9.1 Detection of virus-specific IgG and protective immunity

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The cut-offs for commercial measles and rubella IgG EIAs were established for maximizing specificity as the assays were designed to evaluate the immune response for individual patient management and not for population antibody prevalence calculations [3]. A positive result in a well-validated measles or rubella IgG EIA demonstrates a serologic response to antigenic stimulation elicited by either vaccination or natural infection. Although susceptibility to disease is inferred by a negative or equivocal result for virus-specific IgG, not all individuals with such a result may actually lack immunity to measles or rubella [4,5]. It is understood that immunity is a complex process and that IgG antibody detection provides only a marker or surrogate for immunity. A useful review of the principles of protection elicited by vaccination and interpretation of immune markers is provided in the 2013 WHO publication, Correlates of vaccine-induced protection: methods and implications [6].

In countries and regions with high vaccination coverage that has been sustained over several decades, there are diminishing numbers of individuals with naturally-acquired immunity to measles or rubella. Lower levels of antibody induced by vaccination compared to those from disease are reflected in results obtained from population-based serologic studies [3, 7-8]. Consequently, negative or equivocal IgG results can be expected with commercial IgG EIAs when assessing immunity in populations with strong immunisation programmes. The selection of an EIA for the evaluation of immune status in vaccinated populations requires careful consideration of the assay specifications and validation methodology and may require additional testing of specimens with results in the equivocal range.

When testing a panel of serum specimens for measles- or rubella- specific IgG using different commercial EIAs, the results that are obtained can be discordant. This has been a particularly challenging issue for rubella IgG assays [10]. The variation in results from different assays may be due to one or more factors including the antigen preparation, assay format, assay platform, and the detection system. Commercial IgG kits that offer a quantitative result for IgG by transformation of optical density values obtained in the EIA to a titre or concentration in international units per millilitre (IU/ml) may be designed to allow an evaluation of a rise in titre (e.g., Enzygnost® Anti-Measles Virus/IgG) or are intended to correlate with a protective level of antibodies (e.g., Enzygnost® Anti-Rubella Virus/IgG). Regardless of calibration to a reference standard by the manufacturers of rubella IgG EIAs, the assays are not standardized against each other [10-12].

Analyses of serum specimens with equivocal results for either measles or rubella IgG by respective virus-specific kits have demonstrated that equivocal samples by EIA are usually above the cut-off for protection when tested in virus neutralization assays [11,13,14]. If equivocal results can be included as positive results, the sensitivity is greatly increased as well as the concordance observed between results obtained from different assays. The development, validation and characteristics of widely used commercial IgG EIAs and the specific recommendations for their use are discussed separately for measles and rubella in the sections that follow.

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