Elsevier

The Lancet

Volume 384, Issue 9960, 13–19 December 2014, Pages 2123-2131
The Lancet

Articles
Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

https://doi.org/10.1016/S0140-6736(14)60842-4Get rights and content

Summary

Background

Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18–24-year-olds.

Methods

In this phase 3, observer-blind, randomised controlled trial, university students aged 18–24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850.

Findings

Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8–1·7) or MenACWY-CRM (0·9, [0·6–1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4–30·8] carriage reduction), capsular groups BCWY (26·6% [10·5–39·9] carriage reduction), capsular groups CWY (29·6% [8·1–46·0] carriage reduction), and serogroups CWY (28·5% [2·8–47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3–55·0) carriage reduction for serogroup Y and 36·2% (15·6–51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified.

Interpretation

Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented.

Funding

Novartis Vaccines.

Introduction

An estimated 0·5–1·2 million episodes of meningococcal disease occur every year, causing 50 000–135 000 deaths worldwide.1, 2 Neisseria meningitidis colonises the nasopharynx and is transmitted via large-droplet spread. Asymptomatic carriage is highest among adolescents, associated with social behaviours such as bedroom-sharing, smoking, kissing, and attending bars and clubs.3, 4, 5, 6 The most important disease-associated serogroups are A, B, C, W, and Y, with X being a recent concern in Africa.7 Results of post-implementation analyses of population-scale vaccination programmes show that meningococcal serogroup C conjugate (MCC) vaccines provide benefit not only by direct protection of vaccinated individuals, but also more importantly through the interruption of transmission—ie, herd protection,8, 9, 10 a factor that enhances public health effect and cost-effectiveness.11

In addition to quadrivalent glycoconjugate vaccines against serogroups A, C, W, and Y, such as MenACWY-CRM (Menveo, Novartis Vaccines, Siena, Italy), a multicomponent serogroup B meningococcal vaccine, 4CMenB (Bexsero, Novartis Vaccines) has been licensed in the European Union, Australia, and Canada. 4CMenB contains Neisseria heparin binding antigen (subvariant 1.2) fused with accessory protein 953, Neisserial adhesin A (subvariant 3.1), factor H binding protein (subvariant 1.1) fused with accessory protein 936, and the outer membrane vesicle (OMV) from N meningitidis strain NZ98/254 (OMV NZ) derived from the MeNZB vaccine.12, 13

Our study aimed to assess the effect of 4CMenB and MenACWY-CRM vaccination on meningococcal carriage rates in university students in England.

Section snippets

Study design and participants

This trial was a randomised, observer-blind, controlled phase 3 study undertaken at ten study centres in England.

Patients

Eligible participants were healthy men and women aged 18–24 years attending university, who were available for all scheduled visits with no history of serogroup B meningococcal vaccination, meningococcal disease or contact with it, significant infection of any nature within the previous 7 days, or use of antibiotics within 72 h of enrolment. We excluded pregnant women, nursing

Results

2968 individuals were enrolled (Sept 21 to Dec 21, 2010) and 2954 were randomly assigned (figure 1). 14 participants were not assigned to any of the groups because of protocol deviations; these individuals did not receive any study vaccinations. Table 1 shows the demographic variables and baseline N meningitidis carriage rates in the treatment groups. No serogroup A N meningitidis was detected in any individual. More than 99% of the randomly assigned individuals were included in the MITT

Discussion

During the 1 year of follow-up, the MenACWY-CRM and 4CMenB vaccines significantly reduced carriage of N meningitidis (panel). MenACWY-CRM affected carriage of vaccine serogroups whereas 4CMenB had a broad effect. The broad effect is not surprising, because, although 4CMenB is characterised as a MenB vaccine, antigens in the vaccine are also present in, and able to induce bactericidal antibodies against, non-serogroup B strains as well.15 However, neither vaccine showed any immediate effect on

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