Pediatric Infectious Disease Journal:
Safety and Immunogenicity of a Meningococcal B Bivalent rLP2086 Vaccine in Healthy Toddlers Aged 18–36 Months: A Phase 1 Randomized-controlled Clinical Trial
Marshall, Helen S. MB BS, MD, MPH, DCH*; Richmond, Peter C. MB BS†; Nissen, Michael D. MB BS‡; Jiang, Qin MS§; Anderson, Annaliesa S. PhD§; Jansen, Kathrin U. PhD§; Reynolds, Graham MB BS¶; Ziegler, John B. MB BS‖; Harris, Shannon L. PhD§; Jones, Thomas R. PhD§; Perez, John L. MD§
From the *Vaccinology and Immunology Research Trials Unit, Women’s and Children’s Hospital and School of Paediatrics and Reproductive Health, University of Adelaide, North Adelaide, South Australia; †University of Western Australia School of Paediatrics and Child Health, Vaccine Trials Group, Telethon Institute for Child Health Research, Subiaco, Western Australia; ‡Queensland Paediatric Infectious Diseases Laboratory, Queensland Children’s Medical Research Institute, Royal Children’s Hospital and University of Queensland, Herston, Queensland, Australia; §Pfizer Vaccine Research, Pearl River, NY; ¶Australian National University Medical School, Department of Paediatrics and Child Health, Canberra; and ‖School of Women’s & Children’s Health, University of NSW and Department of Immunology & Infectious Diseases Sydney Children’s Hospital High St., Randwick, New South Wales, Australia.
Accepted for publication May 01, 2012.
This study was sponsored by Wyeth, which was acquired by Pfizer Inc in 2009. The sponsor was involved in all study stages, from the study design to the data analysis and preparation of the manuscript. The lead author wrote thedraft manuscript, with all authors contributing to subsequent versions and had the final responsibility for the decision to submit the manuscript for publication.HSM acknowledges support from the National Health and Medical Research Council of Australia: Career Development Fellowship (1016272).HSM has been a member of vaccine advisory boards for Wyeth and GlaxoSmithKline Biologicals and her institution has received funding for investigatorled research from GlaxoSmithKline and Sanofi-Pasteur, and has received travel support from Pfizer, GlaxoSmithKline Biologicals and CSL to present scientific data at international meetings. PCR has been a memberof vaccine advisory boards for Wyeth and Baxter, has received funding for investigator-initiated research from GlaxoSmithKline Biologicals and Novartis and received travel support from Pfizer and Baxter to present study data at international meetings. MDN has received travel grants from Wyeth Australia and GlaxoSmithKline Biologicals to present independent researchat international meetings, and currently and previously has been the principalinvestigator for clinical trials sponsored by Abbott, Baxter, GlaxoSmithKline, Merck, Novartis, Sanofi-Pasteur, Wyeth and Pfizer. JBZ has received support from Wyeth and Pfizer to present at meetings. GR has received support from Wyeth and Pfizer for research protocol-related meetings and for web facility editing and commentary. ASA, SLH, KUJ, QJ, TRJ and JLP are employees of Pfizer Inc. The authors have no other funding or conflicts ofinterest to disclose.
Address for correspondence: Helen S. Marshall, MBBS, MD, MPH, DCH, NHMRC Career Development Fellow Director, Vaccinology and Immunology Research Trials Unit, Women’s and Children’s Hospital School of Paediatrics and Reproductive Health, University of Adelaide, 72 King William Rd, North Adelaide, SA 5006, Australia. E-mail: email@example.com.
Background: A bivalent, recombinant, factor H–binding protein (rLP2086) vaccine was developed to protect against invasive Neisseria meningitidis serogroup B (MnB) in children and adolescents.
Methods: Healthy toddlers (N = 99) were enrolled to 3 ascending dose-level cohorts (20, 60 or 200 μg). Within each cohort (n = 33), subjects were randomized to receive an initial formulation of the bivalent rLP2086 vaccine at 0, 1 and 6 months or hepatitis A vaccine/placebo control (2:1 ratio). Reactogenicity was assessed by parental reporting of local and systemic reactions using electronic diaries and reports of unsolicited adverse events. Immunogenicity was assessed by serum bactericidal activity assay using human complement and rLP2086-specific IgG binding.
