Limited Specificity of Serologic Tests for SARS-CoV-2 Antibody Detection, Benin

Yadouléton, Anges; Sander, Anna; Moreira-Soto, Andrés; Tchibozo, Carine; Hounkanrin, Gildas; Badou, Yvette; Fischer, Carlo; Krause, Nina; Akogbeto, Petas; Oliveira-Filho, Edmilson F.; Dossou, Anges; Brünink, Sebastian; Aïssi, Melchior A. Joël; Djingarey, Mamoudou Harouna; Hounkpatin, Benjamin; Nagel, Michael; Drexler, Jan Felix

doi:10.3201/eid2701.203281

Cited by 70 publications

(91 citation statements)

References 13 publications

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“…As post-infection antibody kinetics vary by infection severity, age and prior exposures, so can test performance. Through testing pre-pandemic samples from Juba, we found that background anti-SARS-CoV-2 antibody reactivity was higher in Juba than in Boston, consistent with findings from studies conducted in other sites within sub-Saharan Africa [12,15,35,36]. We used these negative controls to estimate test specificity; however, we lack data on the post SARS-CoV-2 infection antibody kinetics and the proportion of infections that are mild or asymptomatic in the Juba population.…”

Section: Discussionsupporting

confidence: 86%

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study

Rumunu

et al. 2021

Preprint

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Background: Relatively few COVID-19 cases and deaths have been reported through much of sub-Saharan Africa, including South Sudan, although the extent of SARS-CoV-2 spread remains unclear due to weak surveillance systems and few population-representative serosurveys. Methods: We conducted a representative household-based cross-sectional serosurvey in Juba, South Sudan. We quantified IgG antibody responses to SARS-CoV-2 spike protein receptor-binding domain and estimated seroprevalence using a Bayesian regression model accounting for test performance. Results: We recruited 2,214 participants from August 10 to September 11, 2020 and 22.3% had anti-SARS-CoV-2 IgG titers above levels in pre-pandemic samples. After accounting for waning antibody levels, age, and sex, we estimated that 38.5% (32.1 - 46.8) of the population had been infected with SARS-CoV-2. For each RT-PCR confirmed COVID-19 case, 104 (87-126) infections were unreported. Background antibody reactivity was higher in pre-pandemic samples from Juba compared to Boston, where the serological test was validated. The estimated proportion of the population infected ranged from 30.1% to 60.6% depending on assumptions about test performance and prevalence of clinically severe infections. Conclusions: SARS-CoV-2 has spread extensively within Juba. Validation of serological tests in sub-Saharan African populations is critical to improve our ability to use serosurveillance to understand and mitigate transmission.

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Section: Discussionsupporting

confidence: 86%

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study

Rumunu

et al. 2021

Preprint

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“…27 USA, California, Marin (Appa et al 2020) 28 USA, California, Orange (Bruckner et al 2021) 29 USA, Connecticut (Mahajan et al 2020) 30 USA, Georgia, DeKalb and Fulton (Biggs et al 2020) 31 USA, Idaho, Blaine (McLaughlin et al 2020) 32 USA, Utah, four counties (Samore et al 2020) 33 Denmark, Faroe Islands (Petersen et al 2020) 34 Germany, Kreis Heinsberg, Gangelt (Streeck et al 2020) 35 Luxembourg (Snoeck et al 2020) 36 Netherlands (Vos et al 2020) 37 Russia, Saint Petersburg (Barchuk et al 2020) 38 Spain (Pollán et al 2020) 39 Switzerland, Geneva (Richard et al 2020) 40 Switzerland, Geneva (Stringhini et al 2020) 41 UK, England (Office of National Statistics 2020) 42 UK, England (Ward et al 2020) 43 UK, Jersey (Government of Jersey 2020) 44 India (Murhekar et al 2020 ) 45 India (Murhekar et al 2021) 46 India, Delhi (Sharma et al 2020) 47 India, Mumbai (Malani et might lead to mis-specification of assay performance. 53 Notably, although WHO has established a generic population-based serological study protocol, standardised guidelines and procedures for laboratory testing are scarce, which might contribute towards such heterogeneity in performance and reporting of results. We call on national and international governance bodies to develop standardised antibody testing protocols and reporting practices and create biobanks of reference standards (eg, monoclonal antibodies), to reduce laboratory-to-laboratory variations, thus facili tating the comparability and interpretability among sero prevalence studies.…”

Section: Discussionmentioning

confidence: 99%

“… 50 , 51 , 52 Furthermore, few independent validations were done in the target population of serosurvey, which might lead to mis-specification of assay performance. 53 Notably, although WHO has established a generic population-based serological study protocol, standardised guidelines and procedures for laboratory testing are scarce, which might contribute towards such heterogeneity in performance and reporting of results. We call on national and international governance bodies to develop standardised antibody testing protocols and reporting practices and create biobanks of reference standards (eg, monoclonal antibodies), to reduce laboratory-to-laboratory variations, thus facilitating the comparability and interpretability among seroprevalence studies.…”

