Abstract
Introduction//BackgroundThe lack of standardization of the currently used commercial anti-rubella IgG antibody assays leads to frequent misinterpretation of results for samples with low/equivocal antibody concentration. The use of alternative approaches in rubella serology could add new information leading to a fuller understanding of rubella protective immunity and neutralizing antibody response after vaccination.MethodsWe applied microarray technology to measure antibodies to all rubella virus proteins in 75 high and 75 low rubella virus-specific antibody responders after two MMR vaccine doses. These data were used in multivariate penalized logistic regression modeling of rubella-specific neutralizing antibody response after vaccination.ResultsWe measured antibodies to all rubella virus structural proteins (i.e., the glycoproteins E1 and E2 and the capsid C protein) and to the non-structural protein P150. Antibody levels to each of these proteins were: correlated with the neutralizing antibody titer (p<0.006); demonstrated differences between the high and the low antibody responder groups (p<0.008); and were components of the model associated with/predictive of vaccine-induced rubella virus-specific neutralizing antibody titers (misclassification error = 0.2).ConclusionOur study supports the use of this new technology, as well as the use of antibody profiles/patterns (rather than single antibody measures) as biomarkers of neutralizing antibody response and correlates of protective immunity in rubella virus serology.
Highlights
Our study supports the use of this new technology, as well as the use of antibody profiles/ patterns as biomarkers of neutralizing antibody response and correlates of protective immunity in rubella virus serology
We have previously described the modified version of the Centers for Disease Control and Prevention (CDC) immuno-colorimetric-based rubella virus-specific neutralization assay, which was optimized by our laboratory to a high-throughput micro-format and used in large population-based studies. [20,27,30,31,32,33,34,35] Each assay contained the following controls: virus-only control; uninfected control; and two reference sera (CDC anti-rubella human serum reference preparation IS2153 and a seronegative serum RP-011 panel member 1 [Biomex GmbH; Heidelberg, Germany])
The proposed correlate of protective immunity for rubella is a rubella-specific Ab titer of 10– 15 international units per milliliter (IU/mL), corresponding to a neutralization Ab titer of 1:8. [39,40,41] The measurement of rubella-specific antibodies in clinical settings is generally performed using quantitative commercial immunoassays, which report the results in IU/mL using the currently available WHO international reference rubella standard
Summary
While rubella virus commonly causes mild fever and rash during childhood, serious complications (i.e., miscarriage or birth defects of the fetus/baby, referred to as congenital rubella syndrome/CRS) can arise if infection develops in women during the first months of pregnancy. [1] Rubella virus is able to cross the placenta and replicate in fetal tissues, causing systemic inflammation and resulting in up to a 90% risk of developing CRS depending upon the timing of infection during the pregnancy. [1,2,3] The most common CRS complications include deafness, cataracts and blindness, congenital heart defects, endocrinopathies, microcephaly, encephalopathy, mental retardation, and death. [1,4]Vaccination programs have drastically reduced the incidence of rubella infection and CRS; current estimates suggest that 100,000 cases of CRS still occur worldwide each year. [1] endemic rubella transmission has been eliminated in the US, 79 rubella cases and six CRS cases were reported in the US during the 2004–2012 period, primarily in unvaccinated individuals who were infected in other countries. [1,5] Combined with decreasing rates of immunization due to vaccine hesitancy, rubella will remain a public health concern as long as it continues to be endemic or circulate in any area of the world. [1,5] Combined with decreasing rates of immunization due to vaccine hesitancy, rubella will remain a public health concern as long as it continues to be endemic or circulate in any area of the world This points to the necessity of timely and accurate diagnosis of new cases, vaccination of susceptible individuals, monitoring and deeper understanding of vaccine-induced immunity, and the development of newer vaccine candidates. [27] In this study, we used a newly developed rubella virusspecific protein microarray chip and probed IgG rubella-specific humoral immune responses in 75 high neutralizing Ab responders and 75 low neutralizing Ab responders (after two MMR vaccine doses) in order to develop rubella vaccine-specific humoral immune profiles (consisting of antibodies to individual rubella virus proteins) associated with neutralization Ab titers. These results may potentially lead to the development of a combined chip for assessment of humoral immunity after MMR vaccination
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