Neisseria meningitidis is a leading cause of bacterial meningitis in infants, adolescents and young adults.1 N. meningitidis serogroup B (MnB) is responsible for nearly 75% of observed meningococcal cases in Europe and approximately 40% in the US.2,3 Case fatality rates approach 20%, with almost 20% of survivors experiencing substantial morbidity.4–6
Disease caused by N. meningitidis serogroups A, C, Y and W can be prevented using capsular polysaccharide conjugate vaccines1; however, conjugate vaccines based on MnB capsular polysaccharides cannot be developed because homology to similar structures on human cells renders them poorly immunogenic.7 Lipoprotein 2086, a conserved surface-exposed bacterial lipoprotein and a human complement factor H binding protein (fHBP), was identified as a vaccine target.8 fHBP protein sequences (termed variants) segregate into 2 immunologically distinct groups (subfamilies A and B). Bivalent rLP2086 (Trumenba®, meningococcal group B vaccine), a vaccine composed of equal amounts of recombinant subfamily A and B LP2086 proteins, received accelerated approval in the US to prevent invasive meningococcal disease caused by MnB in individuals 10–25 years of age.9 Preclinical and clinical studies demonstrated that bivalent rLP2086 elicits serum bactericidal antibodies capable of killing diverse MnB strains expressing fHBPs homologous and heterologous to vaccine components.8,10–14
A growing number of vaccines are recommended for use in adolescents.15 Gardasil®[HPV-4, human papillomavirus quadrivalent (types 6, 11, 16 and 18) vaccine] is recommended for adolescents and young adults for the prevention of several diseases, including cervical, vulvar, vaginal and anal cancers.16,17 However, year 2011 vaccination rates in the US were suboptimal, with only 30% of females aged 13–15 years being fully vaccinated.18
To simplify administration of multiple vaccines indicated for the same age group, increase adherence to vaccination schedules and improve vaccine uptake, the safety and immunogenicity of concomitant vaccine administration should be ascertained. A previous study indicated that bivalent rLP2086 and a combination vaccine containing diphtheria, tetanus and acellular pertussis and inactivated poliomyelitis vaccine are safe and immunogenic when given concomitantly to healthy adolescents aged 11 to <19 years.19 This study is the first to assess the safety, tolerability and immunogenicity of concomitantly administered HPV-4 and bivalent rLP2086 compared with each vaccine administered alone in healthy US adolescents.
The study’s coprimary objectives were to demonstrate that (1) the immune response based on geometric mean titers (GMTs) induced by HPV-4 given with bivalent rLP2086 was noninferior to the immune response induced by HPV-4 alone and (2) the immune response based on GMTs induced by bivalent rLP2086 given with HPV-4 was noninferior to the immune response induced by bivalent rLP2086 alone. Secondary objectives assessed seroconversion rates to HPV-4 antigens. Five additional endpoints included the proportions of subjects achieving prespecified titers in serum bactericidal assays using human complement (hSBAs) for 4 MnB test strains combined (composite response) and a ≥4-fold increase in hSBA titer from baseline for each test strain after dose 3. Driven by discussions with global regulatory bodies including the US Food and Drug Administration, these additional endpoints were designed to demonstrate the breadth of immune responses against invasive MnB strains expressing vaccine-heterologous fHBPs and served as the basis of bivalent rLP2086 licensure in the US. The primary safety objective was to evaluate the safety of bivalent rLP2086 [local reactions, systemic events and adverse events (AEs)].
MATERIALS AND METHODS
In this phase 2, randomized, active-controlled, observer-blind, multicenter study, conducted at 63 sites throughout the US (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C393, which lists sites), subjects were randomly assigned in a 2:2:1 ratio to receive bivalent rLP2086 + HPV-4, bivalent rLP2086 + saline or saline + HPV-4 at each of the 3 vaccination visits (at months 0, 2 and 6). Subjects who received bivalent rLP2086 alone did not receive HPV-4 during the study period because it was not part of the protocol. When the blinding code was revealed, these subjects could receive HPV-4 vaccine through their healthcare provider; study sites were encouraged to give HPV-4 per current vaccine recommendations. Study subjects who did not receive the HPV-4 vaccine during the course of the study were notified as part of a planned unblinding to allow them to coordinate the receipt of HPV-4 as currently recommended with their healthcare provider. Subjects who received HPV-4 alone did not receive bivalent rLP2086, as bivalent rLP2086 vaccine was not licensed for administration during the study period.
