Neisseria meningitidis is a Gram-negative bacterium frequently found in the human nasopharynx.1 Entry of N. meningitidis into the bloodstream can result in invasive meningococcal disease (IMD), which may result in death within 24 hours.2,3 Fatality associated with IMD persists despite antibiotic treatment.4 Patients who survive IMD are also at high risk of suffering at least 1 permanent sequelae, which may include amputation, cognitive difficulties, hearing loss, visual disturbances or behavioral problems.1,5,6
Although IMD causes considerable morbidity and mortality, N. meningitidis is commonly encountered as asymptomatic carriage.7 Rates of IMD infection generally decline with age, but prevalence rises slightly during the teenage years, presumably due to the increased carriage in this group.8 Increased carriage rates during the teenage years may be attributable to increased peer contact and social behavior.7 Indeed, transmission of N. meningitidis among adolescents is 10–30 times higher compared with young children.9
Five serogroups of N. meningitidis (A, B, C, Y and W135) are responsible for the majority of IMD cases.10 Disease caused by 4 N. meningitidis serogroups (A, C, Y and W135) are preventable using conjugate vaccines targeting the respective serogroup-specific polysaccharide capsules.11 The serogroup B capsule is composed of a polysialic acid repeat with glycosidic links that confer structural similarity to adhesion molecules expressed on human fetal brain cells.12,13 This homology is believed to prevent development of immune responses against the serogroup B polysaccharide capsule, and attempts to elicit functional antibodies using chemically modified N. meningitidis serogroup B (MnB) capsules have been unsuccessful.12,14
In response to MnB epidemics, several protein-based vaccines using outer membrane vesicles (OMVs) have been generated.15 The bactericidal activity induced by these OMV vaccines is largely directed at the porin A antigen.16 However, porin A is highly variable, and an OMV vaccine would require an estimated 20 different porin A proteins to cover 80% of endemic MnB strains in the United States alone.17 Thus, OMV vaccines are not generally useful for prevention of endemic IMD caused by diverse strains.15
With no broadly protective MnB vaccine licensed and available for use, MnB has emerged as a leading cause of IMD in parts of the developed world, including Australia, Europe, Latin America and North America.18–20 Effective control of MnB disease requires the development of a vaccine that is effective against epidemic and endemic strains.
One candidate protein antigen for serogroup B vaccination is LP2086.21,22 LP2086 is a surface-exposed lipoprotein found in >98% of meningococcal serogroup B strains examined to date.23,24 Also known as factor H-binding protein (fHBP), LP2086 binds to and recruits human factor H, a negative regulator of the alternate complement pathway.25 This interaction enables LP2086 to downregulate the complement response and protect the bacterium from complement-mediated lysis.25
Based on amino acid sequences, LP2086 protein variants have been divided into 2 subfamilies, A and B.21,23 The LP2086 protein is highly conserved within subfamilies, with 83–99% sequence identity in each subfamily but only 60–75% sequence identity between subfamilies.21,23 These 2 subfamilies can be further divided into 6 major subgroups; subfamily A includes subgroups N1C1, N1C2, N2C1 and N2C2, and subfamily B includes subgroups N4/N5 and N6.23,26 An alternate nomenclature classifies LP2086 as 1 of 3 variants, with variant 1 equivalent to subfamily B, variant 2 equivalent to subfamily A subgroups N2C1 and N2C2, and variant 3 equivalent to subfamily A subgroups N1C1 and N1C2.23,26
In preclinical studies, a bivalent recombinant LP2086 (rLP2086) vaccine that included 1 lipidated antigen from each LP2086 subfamily induced bactericidal activity against a diverse panel of MnB strains.27 Therefore, a bivalent rLP2086 vaccine has been chosen for clinical studies. The purpose of this study was to assess the safety, tolerability and immunogenicity of the bivalent rLP2086 vaccine in healthy children and adolescents.
MATERIALS AND METHODS
Healthy children and adolescents (male and female) aged 8–14 years were enrolled in this randomized, observer-blinded, parallel-group, active-control, phase 1/2 trial conducted at 6 hospital centers in Australia from November 2006 through January 2008. Participants were excluded if they were pregnant; had a history of meningococcal disease; received any previous MnB vaccine; underwent a full schedule of hepatitis A or B vaccination; received any blood products; were participating in another investigational study, had an immunodeficiency disorder, bleeding condition, or a known hypersensitivity to vaccines; or were a direct descendant of study site personnel.
