Share this article on:

A Phase 2, Randomized, Active-controlled, Observer-blinded Study to Assess the Immunogenicity, Tolerability and Safety of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered With Tetanus, Diphtheria and Acellular Pertussis Vaccine and Serogroup A, C, Y and W-135 Meningococcal Conjugate Vaccine in Healthy US Adolescents

Muse, Derek MD; Christensen, Shane MD; Bhuyan, Prakash MD, PhD; Absalon, Judith MD; Eiden, Joseph J. MD, PhD; Jones, Thomas R. PhD; York, Laura J. PhD; Jansen, Kathrin U. PhD; O’Neill, Robert E. PhD; Harris, Shannon L. PhD; Perez, John L. MD, MA

The Pediatric Infectious Disease Journal: June 2016 - Volume 35 - Issue 6 - p 673–682
doi: 10.1097/INF.0000000000001124
Vaccine Reports

Background: Bivalent rLP2086, targeting meningococcal serogroup B, will extend prevention of meningococcal disease beyond that provided by quadrivalent serogroup ACWY vaccines; coadministration with recommended vaccines may improve adherence to vaccine schedules. This phase 2, randomized, active-controlled, observer-blinded study assessed whether immune responses induced by coadministration of Menactra (meningococcal A, C, Y and W-135 polysaccharide conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine [Tdap]) with bivalent rLP2086 (Trumenba [meningococcal serogroup B vaccine], approved in the United States) were noninferior to MCV4 + Tdap or bivalent rLP2086 alone.

Methods: Healthy adolescents aged 10 to <13 years received MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086. Bivalent rLP2086 response was assessed with serum bactericidal assays using human complement with 2 meningococcal serogroup B test strains expressing vaccine-heterologous factor H–binding protein variants; MCV4 with SBAs using rabbit complement; and Tdap with multiplexed Luminex assays. Safety was evaluated.

Results: Two thousand six hundred forty-eight subjects were randomized. Immune responses to MCV4 + Tdap + bivalent rLP2086 were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. Seroprotective serum bactericidal assays using human complement titers were documented for 62.3%–68.0% and 87.5%–90% of MCV4 + Tdap + bivalent rLP2086 recipients after doses 2 and 3, respectively. A ≥4-fold rise in serum bactericidal assays using human complement titers from baseline was achieved by 56.3%–64.3% and 84.0%–85.7% of subjects after doses 2 and 3, respectively. Bivalent rLP2086 alone induced similar responses. Concomitant administration did not substantially increase reactogenicity compared with bivalent rLP2086 alone.

Conclusions: Bivalent rLP2086 given concomitantly with MCV4 + Tdap met all noninferiority immunogenicity criteria without a clinically meaningful increase in reactogenicity. MCV4 and bivalent rLP2086 coadministration would provide coverage against the 5 major disease-causing serogroups.

Supplemental Digital Content is available in the text.

From the *Jean Brown Research and Foothill Family Clinic, Salt Lake City, UT; Pfizer Vaccine Clinical Research, Collegeville, PA; §Pfizer Vaccine Clinical Research, Pfizer Vaccine Research Operations and Strategy, and Pfizer Vaccine Research and Development, Pearl River, NY; and **Pfizer Medical and Scientific Affairs, Collegeville, PA.

Accepted for publication February 13, 2016.

This study and editorial/medical writing support was funded by Pfizer Inc. Prakash Bhuyan, Judith Absalon, Joseph J. Eiden, Thomas R. Jones, Laura J. York, Kathrin U. Jansen, Robert E. O’Neill, Shannon L. Harris, and John L. Perez are employees of Pfizer. Derek Muse and Shane Christensen, as study investigators, received research support from Pfizer for the completion of this study. The authors have no other conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Derek Muse, MD, Jean Brown Research, 1045 E 3900 South St, Salt Lake City, UT 84124. E-mail: dmuse@jbrutah.com

Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in infants, adolescents and young adults.1 N. meningitidis serogroup B (MnB) is responsible for the majority of invasive meningococcal disease cases in Europe and ≈30% to 40% of cases in the United States.2,3 Case fatality is ≈10%,4–7 with almost 20% of survivors experiencing substantial morbidity.1 Recently, MnB outbreaks were observed at several university campuses in the United States,8 making MnB disease a major health concern in adolescent and young adult populations. Currently, 2 MnB vaccines are licensed in the United States: bivalent rLP2086 (Trumenba [meningococcal group B vaccine]; Pfizer Inc, Collegeville, PA) and 4CMenB (Bexsero [meningococcal group B vaccine]; Novartis Inc, Cambridge, MA).

Bivalent rLP2086, composed of equal amounts of recombinant subfamily A and B factor H–binding proteins (fHBP), was the first MnB vaccine approved in the United States to prevent invasive MnB disease in individuals 10 to 25 years of age.9 Preclinical and clinical studies completed to date have demonstrated that bivalent rLP2086 elicits serum bactericidal antibodies capable of killing diverse MnB disease strains expressing fHBPs that are homologous and heterologous to vaccine components.10–16

