Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: A phase 2, randomized, controlled, observer-blind study

Odutola, Aderonke; Ota, Martin O. C.; Antonio, Martín; Ogundare, Ezra Olatunde; Saidu, Yauba; Foster-Nyarko, Ebenezer; Owiafe, Patrick K.; Ceesay, Fatima; Worwui, Archibald; Idoko, Olubukola T.; Owolabi, Olumuyiwa; Bojang, Abdoulie; Jarju, Sheikh; Drammeh, Isatou; Kampmann, Beate; Greenwood, Brian; Alderson, Mark R.; Traskine, Magali; Devos, Nathalie; Schoonbroodt, Sonia; Swinnen, Kristien; Verlant, Vincent; Dobbelaere, Kurt; Borys, Dorota

doi:10.1016/j.vaccine.2017.03.071

Cited by 76 publications

(60 citation statements)

References 29 publications

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“…Another important implication of our work is that immune responses demonstrable in mouse models do not accurately predict those of humans. In light of the recent failure of at least two different protein vaccine formulations (33,34) to provide protection against colonization, one is left wondering whether excessive reliance on mouse models may be responsible. Clearly, murine models are much more convenient (25) a Shown are data for the top 50% of responders from ranked screen results for immunized mice (WCV), exposed mice (exposed), and human IL-17A (human).…”

Section: Figmentioning

confidence: 99%

Screening for Th17-Dependent Pneumococcal Vaccine Antigens: Comparison of Murine and Human Cellular Immune Responses

Oliver

Zhang

et al. 2018

Infect Immun

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Conjugate vaccines against have significantly reduced diseases caused by serotypes included in those vaccines; however, there is still need for vaccines that confer serotype-independent protection. In the current study, we have constructed a library of conserved surface proteins from and screened for IL-17A and IL-22 production in human immune cells obtained from adenoidal/tonsillar tissue of children and IL-17A production from splenocytes from mice that were immunized with a killed whole cell vaccine or previously exposed to pneumococcus. A positive correlation was found between rankings of proteins from human IL-17A and IL-22 screens, but not between human and mouse screens. All proteins were tested for protection against colonization, from which we identified protective antigens that are IL-17A dependent. We found that the likelihood of finding a protective antigen is significantly higher from groups of proteins ranked in the top 50% of all three screens than for groups of proteins ranked in the bottom 50% of all three. The results thus confirmed the value of such screens to identify Th17 antigens. Further, these experiments have evaluated and compared the breadth of human and mouse Th17 responses to pneumococcal colonization and enabled the identification of potential vaccine candidates based on immunological responses in mouse and human cells.

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Section: Figmentioning

confidence: 99%

Screening for Th17-Dependent Pneumococcal Vaccine Antigens: Comparison of Murine and Human Cellular Immune Responses

Oliver

Zhang

et al. 2018

Infect Immun

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“…The relatively larger responses seen in blood than in adenoidal cells occur in the context of a much lower background cytokine production by unstimulated cultures and a known lower T regulatory environment, and has previously been observed by us and others [42,43]; however, further investigation is required to further understand this observed difference. Of particular note were the relative lack of responses to PhtD evident in blood, an antigen which has recently been shown to lack efficacy against pneumococcal colonization in children, although when injected parenterally with aluminium rather than a T cell adjuvant [44]. Although it has been proposed that this and related pneumococcal proteins, which are released extracellularly by the bacterium in large quantities, might act as a sink for potentially opsonophagocytosing antibodies [45], our data suggest that PhtD may also fail to induce cellular immune responses.…”