After signing an informed consent form, participants were registered in the Clinical Operations Randomisation Environment II system, which provided randomization instructions to study personnel at each study site responsible for preparing the study vaccine for administration. Participants were randomly assigned using a block randomization scheme in a 2:2:2:1 ratio to receive bivalent rLP2086 vaccine (20, 60 or 200 µg) or Twinrix hepatitis A and B vaccine (GlaxoSmithKline, Rixensart, Belgium) using a block size of 7. A data monitoring committee was established to evaluate safety after 21 participants received the first dose of the study vaccine (including control). Further participants were not to receive doses until 7 days of safety evaluation occurred for the previous 21 participants.
The rLP2086 vaccine was supplied in a vial containing 0.71 mL of a preformulated liquid preparation with equal amounts (10, 30 or 100 µg) of 2 purified lipidated rLP2086 proteins (variants A05 and B01). Immunizations were administered by intramuscular injection at 0, 1 and 6 months. Personnel administering the immunizations were not blinded due to obvious visual differences between bivalent rLP2086 and Twinrix. However, participants, staff who evaluated participants for adverse events (AEs) and the study sponsor remained blinded throughout the study.
This study was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and was registered at ClinicalTrials.gov (NCT00387725). Independent ethics committees and institutional review boards approved the study.
Safety and Tolerability
Participants were provided with an electronic diary, digital thermometer and calipers for recording local reactions and systemic events. Systemic events (including fever) and local reactions were recorded on the day of vaccination and the following 13 days after each vaccination. All unsolicited AEs were recorded from signing of the informed consent form to the last study visit (29–43 days after final vaccination). The safety endpoints were the incidence of each local reaction, each systemic event and AEs.
Immunogenicity was assessed from serum drawn immediately before each immunization and approximately 1 month after dose 2 and dose 3. Immunogenicity assays were conducted at Early Phase Programs—Clinical Testing and Assay Development, Wyeth, Pearl River, NY, which was acquired by Pfizer Inc in October 2009. Immunoglobulin G (IgG)-binding antibody responses to rLP2086 subfamily A and B proteins were assayed using a Luminex assay28 (Luminex, Austin, TX). Functional antibody responses were measured using a serum bactericidal assay with human complement (hSBA) against MnB strains expressing vaccine-homologous or vaccine-heterologous LP2086 variants. These strains included PMB1745 (LP2086 variant A05), PMB663 (A22), PMB17 (B02), PMB265 (B09) and PMB3556 (B24), representing 4 of the 6 LP2086 subgroups (Table 1). The immunologic endpoints of this study were the rLP2086-specific IgG binding and hSBA results. The primary immunogenicity endpoint was the hSBA seroconversion rate for 2 MnB strains expressing either LP2086 variants A05 or B02. The A05 variant is the same as that included in the bivalent vaccine, and the remainder of the test strains express variants heterologous to the vaccine antigens. Seroconversion was defined as a ≥4-fold increase in hSBA titer from baseline (hSBA titer immediately before the first vaccination) to 1 month after the specified dose (dose 2 or dose 3). Reported immunogenicity results included all participants who had at least 1 assay result available for the proposed analysis.
Assuming the true seroconversion rate was 70%, a sample size of 100 evaluable participants per dose-level group would provide at least 80% power to demonstrate that the lower limit of a 2-sided 95% confidence interval for the estimated response rate at a given dose level of rLP2086 vaccine was ≥52% for strains PMB1745 (A05) and PMB17 (B02), assuming the response rates for the 2 strains were independent. Power was calculated using an exact test. Assuming 10% of participants were not evaluable, approximately 385 participants were needed with a randomization ratio of 2:2:2:1. However, a decision to alter the vaccine formulation for future studies caused enrollment in this study to be curtailed before the determined sample sizes were met.
The proportion of participants achieving seroconversion and the proportion of participants achieving hSBA titers ≥1:4 were summarized with the exact 2-sided 95% confidence interval for each vaccine group for each of the target MnB strains. IgG and hSBA data were summarized with geometric mean titers and 2-sided 95% confidence intervals using Student t distribution. Safety and tolerability data were descriptively summarized.
A total of 127 participants were enrolled in the study; their disposition and demographics are provided in Table 2. Participants were mostly white, with a slightly higher overall percentage of females. During an interim review of immunogenicity data from a concurrent study in healthy adults, the 20-μg dose of rLP2086 was found to be less immunogenic relative to the higher doses, and recruitment into the 20-μg dose was discontinued before full enrolment. As a result, only 16 participants received the 20-µg rLP2086 vaccine in the current study.