Only the study staff dispensing and administering the vaccine were unblinded. All other study participants, including the study subjects, the individuals who evaluated subject safety, the principal investigator and the sponsor, were blinded. Children were not paid for study participation; travel related expenses were covered. Clinical laboratory assessments were performed by Pfizer Vaccine Research—High Throughput Clinical Testing, Pearl River, NY, and Pharmaceutical Product Development, Inc. Laboratory, Wayne, PA. The study was conducted in compliance with the Declaration of Helsinki and with all International Conference on Harmonisation Good Clinical Practice guidelines.
Study participants included healthy subjects aged 11 to <18 years; written informed consent was obtained from parent(s)/legal guardian(s) before enrolment. Children gave assent at visit 1; children who did not give assent were not enrolled. Primary exclusion criteria included previous MnB or HPV vaccination; anaphylactic reaction to any vaccine or vaccine component; any sexually transmitted disease or culture-proven disease caused by N. meningitidis; and current systemic antibiotic use, pregnancy or breastfeeding.
Vaccines and Interventions
Bivalent rLP2086 (120 μg) was administered intramuscularly by injecting 0.5 mL into the upper deltoid muscle of the left arm (bivalent rLP2086 + HPV-4 group and bivalent rLP2086 only group) and HPV-4 was administered intramuscularly into the upper deltoid muscle of the right arm (bivalent rLP2086 + HPV-4 group and HPV-4 only group). Saline (0.9% sodium chloride) was administered intramuscularly into the upper deltoid muscle of the right arm for bivalent rLP2086 only recipients and into the upper deltoid muscle of the left arm for HPV-4 only recipients to maintain study blinding.
Serum Bactericidal Assay Using Human Complement
hSBAs were based on the assay described by the World Health Organization,20 Borrow and Carlone,21 and as reported previously.12 The hSBA titer is the reciprocal of the highest 2-fold test serum dilution resulting in ≥50% reduction of MnB bacteria (50% bacterial survival) compared with the number of bacteria surviving after incubation in assay wells containing all assay components except test serum (100% bacterial survival). Titers were reported as step titers.
Sera were collected immediately before vaccination 1 (visit 1) and 28–42 days (approximately 1 month) after vaccinations 2 and 3 (visits 3 and 5). To assess immune responses elicited by bivalent rLP2086, sera were analyzed in hSBAs with 4 primary MnB test strains: strain PMB80 (expressing fHBP variant A22), PMB2001 (A56), PMB2707 (B44) and PMB2948 (B24). MnB strains were selected randomly using a statistical algorithm and adjusted after consideration of the epidemiologic prevalence of fHBP variants expressed by invasive MnB strains circulating in the US and Europe. More than 90% of disease isolates in the US and Europe express fHBP variants closely related in sequence to 1 of the 4 variants expressed by the MnB test strains.22 PMB80 (A22) and PMB2948 (B24) were used for determination of noninferiority because these strains express the most prevalent fHBP subfamily A and B variants circulating in the US.23 To assess immune responses to each of the four HPV-4 antigens, sera obtained at visits 1 and 5 were tested using a competitive Luminex immunoassay (cLIA).24,25
Safety was evaluated for all subjects who received ≥1 dose of vaccine. Reactogenicity measurements, 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 compared with saline and collected using an electronic diary for 7 days after each injection. Unsolicited AEs were recorded and assessed for severity, relationship to study vaccine and seriousness.
Sample size estimates were based on hSBA titers for 2 primary MnB test strains [PMB80 (A22) and PMB2948 (B24)] and HPV antibody titers to each of the 4 vaccine antigens (HPV-6, HPV-11, HPV-16 and HPV-18 L1).17 The noninferiority margin was 1.5-fold. Assuming that the natural log scale of titers in the bivalent rLP2086 + HPV-4 group was 0.13 less than the groups receiving bivalent rLP2086 or HPV-4, with 700, 700 and 350 evaluable subjects per group, respectively, the overall power for declaring noninferiority for all 6 immunogenicity measurements was 83.6%. Assuming a 30% nonevaluable rate, 2500 subjects were to be enrolled.
The primary analysis population for immunogenicity was the evaluable immunogenicity population, which included randomized subjects who received the scheduled vaccine at visits 1, 2 and 4 had blood drawn within the protocol-specified window before dose 1 and after dose 3, had valid assay results and had no other major protocol violations.