Section: Discussionmentioning

confidence: 99%

Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis

Chen¹,

Chen²,

Azman³

et al. 2021

The Lancet Global Health

218

227

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Background A rapidly increasing number of serological surveys for antibodies to SARS-CoV-2 have been reported worldwide. We aimed to synthesise, combine, and assess this large corpus of data.Methods In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and five preprint servers for articles published in English between Dec 1, 2019, and Dec 22, 2020. Studies evaluating SARS-CoV-2 seroprevalence in humans after the first identified case in the area were included. Studies that only reported serological responses among patients with COVID-19, those using known infection status samples, or any animal experiments were all excluded. All data used for analysis were extracted from included papers. Study quality was assessed using a standardised scale. We estimated age-specific, sex-specific, and race-specific seroprevalence by WHO regions and subpopulations with different levels of exposures, and the ratio of serology-identified infections to virologically confirmed cases. This study is registered with PROSPERO, CRD42020198253.Findings 16 506 studies were identified in the initial search, 2523 were assessed for eligibility after removal of duplicates and inappropriate titles and abstracts, and 404 serological studies (representing tests in 5 168 360 individuals) were included in the meta-analysis. In the 82 studies of higher quality, close contacts (18•0%, 95% CI 15•7-20•3) and highrisk health-care workers (17•1%, 9•9-24•4) had higher seroprevalence than did low-risk health-care workers (4•2%, 1•5-6•9) and the general population (8•0%, 6•8-9•2). The heterogeneity between included studies was high, with an overall I² of 99•9% (p<0•0001). Seroprevalence varied greatly across WHO regions, with the lowest seroprevalence of general populations in the Western Pacific region (1•7%, 95% CI 0•0-5•0). The pooled infection-to-case ratio was similar between the region of the Americas (6•9, 95% CI 2•7-17•3) and the European region (8•4, 6•5-10•7), but higher in India (56•5, 28•5-112•0), the only country in the South-East Asia region with data.Interpretation Antibody-mediated herd immunity is far from being reached in most settings. Estimates of the ratio of serologically detected infections per virologically confirmed cases across WHO regions can help provide insights into the true proportion of the population infected from routine confirmation data.

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“…This is particularly relevant in sub-Saharan Africa, where high rates of false positivity have been described for many serological assays [4-6]. Recently, high rates of false positivity were reported using commercial SARS-CoV-2 serological assays in Benin, Tanzania and Zambia, conceivably due to cross-reactivity with other coronaviruses, or non-specific polyclonal reactivity that may be associated with unrelated conditions, including malaria [7, 8]. False positive tests may cause unnecessary alarm and harm at an individual and population level.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 seroassay optimization and performance in a population with high background reactivity in Mali

Sagara¹,

Woodford²,

Dicko³

et al. 2021

Preprint

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Serological tests are an indispensable tool to understand the epidemiology of the SARS-CoV-2 pandemic, particularly in areas where molecular diagnostics are limited. Poor assay performance may hinder the utility of these tests, including high rates of false-positivity previously reported in sub-Saharan Africa. From 312 Malian samples collected prior to 2020, we measured antibodies to the commonly tested SARS-CoV-2 antigens and four other betacoronaviruses by ELISA, and assessed functional cross-reactivity in a subset by SARS-CoV-2 pseudovirus neutralization assay. We then evaluated the performance of an ELISA developed in the US, using two-antigen SARS-CoV-2 spike protein and receptor-binding domain. To optimize test performance, we compared single and two-antigen approaches using existing assay cutoffs and population-specific cutoffs for Malian control samples (positive and negative). Background reactivity to SARS-CoV-2 antigens was common in pre-pandemic samples compared to US controls (43.4% (135/311) for spike protein, 22.8% (71/312) for RBD, and 33.9% (79/233) for nucleocapsid protein). SARS-CoV-2 reactivity correlated weakly with other betacoronavirus reactivity, varied between Malian communities, and increased with age. No pre-pandemic samples demonstrated functional activity. Regardless of the cutoffs applied, specificity improved using a two-antigen approach. Test performance was optimal using a two-antigen assay with population-specific cutoffs derived from ROC curve analysis [Sensitivity: 73.9% (51.6-89.8), Specificity: 99.4% (97.7-99.9)]. In the setting of high background reactivity, such as sub-Saharan Africa, SARS-CoV-2 serological assays need careful qualification is to characterize the epidemiology of disease, prevent unnecessary harm, and allocate resources for targeted control measures.

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Limited Specificity of Serologic Tests for SARS-CoV-2 Antibody Detection, Benin

Cited by 70 publications

References 13 publications

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study

Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis

SARS-CoV-2 seroassay optimization and performance in a population with high background reactivity in Mali

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