Dimeric immunoglobulin A as a novel diagnostic marker of measles infection

Abstract

ABSTRACT Despite tremendous measles incidence reduction through universal vaccination, elimination efforts rely on improved surveillance. The detection of anti-measles immunoglobulin M (IgM) by enzyme-linked immunosorbent assay is the standard laboratory diagnostic method. However, true infection is rare, and seroconversion following measles, mumps, and rubella vaccination also generates IgM, which results in low positive predictive values of assays in elimination settings, thus necessitating confirmatory testing. Improved diagnostic tests for measles infection are a World Health Organization research priority. We investigated whether dimeric immunoglobulin A (dIgA), the predominant antibody produced in mucosal immunity, may be a marker of recent or acute measles infection. We examined a serological panel of confirmed measles infection (anti-measles IgM positives, n = 50) and non-measles infection with rubella ( n = 36), roseola ( n = 40), chikungunya/dengue/zika ( n = 41), parvovirus ( n = 35), and other fever-rash illnesses of unknown cause ( n = 37). Sera were examined on microimmune anti-measles IgM, Euroimmun anti-measles virus lysate (VL), and nucleoprotein (NP) IgM kits. Assays were then modified to detect dIgA using an in-house protocol based on a recombinant chimeric secretory component protein and an anti-secretory component monoclonal antibody. We observed significantly higher levels of anti-measles VL dIgA in measles samples than in non-measles controls ( P < 0.001), and there was a low correlation with IgM (R 2 : 0.01, P value: 0.487). Unlike IgM, dIgA reactive to measles NP was not detected in most samples. The comparable diagnostic potential of anti-measles dIgA (area under the curve, AUC: 0.920–0.945) to anti-measles IgM (AUC: 0.986–0.995) suggests that dIgA may be a new blood-based marker of acute measles, independent of IgM, which merits further investigation and optimization. IMPORTANCE The world is facing a measles resurgence, and improved diagnostic tests for measles infection are an urgent World Health Organization research priority. Detection of measles-specific immunoglobulin M (IgM) as a standard diagnostic test has low positive predictive value in elimination settings, and there is a need for new biomarkers of measles infection to enable enhanced surveillance and response to outbreaks. We demonstrate the detection of measles-specific dimeric immunoglobulin A (dIgA) in patients with confirmed measles infections using a new indirect enzyme-linked immunosorbent assay protocol that selects for the dIgA fraction from total IgA in the blood. The magnitude of measles-specific dIgA responses showed a low correlation with IgM responses, and our results highlight the potential of dIgA for further development as an alternative and/or complementary biomarker to IgM for serological diagnosis of measles infection.