GMTs for 2 MnB test strains and the 4 HPV antigens were computed along with 2-sided 95% confidence intervals (CIs), which were constructed by back transformation of the confidence limits computed for the mean of the logarithmically transformed assay data based on Student t distribution.
Geometric mean ratios (GMRs; bivalent rLP2086 + HPV-4/bivalent rLP2086) of hSBA titers to PMB80 (A22) and PMB2948 (B24) and cLIA GMRs (bivalent rLP2086 + HPV-4/HPV-4) for HPV-6, HPV-11, HPV-16 and HPV-18 were summarized at 1 month after vaccination 3, along with 95% CIs. The study’s coprimary objectives of noninferiority would be achieved when the lower limits of the 2-sided 95% CI for the GMRs at 1 month after vaccination 3 were >0.67 for each of the 4 HPV antigens and each of the 2 MnB test strains.
For the bivalent rLP2086 immunogenicity analysis, the numbers and proportions of subjects achieving (1) hSBA titers ≥ lower limit of quantification (LLOQ) at each blood sampling time point and (2) a ≥4-fold rise in hSBA titers at 1 month after dose 2 and dose 3, were descriptively summarized along with the exact 2-sided 95% CI for 4 MnB test strains. The LLOQ was established during assay validation as an hSBA titer equal to 1:8 for PMB2001 (A56), PMB2707 (B44) and PMB2948 (B24) and 1:16 for PMB80 (A22). For the HPV-4 immunogenicity analysis, the seroconversion rate was defined as anti-HPV serum cLIA levels of ≥20, ≥16, ≥20 or ≥24 milli-Merck units (mMU)/mL for HPV-6, HPV-11, HPV-16 or HPV-18 L1, respectively; levels less than these cutoff points at visit 1 were considered baseline seronegative; levels greater than or equal to these cutoff points at visit 1 were considered baseline seropositive. The proportion of subjects who were seronegative by cLIA to HPV-6, HPV-11, HPV-16 or HPV-18 L1 proteins at baseline and achieved seroconversion by cLIA for each of the 4 HPV antigens 1 month after the third vaccination with HPV-4 were computed with a 2-sided 95% exact CI for the bivalent rLP2086 + HPV-4 and HPV-4 groups.
Subject Disposition, Demographics and Clinical Characteristics
Of 2499 randomized subjects, 992 received ≥1 dose of bivalent rLP2086 + HPV-4, 990 received ≥1 dose of bivalent rLP2086 and 501 received ≥1 dose of HPV-4 (see Fig., Supplemental Digital Content 2, http://links.lww.com/INF/C394, which presents the study design). The majority [n = 2127 (85.1%)] completed the study; completion rates were similar among groups. One subject randomized to bivalent rLP2086 + HPV-4 received the investigational product from another study at visit 1 and was withdrawn from the study and not included in the safety analysis.
Approximately 12.5% (312/2499) of randomized subjects withdrew from the study during the vaccination phase across the 3 study arms (see Fig., Supplemental Digital Content 2, http://links.lww.com/INF/C394, which presents the study design). Among those who withdrew, 4.7% (117) withdrew because they no longer wanted to participate in the study. Most subjects who were no longer willing to participate did not provide a specific reason for withdrawing and simply withdrew consent [48% (57)]. Approximately 19% (22) withdrew because they no longer wanted to receive a vaccination or have blood drawn. Approximately 25% (29) withdrew because of personal schedule conflicts or changes in residency that prevented the subject from attending scheduled site visits. In addition, 6% (7) refused to comply with protocol-specified procedures.
Demographic characteristics were similar between study groups (Table 1): 66.5% were male; the majority were white (81.6%) and non-Hispanic/non-Latino (82.6%). The mean ± standard deviation age at first vaccination was 13.6 ± 1.92 years (range, 11–17 years). Subjects were generally healthy, with a medical history consistent with a general population of this age. The typical medical history contained a number of acute illnesses, accidents, and other common childhood diseases. None of the children were immunosuppressed, had been diagnosed with malignancies or suffered from other chronic inflammatory illnesses that would have compromised the interpretation of the immunogenicity or safety data.
The 1.5-fold noninferiority criterion (ie, lower limit of the 2-sided 95% CI > 0.67) was met for the 2 MnB test strains and all HPV antigens except HPV-18, which had a lower bound of the 95% CI of 0.62 (Table 2). Seroconversion for all 4 HPV antigens was achieved by ≥99% of subjects in the groups that received HPV-4 (data not shown). The observed HPV GMTs after vaccination 3 were indicative of a robust immune response for both vaccine groups and genders (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/C395, which presents HPV GMTs 1 month after vaccination 3).
