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Breadth of immune response, immunogenicity, reactogenicity, and safety for a pentavalent meningococcal ABCWY vaccine in healthy adolescents and young adults: results from a phase 3, randomised, controlled observer-blinded trial - 06/12/24

Doi : 10.1016/S1473-3099(24)00667-4 
Terry Nolan, ProfPhD a, *, Chiranjiwi Bhusal, MD b, * , Jiří Beran, MD c, Mark Bloch, MBBS d, e, Benhur Sirvan Cetin, MD f, Ener Cagri Dinleyici, MD g, Daniel Dražan, MD h, Satu Kokko, MD i, Susanna Koski, MD j, Outi Laajalahti, MD k, Joanne M Langley, MD l, Mika Rämet, ProfMD m, Peter C Richmond, MBBS n, Peter Silas, MD o, Bruce Tapiero, MD p, Florence Tiong, MD q, Mary Tipton, MD r, Benita Ukkonen, MD s, Betul Ulukol, MD t, Maria Lattanzi, MD u, Mauro Trapani, PharmD u, Arnold Willemsen, MSc CStat b, Daniela Toneatto, MD u
on behalf of the

QUINTET study group

  Listed in the Supplementary Material)
Mark Bloch, Peter Richmond, Eugene Athan, Terry Nolan, Marije Dalebout, Florence Tiong, Ferdinandus de Looze, Ener Cagri Dinleyici, Tolga Ince, Benhur Cetin, Betul Ulukol, Jiří Beran, Daniel Dražan, Renata Adamovska, Martina Spaziererova, Josef Zemanek, Miroslav Pavlasek, Sandra Meisalu, Kaia Kiiroja, Mika Rämet, Ilkka Seppä, Susanna Koski, Benita Ukkonen, Satu Kokko, Outi Laajalahti, Pauliina Paavola, Marc Dionne, Anil Gupta, Joanne Langley, James Kellner, Bruce Tapiero, Noah Vale, Marie-Louise Vachon, Manish Sadarangani, Peter Dzongowski, Mary Tipton, Walter Rok, Martin Schear, William Simon, Jonathan Staben, Paul Grubb, Robert Jeanfreau, Enrique Pelayo, Minesh Patel, Rambod Rouhbakhsh, Peter Silas, Daniel Finn, Joseph Surber, George Freeman, Maia Chakerian, Alexander Osowa, Kwabena Ayesu, Jake Jones, Ryan Gottfredson, John Scott, William Byars, Hemalini Mehta, Robert Carter, Rand Farjo, Ronald Ackerman, David Bernard, Yamirka Sanchez, Maria Lattanzi, Mauro Trapani, Chiranjiwi Bhusal, Daniela Toneatto, Arnold Willemsen, Isabelle Lechevin, Stefanie Raulier, Dominique Wauters, Danielle Morelle

a Vaccine and Immunisation Research Group, Peter Doherty Institute and Murdoch Children’s Research Institute, Melbourne, VIC, Australia 
b GSK, Amsterdam, Netherlands 
c Vaccination and Travel Medicine Centre, Hradec Králové, Czechia 
d Holdsworth House Medical Practice, Sydney, NSW, Australia 
e Kirby Institute, University of New South Wales, Sydney, NSW, Australia 
f Erciyes University, Faculty of Medicine, Kayseri, Türkiye 
g Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Türkiye 
h General Practice for Children and Adolescents, Jindřichův Hradec, Czechia 
i Tampereen yliopisto Oulun rokotetutkimusklinikka, Oulu, Finland 
j Tampereen yliopisto Etelä-Helsingin rokotetutkimusklinikka, Helsinki, Finland 
k Tampereen yliopisto, Seinajoen rokotetutkimusklinikka, Seinajoki, Finland 
l Canadian Center for Vaccinology, Dalhousie University, IWK Health and NS Health, Halifax, NS, Canada 
m Finnish Vaccine Research, and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland 
n School of Medicine, University of Western Australia, Perth Children’s Hospital, Perth, and Telethon Kids Institute, Nedlands, WA, Australia 
o Wee Care Pediatrics, Syracuse, UT, USA 
p CHU Sainte-Justine, Montreal, QC, Canada 
q AusTrials (Wellers Hill), Tarragindi, QLD, Australia 
r Copperview Medical Center, South Jordan, UT, USA 
s Tampereen yliopisto, Espoon rokotetutkimusklinikka, Espoo, Finland 
t Ankara University School of Medicine, Ankara, Türkiye 
u GSK, Siena, Italy 

* Correspondence to: Dr Chiranjiwi Bhusal, GSK, 1101CL, Amsterdam, Netherlands GSK Amsterdam 1101CL Netherlands
Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 06 December 2024

Summary

Background

A multicomponent meningococcal serogroups ABCWY vaccine (MenABCWY) could provide broad protection against disease-causing meningococcal strains and simplify the immunisation schedule. The aim of this trial was to confirm the effect of the licensed meningococcal serogroup B (MenB) vaccine, 4CMenB, against diverse MenB strains, and to assess the breadth of immune response against a panel of 110 MenB strains for MenABCWY containing the antigenic components of 4CMenB and licensed serogroups ACWY vaccine, MenACWY-CRM, the non-inferiority of the immune response with MenABCWY versus 4CMenB and MenACWY-CRM, safety, and MenABCWY lot-to-lot consistency.

