.2 (-10.0, -0.5) -1.9 (-5.4, 1.6) 0.1 (-1.6, 1.7) on November 10, 2018 by guest 23 (16.0) 20 (15.2) -0.8 (-8.0, 6.4) 6 (4.2) 2 (1.5) -2.7 (-5.9, 0.6) 27

28 Group 1 a Group 2 b (N = 144) (N = 132) Difference c Event and intensity n (%) n (%) % (95% CI) Bodyache/muscle weakness 21 (14.6) 28 (21.2) 6.6 (-1.0, 14.2) (4.9) 5 (3.8) Tiredness 39 (27.1) 30 (22.7) 14 (9.7) 8 (6.1) Sore joints 21 (14.6) 12 (9.1) 7 (4.9) 5 (3.8) a Group1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. c Difference = Group 2 rate Group 1 rate. ITT, intent-to-treat; CI, confidence interval; NA, not applicable (-5.1, 2.9) -4.4 (-12.9, 4.2) -3.7 (-9.0, 1.6) -5.5 (-11.8, 0.9) -1.1 (-5.1, 2.9) Downloaded from on November 10, 2018 by guest 28

29 Table 3. Diphtheria and tetanus seroprotection rates as measured by the proportion of participants with antibody levels 0.01 IU/mL or 0.1 IU/mL prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) Group 1 a Group 2 b 0.01 IU/mL 0.1 IU/mL 0.01 IU/mL 0.1 IU/mL Antigen and visit n/n % (95% CI) % (95% CI) n/n % (95% CI) % (95% CI) Diphtheria Prevaccination 142/ (95.1, 99.8) 81.9 (74.7, 87.9) 132/ (75.9, 89.3) 100 (97.2, 100) 1 month 142/ (97.4, 100) 98.6 (95.0, 99.8) 132/ (97.2, 100) 100 (97.2, 100) 3 years 110/ (96.7, 100) 91.8 (85.0, 96.2) 98/ (82.4, 95.1) 98.0 (93.0, 99.8) 5 years 108/ (93.6, 99.8) 76.4 (67.3, 83.9) 96/ (66.3, 84.2) 100 (96.2, 100) 10 years 86/ (95.8, 100) 88.4 (79.7, 94.3) 70/ (72.0, 90.8) 100 (94.9, 100) Tetanus Prevaccination 144/ (97.5, 100) 99.3 (96.2, 100) 132/ (97.2, 100) 100 (97.2, 100) 1 month 142/ (97.4, 100) 100 (97.4, 100) 132/ (97.2, 100) 100 (97.2, 100) 3 years 109/ (96.7, 100) 100 (96.7, 100) 100/ (96.4, 100) 100 (96.4, 100) 5 years 107/ (96.6, 100) 100 (96.6, 100) 96/ (94.3, 100) 100 (96.2, 100) 10 years 80/ (95.5, 100) 100 (95.5, 100) 69/ (89.9, 99.6) 100 (94.8, 100) a Group 1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, confidence interval. 29

30 Table 4. Seroprotection rates for poliovirus ( 1:8 dilution) and hepatitis B ( 10 miu/ml) antigens prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) Group 1 a Group 2 b Antigen and visit n/n % (95% CI) n/n % (95% CI) Poliovirus serotype 1 Prevaccination 1 month 3 years 5 years 10 years Poliovirus serotype 2 Prevaccination 1 month 3 years 5 years 10 years Poliovirus serotype 3 Prevaccination 1 month 3 years 5 years 10 years 138/ / / /118 91/91 143/ / / /118 91/91 137/ / / /118 90/ (91.2, 98.5) 100 (97.4, 100) 100 (96.9, 100) 100 (96.9, 100) 100 (96.0, 100) 99.3 (96.2, 100) 100 (97.4, 100) 100 (96.9, 100) 100 (96.9, 100) 100 (96.0, 100) 95.1 (90.2, 98) 100 (97.4, 100) 100 (96.9, 100) 100 (96.9, 100) 100 (96.0, 100) 124/ / / /106 82/82 132/ / / /106 82/82 126/ / / /106 80/ (88.4, 97.3) 100 (97.2, 100) 100 (96.6, 100) 100 (96.6, 100) 100 (95.6, 100) 100 (97.2, 100) 100 (97.2, 100) 100 (96.6, 100) 100 (96.6, 100) 100 (95.6, 100) 95.5 (90.4, 98.3) 100 (97.2, 100) 100 (96.6, 100) 100 (96.6, 100) 100 (95.5, 100) Hepatitis B c 116/ (96.9, 100) 123/ (97.1, 100) a Goup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. c Hepatitis B data are from samples collected 1 month after dose 3 only. ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, confidence interval. 30