At baseline, the proportion of bivalent rLP2086 recipients and bivalent rLP2086 + HPV-4 recipients with an hSBA titer greater than or equal to assay LLOQ was low, ranging from 1.4% to 16.4% across the strains (Table 3) and <1% for all 4 strains combined (see Table, Supplemental Digital Content 4, http://links.lww.com/INF/C396, which presents the proportion of subjects achieving the LLOQ for all 4 MnB test strains at baseline). In contrast, substantial bactericidal antibody responses elicited by bivalent rLP2086 were observed in a high proportion of vaccinees after doses 2 and 3 (Table 3). After doses 2 and 3, an hSBA titer greater than or equal to assay LLOQ for all 4 test strains (composite response) was achieved by 49.9% and 81.0% of bivalent rLP2086 + HPV-4 recipients and 51.9% and 83.9% of bivalent rLP2086 + saline recipients, respectively (see Table, Supplemental Digital Content 4, http://links.lww.com/INF/C396, which presents the proportion of subjects achieving the LLOQ for all 4 MnB test strains 1 month after dose 2 or 3). A ≥4-fold rise in hSBA titer from baseline was achieved by 92% and 95% of recipients for A56 after doses 2 and 3, respectively, and 46–74% and 77–86% of recipients for A22, B24 and B44 after doses 2 and 3 in both groups that received bivalent rLP2086 (see Table, Supplemental Digital Content 4, http://links.lww.com/INF/C396, which presents the proportion of subjects achieving a ≥4-fold rise in hSBA titer from baseline to 1 month after dose 2 or 3).
Local reactions (most commonly pain at the injection site) and systemic events (most commonly fatigue and headache) were generally mild or moderate (Fig. 1). The incidence did not increase with subsequent dosing. Local reactions were generally transient; the mean durations of systemic events, ranging from 1.0–3.8 days, were similar between groups. Few subjects withdrew because of local or systemic reactions. There were no fevers >40.0°C. Antipyretic medication use was higher among groups that received bivalent rLP2086 + HPV-4 (37.8%) or bivalent rLP2086 (39.8%) than HPV-4 (26.2%). Overall, the incidence and severity of local reactions and systemic events associated with bivalent rLP2086 was similar when administered with HPV-4.
No deaths or cases of anaphylaxis occurred during this study. The incidence of AEs was similar between groups. The most common AEs were upper respiratory tract infections, injection site pain and headache, each occurring in 4–6% of subjects. One subject reported fainting (syncope; described by the subject’s mother as blacking out for a few seconds without dizziness) on the same day after the third dose of bivalent rLP2086 + saline; the investigator considered there was a reasonable possibility that the fainting was related to bivalent rLP2086. The subject completed the study. No serious AEs were considered vaccine related or led to study discontinuation.
DISCUSSION AND CONCLUSION
Data from this study support concomitant administration of bivalent rLP2086 and HPV-4 in adolescents. Robust immunogenicity was observed for both vaccines given concomitantly, as shown by GMTs, seroconversion rates and bactericidal responses. No clinically meaningful safety concerns were noted. Concomitant administration of bivalent rLP2086 with HPV-4 did not result in an increase in reactogenicity compared with bivalent rLP2086 alone.
Approximately two-thirds of study subjects were male. The HPV was initially recommended for use in girls in 200726 but not recommended for use in boys until 2011.27 Because this study was initiated just before the new recommendation for boys, more boys were available for clinical study participation than girls, leading to a higher percentage of male subjects.
