Reference preparations used world-wide (International Standards) are indispensable for reliable diagnostic tests. An international expert group has scrutinised the currently used International Standard for rubella diagnostics. The Lancet Infectious Diseases reports on the outcome in its online version of 6 September 2019.
In its role as one of the official collaboration centres of the World Health Organisation (WHO), the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines , has supported the WHO for many years in the field of standardisingof biomedicines and biological assays. Activities of the PEI include developing and providing reference preparations of the WHO (International Standards) which are used world-wide for calibration of in vitro diagnostics (IVD). Only these international reference preparations make it possible to compare the results between the different tests – an important prerequisite for the reliability of test results, regardless of the currently used assay. Because of fast technological developments in the field of IVD, continuous verification is required as to whether the WHO standards are still suitable as reference. If this is no longer the case, professional circles have to be informed and more suitable reference preparations have to be developed.
An international expert group has taken charge of the diagnostic tests for rubella. This group was chaired by PD Dr Micha Nübling, who worked for the WHO in Geneva from 2015 to 2018 and has been the head of Division Major Policy Issues, Co-Ordination of the PEI since 2018.
"We have to question continously whether established approaches of biological standardisation are also sufficient for new diagnostic developments. The suitability of WHO reference preparations for new tests must be checked and verified time and again" explained PD Dr Micha Nübling.
An infection with rubella virus in the absence of sufficient immune protection is feared a great deal by pregnant women, since the virus can lead to severe damage in the unborn (rubella embryopathy). The immune protection against rubella is based on antibodies which the immune system develops based on a previous infection or vaccination.
To measure the protective antibodies, so-called neutralisation tests were used for a Long-time determining the level of neutralising antibodies. These test systems were calibrated using the WHO International Standard for rubella antibodies. Immune protection was equated to a lower limit value (cut-off value) of neutralising antibodies (10 IU/ml). For young women without a sufficient level of neutralising rubella antibodies ("protective titre") vaccination was urgently recommended to protect them during potential pregnancy.
In the meantime, neutralisation tests have been superseded by a number of other test methods with which all antibodies targeted against rubella virus can be detected – not only neutralising antibodies. This illustrates that different tests can each time recognise a slightly different spectrum of the antibody targeted against the virus, making the calibration of the different tests using one single antibody preparation no longer quite so simple: different tests can lead to different results for the same serum, which may have disastrous consequences in isolated cases such as an erroneous recommendation for an abortion.
For this reason, the expert group established recommendations both for the future restricted use of the WHO reference preparation and for the interpretation of results obtained by current rubella tests. In addition, the expert group recommends the cut-off value for immune protection to be critically checked. This may save young women with low antibody titres from being immunised unnecessarily and recently infected pregnant women suspected of having no sufficient antibody protection from an abortion.
The WHO Expert Committee on Biological Standardization (ECBS) agreed to these recommendations. The ECBS is the global expert committee of the WHO for all questions regarding biological standardisation. Professor Dr Klaus Cichutek, president of the PEI, was the last elected chairman of this committee.
The Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and immunological veterinary medicinal products. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects.
Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the manifold tasks performed at the institute.
The Paul-Ehrlich-Institut, with its roughly 800 members of staff, also has advisory functions nationally (federal government, federal states (Länder)), and internationally (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).
Kempster SL, Almond N, Dimech W, Grangeot-Keros L, Huzly D, Icenogle J, Sittana El Mubarak H, Mulders MN, Nübling M (2019): WHO international standard for anti-rubella: learning from its application.
Lancet Infect Dis Sep 06 [Epub ahead of print].
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30274-9/fullt... - Fulltext of the publication; Registration required, no fees
https://www.pei.de/EN/information/journalists-press/press-releases/2019/17-rubel... - This press release on the PEI-Website
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