Licensed MnB vaccines are now important additions to other vaccines currently available and recommended for preventive care in adolescents in the United States.17 A booster dose of tetanus, diphtheria and acellular pertussis (Tdap) vaccine is recommended by the Advisory Committee on Immunization Practices (ACIP) in adolescents 11−12 years of age, with a booster of Td every 10 years,18,19 to maintain protection against pertussis, tetanus and diphtheria. Pregnant women should receive Tdap at each pregnancy. Vaccination with a quadrivalent meningococcal conjugate vaccine (MCV4) for adolescents 11 or 12 years of age, with a booster dose at 16 years of age, is also recommended by ACIP for the prevention of disease caused by meningococcal serogroups A, C, Y and W-135.1,20 In practice, many children in the United States receive both MCV4 and Tdap vaccines at 10 years of age because of school entry requirements.21,22 In addition, 3 doses of the bivalent, quadrivalent or nonavalent human papillomavirus vaccine (HPV2, HPV4 or HPV9) are recommended for both adolescent males and females.23

Earlier studies have identified the lack of concomitant vaccination as a significant contributor to missed vaccination opportunities.24 The ACIP has recommended the concomitant administration of MCV4 with Tdap in adolescents 11–18 years of age as a mechanism to increase adherence and simplify vaccine administration.18 Therefore, a study demonstrating that coadministration of bivalent rLP2086 with these currently recommended adolescent vaccines does not alter their safety and immunogenicity profiles can lend support for additional guidance regarding concomitant vaccine administration.

Previous studies in healthy adolescents have shown the safety and immunogenicity of concomitant administration of bivalent rLP2086 with the diphtheria, tetanus and acellular pertussis and inactivated poliomyelitis vaccine or HPV4.25,26 The current study assessed the safety, tolerability and immunogenicity of bivalent rLP2086 vaccine administered concomitantly with MCV4 and Tdap in healthy adolescents aged 10 to <13 years.

Back to Top | Article Outline

MATERIALS AND METHODS

Study Design

This phase 2, randomized, active-controlled, observer-blind multicenter study (ClincalTrials.gov Identifier: NCT01461980) conducted in the United States at 80 sites evaluated the immunogenicity and safety of concomitant administration of bivalent rLP2086, Tdap and MCV4. Subjects 10 to <13 years were randomly assigned to 1 of 3 groups in a 1:1:1 ratio to receive either MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086 alone. Bivalent rLP2086 was administered at months 0, 2 and 6 for both the MCV4 + Tdap + bivalent rLP2086 and bivalent rLP2086 only groups. MCV4 + Tdap was administered at month 0 for both the MCV4 + Tdap + bivalent rLP2086 and MCV4 + Tdap groups. Subjects in the bivalent rLP2086 only group also received a dose of MCV4 + Tdap after the last blood draw at month 7 to ensure receipt of ACIP recommended vaccines by all study subjects (Fig. 1).

FIGURE 1

FIGURE 1

Allocation of subjects in a 1:1:1 ratio to vaccine groups proceeded through the use of an interactive voice response system, interactive web-based response system or an equivalent system. The site was provided with a subject randomization number and kit randomization number, and study injections were performed by a qualified, unblinded individual who was not involved in safety assessment. Study subjects, investigators and the sponsor were blinded to subject allocation to study group.

The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki, in compliance with all Good Clinical Practice guidelines and in accordance with the general principles set forth by the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Participants’ parents or legal guardians gave written informed consent.

Back to Top | Article Outline

Study Objectives

Coprimary immunogenicity objectives were to demonstrate that immune responses induced by MCV4 + Tdap when given with bivalent rLP2086 are noninferior to those induced by MCV4 + Tdap alone and to demonstrate that immune responses induced by bivalent rLP2086 when given with MCV4 + Tdap are noninferior to the immune responses induced by bivalent rLP2086 alone. Secondary immunogenicity objectives were to describe the immune responses to bivalent rLP2086 as measured by serum bactericidal assays using human complement (hSBA) 1 month after doses 2 and 3 and to describe the immune responses to MCV4 or Tdap as measured by serum bactericidal assays with rabbit complement (rSBA) or binding antibody assays to Tdap antigens, respectively, 1 month after vaccination 1. Other immunogenicity objectives described the immunogenicity of bivalent rLP2086 as a 4-fold rise in hSBA responses to 2 MnB test strains compared with baseline, 1 month after doses 2 and 3.

The primary safety objectives evaluated the safety profile of bivalent rLP2086 as measured by the proportion of subjects reporting local reactions, systemic events and adverse events (AEs).

Back to Top | Article Outline

Study Participants

Children were recruited for the study by experienced vaccine clinical investigators. The children’s medical history was reviewed, and the children were given a physical examination. In general, children were considered healthy by their physician if they were able to participate in the protocol procedures and did not have a medical condition that would place them at increased risk by participating in the study (eg, a bleeding disorder). Additionally, children could not be on medication or in treatment for a disorder that would prevent them from responding to bivalent rLP2086, Tdap or MCV4.

Study participants included healthy males or nonpregnant females 10 to <13 years of age. Written informed consent was obtained from parent(s)/legal guardian(s) of each subject before enrollment and before performance of any study-related procedures. Each subject must have received a full series (5-dose series was preferred, 4-dose catch up series was allowed) of diphtheria, tetanus and pertussis (whole cell or acellular) vaccines as recommended at study entry. Exclusion criteria included previous vaccination with any MnB, MCV4, diphtheria, tetanus or pertussis vaccine within 5 years of the first study vaccination; previous anaphylactic reaction to any vaccine or vaccine component; contraindication to vaccination with MCV4 or Tdap; receipt of allergen immunotherapy (nonlicensed or not on a stable dose); a history of culture-proven disease caused by N. meningitidis or Neisseria gonorrhoeae; receipt of blood products within 6 months before first vaccination; a severe acute or chronic medical or psychiatric condition or laboratory abnormality; or subjects who were pregnant or breastfeeding.

