Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: A phase III, randomized, multicentre, lot-to-lot consistency study
Introduction
Over the last two decades, substantial progress has been made in reducing the burden of disease caused by Neisseria meningitidis through vaccination. Successful mono- and multivalent vaccines against serogroups A, C, W and Y have been developed based on serogroup-specific capsular polysaccharides and enhanced with polysaccharide–protein conjugate technology. However, this vaccine strategy cannot be employed for serogroup B, the last of the five major pathogenic meningococcal groups, due to the capsule's structural homology to human fetal neural tissues, resulting in poor immunogenicity [1], [2]. Serogroup B Neisseria meningitidis (MenB) is now the leading cause of meningococcal disease in infants and young children, accounting for over 80% of cases in Australia and some Latin American countries, over 70% in Europe, 66% in the UK, 50–80% in Canada and one-third in the USA [3], [4], [5], [6], [7].
Previously, tailor-made MenB vaccines have been developed from strain-specific outer membrane vesicles (OMV) and successfully used to combat homologous strains in clonal outbreaks [8], [9], [10], [11]. However, due to limited or no effectiveness against heterologous strains they are not suitable for use as a general serogroup B vaccine [12]. Recently, important advances have been made in the quest for a universal MenB vaccine with the identification of conserved sub-capsular meningococcal proteins [13], [14].
One four-component recombinant vaccine, 4CMenB, contains three recombinant proteins: factor H binding protein (fHbp), Neisseria adhesin A (NadA) protein and Neisseria heparin binding antigen (NHBA), along with porin A (PorA) containing OMV derived from the meningococcal NZ98/254 strain (previously used to control a MenB clonal outbreak in New Zealand (NZ), the main PorA antigen is P1.4) [15]. Since development, the 4CMenB vaccine has been administered in phase I, and pivotal phase IIb and III studies to over 8000 adults, adolescents and infants and has been shown to be immunogenic, as measured by serum bactericidal assay using human complement (hSBA), to a majority of tested strains within hypervirulent clusters responsible for MenB disease [16], [17], [18], [19], [20], [21].
This study was aimed to evaluate the consistency of two lots of 4CMenB (manufactured at different sites), the early immune response (at two and four weeks) and the safety of a two-dose vaccination schedule, in healthy Australian and Canadian adolescents.
Section snippets
Study design and participants
The study (NCT01423084) was a phase III, multicentre, observer-blind, randomized trial which involved healthy 11 to 17-year-old adolescents across five centers in Australia and seven in Canada between August and December 2011. Written assent was obtained from each adolescent and written informed consent was obtained from participant's parents or legal guardians. Approvals were obtained from ethics committees at each participating research center.
Participants were randomized in a 1:1 ratio to
Results
Of the 344 participants enrolled into the study, 170 were included in Lot 1 (Rosia) and 174 in Lot 2 (Siena) of whom 99% and 98% of participants completed the study, respectively. The per-protocol immunogenicity population (299 participants) included adolescents with no major protocol violations who provided sera for testing (147 and 152 participants from Lot 1 and 2, respectively) (Fig. 1). The safety population comprised 342 participants (169 participants from Lot 1 and 173 from Lot 2). The
Discussion
We evaluated the consistency and kinetics of the immune response following vaccination with one of two lots of 4CMenB administered as two doses, one month apart in healthy 11–17 year old adolescents. We found immunological equivalence between two lots of 4CMenB at one month after second vaccination in terms of hSBA GMTs against each of the three MenB reference strains for fHbp, NadA and PorA antigens and ELISA IgG GMCs against the NHBA antigen. A variable but substantial decline in GMTs/GMCs
Acknowledgements
We are grateful to the participants of this study and their family members. We thank the contributions of the staff members of the Vaccine and Immunization Research Group (Melbourne), Marita Kefford, Sharon Trevorrow, Mairead Phelan, Annmarie McEvoy, Jane Ryrie, Clare Brophy, Janet Briggs, Marie West, Jacinta Sonego, Jacinta O’Keefe, Judith Spotswood, Paula Nathan and Bernie McCudden; Dr. Tanya Stoney, Caroline Talbot and Jennifer Kent of the Vaccine Trials Group (Perth); Chris Heath, Susan
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Recent advances in various bio-applications of bacteria-derived outer membrane vesicles
2023, Microbial PathogenesisAntibody persistence and booster response in adolescents and young adults 4 and 7.5 years after immunization with 4CMenB vaccine
2019, VaccineCitation Excerpt :Myalgia was the most common systemic reaction reported in other trials in adolescents and young adults [17,19], whereas in our study, headache and fatigue were reported as the most common systemic reactions. As expected for an adolescent population in light of previous studies [16,17], fever was not a common systemic reaction, and no participant reported high fever. No new safety clinical concerns were reported during this study.
Immunogenicity and safety of the multicomponent meningococcal B vaccine (4CMenB) in children and adolescents: a systematic review and meta-analysis
2018, The Lancet Infectious DiseasesCitation Excerpt :The 4CMenB vaccine was developed by the addition of an outer membrane vesicle porin protein (OMV-PorA) extracted from the New Zealand outbreak strain NZ98/254.11 Evidence about the effectiveness and safety of 4CMenB relies largely on immunogenicity and safety data from phase 1–3 randomised controlled trials,13–35 in which 4CMenB was compared against rMenB or against different routine vaccines, using various schedules. However, the available evidence is highly heterogeneous, the results are too complex to interpret by examining single trials, and several uncertainties remain about the lowest number of doses needed to induce a satisfactory immune response.10,36