Results: The vaccine was considered to be well tolerated. Tenderness was the most frequently reported local reaction. Upper respiratory tract infection was the most commonly reported adverse event and occurred more frequently in the control group. Three cases (200 μg dose) of severe erythema that did not interfere with limb movement were reported. Four toddlers developed fever >40.0°C, 3 in the 200 μg group and 1 in the 60 μg group. Postdose 3, seroconversion (serum bactericidal activity assay using human complement ≥4-fold rise from baseline) was observed in 61.1–88.9% of participants against MnB strains expressing LP2086 variants homologous or nearly homologous to vaccine antigens and 11.1–44.4% against MnB strains expressing heterologous LP2086 variants. Seroconversion was observed in 77.8–100% of participants against additional, exploratory MnB strains expressing vaccine-homologous or heterologous LP2086 variants.
Conclusions: This study shows that the bivalent rLP2086 vaccine is well tolerated and immunogenic in toddlers.
Neisseria meningitidis is a Gram-negative diplococcus commonly found in the human upper respiratory tract. Twelve serogroups of N. meningitidis have been identified, but 5 (A, B, C, W-135 and Y) are responsible for most cases of invasive meningococcal disease (IMD).1,2 The incidence of IMD is highest in infants and children up to 4 years of age.3–5 Invasive disease caused by serogroups A, C, Y and W-135 can be prevented with capsular polysaccharide conjugate vaccines.6 Following the introduction of national meningococcal C vaccine campaigns, 90% of IMD cases in the United Kingdom and 83% of IMD cases in Australia are now caused by serogroup B meningococci (MnB), for which no broadly protective vaccine is licensed.5,7,8
The MnB polysaccharide does not elicit serum bactericidal antibodies and research has focused on protein antigens in the outer membrane to provide a protective vaccine against serogroup B.9,10 One potential target protein, porin A (PorA), is the predominant antigen found in outer membrane vesicle vaccines developed to prevent epidemic IMD.11 Outer membrane vesicle vaccines are less effective against endemic MnB disease strains due to the high degree of strain-to-strain variation of the PorA antigen.12,13
An ideal vaccine antigen candidate should be highly conserved and protect against endemic as well as epidemic strains of MnB. LP2086 is a Neisseria-specific outer membrane lipoprotein that elicits bactericidal antibodies against a broad range of MnB strains.14,15 LP2086 is a human factor H–binding protein that downregulates complement-mediated lysis.16 Translated nucleic acid sequence analysis of LP2086 from >1800 MnB strains obtained from national reference laboratories in the United States, Europe and South Africa identified 2 LP2086 subfamilies, designated A and B.17 The amino acid sequence of LP2086 is highly conserved, with >83% sequence identity within each subfamily, but only 60–75% sequence identity between subfamilies A and B.14,17 Within each subfamily are numerous LP2086 variants that differ from each other by 1 or more amino acids. The value and necessity of a bivalent vaccine approach has been suggested by preclinical and clinical studies. A vaccine composed of equal amounts of 1 variant from each human factor H–binding protein subfamily was required to generate broadly protective bactericidal antibodies against diverse MnB isolates in rabbits (87/100 strains tested were killed) and humans (35/45 strains tested were killed), suggesting that LP2086 proteins within subfamilies are antigenically related.18
In the present study, a 3-dose series of an initial formulation of the bivalent rLP2086 vaccine was investigated in toddlers who had not previously been vaccinated against MnB. The primary objective of this study was to assess the safety and tolerability of the vaccine. Secondary objectives included assessment of vaccine immunogenicity determined by rLP2086-specific IgG binding to subfamily A and B LP2086 proteins and by activity in serum bactericidal assays with human complement (hSBA) against MnB strains expressing diverse LP2086 proteins.