Back to Top | Article Outline

Vaccines and Interventions

Bivalent rLP2086, recently licensed in the United States under accelerated approval as Trumenba, was administered intramuscularly into the upper deltoid muscle of the left arm. Bivalent rLP2086 was formulated as described in the prescribing information.16 Menactra (meningococcal [Groups A, C, Y, and W-135] polysaccharide diphtheria toxoid conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed [Tdap]) were administered by intramuscular injection into the upper deltoid muscle of the right arm as described in the prescribing information.27,28 For the MCV4 + Tdap group, saline (0.9% sodium chloride) was administered as a placebo by intramuscular injection into the upper deltoid muscle of the left arm for 3 injection visits; subjects in the bivalent rLP2086 only group received 2 saline injections in right arm for their first vaccination visit to maintain the study blind.

Back to Top | Article Outline

Immunogenicity Analysis

Approximately 10–20 mL of blood was collected at baseline and 1 month after each vaccination. The primary analysis population for immunogenicity was the evaluable immunogenicity population, which included subjects who received the scheduled vaccines as randomized, had blood drawn within the protocol-specified window, had valid assay results, were eligible for the study and had no major protocol violations. Serum samples from the evaluable immunogenicity population after dose 1 were used to assess responses to MCV4 + Tdap. hSBA responses to bivalent rLP2086 were assessed using serum samples from the evaluable immunogenicity population after dose 3.

Bactericidal antibodies were measured using hSBA for bivalent rLP2086; hSBA titers ≥1:4 are considered to correlate with protection against invasive meningococcal disease.29 For the analyses in this study, hSBA titers at or above the lower limit of quantitation (LLOQ) were used and were defined as 1:8 and 1:16 for the MnB test strains PMB2948 (B24) and PMB80 (A22), respectively. hSBAs in the current study were based on the assay described by the World Health Organization30 and Borrow and colleagues31 and performed as reported previously.12 Titers were reported as step titers (ie, 1:4, 1:8, 1:16, etc).25,26

To assess the immunogenicity of bivalent rLP2086, sera were analyzed with hSBAs using 2 primary MnB test strains (PMB2948 and PMB80) that are included in the phase 3 studies for bivalent rLP208632 and express the 2 most prevalent fHBP variants in the United States, B24 and A22, respectively.33 These fHBP variants are heterologous to those in bivalent rLP2086.34 Responses were assessed by hSBA before the first vaccination with bivalent rLP2086, 1 month after the second vaccination with bivalent rLP2086 and 1 month after the third vaccination with bivalent rLP2086. A 4-fold increase was defined as follows: (1) for subjects with a baseline hSBA titer <1:4, a response was defined as an hSBA titer ≥1:16; and (2) for subjects with a baseline hSBA titer ≥1:4, a 4-fold response was defined as an hSBA titer ≥4 times the LLOQ or ≥4 times the baseline titer, whichever was higher. These criteria were the same as those used in the phase 3 studies for bivalent rLP2086.32

For MCV4, functional antibodies were analyzed in rSBAs with meningococcal test strains representing meningococcal serogroups A, C, Y and W-13535 before and 1 month after vaccination with MCV4. Previous studies found that rSBA cutoffs in the range of 1:4 to 1:64 at 1 month after vaccination with a meningococcal C conjugate vaccine were consistent with the observed efficacy.36 In the current study, for each serogroup in subjects with baseline rSBA titers <LLOQ, the baseline rSBA titer was imputed as 0.5 × LLOQ. For such subjects, seroconversion was indicated by postvaccination rSBA titers ≥4 times 0.5 × LLOQ (ie, ≥2 times LLOQ). In subjects with baseline rSBA titers ≥LLOQ, seroconversion was indicated by postvaccination rSBA titers ≥4 times the baseline titer. Additional assessments of MCV4 responses were performed using antibody binding assays based on a Luminex platform.37,38

For Tdap, immune responses to the 6 vaccine antigens were assessed using a 6-plex Luminex immunoassay before and 1 month after vaccination with Tdap. A positive response to the booster dose was assessed and defined as a ≥4-fold rise in antibody concentration if the baseline concentration was less than or equal to the cutoff value for each Tdap antigen or a ≥2-fold rise in antibody concentration if the baseline concentration was greater than the cutoff value. For diphtheria and tetanus, ≥0.1 IU/mL is considered a clinical response and was used as a cutoff value. For pertussis antigens, the 6-plex Luminex assay LLOQ was used as the cutoff value. The LLOQ values for pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2 and 3 were 0.9, 2.9, 3.0 and 10.6 EU/mL, respectively.39–43

Back to Top | Article Outline

Safety

Safety was evaluated for all subjects who received at least 1 dose of any investigational product. Reactogenicity measurements of local reactions (redness, swelling and pain), systemic events (fever, vomiting, diarrhea, headache, fatigue, chills, muscle pain other than muscle pain at the injection site and joint pain) and use of antipyretic medications were collected using an electronic diary for 7 days after each study injection. Reactogenicity measurements were recorded for the bivalent rLP2086 vaccine arm compared with saline or the MCV4 + Tdap + bivalent rLP2086 group. Reactogenicity measurements were not recorded separately by arm for the MCV4 + Tdap + bivalent rLP2086 group. Specifically, after vaccination at visit 1, subjects were asked to evaluate the local reactions in the left arm only. This would be at the injection site for bivalent rLP2086 for the bivalent rLP2086 only and MCV4 + Tdap + bivalent rLP2086 groups and at the saline injection site for the MCV4 + Tdap only group. Subjects were not asked to evaluate local reactions in their right arm where MCV4 + Tdap were given.

