Cellular immune responses to Neisseria meningitidis in children

Abstract

There is an urgent need for effective vaccines against serogroup B Neisseria meningitidis. Current experimental vaccines based on the outer membrane proteins (OMPs) of this organism provide a measure of protection in older children but have been ineffective in infants. We postulated that the inability of OMP vaccines to protect infants might be due to age-dependent defects in cellular immunity. We measured proliferation and in vitro production of gamma interferon (IFN-gamma), tumor necrosis factor alpha, and interleukin-10 (IL-10) in response to meningococcal antigens by peripheral blood mononuclear cells (PBMCs) from children convalescing from meningococcal disease and from controls. After meningococcal infection, the balance of cytokine production by PBMCs from the youngest children was skewed towards a TH1 response (low IL-10/IFN-gamma ratio), while older children produced more TH2 cytokine (higher IL-10/IFN-gamma ratio). There was a trend to higher proliferative responses by PBMCs from older children. These responses were not influenced by the presence or subtype of class 1 (PorA) OMP or by the presence of class 2/3 (PorB) or class 4 OMP. Even young infants might be expected to develop adequate cellular immune responses to serogroup B N. meningitidis vaccines if a vaccine preparation can be formulated to mimic the immune stimulus of invasive disease, which may include stimulation of TH2 cytokine production.

FIG. 1

Proliferative responses of PBMCs from 15 adult volunteers, 49 children convalescing from meningococcal disease, 22 siblings of meningococcal disease patients, 19 healthy children, and 5 umbilical cords in response to whole meningococci (bars A) and six different meningococcal OMVs (bars B to G). Results are expressed as the stimulation index (mean and standard error; stimulation index = counts per minute in stimulated cells divided by counts per minute in unstimulated cells for triplicate cultures).

FIG. 2

Proliferative responses of PBMCs from children after natural infection with N. meningitidis in response to whole meningococci (H44/76) or six different meningococcal OMVs in relation to age. Results are expressed as the stimulation index (mean and standard error; stimulation index = counts per minute in stimulated cells divided by counts per minute in unstimulated cells for triplicate cultures).

FIG. 3

TNF-α (a), IL-10 (b), and IFN-γ (c) concentrations (means and standard errors) in supernatants after 7 days of stimulation of PBMCs from 14 adult volunteers, 35 children convalescing from meningococcal disease, 15 siblings of meningococcal disease patients, and 19 healthy children with whole meningococci or three different meningococcal OMVs. Data for IFN-γ levels from cord blood mononuclear cells are shown in panel c.

FIG. 3

TNF-α (a), IL-10 (b), and IFN-γ (c) concentrations (means and standard errors) in supernatants after 7 days of stimulation of PBMCs from 14 adult volunteers, 35 children convalescing from meningococcal disease, 15 siblings of meningococcal disease patients, and 19 healthy children with whole meningococci or three different meningococcal OMVs. Data for IFN-γ levels from cord blood mononuclear cells are shown in panel c.

FIG. 3

TNF-α (a), IL-10 (b), and IFN-γ (c) concentrations (means and standard errors) in supernatants after 7 days of stimulation of PBMCs from 14 adult volunteers, 35 children convalescing from meningococcal disease, 15 siblings of meningococcal disease patients, and 19 healthy children with whole meningococci or three different meningococcal OMVs. Data for IFN-γ levels from cord blood mononuclear cells are shown in panel c.

FIG. 4

IL-10/IFN-γ ratio in relation to age for patients (a) and controls (b) following stimulation of PBMCs with whole meningococci or three different OMVs. Means and standard errors are shown.

FIG. 5

TNF-α production in relation to age for patients (a) and controls (b) following stimulation of PBMCs with whole meningococci or three different OMVs. Means and standard errors are shown.