The 2024/25 application process is now closed
Visit the MRC DTP/CASE at LSTM pages for further information.
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Abstract |
Infections in infants cause 2-million deaths yearly, of which more than 1 million occur in sub-Saharan Africa (SSA). Vaccination is the most cost-effective means to reduce deaths, but many vaccines underperform in African infants, where the burden is highest.
Effective vaccination induces long-term memory through a complex cascade of cellular changes. There are marked differences in these response in infants vs. adults (e.g., polysaccharide vaccines produce robust responses in adults but minimal response in infancy) and between Africans and Europeans (e.g., rotavirus vaccine is >90% effective in European but 40-60% effective in SSA). Single-cell and systems vaccinology approaches have transformed our understanding of immune responses to vaccines in adults of European ancestry. Surprisingly, there are few systems biology data in infants, none in African infants, and no single-cell vaccine response data in infants in any setting.
Our work focuses on understanding immune trajectories over the first year of life in infants from Malawi, an LIC. We have recruited healthy infants starting at their first vaccine appointment (6-weeks old) and over multiple timepoints during their first year of life. Our preliminary immunophenotyping data shows differences in effector T-cells between infants that seroconvert vs. do not seroconvert after administration of the rotavirus vaccine.
We next plan to carry out single-cell, B/T-cell repertoire and cell surface protein sequencing on infants to deeply characterize immune trajectories over the first year of life and correlates of vaccine failure. This work will provide an atlas of infant immune development and help inform next generation vaccines, a public health need.
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Where does the project lie on the Translational Pathway? |
T1-T2 |
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Expected Outputs |
This is one of the first comprehensive analysis of infant development at the single cell level and we expect will lead to high impact publications. This study is a multi-disciplinary and multi-omics study with excellent collaboration will also have the ability to jump on other analysis. The single cell space is quickly moving and experience in this space would lead to competitive postdocs of industry positions. The overall goal of the study is to inform better vaccines for Low-income countries so there is also a major translational outcome with potential for public health importance |
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Training Opportunities |
This project provides training is one of the most cutting-edge institutions in the single cell space. The goal is training at the Broad will provide the candidate with skills need to independently analyse a large dataset as well as open up collaborations for future projects and postdocs. In addition, LSTM is committed to expanding their single cell programme so there is option to work across groups. |
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Skills Required |
An ideal candidate should have a math or computer science background. This project will be computational complex as, although some pipelines exist, single cell analysis is still largely bespoke.
Candidate should be proficient in R and/or Python and ideally have experience with Jupyter notebooks or equivalent (deepnote, anaconda).
There will be extensive training and computational support throughout the PhD from Drs. Jewells and Barnes |
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Key Publications associated with this project |
van Dorst, M.M.A.R., Pyuza, J.J., Nkurunungi, G. et al. Immunological factors linked to geographical variation in vaccine responses. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00941-2
Great review on variation in vaccine response |
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Clark, A. et al. Efficacy of live oral rotavirus vaccines by duration of follow-up: a meta-regression of randomized controlled trials. Lancet Infect. Dis. 19, 717–727 (2019).
Meta-analysis of trials showing that rotavirus vaccine efficacy and durability are lowest in countries with highest child mortality. |
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Kotliar D*, Lin AE*, Logue J, Hughes TK, Khoury KM, Raju SS, WadsworthMH, Chen H, Kurtz JR, Dighero-Kemp B, Bjornson ZB, Mukherjee N, Sellers BA, Tran N, Bauer MB, Adams GC, Adams R, Rinn JL, Melé M, Nolan GP*, Barnes KG*, Hensley LE*, McIlwain DR*, Shalek EK*, Sabeti PC*, Bennett RC*. Single-cell profiling of Ebola virus infection in vivo reveals viral and host transcriptional dynamics. Cell. (2020) 10.1016/j.cell.2020.10.002
Single cell work by the PI |
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Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Variation in immune response of twins to vaccination or an infection is largely determined by exposure to environmental factors and authored by a collaborator Petter Brodin. |
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Ding, J., Adiconis, X., Simmons, S.K. et al. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods. Nat Biotechnol 38, 737–746 (2020). https://doi.org/10.1038/s41587-020-0465-8
Good overview for the technology and authored by the Co-I Alex Shalek |