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T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.

ABSTRACT: A pneumococcal whole-cell vaccine (WCV) confers T(H)17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating T(H)17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization of Tlr2(-/-) mice with WCV conferred significantly lower IL-17A levels and reduced protection against NP carriage, compared to wild-type (WT) mice, suggesting that host TLR2 engagement is required for effective immunity and protection elicited by WCV immunization. Using a WCV with deletion of lgt, the gene encoding the enzyme required for lipidation and membrane attachment of prolipoproteins, we show that lipidation and membrane localization of these proteins are critical for the immunogenicity and protective efficacy of the WCV. To evaluate the roles of diacylglyceryl transferase (Lgt)-mediated processes in the recall of WCV-induced protective responses, we colonized WCV-immunized animals with a strain in which lgt was deleted. WCV-immunized animals still had significantly reduced colonization burdens, compared to control animals, which suggests that lipidation and membrane localization of pneumococcal prolipoproteins are less critical for the recall of the immune responses elicited by WCV immunization than for the priming of such responses. Elucidation of underlying immune mechanisms and the optimal characteristics of WCV formulations can help guide vaccine development and enhance our understanding of host-pneumococcus interactions.

SUBMITTER: Moffitt K

PROVIDER: S-EPMC4519727 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.

Moffitt K K Howard A A Martin S S Cheung E E Herd M M Basset A A Malley R R

Clinical and vaccine immunology : CVI 20150603 8

A pneumococcal whole-cell vaccine (WCV) confers T(H)17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating T(H)17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization of Tlr2(-/-) mice with ...[more]

PMID: 26041040

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Project description:BackgroundPrior studies have demonstrated hyporesponsiveness to pneumococcal conjugate vaccines (PCVs) when administered in the presence of homologous carriage. This may be substantially more important in Africa where carriage prevalence is high. Deriving a correlate of protection (CoP) for carriage is important in guiding the future use of extended PCVs as population control of pneumococcal disease by vaccination is now focused principally on its indirect effect. We therefore explored the complex relationship between existing carriage and vaccine responsiveness, and between serum IgG levels and risk of acquisition.MethodsWe undertook secondary analyses of data from two previously published clinical trials of the safety and immunogenicity of PCV in Kenya. We compared responses to vaccination between serotype-specific carriers and non-carriers at vaccination. We assessed the risk of carriage acquisition in relation to PCV-induced serum IgG levels using either a step- or continuous-risk function.ResultsFor newborns, the immune response among carriers was 51-82% lower than that among non-carriers, depending on serotype. Among toddlers, for serotypes 6B, 14 and 19F the post-vaccination response among carriers was lower by between 29 and 70%. The estimated CoP against acquisition ranged from 0.26 to 1.93?g/mL across serotypes, however, these thresholds could not be distinguished statistically from a model with constant probability of carriage independent of assay value.ConclusionWe have confirmed hyporesponsiveness in an equatorial African setting in both infants and toddlers. Population responses to vaccination are likely to improve with time as carriage prevalence of vaccine serotypes is reduced. We have not found clear correlates of protection against carriage acquisition among toddlers in this population. Assessing the potential of new vaccines through the use of CoP against carriage is still difficult as there are no clear-cut serotype specific correlates.

Dataset Information

T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.

Publications

T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.

Similar Datasets

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