Performance of Immunoglobulin G Serology on Finger Prick Capillary Dried Blood Spot Samples to Detect a SARS-CoV-2 Antibody Response

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ABSTRACT

We investigate the diagnostic accuracy and predictive value of finger prick capillary dried blood spot (DBS) samples tested by a quantitative multiplex anti-immunoglobulin G (IgG) assay to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies after infection or vaccination. This cross-sectional study involved participants ( n = 6,841) from several serological surveys conducted in nonhospitalized children and adults throughout 2020 and 2021 in British Columbia (BC), Canada. Analysis used paired DBS and serum samples from a subset of participants ( n = 642) prior to vaccination to establish signal thresholds and calculate diagnostic accuracy by logistic regression. Discrimination of the logistic regression model was assessed by receiver operator curve (ROC) analysis in an n = 2,000 bootstrap of the paired sample ( n = 642). The model was cross-validated in a subset of vaccinated persons ( n = 90). Unpaired DBS samples ( n = 6,723) were used to evaluate anti-IgG signal distributions. In comparison to paired serum, DBS samples from an unvaccinated population possessed a sensitivity of 79% (95% confidence interval [95% CI]: 58 to 91%) and specificity of 97% (95% CI: 95 to 98%). ROC analysis found that DBS samples accurately classify SARS-CoV-2 seroconversion at an 88% percent rate (area under the curve [AUC] = 88% [95% CI: 80 to 95%]). In coronavirus disease 2019 (COVID-19) vaccine dose one or two recipients, the sensitivity of DBS testing increased to 97% (95% CI: 83 to 99%) and 100% (95% CI: 88 to 100%). Modeling found that DBS testing possesses a high positive predictive value (98% [95% CI: 97 to 98%]) in a population with 75% seroprevalence. We demonstrate that DBS testing should be considered to reliably detect SARS-CoV-2 seropositivity from natural infection or vaccination.

IMPORTANCE Dried blood spot samples have comparable diagnostic accuracy to serum collected by venipuncture when tested by an electrochemiluminescent assay for antibodies and should be considered to reliably detect seropositivity following SARS-CoV-2 infection and/or vaccination.

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Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein

Sandrine Belouzard, Jean K. Millet, Beth N. Licitra … (2012)

Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S) mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes—A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses.

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Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination

Alicia T. Widge, Nadine G Rouphael, Lisa A Jackson … (2020)

To The Editor: We recently reported the results of a phase 1 trial of a messenger RNA vaccine, mRNA-1273, to prevent infection with SARS-CoV-2; those interim results covered a period of 57 days after the first vaccination. 1,2 Here, we describe immunogenicity data 119 days after the first vaccination (90 days after the second vaccination) in 34 healthy adult participants in the same trial who received two injections of vaccine at a dose of 100 μg. The injections were received 28 days apart. The recipients were stratified according to age (18 to 55 years, 56 to 70 years, or ≥71 years), and the assays used have been described previously. 1,2 At the 100-μg dose, mRNA-1273 produced high levels of binding and neutralizing antibodies that declined slightly over time, as expected, but they remained elevated in all participants 3 months after the booster vaccination. Binding antibody responses to the spike receptor–binding domain were assessed by enzyme-linked immunosorbent assay. At the day 119 time point, the geometric mean titer (GMT) was 235,228 (95% confidence interval [CI], 177,236 to 312,195) in participants 18 to 55 years of age, 151,761 (95% CI, 88,571 to 260,033) in those 56 to 70 years of age, and 157,946 (95% CI, 94,345 to 264,420) in those 71 years of age or older (Figure 1). Serum neutralizing antibodies continued to be detected in all the participants at day 119. On a pseudovirus neutralization assay, the 50% inhibitory dilution (ID50) GMT was 182 (95% CI, 112 to 296) in participants who were between the ages of 18 and 55 years, 167 (95% CI, 88 to 318) in those between the ages of 56 and 70 years, and 109 (95% CI, 68 to 175) in those 71 years of age or older. On the live-virus focus reduction neutralization test mNeonGreen assay, the ID50 GMT was 775 (95% CI, 560 to 1071), 685 (95% CI, 436 to 1077), and 552 (95% CI, 321 to 947) in the same three groups, respectively. On the live-virus plaque-reduction neutralization testing assay, the 80% inhibitory dilution GMT was similarly elevated at 430 (95% CI, 277 to 667), 269 (95% CI, 134 to 542), and 165 (95% CI, 82 to 332) in the same three groups, respectively (Figure 1). At day 119, the binding and neutralizing GMTs exceeded the median GMTs in a panel of 41 controls who were convalescing from Covid-19, with a median of 34 days since diagnosis (range, 23 to 54). 2 No serious adverse events were noted in the trial, no prespecified trial-halting rules were met, and no new adverse events that were considered by the investigators to be related to the vaccine occurred after day 57. Although correlates of protection against SARS-CoV-2 infection in humans are not yet established, these results show that despite a slight expected decline in titers of binding and neutralizing antibodies, mRNA-1273 has the potential to provide durable humoral immunity. Natural infection produces variable antibody longevity 3,4 and may induce robust memory B-cell responses despite low plasma neutralizing activity. 4,5 Although the memory cellular response to mRNA-1273 is not yet defined, this vaccine elicited primary CD4 type 1 helper T responses 43 days after the first vaccination, 2 and studies of vaccine-induced B cells are ongoing. Longitudinal vaccine responses are critically important, and a follow-up analysis to assess safety and immunogenicity in the participants for a period of 13 months is ongoing. Our findings provide support for the use of a 100-μg dose of mRNA-1273 in an ongoing phase 3 trial, which has recently shown a 94.5% efficacy rate in an interim analysis.