31 Table 5. Geometric mean titers for diphtheria (IU/mL), tetanus (IU/mL), and poliovirus ( 1:8 dilution) antigens prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) Group 1 a Group 2 b Combined Groups 1 and 2 Antigen and visit N GMT (95% CI) N GMT (95% CI) N GMT (95% CI) Diphtheria Prevaccination (0.24, 0.39) (0.31, 0.49) (0.29, 0.40) 1 month (4.21, 6.21) (4.97, 7.00) (4.81, 6.24) 3 years (0.41, 0.63) (0.44, 0.74) (0.45, 0.63) 5 years (0.17, 0.27) (0.18, 0.28) (0.19, 0.26) 10 years (0.26, 0.45) (0.23, 0.39) (0.27, 0.39) Tetanus Prevaccination (0.51, 0.65) (0.54, 0.69) (0.54, 0.64) 1 month (6.79, 8.59) (6.12, 7.90) (6.70, 7.95) 3 years (1.19, 1.50) (1.15, 1.50) (1.22, 1.45) 5 years (0.77, 1.04) (0.80, 1.10) (0.82, 1.02) 10 years (0.54, 0.79) (0.58, 0.87) (0.59, 0.78) Poliovirus serotype 1 Prevaccination (60.01, 104.6) (65.05, 117.8) (67.92, 101.6) 1 month (30950, 53040) (19460, 31100) (26590, 38180) 3 years (1749, 2996) (1264, 2265) (1625, 2412) 5 years (475.4, 722.4) (410.7, 613.8) (471.3, 629.5) 10 years (411.1, 657.4) (412.0, 641.6) (440.5, 607.2) 31

32 Group 1 a Group 2 b Combined Groups 1 and 2 Antigen and visit N GMT (95% CI) N GMT (95% CI) N GMT (95% CI) Poliovirus serotype 2 Prevaccination 1 month 3 years 5 years 10 years (129.50, ) (41590, 67883) (3952.8, ) (966.53, ) (580.47, ) (147.94, ) (27344, 40717) (3375.6, ) (894.97, ) (521.63, ) Poliovirus serotype 3 Prevaccination (38.32, 61.75) (36.95, 57.20) 1 month (174400, ) (104900, ) 3 years (4431, 7663) (4021, 7283) 5 years (664.4, 1077) (642.0, 1061) 10 years (584.7, 983.6) (583.6, 1050) a Goup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. GMT, geometric mean titer; ITT, intent-to-treat; CI, confidence interval (145.99, ) (36168, 49860) (3984.9, ) (997.72, ) (594.19, ) (40.28, 55.65) (147600, ) (4605, 6869) (703.4, 993.9) (634.6, 933.7)