MATERIALS AND METHODS
This was a phase 1, observer-blind, ascending-dose, randomized, active-comparator/placebo-controlled study conducted at 4 hospital centers in Australia from October 2006 to March 2008. Recruitment of participants from the community occurred through advertisements, patient databases and referrals from other departments within the institutions. As this was the first time the vaccine was being administered to young children, participants were enrolled into 1 of 3 successive ascending-dose cohorts (Fig. 2). Safety and reactogenicity data for each cohort were monitored for 7 days postvaccination by an unblinded data monitoring committee before proceeding to the next dose-level cohort. Criteria for enrollment of the next-highest dose cohort included the occurrence of fewer than 2 severe local reactions, occurrence of fewer than 2 fevers >40°C and the absence of local site reactions, systemic events or other adverse events (AEs) that would jeopardize the safety of participants upon further dosing. Participants within each cohort were randomized to receive vaccine or active control in a 2:1 ratio using a Clinical Operations Randomization Environment system with a block size of 3 for each study site. Vaccination was administered by intramuscular injection into the upper deltoid at 0, 1 and 6 months. Due to visual differences between the study vaccine and controls, study staff administering the vaccine was not blinded. All other study personnel, including those interpreting electronic diary entries (details in the subsequent section), were blinded until study assays were complete and all data queries were resolved.
Male and female toddlers aged 18–36 months were required to be in good health as determined by medical history and physical examination. Exclusion criteria included a history of any IMD or prior MnB or hepatitis A virus (HAV) vaccination, previous anaphylactic or severe vaccine-associated adverse reaction or known hypersensitivity to any study vaccine components; any clinically significant chronic disease; bleeding diathesis; or impaired immunity. Participants who received immunosuppressive therapy (including systemic corticosteroids) or any blood products in the previous 6 months were also ineligible.
Caregivers of participants gave written informed consent before inclusion in the study. Institutional research boards or independent ethics committees at each center approved the study protocol and consent forms. The study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and registered with Clinicaltrials.gov (NCT00387569).
The rLP2086 vaccine was formulated with 0.125mg aluminum phosphate as a stabilizer in an isotonic buffer containing 0.025% polysorbate 80 for each 0.5mL dose. Each vaccine dose contained a final concentration of 20, 60 or 200 μg rLP2086 (equal parts of A and B subfamily proteins). The active control was the commercially available HAV vaccine (VAQTA, CSL Biotherapies/Merck & Co., Inc., Parkville, Victoria, Australia) administered in a 2-dose schedule, with a saline placebo administered at the second of the 3 vaccination time points. The HAV vaccine contained 25 units of inactivated HAV; the placebo was identical to the rLP2086 vaccine but lacked the subfamily A and B proteins.
Safety and Reactogenicity
Caregivers were provided with electronic diaries, digital thermometers and measuring callipers for recording solicited reactions. Occurrences of injection site reactions and systemic events were recorded for 14 days. Local reactions were graded as mild, moderate or severe based on severity of tenderness or diameter of induration or erythema. Other unsolicited AEs were reported from enrollment to the last visit, 29–43 days after the final vaccination.
Functional antibody titers were determined by hSBA. The hSBA measures antibodies in human sera that result in complement-dependent killing of the target meningococcal strain.18,19 Five MnB isolates were initially selected based on the diversity of LP2086 amino acid sequences: multilocus sequence types and PorA types (Table 3, Fig. 1). A subset of serum samples were also tested against 4 additional diverse strains selected from a representative pool of >1800 IMD isolates.17 The hSBA titers were calculated as the reciprocal of the interpolated test serum dilution that resulted in a 50% reduction of viable meningococci. Anti-rLP2086–specific IgG antibodies were measured using a multiplex Luminex assay (Luminex, Austin, TX). Sample processing and immunologic assays were performed in the high-throughput clinical testing laboratory at Wyeth (Pearl River, NY), which was acquired by Pfizer Inc., in October 2009.
As a phase 1 study, the sample size was not powered for hypothesis testing. Each dose cohort was planned to comprise 10 participants receiving control and 20 receiving vaccine. This sample size for each cohort provided at least 73% power to detect differences in AEs (local site reactions and systemic events, including fever) when the rate was 60% in the vaccine group and no more than 10% in the control group using Fisher exact test with type I error of 5%. The safety analysis included all participants that received at least 1 vaccination and had safety data for that vaccination. Immunogenicity analyses included all participants who had at least 1 valid and determinable assay result for the proposed analysis. Data for the placebo groups from different cohorts were pooled for both safety and immunogenicity analyses.