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Machine learning algorithm validation with a limited sample size

Andrius Vabalas, Emma Gowen, Ellen Poliakoff … (2019)

Advances in neuroimaging, genomic, motion tracking, eye-tracking and many other technology-based data collection methods have led to a torrent of high dimensional datasets, which commonly have a small number of samples because of the intrinsic high cost of data collection involving human participants. High dimensional data with a small number of samples is of critical importance for identifying biomarkers and conducting feasibility and pilot work, however it can lead to biased machine learning (ML) performance estimates. Our review of studies which have applied ML to predict autistic from non-autistic individuals showed that small sample size is associated with higher reported classification accuracy. Thus, we have investigated whether this bias could be caused by the use of validation methods which do not sufficiently control overfitting. Our simulations show that K-fold Cross-Validation (CV) produces strongly biased performance estimates with small sample sizes, and the bias is still evident with sample size of 1000. Nested CV and train/test split approaches produce robust and unbiased performance estimates regardless of sample size. We also show that feature selection if performed on pooled training and testing data is contributing to bias considerably more than parameter tuning. In addition, the contribution to bias by data dimensionality, hyper-parameter space and number of CV folds was explored, and validation methods were compared with discriminable data. The results suggest how to design robust testing methodologies when working with small datasets and how to interpret the results of other studies based on what validation method was used.

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Author and article information

Contributors

Agatha N. Jassem

Angela Bordin: Role: Editor

Journal

Journal ID (nlm-ta): Microbiol Spectr

Journal ID (iso-abbrev): Microbiol Spectr

Journal ID (publisher-id): spectrum

Title: Microbiology Spectrum

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2165-0497

Publication date (Electronic, pub): 10 March 2022

Publication date (Electronic, collection): Mar-Apr 2022

Publication date PMC-release: 10 March 2022

Volume: 10

Issue: 2

Electronic Location Identifier: e01405-21

Affiliations

[a ] British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

[b ] School of Population and Public Health, University of British Columbiagrid.17091.3e, , Vancouver, British Columbia, Canada

[c ] Department of Pathology and Laboratory Medicine, University of British Columbiagrid.17091.3e, , Vancouver, British Columbia, Canada

[d ] Department of Experimental Medicine, University of British Columbiagrid.17091.3e, , Vancouver, British Columbia, Canada

[e ] Department of Pathology and Laboratory Medicine, British Columbia Children’s and Women’s Hospital, Vancouver, British Columbia, Canada

[f ] Vaccine Evaluation Center, British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

[g ] Women's Health Research Institute, Vancouver, British Columbia, Canada

[h ] Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada

Texas A&M University

Author notes

The authors declare no conflict of interest.

Author information

Aidan M. Nikiforuk https://orcid.org/0000-0002-7137-2819

David M. Goldfarb https://orcid.org/0000-0003-0835-9504

Manish Sadarangani https://orcid.org/0000-0002-9985-6452

Article

Publisher ID: 01405-21 Publisher ID: spectrum.01405-21

DOI: 10.1128/spectrum.01405-21

PMC ID: 9045222

PubMed ID: 35266818

SO-VID: 3e733c5e-68e3-456c-8dcd-601ed2117270

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 29 August 2021

Date accepted : 15 February 2022

Page count

supplementary-material: 1, Figures: 3, Tables: 2, Equations: 0, References: 40, Pages: 10, Words: 6367

Funding

Funded by: Michael Smith Foundation for Health Research (MSFHR), FundRef https://doi.org/10.13039/501100000245;

Award ID: COV-2020-1120

Award ID: COV-2020-1279

Award Recipient : Muhammad G. Morshed Award Recipient : Inna Sekirov Award Recipient : Agatha N. Jassem

Funded by: Public Health Agency of Canada (PHAC), FundRef https://doi.org/10.13039/100011094;

Award ID: 2021-HQ-000141

Award Recipient : Agatha N. Jassem

Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (IRSC), FundRef https://doi.org/10.13039/501100000024;

Award ID: #434951

Award Recipient : Aidan McKerrell Nikiforuk Award Recipient : David M. Patrick Award Recipient : Agatha N. Jassem

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cover-date March/April 2022

Keywords: sars-cov-2,dried blood spots,seropositivity,diagnostic accuracy,vaccine evaluation,public health,covid-19,data analysis,epidemiology

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Keywords: sars-cov-2, dried blood spots, seropositivity, diagnostic accuracy, vaccine evaluation, public health, covid-19, data analysis, epidemiology

Performance of Immunoglobulin G Serology on Finger Prick Capillary Dried Blood Spot Samples to Detect a SARS-CoV-2 Antibody Response

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ABSTRACT

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Novel Coronavirus Disease COVID-19

Most cited references 38

Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein

Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination

Machine learning algorithm validation with a limited sample size

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