Comparison of measles IgG enzyme immunoassays (EIA) versus plaque reduction neutralization test (PRNT) for measuring measles serostatus: a systematic review of head-to-head analyses of measles IgG EIA and PRNT

Abstract

Background As countries move towards or achieve measles elimination status, serosurveillance is an important public health tool. However, a major challenge of serosurveillance is finding a feasible, accurate, cost-effective, and high throughput assay to measure measles antibody concentrations and estimate susceptibility in a population. We conducted a systematic review to assess, characterize, and – to the extent possible – quantify the performance of measles IgG enzyme-linked assays (EIAs) compared to the gold standard, plaque reduction neutralization tests (PRNT). Methods We followed the PRISMA statement for a systematic literature search and methods for conducting and reporting systematic reviews and meta-analyses recommended by the Cochrane Screening and Diagnostic Tests Methods Group. We identified studies through PubMed and Embase electronic databases and included serologic studies detecting measles virus IgG antibodies among participants of any age from the same source population that reported an index (any EIA or multiple bead-based assays, MBA) and reference test (PRNT) using sera, whole blood, or plasma. Measures of diagnostic accuracy with 95% confidence intervals (CI) were abstracted for each study result, where reported. Results We identified 550 unique publications and identified 36 eligible studies for analysis. We classified studies as high, medium, or low quality; results from high quality studies are reported. Because most high quality studies used the Siemens Enzygnost EIA kit, we generate individual and pooled diagnostic accuracy estimates for this assay separately. Median sensitivity of the Enzygnost EIA was 92.1% [IQR = 82.3, 95.7]; median specificity was 96.9 [93.0, 100.0]. Pooled sensitivity and specificity from studies using the Enzygnost kit were 91.6 (95%CI: 80.7,96.6) and 96.0 (95%CI: 90.9,98.3), respectively. The sensitivity of all other EIA kits across high quality studies ranged from 0% to 98.9% with median (IQR) = 90.6 [86.6, 95.2]; specificity ranged from 58.8% to 100.0% with median (IQR) = 100.0 [88.7, 100.0]. Conclusions Evidence on the diagnostic accuracy of currently available measles IgG EIAs is variable, insufficient, and may not be fit for purpose for serosurveillance goals. Additional studies evaluating the diagnostic accuracy of measles EIAs, including MBAs, should be conducted among diverse populations and settings (e.g., vaccination status, elimination/endemic status, age groups).

Immunogenicity and reactogenicity following MMR vaccination in 5–7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants

“…The inconsistency of SPR between measles PRNT and measles IgG ELISA is a well described phenomenon. 10 , 14 Although PRNT is the gold standard for measuring seroprotection, it is labor-intensive, why other ways to measure responses are useful. Measles IgG ELISAs have lower sensitivity (underestimating SPR by around 10 percentage points), which causes false negative results.…”

“…Measles IgG ELISAs have lower sensitivity (underestimating SPR by around 10 percentage points), which causes false negative results. 10 Samples in the ELISAs were run in unicate causing uncertainty for the estimated level of antibodies in each individual sample, however, this was mitigated by a high number of samples, and reading of controls being very similar across plates underlining the uniform performance of the assay and the laboratory work.…”

“… 8 , 9 Evaluation of measles immunogenicity is most precisely done by the gold standard plaque reduction neutralization test, but other high throughput, less labor-intensive methods like enzyme immunoassays are needed for serosurveillance of population immunity, thus, both methods are applied in the current trial. 10 …”

Serodynamics: a review of methods for epidemiological inference using serological data

“…Binding and neutralization assays measure immunologically different processes, and functional assays (neutralization) tend to be a closer proxy of immunologically relevant quantities (i.e., antigen-specific immunity). However, functional assays are much more resource-intensive to perform than binding assays, and binding assays are often used for seroepidemiological applications as the binary and quantitative measurements tend to be well-correlated between the two assay types [53][54][55]. Binding assays and neutralization assays tend to have similar considerations for epidemiological analysis, and samples go through a similar series of processing steps between sample collection and data reporting (Figure 3).…”

Evaluating Scope and Bias of Population-Level Measles Serosurveys: A Systematized Review and Bias Assessment

“…The interpretation of seroprevalence data is complicated, however, because of the potential for bias. Some of this bias can be due to inadequate sensitivity of the laboratory assays [ 9 ] and/or specimen types [ 10 ] used for measuring antibody levels. Additionally, bias from assay procedures can be suspected when protocols or commercial details are not reported or if no quality control was performed.…”