Unsolicited AEs were also recorded and assessed for severity, relationship to the study vaccine and seriousness. The severity of AEs was graded as mild if the event did not interfere with the subject’s usual function, moderate if the event interfered to some extent with the subject’s usual function and severe if the event interfered significantly with the subject’s usual function.

Back to Top | Article Outline

Statistical Analysis

Estimates of sample size for noninferiority were based on bivalent rLP2086-specific hSBA titers for the 2 primary strains with the common standard deviations of hSBA titers in natural logarithm scale12 and MCV4 and Tdap with common standard deviations in natural scale from the package insert (MCV4 or Tdap)27,28 or as previously described.44,45 The immune responses to the 6 vaccine antigens and 6 meningococcal strains were assumed to be independent. The study was powered using a type 1 error rate of 2.5% (1-sided test of noninferiority). The noninferiority margin was established when the lower limits of 95% confidence interval (CI) of each geometric mean (GM) ratio were above 0.67 (1.5 fold criteria). Assuming the natural log scale of the titers in the MCV4 + Tdap + bivalent rLP2086 group is the same as those in the MCV4 + Tdap group for MCV4 antigens/strains and the remaining antigens/strains are 0.13 less than that of MCV4 + Tdap alone or bivalent rLP2086 alone, with 700 evaluable subjects in each group, the overall power for declaring noninferiority for all 12 antigens/strains is 82.8%.

For the first coprimary noninferiority objective, each of the MCV4 antibody titers and Tdap antigen concentrations measured at 1 month after vaccination 1 was logarithmically transformed for analysis, and GMs were computed for the MCV4 + Tdap + bivalent rLP2086 and the MCV4 + Tdap groups, as well as the 2-sided 95% CI of the ratio ([MCV4 + Tdap + bivalent rLP2086]/[MCV4 + Tdap]) of GMs.

For the second coprimary noninferiority objective, the hSBA titers to each of the 2 primary MnB test strains measured at 1 month after dose 3 were logarithmically transformed for analysis, and GM titers (GMTs) were determined for the MCV4 + Tdap + bivalent rLP2086 and bivalent rLP2086 groups. The 2-sided 95% CI of the ratio ([MCV4 + Tdap + bivalent rLP2086]/bivalent rLP2086) of GMTs was determined for each of the 2 MnB strains. The ratio is equivalent to the mean difference of the logarithmically transformed results: log ([MCV4 + Tdap + bivalent rLP2086]/MCV4 + Tdap) = log (MCV4 + Tdap + bivalent rLP2086) – log (MCV4 + Tdap). The 2-sided 95% CIs for the ratio were constructed by back transformation of the CIs for the mean difference of the logarithmically transformed assay results computed using the Student t distribution.

For each of the coprimary objectives, noninferiority was achieved when the lower limit of the 2-sided 95% CI for the GM ratios 1 month after vaccination 1 for [MCV4 + Tdap + bivalent rLP2086]/[MCV4 + Tdap] and 1 month after vaccination 3 for [MCV4 + Tdap + bivalent rLP2086]/[bivalent rLP2086] were greater than 0.67 for MCV4 + Tdap antigens and each of the 2 primary MnB test strains.

For analysis of bivalent rLP2086 immunogenicity, the number and proportion of subjects who achieved hSBA titers ≥LLOQ at each blood sampling time point and the proportion of subjects achieving hSBA titers with a ≥4-fold rise from baseline were descriptively summarized along with the exact 2-sided 95% CI for each of the 2 MnB test strains after bivalent rLP2086 doses 2 and 3. The LLOQ was established during assay validation as an hSBA titer equal to 1:8 for PMB2948 (B24) and 1:16 for PMB80 (A22). GMTs and 2-sided 95% CIs were calculated for each of the 2 MnB strains at each blood sampling time point. CIs for the GMTs were constructed by back transformation of the confidence limits computed for the mean of the logarithmically transformed assay data based on the Student t distribution.

To determine seroresponse rates for MCV4 and Tdap antigens in the MCV4 + Tdap + bivalent rLP2086 and MCV4 + Tdap groups, the proportion of subjects achieving a ≥4-fold rise in rSBA titers compared with baseline was determined. The difference in proportions between the MCV4 + Tdap + bivalent rLP2086 and MCV4 + Tdap groups were calculated along with 2-sided 95% exact CIs.

Safety data were summarized using descriptive statistics.

Back to Top | Article Outline

RESULTS

Subjects Disposition, Demographics and Clinical Characteristics

Of the 2648 subjects randomized, 888 subjects were in the MCV4 + Tdap + bivalent rLP2086 group, 878 subjects were in the MCV4 + Tdap group and 882 subjects were in the bivalent rLP2086 group (Fig. 2). The majority of subjects completed the study (n = 2172 [82.0%]); completion rates were similar among groups.

FIGURE 2

FIGURE 2

Demographic characteristics were similar between groups (Table 1): 51.0% were male; the majority of subjects were white (82.6%), non-Hispanic/non-Latino (78.9%). The mean age ± standard deviation at first vaccination was 10.6 ± 0.7 years (range, 10–12 years). Subjects were generally healthy with a medical history consistent with that of a general population of this age.