Within each group, anti-rLP2086 IgG geometric mean titers were calculated for each visit with a blood draw. Two-sided 95% confidence intervals were constructed by backtransformation of the confidence intervals for the mean of the logarithmically transformed assay results computed using the Student t distribution. In addition, the proportion of subjects achieving seroconversion in hSBAs (≥4-fold rise from baseline) at 1 month after dose 2 and 1 month after dose 3 were computed along with a 95% exact confidence interval for the proportion based on the F-distribution. The proportion of subjects with local reactions and systemic events reported on any day within the 14-day period after each vaccination was descriptively summarized for each vaccine group.
A total of 99 participants were enrolled in this study and received at least 1 vaccination. Baseline characteristics were similar across all dose-level cohorts with respect to race and age (Table 1). The study completion rate was similar across all 4 groups (Fig. 2). Six participants were withdrawn for AEs. Four of the AEs (asthma, diarrhea, urticaria and accidental overdose) occurred in vaccine recipients and 2 (febrile convulsion and oral herpes) occurred in the control group. The episode of asthma that led to withdrawal occurred 16 days after the first 60 μg dose of rLP2086 vaccine in a participant with a history of wheezing. Another participant withdrew following an episode of diarrhea that occurred 55 days after the second 60 μg rLP2086 vaccination. Urticaria, a serious AE resulting in withdrawal of 1 participant, occurred 22 hours after the first 60 μg rLP2086 vaccination, resolved following antihistamine and paracetamol treatment, and was considered possibly vaccine-related. One recipient randomly assigned to receive the 20 μg dose received a 200 μg dose in error. This recipient was included in the 200 μg dose group for safety evaluations but was excluded from the immunogenicity population because no blood was collected for assay testing. Other reasons for withdrawal were parent/legal guardian request (n = 4) and other (n = 1; travel).
After each vaccination, tenderness was the most common injection site reaction. Occurrence of tenderness was numerically greater in the rLP2086 dose groups. No clear association was observed between reports of tenderness and vaccine dose level or immunization schedule. For example, following the first vaccination, tenderness occurred in 59.1% of participants at the lowest (20 μg) dose level, 39.1% at the 60 μg dose level, and 68.2% at the highest (200 μg) dose level (Table 2). Occurrence of tenderness interfering with limb movement increased numerically over the course of immunization at the 200 μg dose level, but not at the 20 μg or 60 μg dose levels (Table 2). One episode (3.2%) of tenderness interfering with limb movement was reported after HAV/placebo vaccination.
Erythema and induration, both of mild to moderate severity, tended to be reported more frequently in the MnB vaccine recipients. The incidence of erythema was similar after each rLP2086 immunization within each dose level, and increased with increasing dose levels (Table 2). Three cases of severe erythema (>7.0cm in diameter) were reported in the 200 μg dose group. Mild or moderate induration was reported in up to approximately one third of participants receiving rLP2086 vaccine in the lower dosing groups (range: 5–32%) and in 20–45% of participants receiving the 200 μg dose. In contrast, reports of induration ranged from 3.1% to 7.1% in the HAV/placebo group. Following rLP2086 vaccination, there were no reports of severe induration in any vaccine group.
In general, the total and individual frequencies of systemic events in each rLP2086 vaccine group were numerically comparable with HAV/placebo (Table 2). Irritability, which occurred in at least 50% of rLP2086 vaccine recipients, was the most commonly reported systemic event. Fever occurred in 0–40.9% of toddlers receiving any rLP2086 vaccine dose, but was mostly mild or moderate in severity. By comparison, 9.7–18.8% of participants receiving HAV reported any fever. Four cases of fever >40.0°C were reported (3 in the 200 μg group and 1 in the 60 μg group), each of which lasted for 1 to 2 days.
