Abstract
The capsular group B meningococcal (MenB) four component vaccine (4CMenB) has been licensed for the prevention of invasive disease caused by MenB. The vaccine causes fever in infants, particularly when given in combination (concomitant) with other routinely-administered vaccines (routine), such as the standard diphtheria, tetanus, pertussis (DTP)-containing vaccine. To assess the suitability of a mouse immunisation model to study this phenomenon, we monitored temperature in mice after a second dose of routine vaccines, with or without 4CMenB, and compared the results with those in humans. Using this mouse model, we explored the reactogenicity of 4CMenB components by measuring changes in temperature, cytokines, and gene expression induced by 4CMenB, one of its components, wild-type or attenuated endotoxin outer membrane vesicles (OMVs), or lipopolysaccharide (LPS). A significant rise (p < 0.01) in temperature was observed in mice immunised with 4CMenB, wild-type OMVs, and LPS. RNA-sequencing of mouse whole blood revealed a gene signature shared by the 4CMenB, OMV, and LPS groups consisting of bacterial pattern recognition receptors and neutrophil activation marker genes. Sequencing of neutrophils isolated after concomitant 4CMenB identified cells expressing the OMV-associated genes Plek and Lcp1. Immunisation with 4CMenB or OMVs led to increased IL-6 in serum and significant upregulation (p < 0.0001) of prostaglandin-synthesising enzymes on brain tissue. These data demonstrate the suitability of a mouse model for assessing vaccine reactogenicity and strongly indicate that the fever following vaccination with 4CMenB in human infants is induced by endotoxin contained in the OMV component of the vaccine.
Highlights
The Gram-negative bacterium Neisseria meningitidis (N. meningitidis) is the causative agent of invasive meningococcal disease (IMD), a fulminant bacterial infection with the highest incidence in the first year of life[1,2]
The outer membrane vesicle (OMV) component of the vaccine contributes to the reactogenicity of the vaccine; early studies of 4CMenB recombinant proteins – the factor H binding protein, neisserial heparin-binding antigen (NHBA), and neisserial adhesin A (NadA) – in infants found a slight increase in local and systemic reactogenicity associated with the inclusion of OMVs9,10
This is likely due to quantities of membrane-bound endotoxin found in OMV preparations, OMVs prepared by deoxycholate extraction, such as those in 4CMenB and other OMV-based vaccines, have reduced proportions of endotoxin compared with untreated native OMVs11
Summary
The Gram-negative bacterium Neisseria meningitidis (N. meningitidis) is the causative agent of invasive meningococcal disease (IMD), a fulminant bacterial infection with the highest incidence in the first year of life[1,2]. Post-implementation surveillance in the UK indicated that 4CMenB was effective at preventing invasive disease caused by MenB, with an effectiveness of 83% resulting in a halving of all cases in the vaccine-eligible group within 10 months of the introduction of the two-dose schedule[7]. The outer membrane vesicle (OMV) component of the vaccine contributes to the reactogenicity of the vaccine; early studies of 4CMenB recombinant proteins – the factor H binding protein (fHbp), neisserial heparin-binding antigen (NHBA), and neisserial adhesin A (NadA) – in infants found a slight increase in local and systemic reactogenicity associated with the inclusion of OMVs9,10 This is likely due to quantities of membrane-bound endotoxin found in OMV preparations, OMVs prepared by deoxycholate extraction (dOMVs), such as those in 4CMenB and other OMV-based vaccines, have reduced proportions of endotoxin compared with untreated native OMVs (nOMVs)[11]. These data provide novel insights into 4CMenB reactogenicity through comparative analyses of its components
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