Obstacles to Developing Vaccines for the Third World

Robbins, Anthony; Freeman, Phyllis

doi:10.1038/scientificamerican1188-126

Cited by 48 publications

(29 citation statements)

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“…Neisseria meningitidis is a devastating human pathogen that causes fulminant, rapidly fatal sepsis and meningitis worldwide, often in large epidemics (30). The morbidity and mortality of meningococcal bacteremia has been directly correlated with circulating meningococcal endotoxins (lipopoly [oligo]saccharides [LOS]) (2,4,45).…”

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Neisseria meningitidisLipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway

et al. 2004

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Meningococcal lipopoly(oligo)saccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis. Highly purified wild-type meningococcal LOS and LOS from genetically defined mutants of Neisseria meningitidis that contained specific mutations in LOS biosynthesis pathways were used to confirm that meningococcal LOS activation of macrophages was CD14/Toll-like receptor 4 (TLR4)-MD-2 dependent and to elucidate the LOS structural requirement for TLR4 activation. Expression of TLR4 but not TLR2 was required, and antibodies to both TLR4 and CD14 blocked meningococcal LOS activation of macrophages. Meningococcal LOS ␣ or ␤ chain oligosaccharide structure did not influence CD14/TLR4-MD-2 activation. However, meningococcal lipid A, expressed by meningococci with defects in 3-deoxy-D-mannooctulosonic acid (KDO) biosynthesis or transfer, resulted in an ϳ10-fold (P < 0.0001) reduction in biologic activity compared to KDO 2 -containing meningococcal LOS. Removal of KDO 2 from LOS by acid hydrolysis also dramatically attenuated cellular responses. Competitive inhibition assays showed similar binding of glycosylated and unglycosylated lipid A to CD14/TLR4-MD-2. A decrease in the number of lipid A phosphate head groups or penta-acylated meningococcal LOS modestly attenuated biologic activity. Meningococcal endotoxin is a potent agonist of the macrophage CD14/TLR4-MD-2 receptor, helping explain the fulminant presentation of meningococcal sepsis and meningitis. KDO 2 linked to meningococcal lipid A was structurally required for maximal activation of the human macrophage TLR4 pathway and indicates an important role for KDO-lipid A in endotoxin biologic activity.

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Neisseria meningitidisLipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway

et al. 2004

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“…[1] The morbidity and mortality of meningococcal bacteremia has been linked to a systematic inflammatory response to lipooligosaccharides (LOS) in the blood of affected patients. [2][3][4] LOS, a major component of the outermembrane of N. meningitidis, initiates the production of multiple host-derived inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interferon beta (IFN-β), interleukin 1 (IL-1), IL-6, arachidonic acid metabolites, and leukotrienes.…”

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Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Zhang

Gaekwad

Wolfert

et al. 2007

Chemistry A European J

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Differences in the pattern and chemical nature of fatty acids of lipid A of Neisseria meningitides lipooligosaccharides (LOS) and Escherichia coli lipopolysaccharides (LPS) may account for differences in inflammatory properties. Furthermore, there are indications that dimeric 3-deoxy-Dmanno-oct-2-ulosonic acid (KDO) moieties of LOS and LPS enhance biological activities. Heterogeneity in the structure of lipid A and possible contaminations with other inflammatory components have made it difficult to confirm these observations. To address these problems, a highly convergent approach for the synthesis of a lipid A derivative containing KDO has been developed, which relies on the ability to selectively remove or unmask in a sequential manner an isopropylidene acetal, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonate (Alloc), azide, and thexyldimethylsilyl (TDS) ether. The strategy was employed for the synthesis of N. meningitidis lipid A containing KDO (3). Mouse macrophages were exposed to the synthetic compound and its parent LOS, E. coli lipid A (2), and a hybrid derivative (4) that has the asymmetrical acylation pattern of E. coli lipid A, but the shorter lipids of meningococcal lipid A. The resulting supernatants were examined for tumor necrosis factor alpha (TNF-α) and interferon beta (IFN-β) production. The lipid A derivative containing KDO was much more active than lipid A alone and just slightly less active than its parent LOS, indicating that one KDO moiety is sufficient for full activity of TNF-α and IFN-β induction. The lipid A of N. meningitidis was a significantly more potent inducer of TNF-α and IFN-β than E. coli lipid A, which is due to a number of shorter fatty acids. The compounds did not demonstrate a bias towards a MyD88-or TRIF-dependent response.

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“…CFRs for septicemia can, however, be as high as 70% in developing countries and 19% in developed countries. It has been estimated that in Third World countries 1310,000 persons per year suffer from infections caused by N. meningitidis, resulting in 35,000 deaths [13].…”

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Meningococcal Disease and Travel

Memish

2002

Clinical Infectious Diseases

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Invasive meningococcal disease, in both endemic and epidemic forms, is the cause of significant morbidity and mortality worldwide. Despite all advances in therapy, the fatality rate of meningococcal meningitis remains unacceptably high, between 5% and 10%, and a similar proportion suffers long-term neurological sequalae. Prevention of this rapidly fatal disease is of paramount importance. The use of the available internationally licensed meningococcal vaccines would be indicated for individuals with medical conditions that increase the risk of the disease and for travelers to high-risk countries. In the last 2 years, there has been a shift in the epidemic pattern of meningococcal disease during the Hajj (pilgrimage) season, with predominance of Neisseria meningitidis serogroup W135. Recent changes have been made in the policy issued by the Saudi Ministry of Health (Riyadh, Saudi Arabia), which requires visitors from all over the world arriving for purposes of umra and Hajj to show evidence of vaccination against meningitis with the quadrivalent meningococcal vaccine.

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Obstacles to Developing Vaccines for the Third World

Cited by 48 publications

References 0 publications

Neisseria meningitidisLipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway

Neisseria meningitidisLipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Meningococcal Disease and Travel

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