The frequency of AEs was generally comparable between the control and the rLP2086 vaccine groups. Upper respiratory tract infection was the most common AE and occurred in 75.0% of participants in the control group and 52.6–63.6% of rLP2086 vaccine recipients. The next most common AE was cough, which occurred in 9.4% of controls and 21.7–22.7% of rLP2086 vaccine recipients. Serious AEs were reported for 5 participants. For participants receiving rLP2086, 2 reported serious AEs (urticaria and accidental overdose, details described earlier) were considered to be vaccine-related, and 1 (otitis media) was not. Two serious AEs (oral herpes and pneumonia) occurred in the HAV/placebo group.
Bactericidal Antibody Responses
A total of 98 participants had data available from serum samples after any dose and were included in the immunogenicity analysis. Sera were evaluated for bactericidal activity against 5 MnB test strains. Compared with vaccine antigens, the LP2086 variants expressed by MnB test strains had amino acid sequence identity ranging from 88.9% to 100% (vaccine rLP2086 variant A05) and 86.2–92% (vaccine rLP2086 variant B01; Table 3). hSBA titers at baseline (predose 1) were below the limit of quantitation of the assay (hSBA titer of ≤1:4) for nearly all participants receiving rLP2086 (95.0–100%) or HAV/placebo (87.5–100%). Seroconversion rates from baseline were determined for postdose 2 and postdose 3. Postdose 3, seroconversion rates of 61.1–83.3% (rate dependent on dose-level group) were observed against strain PMB1745 expressing homologous LP2086 variant A05 and 77.8–88.9% against strain PMB17 expressing heterologous LP2086 variant B02 (Fig. 3A, 3B). Seroconversion rates against strains expressing heterologous LP2086 variants A22 (PMB663), B09 (PMB265) and B24 (PMB3556) ranged from 11.1% to 44.4% postdose 3 at the 200 μg dose (Fig. 3C–E). Seroprotection rates (hSBA titers ≥1:4) were numerically comparable with seroconversion rates across all MnB test strains (data not shown).
To address whether the relatively lower hSBA responses noted for some strains were due to LP2086 variant identity or other strain-specific differences, additional hSBA evaluations were performed using 4 additional MnB strains. Sera from a subset of participants receiving 20 μg and 200 μg rLP2086 vaccine doses (selected on the basis of serum availability) were evaluated by hSBA against strains PMB1168 (LP2086 variant A05), PMB1321 (A22), PMB1256 (B03) and PMB147 (B44; Table 3). Of these strains, PMB1168 expressed the LP2086 vaccine-homologous variant A05; the other 3 strains expressed variants heterologous to the LP2086 vaccine antigen (Fig. 1) and had different genetic backgrounds (ie, PorA and multilocus sequence type [Table 3]). After the third 200 μg vaccination, all participants (100%) achieved seroconversion against MnB strains expressing subfamily A proteins, and 81.8–94.4% achieved seroconversion against MnB strains expressing subfamily B proteins (Fig. 4). Of those receiving the 20 μg dose, 77.8–100% achieved seroconversion against the MnB strains expressing subfamily A, and 33.3–71.4% achieved seroconversion against MnB strains expressing subfamily B LP2086 variants. Seroprotection rates were also numerically similar to seroconversion rates across all additional hSBA strains (data not shown). Geometric mean titers for hSBA analyses are shown in Table 4.
IgG Geometric Mean Titers
The rLP2086 vaccine induced IgG antibody responses with specificity for both subfamily A and B proteins (Fig. 5A, 5B). The majority of rLP2086 recipients had IgG titer fold rises ≥4 from baseline to postdose 2 and from baseline to postdose 3 (range: 76.5–100%) regardless of dose level. The geometric mean fold rises from baseline to postdose 3 for subfamily A and B antigens, respectively, were 231.1 and 141.1 at the 20 μg dose level, 147.9 and 178.6 at 60 μg, and 200.1 and 316.8 at 200 μg (data not shown). By comparison, HAV/placebo vaccination elicited geometric mean fold rises of 0.9 to subfamily A and 1.3 to subfamily B proteins.