TABLE 1

TABLE 1

Back to Top | Article Outline

Immunogenicity Analysis

The 1.5-fold noninferiority criterion was met for all primary objective end points, including analysis of assay results for all 6 Tdap antigens, all 4 MCV4 strains and the 2 MnB test strains (Table 2). The GM ratios between study groups ranged from 0.88 to 1.02, with only one ratio less than 0.90 (pertussis pertactin antigen).

TABLE 2

TABLE 2

Substantial bactericidal antibody responses were observed in a high proportion of vaccinated individuals based on an hSBA titer ≥1:8 (B24) or ≥1:16 (A22), a more stringent criterion than the accepted correlate of protection (ie, an hSBA titer ≥1:429), after 2 and 3 doses of bivalent rLP2086 when given alone or concomitantly with MCV4 + Tdap (Table 3). The majority of recipients receiving the 3 vaccines concomitantly achieved seroprotective hSBA titers to each of the 2 MnB test strains 1 month after dose 2 (PMB80 [A22], 68.0%; PMB2948 [B24], 62.3%) and dose 3 (PMB80 [A22], 87.5%; PMB2948 [B24], 90.0%). Only a small proportion of subjects had seroprotective hSBA titers at baseline (PMB80 [A22], 4.4%; PMB2948 [B24], 1.6%). Results were similar among subjects who received bivalent rLP2086 alone. After vaccination 2, a ≥4-fold rise in hSBA titers from baseline was achieved by 64.3% and 56.3% of MCV4 + Tdap + bivalent rLP2086 recipients for PMB80 (A22) and PMB2948 (B24), respectively; after dose 3, this increased to 84.0% and 85.7%, respectively. Results were similar among subjects who received bivalent rLP2086 alone.

TABLE 3

TABLE 3

Prespecified responses to all MCV4 + Tdap antigens 1 month after vaccination 1 were achieved by 68.1%–98.6% of the subjects who received MCV4 + Tdap concomitantly with bivalent rLP2086 and 72.7% to 98.3% of subjects who received MCV4 + Tdap only (Table 4).

TABLE 4

TABLE 4

Back to Top | Article Outline

Safety Analysis

Pain at the injection site was the most commonly reported local reaction among subjects receiving bivalent rLP2086 (Fig.3A; Table, Supplemental Digital Content 1, http://links.lww.com/INF/C417, which presents all local reactions by severity and vaccine dose for each vaccine group). Local reactions (ie, redness, pain or swelling) were generally most common after vaccination 1 in all groups, occurring in 95.6%, 46.5% and 91.4% of subjects in the MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap and bivalent rLP2086 alone groups, respectively, after dose 1; 87.9%, 24.3% and 85.7% of subjects after dose 2; and 88.6%, 20.1% and 86.5% of subjects after dose 3. Local reactogenicity did not increase with subsequent dosing. Most reactions were mild or moderate in severity and transient.

FIGURE 3

FIGURE 3

Systemic events, including fever, vomiting, diarrhea, headache, fatigue, chills, and muscle or joint pain, in all groups were generally mild and moderate in severity. Headache and fatigue were the most commonly reported events (Fig.3B; Table, Supplemental Digital Content 2, http://links.lww.com/INF/C418, which presents all systemic events by severity and vaccine dose for each vaccine group). Severe events were relatively infrequent. Only 1 subject in the study (a subject in the MCV4 + Tdap + bivalent rLP2086 group, on the second day after vaccination 1) reported a fever >40.0°C (105.4°F). The subject was assessed by the investigator the following day, and the subject’s temperature was found to be normal. The use of antipyretic medications through the 7 days after any study vaccination was higher among subjects receiving MCV4 + Tdap + bivalent rLP2086 and bivalent rLP2086 alone (52.0−53.2%) compared with those who received MCV4 + Tdap (30.4%). Systemic events were most common after vaccination 1 in all groups, occurring in 87.0%, 74.8% and 81.7% of subjects in the MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap and bivalent rLP2086 alone groups, respectively, after dose 1; 73.8%, 50.6% and 70.1% after dose 2; and 70.3%, 44.4% and 66.6% after dose 3. The incidence of systemic events did not increase with subsequent dosing. The incidence and severity of systemic events associated with bivalent rLP2086 remained similar after concomitant administration of MCV4 + Tdap. Importantly, local and systemic reactions were generally similar between the MCV4 + Tdap + bivalent rLP2086 and bivalent rLP2086 + saline groups. Pain at the injection site was reported by a greater proportion of subjects in the MCV4 + Tdap + bivalent rLP2086 group and in the bivalent rLP2086 group compared with subjects in the MCV + Tdap group. Most reports of pain were mild or moderate in intensity.

No clinically relevant unsolicited AEs were reported by subjects receiving rLP2086. AEs were most common after vaccination 1 in all groups, with 16.1%, 14.0% and 14.5% of subjects in the MCV4 + Tdap + rLP2086 group, MCV4 + Tdap group and bivalent rLP2086 alone group, respectively, reporting any AE after dose 1; this decreased to 11.1%, 11.4% and 14.3% after dose 2 and to 8.9%, 11.6% and 11.8% after dose 3. Eighteen serious AEs (SAEs) were reported in the MCV4 + Tdap + LP2086 group, 13 SAEs were reported in the MCV4 + Tdap group and 12 SAEs were reported in the bivalent LP2086 only group (most commonly infections and infestations and psychiatric disorders); none of these were considered to be vaccine related. No noteworthy differences were observed in the incidence of AEs or SAEs between groups.

