Elsevier

Vaccine

Volume 33, Issue 39, 22 September 2015, Pages 5217-5224
Vaccine

Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: A phase III, randomized, multicentre, lot-to-lot consistency study

https://doi.org/10.1016/j.vaccine.2015.06.103Get rights and content

Abstract

Background

For decades, a broadly effective vaccine against serogroup B Neisseria meningitidis (MenB) has remained elusive. Recently, a four-component recombinant vaccine (4CMenB) has been developed and is now approved in Europe, Canada, Australia and some Latin American countries. This phase III, randomized study evaluated the lot consistency, early immune responses and the safety profile of 4CMenB in 11 to 17-year-old adolescents in Australia and Canada (NCT01423084).

Methods

In total, 344 adolescents received two doses of one of 2 lots of 4CMenB, 1-month apart. Immunogenicity was assessed before, 2-weeks and 1-month following the second vaccination. Serum bactericidal activity using human complement (hSBA) was measured against three reference strains 44/76-SL, 5/99 and NZ98/254, selected to express one of the vaccine antigens; Neisseria adhesin A (NadA), factor H binding protein (fHbp) and porin A (PorA) containing outer membrane vesicle (OMV), respectively. Responses to the Neisseria heparin binding antigen (NHBA) were assessed with enzyme linked immunosorbent assay (ELISA). Local and systemic reactions were recorded for 7 days following each vaccination; unsolicited adverse events were monitored throughout the study.

Results

Immunological equivalence of the two lots of 4CMenB was established at 1-month. At baseline, ≤7% of participants had hSBA titers ≥5 to all three reference strains. Two weeks following the second dose of 4CMenB, all participants had hSBA titers ≥5 against fHbp and NadA compared with 84–96% against the PorA reference strains. At 1-month, corresponding proportions were 99%, 100% and 70–79%, respectively. Both lots were generally well tolerated and had similar adverse event profiles.

Conclusions

Two doses of 4CMenB had an acceptable safety profile and induced a robust immune response in adolescents. Peak antibody responses were observed at 14 days following vaccination. While a substantial non-uniform antigen-dependent early decline in antibody titers was seen thereafter, a significant percentage of participants continued to maintain protective hSBA titers at 1-month.

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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