This first-in-toddler study demonstrated that an initial formulation of the bivalent rLP2086 vaccine was well tolerated and immunogenic. Local reactions were mostly mild. Fever, when present, was ≤39°C in most toddlers across all treatment groups. Sera from recipients of the bivalent rLP2086 vaccine mediated bactericidal lysis of MnB strains expressing vaccine-homologous (A05) and heterologous LP2086 variants (A22, B02, B44, B09, B24 and B03). Vaccinees appeared to have somewhat lower bactericidal antibody levels against the strains expressing LP2086 variants B09 and B24, whereas bactericidal responses to strains expressing other LP2086 variants (eg, B44 and B03) were very robust. Notably, we observed different levels of hSBA responses against 2 strains expressing the LP2086 variant A22 (Figs. 1 and 4). Because serum samples were limited, future studies will aim to address whether this result is a reflection of strain-specific differences or assay-specific differences (eg, human complement sources). IgG titers specific for LP2086 subfamily A and B proteins tended to increase with each subsequent rLP2086 vaccination for all 3 dose groups. The slight predominance of male toddlers enrolled in the study is unlikely to have impacted reactogenicity or immunogenicity results.
The ability to generalize the current data to a larger pediatric setting must be carefully considered due to the small sample size in this phase 1 study. Demonstrating true vaccine efficacy in clinical trials requires a prohibitively large number of participants because of the relatively low incidence of IMD. However, seroconversion (≥4-fold rises in hSBA titers) and seroprotection (hSBA titers ≥1:4) following vaccination are considered a valid measure of response consistent with immune protection.20 The number of naturally occurring N. meningitidis variants creates a challenge in estimating the breadth of coverage or clinical effectiveness. The panel of MnB test strains used here expressed LP2086 variants with 86.2–100% identity to vaccine antigens (Fig. 1). These variants cover a considerable range of LP2086 sequence diversity, and the results from this study suggest that the bactericidal antibodies elicited by the rLP2086 vaccine are potentially effective at killing many diverse endemic and epidemic MnB strains, given that nearly all MnB strains tested to date express either subfamily A or B LP2086 protein.17,21 Future studies using additional clinically and epidemiologically relevant and diverse MnB hSBA strains selected in an unbiased fashion from a large representative strain pool17 will ensure that immunogenicity data is properly bridged to the current population of circulating IMD-causing strains.
Another MnB vaccine, 4CMenB, is currently undergoing phase 3 trials in Europe and contains several protein antigens, including a single nonlipidated LP2086 subfamily B variant (B24).17,22,23 Clinical trials of this vaccine have demonstrated high serum bactericidal antibody responses against MnB test strains expressing the same or closely related LP2086 variants and lower response rates against strains expressing heterologous LP2086 variants.22–24
The present study suggests that the bivalent rLP2086 investigational vaccine is immunogenic and has an acceptable safety profile in toddlers. Evidence of safety and immunogenicity of the bivalent rLP2086 vaccine in infants and adolescents will inform future immunization programs.
A revised vaccine formulation with modified vaccine excipients has been developed to enhance stability and potentially to improve further the immunogenicity and safety profile. The new formulation is now being tested in phase 2 clinical trials in adolescents. If additional trials of the final vaccine formulation confirm the observations described herein, the bivalent rLP2086 vaccine could help protect at-risk age groups from IMD dueto serogroup B meningococci and provide substantial health benefit.
The authors acknowledge and thank all the parents and children who took part in this study. The authors also thank all the staff at research centers who contributed to the study including Dr. Susan Evans, Dr. Jan Walker, Dr. Rachel Chen, Ms. Susan Lee, Mrs. Chris Heath, Mrs. Jane Tidswell, Mrs. Michele Clarke, Mrs. Di Weber and Mrs. Louise DeGaris at the Women’s and Children’s hospital, Adelaide, Jan Adams, Dr. Gabriella Dixon, Jennifer Kent, Larissa Rhind, Dr. Tanya Stoney at the Vaccine Trials Group in Perth. Editorial/medical writing support was provided by John Clinton Earnheart, PhD, at Scientific Strategy Partners and was funded by Pfizer Inc.
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Neisseria meningitidis serogroup B; meningococcal vaccine; factor H–binding protein; bactericidal antibodies; protein-based vaccine antigens
© 2012 Lippincott Williams & Wilkins, Inc.
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