Back to Top | Article Outline

DISCUSSION AND CONCLUSION

The results of this study indicate that bivalent rLP2086, MCV4 and Tdap can be coadministered safely to adolescents while maintaining the immune responses to these vaccines. Both coprimary objectives of noninferiority for MCV4, 6 Tdap antigens and 2 MnB test strains examined in the current study were achieved. No clinically meaningful safety concerns were noted with concomitant administration of MCV4, Tdap and bivalent rLP2086; reactogenicity did not increase with subsequent dosing. One subject reported a fever >40.0°C that resolved within one day; no other symptoms were identified.

Bivalent rLP2086 was the first vaccine approved by the US Food and Drug Administration for prevention of MnB disease in individuals 10 to 25 years of age.9 Licensure of bivalent rLP2086 was based on 5 coprimary endpoints that demonstrated substantial immune responses across epidemiologically representative invasive MnB test strains that express antigen sequences different from vaccine antigens.16 The results of the current study are consistent with the responses observed in the licensure studies of bivalent rLP2086.29

MCV4 vaccination is recommended upon college entry46 because these adolescents were identified as a special population with increased risk of meningococcal disease. The recent MnB outbreaks on college campuses in the United States highlights the urgent need for a vaccination strategy that also includes a MnB vaccine. The recently licensed bivalent rLP2086 has the potential to substantially reduce the occurrence of outbreaks and the incidence of disease if recommended and successfully implemented into the adolescent vaccination schedule. Concomitant administration is an important means of simplifying vaccination schedules and improving adherence.24 In clinical practice, the ability to administer bivalent rLP2086 with other vaccines recommended in adolescents will help achieve higher vaccine acceptance and therefore decrease devastating cases of MnB disease. Thus, it is important to provide evidence to providers that they can simultaneously administer bivalent rLP2086 with other preventive vaccines without altering the safety or immunogenicity profiles of these vaccines.

The ACIP recommends vaccination with one of the 2 serogroup B vaccines as either a 2- or 3-dose series, depending on the vaccine used, in at-risk persons aged 10 years and older.47 At-risk individuals include those with persistent complement component deficiencies, those with anatomic or functional asplenia, microbiologists routinely exposed to N. meningitidis isolates, and those identified as being at increased risk because of an outbreak of meningococcal B disease. The ACIP also recommends that an MnB vaccine series may be administered to adolescents and young adults 16–23 years of age and that decisions to vaccinate should be made at the individual level with healthcare providers.48 The ACIP voted on this age-based recommendation at the June 2015 meeting, although this has not yet been published. The ACIP also provided guidance that these vaccines may be administered concomitantly with quadrivalent meningococcal conjugate vaccines, such as MCV4.

In addition to the data from the current study supporting concurrent administration of bivalent rLP2086 with MCV4 and Tdap, previous studies have also shown that bivalent rLP2086 can be given concomitantly with diphtheria, tetanus and acellular pertussis and inactivated poliomyelitis vaccine or HPV4 in healthy adolescents 11–18 years of age.25,26 Coadministration of bivalent rLP2086 + HPV4 induced immune responses that were noninferior to either vaccine alone, with the exception of the response to HPV18, which was just below the noninferiority margin.26 Similar results were observed in a study examining another vaccine that contains diphtheria, tetanus and acellular pertussis used in adolescents in Europe with bivalent rLP2086.25

Other published studies have also supported concomitant administration of MCV4 and Tdap, as well as MCV4, Tdap and HPV4 in adolescents and young adults.49–51 MCV4 immunogenicity has generally not been impaired by concomitant administration of the other vaccines.49–51 Moreover, when examining seroresponse data from other studies, noninferiority of sequential administration of MCV4 1 month after Tdap and HPV4 administration was demonstrated for all serogroups, except W-135. Importantly, the response to serogroup W-135 was still robust, suggesting this is not clinically meaningful. However, immune responses to the pertussis antigens were moderately attenuated, although this is likely not clinically relevant.50,51 In general, concomitant administration of these vaccines, either as MCV4 and Tdap or MCV4, Tdap and HPV4 did not result in an increase in reactogenicity when compared with either vaccine alone. Together, these reports support the concomitant administration of MCV4, Tdap and HPV4.

Of note, previous studies examined coadministration of Tdap and MCV4 in subjects ranging from 11 to 18 or 25 years of age,49–51 whereas the current study examines immune responses in a younger, more limited age group of subjects (ie, 10−12 years of age) chosen based on Tdap and MCV4 vaccination recommendations from ACIP in addition to state school entry immunization mandates in the United States. Because school vaccination requirements are often based on educational grade rather than age, students younger than 11 years of age are often required to receive these vaccines to enter school.1,18,20–22,52 Thus, the age group used in the current study more closely approximates the population to whom these vaccines would be administered in clinical practice. Additionally, the lower age at enrollment allowed for all children to receive MCV4 and Tdap vaccines within the ACIP-recommended age range, including subjects randomized to receive only bivalent rLP2086 who then received MCV4 + Tdap at month 7 of the study. Data from this study therefore will further reassure providers of the efficacy and safety of concomitant administration of these vaccines under real-life conditions.

