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.
-
Streptococcus pneumoniae RM200 Rx1E PdT ΔlytAEuropean Nucleotide Archived, ERS2169631.
-
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.
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.
Metrics
-
- 1,585
- views
-
- 267
- downloads
-
- 27
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination
eLife 7:e37015.
https://doi.org/10.7554/eLife.37015
Further reading
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.