Although the primary study immunogenicity objective was not met for HPV-18 L1, immune responses to all HPV antigens including HPV-18 L1 in this study are similar to those previously achieved in the pivotal HPV-4 efficacy trials, including a US registration study of subjects aged 16–26 years. Importantly, the assays used in those pivotal trials were the same as those in this study.17 Specifically, 1 month after the third HPV-4 dose, the anti–HPV-18 GMT was 685.7 mMU/mL in female bivalent rLP2086 + HPV-4 recipients and 1019.9 mMU/mL in female HPV-4 recipients (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/C395, which presents HPV GMTs 1 month after vaccination 3) compared with 475.2 mMU/mL in female subjects in the US registration study.17 In addition, 1 month after the third HPV-4 dose, the anti-HPV GMT was 777.5 mMU/mL in male bivalent rLP2086 + HPV-4 recipients and 1062.2 mMU/mL in male HPV-4 recipients (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/C395, which presents HPV GMTs 1 month after vaccination 3) compared with 402.6 mMU/mL in male subjects in the US registration study.17 Seroconversion for all 4 HPV antigens was achieved by ≥99% of subjects in the groups that received HPV-4 in this study, comparable to results observed in the pivotal efficacy studies of HPV-4, in which >99% of female subjects and 97% of male subjects seroconverted after 3 doses of HPV-4, and HPV-4 demonstrated a high level of efficacy.17 Although the minimum anti-HPV titers that confer protective efficacy remain undetermined, anti-HPV GMTs achieved in the bivalent rLP2086 + HPV-4 group surpassed those observed in the pivotal HPV-4 efficacy studies, including titers for HPV-18 L1. Therefore, clinical effectiveness would be expected to be maintained when HPV-4 is coadministered with bivalent rLP2086.
For both groups receiving bivalent rLP2086, substantial bactericidal responses to the 4 MnB test strains (all expressing fHBP variants different in amino acid sequence from those in bivalent rLP2086) were observed 1 month after doses 2 and 3, consistent with the results of a phase 2 dosing study of bivalent rLP2086.28 Importantly, only a small proportion of subjects had measurable hSBA titers greater than or equal to this prespecified level (ie, assay LLOQ) before vaccination, which is expected in a population vulnerable to MnB infection. Moreover, a high proportion of subjects achieved hSBA response rates at or above hSBA LLOQs equal to 1:8 for MnB strains expressing fHBP variants A56, B44 and B24 and 1:16 for the strain expressing fHBP variant A22. The prespecified threshold hSBA titers (LLOQs) are conservative thresholds exceeding the seroprotective hSBA titer of 1:4, widely considered to correlate with protection against meningococcal disease.1,29,30
Data from this study were pivotal in supporting accelerated approval of bivalent rLP2086 by the US Food and Drug Administration.9,31 The prospectively defined clinical study endpoints clearly demonstrated the benefit of vaccination, with most bivalent rLP2086 recipients achieving a 4-fold rise in hSBA titer against each test strain and protective responses capable of recognizing diverse fHBP sequences from different vaccine antigens. Because all 4 hSBA test strains are antigenically distinct from vaccine fHBP antigens, the clinical trial results provide evidence of breadth of coverage beyond that demonstrated by use of test strains that share antigenic identity with vaccine antigens, as published for other meningococcal vaccines.32–35 The robust functional, bactericidal immune responses to heterologous hSBA test strains after immunization with bivalent rLP2086 indicate the potential for broadly protective responses against invasive disease due to MnB.
Vaccines are emerging at the core of preventive care for adolescents, with invaluable long-term health benefits. Increased use of the recommended HPV-4 vaccine among adolescents will diminish the substantial health and economic burdens caused by HPV-associated diseases.18 Bivalent rLP2086 (Trumenba) has recently been licensed in the US to prevent invasive MnB disease, a major health concern in adolescents and young adults and the cause of meningococcal outbreaks (some with fatal outcomes) that continue to threaten the health and lives of this population.36–38 Despite the importance of vaccination in preventive care in this vulnerable age group, rates of adolescent vaccination in the US remain low.39 Finding effective ways to improve adherence to vaccination schedules remains an important challenge.
Studies have shown that the lack of concurrent vaccination is a large contributor to missed vaccination opportunities.39 Data from this study are important for reassuring providers that bivalent rLP2086 and HPV-4 vaccines can be administered simultaneously without altering safety and immunogenicity profiles. Concomitant administration of bivalent rLP2086 and HPV-4 vaccines elicits robust immune responses to both vaccines without increasing reactogenicity compared with administration of bivalent rLP2086 alone. The safety and immunogenicity of bivalent rLP2086, given alone or with HPV-4, are comparable with that seen in other bivalent rLP2086 studies.10,12,13,19,28 Anti-HPV GMTs achieved with concomitant administration of bivalent rLP2086 and HPV-4 surpassed those observed in the pivotal HPV-4 efficacy studies using the same assays, including titers for HPV-18 L1. Therefore, clinical effectiveness would be expected to be maintained when HPV-4 is coadministered with bivalent rLP2086. Concomitant administration of bivalent rLP2086 and HPV-4 may increase adherence to the schedules of both vaccines.
Editorial/medical writing support was provided by Nicole Gudleski O’Regan, PhD, of Complete Healthcare Communications, LLC.
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