Section: Discussionmentioning

confidence: 99%

Th17 responses to pneumococcus in blood and adenoidal cells in children

Oliver

Pope

Clarke

et al. 2018

Clinical and Experimental Immunology

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Summary Pneumococcal infections cause a large global health burden, and the search for serotype‐independent vaccines continues. Existing conjugate vaccines reduce nasopharyngeal colonization by target serotypes. Such mucosal effects of novel antigens may similarly be important. CD4+ Th17 cell‐dependent, antibody‐independent reductions in colonization and enhanced clearance have been described in mice. Here we describe the evaluation of T helper type 17 (Th17) cytokine responses to candidate pneumococcal protein vaccine antigens in human cell culture, using adenoidal and peripheral blood mononuclear cells. Optimal detection of interleukin (IL)‐17A was at day 7, and of IL‐22 at day 11, in these primary cell cultures. Removal of CD45RO+ memory T cells abolished these responses. Age‐associated increases in magnitude of responses were evident for IL‐17A, but not IL‐22, in adenoidal cells. There was a strong correlation between individual IL‐17A and IL‐22 responses after pneumococcal antigen stimulation (P < 0·015). Intracellular cytokine staining following phorbol myristate acetate (PMA)/ionomycin stimulation demonstrated that > 30% CD4+ T cells positive for IL‐22 express the innate markers γδT cell receptor and/or CD56, with much lower proportions for IL‐17A+ cells (P < 0·001). Responses to several vaccine candidate antigens were observed but were consistently absent, particularly in blood, to PhtD (P < 0·0001), an antigen recently shown not to impact colonization in a clinical trial of a PhtD‐containing conjugate vaccine in infants. The data presented and approach discussed have the potential to assist in the identification of novel vaccine antigens aimed at reducing pneumococcal carriage and transmission, thus improving the design of empirical clinical trials.

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“…Many in vitro and in vivo assays have shown the bioactivities of many pneumococcal proteins, but adding them into vaccines requires assays that accurately correlate a functional assay with protection, often independent of prevention of sepsis. The difficulty of implementing this requirement was illustrated by a recent Phase II clinical trial of a combination of 10 polysaccharides with the histidine triad protein PhtD and a pneumolysin toxoid [12]. PhtD is believed to participate in zinc homeostasis in the nasopharynx, and the toxin pneumolysin causes damage to respiratory epithelial cells during pneumonia; both vaccine antigens decreased nasopharyngeal carriage in preclinical models [13,14].…”

Section: Multi-modal Protection: Protein Functions Enter the Vaccine mentioning

confidence: 99%

“…This is essentially an OPK assay, which is not expected to be highly relevant to nasopharyngeal carriage. One trial in Gambian infants reported that the proteins produced high titer antibodies but failed to decrease nasopharyngeal carriage of any pneumococci (serotypes within or outside those in the vaccine) [12]. The key question remains: Did this failure arise because the antigens failed to generate antibodies (quality and quantity) directed to mucosal events in disease?…”

Section: Multi-modal Protection: Protein Functions Enter the Vaccine mentioning

confidence: 99%

Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

et al. 2019

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Pneumococcal vaccine development is driven by the achievement of high activity in a single gatekeeper assay: the bacterial opsonophagocytic killing (OPK) assay. New evidence challenges the dogma that anti-capsular antibodies have only a single function that predicts success. The emerging concept of multi-modal protection presents an array of questions that are fundamental to adopting a new vaccine design process. If antibodies have hidden non-opsonic functions that are protective, should these be optimized for better vaccines? What would protein antigens add to protective activity? Are cellular immune functions additive to antibodies for success? Do different organs benefit from different modes of protection? Can vaccine activities beyond OPK protect the immunocompromised host? This commentary raises these issues at a time when capsule-only OPK assay-based vaccines are increasingly seen as a limiting strategy.

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Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: A phase 2, randomized, controlled, observer-blind study

Abstract: PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.

Cited by 76 publications

References 29 publications

Screening for Th17-Dependent Pneumococcal Vaccine Antigens: Comparison of Murine and Human Cellular Immune Responses

Screening for Th17-Dependent Pneumococcal Vaccine Antigens: Comparison of Murine and Human Cellular Immune Responses

Th17 responses to pneumococcus in blood and adenoidal cells in children

Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

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