A total of 122 participants completed the 3-dose vaccination regimen (Fig. 1 and Table 2). Study completion rates were similar among all 3 vaccine doses and active control. A total of 6 (4.7%) participants were withdrawn from the study, including 1 participant who was discontinued after the third dose. One participant was withdrawn for an AE, which was a prolonged cough reported 1 day after immunization at the 200-μg dose; this participant had a medical history of eczema as a child and a strong family history of atopic disease (including hay fever and asthma). Other reasons for withdrawal included parent/legal guardian request (n = 2), participant request (n = 2) and protocol violation (simultaneous participation in another study; n = 1). One parent/legal guardian requested withdrawal of a participant after the first 200-μg rLP2086 vaccination due to injection site pain associated with fatigue, chills, nausea, vomiting, muscle pain and joint pain. One participant in the 60-μg rLP2086 group requested withdrawal due to diarrhea and vomiting. Detailed circumstances regarding the remaining 2 withdrawals were not provided.
Safety and Tolerability
Incidence and severity of local reactions (pain, induration and erythema) and incidence of systemic events are provided in Table 3. Frequencies of local reactions in participants receiving the rLP2086 vaccine tended to be higher than those receiving active control but were mostly mild to moderate in severity. Reports of severe local reactions were more common in the 200-μg dose group than in either of the lower vaccine doses.
Frequencies of systemic events in the 20-µg and 60-µg rLP2086 dose groups were generally comparable with those receiving control (Table 3). However, most systemic events occurred at a higher rate in the 200-µg rLP2086 dose group. Notably, occurrence of fever ≥38°C in the 200-µg rLP2086 dose group appeared to decrease with subsequent immunizations. The most common systemic event, headache, was observed with similar frequency among all vaccine and control participants. Frequency of chills and muscle or joint pain (not at the injection site) was also comparable with control among rLP2086 dose groups and immunizations.
AEs reported in over 5% of all 3 rLP2086 dose groups are provided in Table 4. The most common individual AEs reported were upper respiratory tract infection and headache, each of which occurred with similar frequency in the active control and rLP2086 groups. Overall, a total of 79 vaccine-related AEs were reported (10 in the control group, 12 in the 20-µg group, 28 in the 60-µg group and 29 in the 200-µg group). Vaccine-related AEs did not show a discernible trend across doses, and most were not reported in more than 1 participant in any dose group or after any vaccination.
Severe AEs were reported by 32 participants and included AEs that would be expected in this patient population, such as tonsillitis (n = 3), toothache (n = 3) and appendicitis (n = 2). A total of 6 participants, 4 in the 60-μg group and 2 in the 200-μg group, reported 9 severe AEs that were considered related to the rLP2086 vaccination. These events included erythema, pain and swelling at the injection site, anorexia, otitis media, nausea (n = 2), headache and earache. There was no apparent trend suggesting a relationship between severe vaccine-related AEs and dose number or dose level.
Eight participants reported serious AEs. One participant had serious AEs that were considered by the investigator to be vaccine related. This participant developed moderate injection-site erythema and swelling, severe injection-site pain, fever, nausea, vomiting (1 episode), muscle aches and joint aches on day 2 after the first vaccination at the 200-µg vaccine dose. He was admitted to the hospital with a provisional diagnosis of cellulitis. By the following day, he was afebrile and diagnosed with a “large localized reaction.” This participant was discharged from the hospital on postvaccination day 4, remained in the study and completed all subsequent vaccinations. No AEs were reported in this participant after the second vaccination but severe pain and erythema were reported after the third vaccination. There were no deaths in this study.
Serum samples from participants were analyzed for seroprotective hSBA titers (titers ≥1:4). Before the first immunization, the majority of participants (81.2–100%) showed no evidence of seroprotection against any of the MnB strains (Fig. 2). After dose 3, 68.8–97.7% of participants across all rLP2086 dose levels exhibited hSBA titers ≥1:4 against MnB strains expressing the vaccine-homologous A05 or the heterologous B02 LP2086 variants (Fig. 2A, B). Against MnB strains expressing other heterologous variants, post-dose 3 sera from participants receiving bivalent rLP2086 dose levels of 60 µg and 200 µg conferred greater seroprotection than the Twinrix active control (Fig. 2C–E).