Methods

We conducted a phase 3 randomised, controlled, observer-blinded trial of healthy adolescents and young adults (age 10–25 years) across 114 centres in Australia, Canada, Czechia, Estonia, Finland, Türkiye, and the USA. Exclusion criteria included previous vaccination with a MenB vaccine or (within the last 4 years) MenACWY vaccine. Participants were randomly allocated (5:5:3:3:3:1 ratio) via a central randomisation system using a minimisation procedure to receive 4CMenB at months 0, 2, and 6 (referred to as 4CMenB 0–2–6 hereafter); or 4CMenB at months 0 and 6 (referred to as 4CMenB 0–6 hereafter); or MenABCWY (three groups, each receiving one production lot of the MenACWY-CRM component) at months 0 and 6; or MenACWY-CRM at month 0. Demonstration in the per-protocol set of the consistency of three MenACWY-CRM component lots of the MenABCWY vaccine was a primary objective (demonstrated with two-sided 95% CIs for the ratio of human serum bactericidal antibody [hSBA] geometric mean titres against each serogroup within predefined criteria [0·5–2·0]). The primary endpoints (breadth of immune response) for the MenB component of MenABCWY and 4CMenB were measured using the endogenous complement hSBA (enc-hSBA) assay against a panel of 110 diverse MenB invasive disease strains. For each serum sample, 35 strains from the 110 MenB strain panel were randomly selected for testing. The 4CMenB breadth of immune response data have been published separately. For MenABCWY, breadth of immune response was assessed in two analyses: a test-based analysis of the percentage of samples (tests) without bactericidal serum activity against MenB strains 1 month after two MenABCWY doses versus the percentage after one MenACWY-CRM dose in the per-protocol set, and a responder-based analysis of the percentage of participants (responders) whose sera killed 70% or more strains at 1 month after two MenABCWY doses in the full analysis set. A lower limit of two-sided 95% CI above 65% would demonstrate breadth of immune response. Other primary outcomes included non-inferiority (5% margin) of two MenABCWY doses versus two 4CMenB doses by enc-hSBA assay in the per-protocol set, non-inferiority (10% margin) of two MenABCWY doses versus one MenACWY-CRM dose in MenACWY vaccine-naive participants by traditional hSBA assay in the per-protocol set, and safety in all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT04502693, and is complete.

Findings

Between Aug 14, 2020, and Sept 3, 2021, 3651 participants were enrolled and randomly allocated (900 in the 4CMenB 0–2–6 group and 908 in the 4CMenB 0–6 group, 1666 in the three MenABCWY groups combined, and 177 in the MenACWY-CRM group). All primary objectives for MenABCWY were met. Consistency of immune responses against the three production lots of the MenACWY component of MenABCWY was demonstrated since two-sided 95% CIs for the ratios of hSBA geometric mean titres against serogroups A, C, W, and Y for each pair of lots were within the predefined equivalence criteria. The lot data were pooled for the remainder of MenABCWY endpoints. By enc-hSBA assay, breadth of immune response against the MenB strain panel was 77·9% (95% CI 76·6 to 79·2) in the test-based analysis and 84·1% (81·4 to 86·5; 687 of 817 participants) in the responder-based analysis. Non-inferiority of MenABCWY to 4CMenB was demonstrated by enc-hSBA assay: the difference in percentage of samples with bactericidal serum activity between the MenABCWY group (82·5% [95% CI 82·1 to 83·0]; 21 222 of 25 715) and 4CMenB 0–2 group (83·1% [82·7 to 83·6]; 22 921 of 27 569) was –0·61% (–1·25 to 0·03). Non-inferiority of two-dose MenABCWY to one-dose MenACWY-CRM was demonstrated by traditional hSBA assay, with differences between the MenABCWY group and MenACWY group in percentages of participants with a four-fold rise in hSBA titres of 11·3% (5·9 to 19·0) for serogroup A, 47·2% (38·1 to 56·3) for serogroup C, 35·3% (26·9 to 44·5) for serogroup W, and 27·0% (19·4 to 35·8) for serogroup Y. MenABCWY reactogenicity was mostly of mild or moderate severity and transient, with similar frequencies of adverse events in the MenABCWY and 4CMenB groups and no safety concerns were identified.

Interpretation

This study demonstrates breadth of immune response against a panel of 110 MenB strains for the MenB component of the investigational MenABCWY vaccine, when administered as a 0–6 months schedule to the target population of adolescents and young adults, with predefined criteria for success met for both breadth of immune response endpoints and for non-inferiority versus 4CMenB. This investigational vaccine could provide broad meningococcal serogroup coverage in a simplified immunisation schedule, thus aiding the public health attempt in preventing invasive meningococcal disease due to five Neisseria meningitidis serogroups in adolescents and young adults.

Funding

GSK.

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