Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination
- Antigen Discovery Inc, United States
- University of Maryland, United States
- PATH, United States
- Harvard TH Chan School of Public Health, United States
- Boston Children's Hospital, United States
- Imperial College London, United Kingdom
Abstract
Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody 'fingerprints', responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV's surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity.
Data availability
Sequencing data have been deposited in the ENA under accession code ERS2169631. Proteome array data analysed in this study is available as source data files for figures one and two.
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Streptococcus pneumoniae RM200 Rx1E PdT ΔlytAEuropean Nucleotide Archived, ERS2169631.
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Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniaeDryad Digital Repository, 10.5061/dryad.t55gq.
Article and author information
Author details
Nicholas J Croucher
Funding
Bill and Melinda Gates Foundation
- Joseph J Campo
- Timothy Q Le
- Jozelyn V Pablo
- Christopher Hung
- Andy A Teng
National Institutes of Health (R01AI066304)
- Marc Lipsitch
Wellcome (104169/Z/14/Z)
- Nicholas J Croucher
Royal Society (104169/Z/14/Z)
- Nicholas J Croucher
PATH
- Andrea Tate
- Mark R Alderson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The VAC-002 phase 1 study (ClinicalTrials.gov identifier: NCT01537185) was reviewed and approved by the Western Institutional Review Board and conducted in compliance with the study protocol, international standards of Good Clinical Practice and the Declaration of Helsinki. Participants were healthy adults aged 18 to 40 years at the time of consent, and had no evidence of chronic health issues, and nor any history of invasive pneumococcal disease or pneumococcal vaccination.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
Publication history
- Received: March 27, 2018
- Accepted: December 25, 2018
- Accepted Manuscript published: December 28, 2018 (version 1)
- Version of Record published: January 23, 2019 (version 2)
Copyright
© 2018, Campo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination
eLife 7:e37015.
https://doi.org/10.7554/eLife.37015
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The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.
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