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From tailor-made to ready-to-wear meningococcal B vaccines: longitudinal study of a clonal meningococcal B outbreak

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Summary

Background

Outer-membrane-vesicle vaccines for meningococcal B outbreaks are complex and time consuming to develop. We studied the use of already available vaccine to control an outbreak caused by a genetically close strain.

Methods

From 2006 to 2009, all individuals younger than 20 years living in the region of Normandy, France, in which an outbreak caused by a B:14:P1.7,16 strain occurred, were eligible to receive MenBvac, a Norwegian vaccine designed 20 years earlier against a strain sharing the same serosubtype (B:15:P1.7,16). The immunogenicity (in a randomly selected cohort of 400 children aged 1–5 years), safety, and epidemiological effect of the vaccination were assessed.

Findings

26 014 individuals were eligible to receive the vaccine. Shortage of vaccine production prompted start of the campaign in the highest incidence groups (1–5 years). 16 709 (64%) received a complete vaccination schedule of whom 13 589 (81%) received a 2+1 dose schedule (week 0, week 6, and month 8). At 6 weeks after the third dose, of 235 vaccinees for whom samples were available, 206 (88%) had a seroresponse, and 108 (56 %) of 193 had a seroresponse at 15 months. These results were similar to those described for tailor-made vaccines and their homologous strain. Only previously described adverse effects occurred. The incidence of B:14:P1.7,16 cases decreased significantly in the vaccine targeted population after the primary vaccination period (from 31·6 per 100 000 to 5·9 per 100 000; p=0·001).

Interpretation

The ready-to-wear approach is reliable if epidemic and vaccine strains are genetically close. Other meningococcal B clonal outbreaks might benefit from this strategy; and previously described outer-membrane-vesicle vaccines can be effective against various strains.

Funding

French Ministry of Health.

Introduction

Neisseria meningitidis is a leading cause of bacterial meningitis worldwide.1 Invasive meningococcal infections also include severe meningococcaemia, an even more serious presentation of the disease. N meningitidis isolates are classified into 12 serogroups according to their capsular polysaccharide and into serotypes and serosubtypes according to their outer membrane proteins. Serogroup B isolates cause more than 50% of the invasive meningococcal infections in Europe.2 Outbreaks occur mainly with the introduction of new meningococcal virulent clones in the population.1 Compared with serogroup C, serogroup B outbreaks begin slowly and can persist longer, to up to more than a decade.3, 4, 5, 6, 7

In the past 25 years, the annual incidence of invasive meningococcal infections in France has been low (0·7–1·6 cases per 100 000), with about 60% of the cases being of group B (0·4–0·8 per 100 000) of a large diversity of strains.8 In 2003, the annual incidence of invasive meningococcal B infections reached 2 per 100 000 in Seine-Maritime (a district in Normandy, France) because of the expansion of a particular clone of serogroup B, serotype 14, serosubtype P1.7,16, and sequence type 32 (B:14:P1.7,16/ST-32) that had been present in this part of France since the 1990s. The most affected region of Seine-Maritime was the city of Dieppe and its immediate surroundings (Dieppe area), in which 60% of the cases of B:14:P1.7,16 occurred, although its population (92 770 inhabitants) represented only 7% of the total district population (1 243 800 inhabitants).9

The control of invasive meningococcal infections of serogroup B is still a major public health challenge because of the absence of commercially available vaccines. Indeed, capsule-based vaccines are available only against serogroups A, C, Y, and W-135. They act universally against all the strains of each targeted serogroup. Attempts to process serogroup B capsular vaccines have failed because of poor immunogenicity and risk of autoimmunity. Promising new recombinant meningococcal B vaccines that offer large or universal coverage are expected in the near future.10, 11, 12 Since the late 1980s, a few licensed tailor-made meningococcal B vaccines have been developed in response to a particular outbreak strain by use of outer membrane vesicles and all of them are reputed to be strain specific, especially in infants (cross-immune response has been described in children and adults).13, 14, 15, 16 The clinical efficacy and effectiveness of such vaccines have been proved in adolescents and young children.17, 18, 19, 20

We postulated that the complexity and delay in the manufacture of a new outer-membrane-vesicle meningococcal B vaccine would prevent its availability early enough to control the outbreak. We aimed to use an already available vaccine since the outbreak and the vaccine strains shared enough common features.21 Our objective was to control the B:14:P1.7,16 outbreak in Seine-Maritime with a vaccination campaign using an outer-membrane-vesicle meningococcal B vaccine (MenBvac), designed 20 years earlier by the Norwegian Institute of Public Health (NIPH, Oslo, Norway) for a different but genetically close strain (B:15:P1.7,16).13

Section snippets

Case definitions and classification of bacterial strains

Until 2001, French criteria for notification of an invasive meningococcal infection were based solely on a meningococcal positive culture or presence of N meningitidis antigen in blood, urine, or cerebrospinal fluid samples. Since 2002, these criteria were modified22 and include positive culture, PCR, or direct examination; cerebrospinal fluid findings suggestive of bacterial meningitis associated to the detection of N meningitidis antigen or to a petechial rash; or diagnosis of a purpura

Results

Between 1990 and 2001, 149 cases of invasive meningococcal infection were reported in Seine-Maritime. Of 139 cases with known serogroup, 118 (85%) had serogroup B. Of 108 B strains of N meningitidis that were phenotyped, 37 (34%) were attributed to B:14:P1.7,16 and 71 (66%) to other strains (figure 1). From 1999 to 2001, the mean number of cases of B:14:P1.7,16 per year was three. Between 2002 and 2003, the number of cases increased from three to 14 cases.

From January, 2003, to June, 2006

Discussion

MenBvac produced antibody response against B:14:P1.7,16 in Norman children, its tolerance was good, and the outbreak has been controlled in the treated area until 2010. Management of meningococcal B outbreaks remains a major public health challenge in the absence of universally effective vaccines. Although the affected district in Normandy accounts for only 2% of the total French population, it included 46% of the nationwide cases of invasive meningococcal infections caused by the B:14:P1.7,16

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