When this study was conducted, although MCV4, Tdap and HPV vaccines all were recommended for US adolescents, HPV vaccines were being received by a substantially smaller proportion of eligible adolescents than MCV4 and Tdap (ie, HPV vaccines were typically administered to only a subset of those receiving the other 2 vaccines and were delayed to an older age). Thus, these differences in actual administration of the vaccines in the community made conducting 2 studies more feasible. Even several years after initiation of this study, the proportion of adolescents in the United States who receive HPV vaccines is much lower than the proportion who adhere to the recommendation for vaccination and receive booster Tdap and MCV4 vaccines.53

In conclusion, data generated from the study described here suggest that bivalent rLP2086 administered concomitantly with MCV4 + Tdap had an immunogenicity profile comparable to that of MCV4 + Tdap or bivalent rLP2086 alone. A high proportion of subjects achieved a seroprotective hSBA response to the 2 MnB test strains after the second bivalent MnB vaccination and that proportion increased after the third vaccination. Although local reactions and systemic events were reported more frequently after administration of bivalent rLP2086 alone in comparison with administration of MCV4 + Tdap, these differences are not believed to be clinically meaningful. No notable difference was observed in the incidence of AEs between groups. These data support the recent recommendation by ACIP that licensed serogroup B vaccines may be administered concomitantly with ACWY vaccines.47 Concomitant administration of these vaccines offers the potential for increased adherence to recommended immunization schedules.

Back to Top | Article Outline

ACKNOWLEDGMENTS

Editorial/medical writing support was provided by Nicole Gudleski O’Regan, PhD, of Complete Healthcare Communications, LLC. The authors acknowledge Roger Maansson, Qin Jiang, Harpeet Seehra, and Ryan Newton, Pfizer Inc., for their contributions in the completion of this study.