The percentage of participants achieving seroconversion (defined as a ≥4-fold increase in hSBA titer from baseline) against strains PMB1745 (A05) and PMB17 (B02) ranged from 68.8%–95.3% after dose 3 across all dose levels (Fig. 3A, B). Seroconversion rates against other LP2086 variants were lower but still reached levels of 39.5%–66.7% at the higher vaccine dose levels (Fig. 3C–E).
After vaccination, levels of IgG antibodies with specificity for both subfamily A and B proteins were dramatically increased (Fig. 4). The levels of LP2086-specific IgG antibodies increased from pre-dose 1 to post-dose 2 and again to post-dose 3 for all vaccine doses and tended to increase with increasing dose levels.
This study investigated the safety, tolerability and immunogenicity of an initial bivalent rLP2086 vaccine formulation in healthy children and adolescents. Overall, the rLP2086 vaccine was found to be well-tolerated, with no major safety concerns noted by any of the investigators. One participant receiving the 200-μg dose was withdrawn from the study after the first vaccination due to an AE (moderate cough). Given the similar percentages of patients with upper respiratory tract infection (and other common AEs) in the active control and each of the rLP2086 vaccine groups (Table 4), these events were unlikely to be due to the rLP2086 vaccine.
An elevated frequency of local events was observed in participants receiving the bivalent rLP2086 vaccination (particularly at higher dose levels) when compared with participants receiving the Twinrix control. The majority of these events were mild to moderate and are consistent with results observed in healthy adults29 and toddlers.30 The incidence of systemic events was also comparable between groups, although these events tended to be more frequent in the 200-μg group. This differs from the adult and toddler studies, where systemic reactions at the 200-μg vaccine dose were similar to, or in some cases, lower than the 60-μg group.29,30 Because the current study was not powered for statistical comparisons of vaccine tolerability among randomized groups, any trends in tolerability should be interpreted with caution.
The bivalent rLP2086 vaccine was effective in eliciting rLP2086-specific antibodies, as the IgG geometric mean titers greatly increased in the majority of vaccinated participants after each immunization. Bactericidal efficacy of these elicited antibodies was examined by hSBA using diverse MnB strains from multiple sequence type clonal complexes selected to cover 4 of the 6 major subgroups within the LP2086 subfamilies (Table 1).21,23,26 Importantly, only 1 strain (PMB1745) expressed an LP2086 variant (A05) identical to that included in the vaccine. The remaining 5 strains expressed diverse LP2086 antigens with amino acid sequence identities ranging from 86.2%–92.0% with their respective subfamily A or B vaccine components. An hSBA titer of ≥1:4 is a commonly accepted correlate of protection and a surrogate employed for licensure of other meningococcal vaccines,31 and at least 68.8% of participants had titers ≥1:4 after the third immunization against MnB strains expressing the vaccine-homologous A05 or vaccine-heterologous B02 LP2086 variants across all 3 dose groups. In general, the hSBA responses in children and adolescents in this study were higher than those in toddlers but lower than in healthy adult volunteers.29,30
Currently, no broadly protective MnB vaccines are available for use in any age group. In addition to the bivalent rLP2086 vaccine, other MnB vaccines containing fHBP are currently in development.32,33 4CMenB is a vaccine containing multiple meningococcal outer membrane proteins identified by reverse vaccinology.34,35 Among the antigens included in the 4CMenB vaccine is a nonlipidated subfamily B/variant 1fHBP (B24). Another vaccine developed at the Walter Reed Army Institute of Research combines native OMVs expressed by 3 genetically modified MnB strains that overexpress candidate antigens; this vaccine includes different variants of fHBP and overexpresses fHBP variant B24.32,33,36 Both vaccines are being tested in human clinical trials.
The results of this study suggest that bivalent rLP2086 is a strong candidate for further evaluation as a broadly effective MnB vaccine in children and adolescents, similar to results recently reported in toddlers.30 Recently, the vaccine product has undergone formulation enhancements to improve stability. The new formulation is being evaluated in clinical studies and has already shown acceptable tolerability and the potential for broad coverage of MnB strains in adolescents.37 Strong antibody responses and an acceptable tolerability profile have also been reported in adult volunteers.29,38 Further studies using additional target MnB strains should help to predict the ability of this vaccine to elicit broadly protective immune responses against MnB disease-causing strains.
The authors thank the participants involved in this study as well as the staff at the research centers where this study was conducted. Editorial/medical writing support was provided by Alexander Bounoutas, PhD, at Scientific Strategy Partners, New York, NY, and was funded by Pfizer Inc (Pearl River, NY).
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
meningococcal vaccines; Neisseria meningitidis serogroup B; factor H binding protein; children; adolescents