Standardization of rubella immunoassays

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Highlights

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    Immunity to rubella virus is commonly determined by measuring rubella-specific IgG.

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    Standardization of rubella-specific IgG assays is not effective.

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    Lack of standardization may lead to misinterpretation of results.

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    Low levels of rubella-specific IgG are sufficient to prevent clinical consequences of reinfection.

Abstract

Currently, rubella and congenital rubella has been eliminated or is becoming a rare disease in many countries that have implemented effective vaccination programs. In most of these countries, it is recommended and of major importance to screen childbearing age women in order to identify susceptible women and offer them vaccination before pregnancy or after delivery. Immunity to rubella virus (RV) is commonly determined by measuring rubella-specific IgG (RV-IgG). However, looking at literature, it is obvious that standardization of RV-IgG assays is not effective, with different levels of International Units per milliliter (IU/mL) reported for a same sample, and consequently different interpretations of the result. This situation leads to misinterpretation of results, sometimes causing adverse clinical outcomes. This article aimed to review several factors, such as the introduction of large-scale vaccination programs and changes in epidemiology of RV infection, along with the development of new technologies that have complicated appreciation of the immune status of patients. However, there is currently no evidence that these factors may be of any influence on rubella resurgence.

Section snippets

Background

Rubella virus (RV) is only found in humans and is transmitted by aerosol via the respiratory tract. It is responsible of a mild viral disease that typically occured in childhood before introduction of vaccination. The risks of congenital infection and defects depend on the gestational age at infection. A RV infection during embryogenesis often leads to the classic triad of cataracts, cardiac abnormalities and sensorineural deafness, but many other defects may be observed. RV was first isolated

History of RV-IgG testing

When RV-IgG testing started in the 1960s, the reference method for determination of immunity was the neutralization test (NT) which is not suitable for laboratory routine testing. Therefore, hemagglutination inhibition assay (HAI) was the most widely assay used until the 1980s, even if variability between laboratories was high [[5], [6], [7], [8]]. In 1970, the WHO Expert Committee on Biological Standardization established a preparation of human normal immunoglobulin as an International

Lack of standardization of RV-IgG immunoassays

Immunity to RV is commonly determined by measuring RV-IgG. Currently, in many countries, where immunity is now mainly due to vaccination, RV-IgG testing mainly relies on CIAs using enzymatic or chemiluminescent detection systems. Each manufacturer uses different technologies and varied in the choice of the solid phase, the platform, the antigens, the detection system, the conjugate, and the substrate, and many authors have compared the CIAs’ performance [[17], [18], [19], [20], [21]].

Reinfections

Sporadic publications report cases of symptomatic rubella reinfection in immune persons (by vaccination or naturally acquired rubella), and proven cases of reinfection have been reported in patients with RV-IgG titers above 15 IU/mL indicating that even high RV-IgG titers do not always protect against reinfection [[31], [32], [33], [34]]. However, our main concern in these situations is the risk of transmission to the fetus and subsequent congenital rubella syndrome (CRS). Such cases have been

Variability of the immune response and impact of vaccination

RV-IgG become detectable several weeks after onset of infection and usually remain detectable lifelong [48]. Post-vaccination studies indicate that, although the immune response to vaccination mimics that of wild-type infection, the level of specific antibodies is lower than after natural infection. It was determined that the development of anti-E1 glycoprotein IgG was the dominant immunogenic response in individuals infected with wild-type RV, in CRS and following vaccination, as most of the

Protection

Cell-mediated immunity is not routinely investigated for diagnostic purposes but it plays also an important role in elimination of virus-infected cells. Although it has been extensively studied for other viruses, very few recent studies involve cell-mediated immunity against RV, and its role in protection against rubella has not been determined. Lymphoproliferative assays showed that cell-mediate immunity responses develop a few days after onset of rash and persist at low levels for many years,

Conclusion

A possible consequence of rubella vaccination is an overall reduction in the levels of RV-IgG in vaccinated individuals compared with those acquiring immunity through natural infection. Several studies confirm that the cut-offs currently recommended for CIAs guarantee their specificity and ensure that all susceptible women are targeted for rubella vaccination. However, standardization of these CAIs is not effective and establishing new CIA cut-offs could improve correlation with the true immune

Conflict of interest

The author declares to have received support from Roche Diagnostics, Siemens Healthcare and bioMérieux for intellectual support and teaching sessions. I approved the final manuscript.

Funding

None.

Ethical approval

Not applicable.

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