Back to Top | Article Outline

REFERENCES

1. Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-2):1–28.
2. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network, Neisseria meningitidis, 2012. Available at: http://www.cdc.gov/abcs/reports-findings/survreports/mening12.pdf. Accessed September 11, 2014.
3. EU-IBIS Network. Invasive Neisseria meningitidis in Europe 2006. Available at: http://www.hpa-bioinformatics.org.uk/euibis/documents/2006_meningo.pdf. Accessed March 27, 2015.
4. Azzari C, Canessa C, Lippi F, et al; Italian Group for the Study of Invasive Bacterial Disease. Distribution of invasive meningococcal B disease in Italian pediatric population: implications for vaccination timing. Vaccine. 2014;32:1187–1191.
5. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196–2210.
6. Thigpen MC, Whitney CG, Messonnier NE, et al; Emerging Infections Programs Network. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011;364:2016–2025.
7. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin Infect Dis. 2010;50:184–191.
8. Centers for Disease Control and Prevention. Serogroup B Meningococcal Vaccine & Outbreaks. Available at: http://www.cdc.gov/meningococcal/outbreaks/vaccine-serogroupB.html. Accessed September 5, 2014.
9. US Food and Drug Administration. First Vaccine Approved by FDA to Prevent Serogroup B Meningococcal Disease. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm420998.htm. Accessed October 29, 2014.
10. Marshall HS, Richmond PC, Nissen MD, et al. A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults. Vaccine. 2013;31:1569–1575.
11. Nissen MD, Marshall HS, Richmond PC, et al. A randomized, controlled, phase 1/2 trial of a Neisseria meningitidis serogroup B bivalent rLP2086 vaccine in healthy children and adolescents. Pediatr Infect Dis J. 2013;32:364–371.
12. Richmond PC, Marshall HS, Nissen MD, et al.; 2001 Study Investigators. Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012;12:597–607.
13. Richmond PC, Nissen MD, Marshall HS, et al. A bivalent Neisseria meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial. Vaccine. 2012;30:6163–6174.
14. Fletcher LD, Bernfield L, Barniak V, et al. Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun. 2004;72:2088–2100.
15. Jiang HQ, Hoiseth SK, Harris SL, et al. Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease. Vaccine. 2010;28:6086–6093.
16. Rodrigo C, Bewick T, Sheppard C, et al. Pneumococcal serotypes in adult non-invasive and invasive pneumonia in relation to child contact and child vaccination status. Thorax. 2014;69:168–173.
17. Recommended immunization schedules for persons aged 0 through 18 years, United States, 2015. Available at: http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf. Accessed March 26, 2015.
18. Broder KR, Cortese MM, Iskander JK, et al.; Advisory Committee on Immunization Practices (ACIP). Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-3):1–34.
19. Center for Disease Control (CDC). Immunization Schedules. Available at: http://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html.
20. Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7):1–21.
21. Immunization Action Coalition. State Information: Tdap Booster Requirements for Secondary Schools. Available at: http://www.immunize.org/laws/tdap.asp. Accessed February 24, 2015.
22. Immunization Action Coalition. State Information: Meningococcal State Mandates for Elementary and Secondary Schools. Available at: http://www.immunize.org/laws/menin_sec.asp. Accessed February 24, 2015.
23. Petrosky E, Bocchini JA Jr, Hariri S, et al.; Centers for Disease Control and Prevention (CDC). Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2015;64:300–304.
24. Wong CA, Taylor JA, Wright JA, et al. Missed opportunities for adolescent vaccination, 2006-2011. J Adolesc Health. 2013;53:492–497.
25. Vesikari T, Wysocki J, Kieninger D, et al. Immunogenicity and safety of meningococcal serogroup B vaccine (bivalent rLP2086) when administered concomitantly with Repevax® in healthy adolescents.32nd Annual Meeting of the European Society for Paediatric Infectious Diseases, Dublin, Ireland, May 6–10, 2014.
26. Bhuyan P, Eiden J, Jones TR, et al. Immunogenicity of human papilloma vaccine coadministered with an investigational bivalent rLP2086 vaccine against meningococcal serogroup B in healthy adolescents.IDWeek 2014,Philadelphia, PA, October 8–12, 2014.
27. Menactra® (MCV4). Full Prescribing Information. 2014.Swiftwater, PA: Sanofi Pasteur Inc..
28. Adacel® Full Prescribing Information. 2005.Swiftwater PA: Sanofi Pasteur Inc..
29. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969;129:1307–1326.
30. World Health Organization. Standardization and Validation of Serological Assays for the Evaluation of Immune Responses to Neisseria meningitidis Serogroup A/C Vaccines. Geneva, Switzerland. WHO/V&B/99/19.
31. Borrow R, Carlone GM, Rosenstein N, et al. Neisseria meningitidis group B correlates of protection and assay standardization–international meeting report Emory University, Atlanta, Georgia, United States, 16-17 March 2005. Vaccine. 2006;24:5093–5107.
32. Trumenba™ (Meningococcal Group B Vaccine) Prescribing Information. 2014.Philadelphia, PA: Wyeth Pharmaceuticals.
33. Murphy E, Andrew L, Lee KL, et al. Sequence diversity of the factor H binding protein vaccine candidate in epidemiologically relevant strains of serogroup B Neisseria meningitidis. J Infect Dis. 2009;200:379–389.
34. Zlotnick GW, Jones TR, Liberator P, et al. The discovery and development of a novel vaccine to protect against Neisseria meningitidis Serogroup B Disease. Hum Vaccin Immunother. 2015;11:5–13.
35. Maslanka SE, Gheesling LL, Libutti DE, et al. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The Multilaboratory Study Group. Clin Diagn Lab Immunol. 1997;4:156–167.
36. Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10:780–786.
37. Lal G, Balmer P, Joseph H, et al. Development and evaluation of a tetraplex flow cytometric assay for quantitation of serum antibodies to Neisseria meningitidis serogroups A, C, Y, and W-135. Clin Diagn Lab Immunol. 2004;11:272–279.
38. de Voer RM, van der Klis FR, Engels CW, et al. Development of a fluorescent-bead-based multiplex immunoassay to determine immunoglobulin G subclass responses to Neisseria meningitidis serogroup A and C polysaccharides. Clin Vaccine Immunol. 2008;15:1188–1193.
39. Björkholm B, Böttiger M, Christenson B, et al. Antitoxin antibody levels and the outcome of illness during an outbreak of diphtheria among alcoholics. Scand J Infect Dis. 1986;18:235–239.
40. Efstratiou A, Maple PAC.Laboratory Diagnosis of Diptheria. 1994.
41. IPSEN J. Circulating antitoxin at the onset of diphtheria in 425 patients. J Immunol. 1946;54:325–347.
42. McComb JA. The prophylactic dose of homologous tetanus antitoxin. N Engl J Med. 1964;270:175–178.
43. Newell KW, Leblanc DR, Edsall G, et al. The serological assessment of a tetanus toxoid field trial. Bull World Health Organ. 1971;45:773–785.
44. Reisinger KS, Block SL, Collins-Ogle M, et al.; Protocol 025 Investigators. Safety, tolerability, and immunogenicity of gardasil given concomitantly with Menactra and Adacel. Pediatrics. 2010;125:1142–1151.
45. Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA. 2005;293:3003–3011.
46. Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7):1–21.
47. Folaranmi T, Rubin L, Martin SW, et al.; Centers for Disease Control (CDC). Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015;64:608–612.
48. CDC Advisory Committee on Immunization Practices Votes to Recommend Serogroup B Meningococcal Disease Vaccination including TRUMENBA® for Adolescents and Young Adults 16 through 23 Years of Age. Available at: http://www.pfizer.com/news/press-release/press-release-detail/cdc_advisory_committee_on_immunization_practices_votes_to_recommend_serogroup_b_meningococcal_disease_vaccination_including_trumenba_for_adolescents_and_young_adults_16_through_23_years_of_age. Accessed June 1, 2015.
49. Arguedas A, Soley C, Loaiza C, et al. Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines. Vaccine. 2010;28:3171–3179.
50. Gasparini R, Conversano M, Bona G, et al. Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults. Clin Vaccine Immunol. 2010;17:537–544.
51. Weston WM, Friedland LR, Wu X, et al. Immunogenicity and reactogenicity of co-administered tetanus-diphtheria-acellular pertussis (Tdap) and tetravalent meningococcal conjugate (MCV4) vaccines compared to their separate administration. Vaccine. 2011;29:1017–1022.
52. Immunization Division of Indiana Government. School Immunization Requirements IN State Department of Health 2014–2015 School Year. Available at: http://www.in.gov/isdh/files/Provider_FAQs_School_Immunization_Requirements_2014-2015.pdf. Accessed February 24, 2015.
53. Reagan-Steiner S, Yankey D, Jeyarajah J, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years–United States, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:784–792.
Keywords:

meningococcal B; bivalent rLP2086; adolescents; tetanus; diphtheria, and acellular pertussis vaccine; quadrivalent meningococcal conjugate vaccine

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.