33 Table 6. Seropositivity rates for pertussis antigens ( LLOQ) prevaccination and at 1 month and 3, 5, and 10 years postvaccination (ITT analysis set) Group 1 a Group 2 b Combined Groups 1 and 2 Antigen and visit n/n % (95% CI) n/n % (95% CI) n/n % (95% CI) PT Prevaccination 121/ (77.0, 89.6) 105/ (71.7, 86.1) 226/ (76.8, 86.2) 1 month 142/ (97.4, 100) 132/ (97.2, 100) 274/ (98.7, 100) 3 years 107/ (91.0, 99.0) 100/ (90.4, 98.9) 207/ (92.8, 98.4) 5 years 114/ (93.9, 99.8) 97/ (87.8, 97.8) 211/ (92.9, 98.4) 10 years 63/ (61.0, 80.7) 60/ (66.0, 85.7) 123/ (66.7, 80.6) FHA Prevaccination 142/ (96.2, 100) 130/ (94.6, 99.8) 272/ (96.8, 99.8) 1 month 142/ (97.4, 100) 132/ (97.2, 100) 274/ (98.7, 100) 3 years 114/ (96.8, 100) 104/ (96.5, 100) 218/ (98.3, 100) 5 years 116/ (96.9, 100) 102/ (96.4, 100) 218/ (98.3, 100) 10 years 89/ (94.0, 100) 78/ (91.3, 99.7) 167/ (94.9, 99.6) PRN Prevaccination 115/ (72.4, 86.1) 108/ (74.2, 88.0) 223/ (75.6, 85.3) 1 month 142/ (97.4, 100) 132/ (97.2, 100) 274/ (98.7, 100) 3 years 113/ (95.2, 100) 104/ (96.5, 100) 217/ (97.5, 100) 5 years 114/ (93.9, 99.8) 102/ (94.7, 100) 215/ (96.0, 99.7) 10 years (89.0, 98.8) 78/ (91.3, 99.7) 164/ (92.5, 98.7) 33

34 Group 1 a Group 2 b Combined Groups 1 and 2 Antigen and visit n/n % (95% CI) n/n % (95% CI) n/n % (95% CI) FIM Prevaccination 1 month 3 years 5 years 10 years 113/ / / /115 87/ (71.4, 85.4) 100 (97.4, 100) 99.1 (95.2, 100) 100 (96.8, 100) 96.7 (90.6, 99.3) 113/ / / /103 78/ (79.2, 91.6) 100 (97.2, 100) 99.0 (94.8, 100) 98.1 (93.2, 99.8) 97.5 (91.3, 99.7) 226/ / / / / (77.5, 86.8) 100 (98.7, 100) 99.1 (96.7, 99.9) 99.1 (96.7, 99.9) 97.1 (93.3, 99.0) a Goup1 received Tdap-IPV at month 0 and HepB at months 1, 2, and 7. b Group 2 received Tdap-IPV + HepB at month 0 and HepB at months 1 and 6. ITT, intent-to-treat; n, number of participants with result; N, number of participants with available data; CI, confidence interval; PT, pertussis toxin; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, fimbrae 2 and 3. 34

35 FIGURE LEGENDS Figure 1. Participant disposition. AE, adverse event; ITT, intent-to-treat; PP, per-protocol Figure 2. Reverse cumulative distribution curves of antibody responses to pertussis antigens. Reverse cumulative distribution curves for antibodies to (A) PT (LLOQ, 4-5 EU/mL), (B), FHA (LLOQ, 3 EU/mL), (C) PRN (LLOQ, 3-4 EU/mL), and (D) FIM (LLOQ, 4-17 EU/mL) are shown for samples collected prevaccination (black lines) and at 1 month (brown lines), 3 years (dark blue lines), 5 years (light blue lines), and 10 years (red lines) postvaccination are shown. PT, pertussis toxin; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, fimbriae 2 and 3; EU, ELISA units; LLOQ, lower limit of quantitation. 35

36 Participants enrolled N = 280 Allocated to Group 1 TdcP-IPV, HepB N = 145 Allocated to Group 2 TdcP-IPV+HepB N = did not receive study vaccine 3 discontinued from study: Voluntary withdrawal not due to AE (n=2) Other reason (n=1) 144 in ITT analysis set 118 in PP analysis set 142 completed vaccination 116 completed 3-year follow-up 118 completed 5-year follow-up 2 did not receive study vaccine 6 discontinued from study: Voluntary withdrawal not due to AE (n=6) 132 in ITT analysis set 123 in PP analysis set 129 completed vaccination 108 completed 3-year follow-up 107 completed 5-year follow-up Downloaded from completed 10-year follow-up 83 completed 10-year follow-up on November 10, 2018 by guest 36

37 468 Downloaded from on November 10, 2018 by guest 37