Introduction: Since the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause significant disease and is identified in colonisation epidemiological studies as one of the top circulating serotypes in adults in the UK. Consequently, new vaccines that provide greater protection against SPN3 colonisation/carriage are urgently needed. The Experimental Human Pneumococcal Challenge (EHPC) model is a unique method of determining pneumococcal colonisation rates, understanding acquired immunity, and testing vaccines in a cost-effective manner. To enhance the development of effective pneumococcal vaccines against SPN3, we aim to develop a new relevant and safe SPN3 EHPC model with high attack rates which could be used to test vaccines using small sample size.
Methods And Analysis: This is a human challenge study to establish a new SPN3 EHPC model, consisting of two parts. In the dose-ranging/safety study, cohorts of 10 healthy participants will be challenged with escalating doses of SPN3. If first challenge does not lead into colonisation, participants will receive a second challenge 2 weeks after. Experimental nasopharyngeal (NP) colonisation will be determined using nasal wash sampling. Using the dose that results in ≥50% of participants being colonised, with a high safety profile, we will complete the cohort with another 33 participants to check for reproducibility of the colonisation rate. The primary outcome of this study is to determine the optimal SPN3 dose and inoculation regime to establish the highest rates of NP colonisation in healthy adults. Secondary outcomes include determining density and duration of experimental SPN3 NP colonisation and characterising mucosal and systemic immune responses to SPN3 challenge.
Ethics And Dissemination: This study is approved by the NHS Research and Ethics Committee (reference 22/NW/0051). Findings will be published in peer-reviewed journals and reports will be made available to participants.
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http://dx.doi.org/10.1136/bmjopen-2023-075948 | DOI Listing |
Sci Rep
August 2024
Institute of Structural and Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK.
Cryogenic electron microscopy (cryo-EM) has emerged as a powerful method for the determination of structures of complex biological molecules. The accurate characterisation of the dynamics of such systems, however, remains a challenge. To address this problem, we introduce cryoENsemble, a method that applies Bayesian reweighting to conformational ensembles derived from molecular dynamics simulations to improve their agreement with cryo-EM data, thus enabling the extraction of dynamics information.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
July 2024
Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080.
Machine learning has been proposed as an alternative to theoretical modeling when dealing with complex problems in biological physics. However, in this perspective, we argue that a more successful approach is a proper combination of these two methodologies. We discuss how ideas coming from physical modeling neuronal processing led to early formulations of computational neural networks, e.
View Article and Find Full Text PDFWellcome Open Res
January 2024
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Southern Region, Malawi.
As well as suffering a high burden of pneumococcal disease people living with HIV (PLHIV) may contribute to community transmission in sub-Saharan African (sSA) settings. Pneumococcal vaccination is not currently offered to PLHIV in sSA but may prevent disease and reduce transmission. More evidence of vaccine effectiveness against carriage in PLHIV is needed.
View Article and Find Full Text PDFBMJ Open
January 2024
Liverpool Vaccine Group, Liverpool School of Tropical Medicine, Liverpool, UK
Introduction: Since the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause significant disease and is identified in colonisation epidemiological studies as one of the top circulating serotypes in adults in the UK. Consequently, new vaccines that provide greater protection against SPN3 colonisation/carriage are urgently needed.
View Article and Find Full Text PDFWellcome Open Res
June 2022
Lung Health, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation. For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011.
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