Statement of the Joint Diagnostics Commission of the DVV and GfV on the determination of anti-measles IgG from dried blood drops on filter paper cards

STIKO recommendation for measles vaccination:

To ensure adequate protection against measles, the STIKO recommends carrying out the vaccinations listed in the corresponding STIKO recommendation if the vaccination status is unknown [1]. If two vaccinations against measles are documented, it can be assumed with a high degree of probability that there is sufficient protection against measles. A serological antibody check of immunity is not necessary in this case.

Background information on the double MMR vaccination

Double vaccination with an MMR combination vaccine follows the WHO's vaccination recommendations, supports the WHO's elimination target for measles and rubella, improves infection protection in community facilities and medical institutions and simplifies individual immunity testing, as immunity can be assumed with two documented MMR vaccinations. This applies, for example, to people before taking up employment in medical facilities, student exchanges or study visits abroad as well as aspects of infection protection when pregnancy is detected. The protection against mumps provided by the first vaccination is also significantly improved.

Requirements of the Measles Protection Act:

The Measles Protection Act requires proof of measles immunity for a certain group of people, which can be provided either by two MMR vaccinations documented in the vaccination record or a positive anti-measles IgG test.
If the determination of anti-measles IgG is positive after an administered dose of the MMR vaccine, this can be used as proof of immunity; a second vaccination is not mandatory in this case. However, this procedure does not correspond to the STIKO recommendation cited and is also not supported by the Joint Diagnostics Commission of the DVV and GfV from a professional diagnostic point of view for the reasons mentioned above.

Detection of anti-measles IgG in serum or from dried blood spots (DBS) on filter paper cards (FPK)

Procedure:

A serum sample is usually obtained by puncturing the brachial vein in the crook of the arm. As a minimally invasive alternative, capillary blood can be taken from the fingertip to determine anti-measles IgG. The blood is dripped onto an FPK. After loading, the FPK is dried and sent to a laboratory. There, areas loaded with blood are punched out of the card and eluted in a buffer. The anti-measles IgG status is determined from the eluate. The result is sent from the laboratory to the doctor's surgery. The attending physician issues a certificate in accordance with the requirements of the Measles Protection Act if the result is positive, i.e. anti-measles IgG antibodies have been detected.

The question of whether these immunity provisions from DBS are to be recognized on FPK has been raised repeatedly. We refer to the following points:

Suitability of DBS on FPK:

The use of FPK and the comparability / correlation of results obtained with serum or DBS have already been described many times in relation to other parameters of infectious serology (e.g. HIV and HCV antibodies) [2]. A literature search via Pubmed (https://pubmed.ncbi.nlm.nih.gov/?term=dried+blood+spot+testing+infectious&sort=date) using the keywords "Dried blood spot testing infectious" resulted in over 200 hits. The use of DBS on FPK is also recommended internationally, e.g. by the WHO for the determination of anti-measles IgM, at least for those countries in which the cold chain cannot be safely maintained during transportation of test materials [3].

Suitability of the test method used:

If the use of DBS on FPK for the anti-measles IgG test is listed as a validated matrix in the corresponding description of the test manufacturer, it is an IVDR-compliant application (IVDR - Regulation (EU) 2017/746 on in vitro diagnostic medical devices of April 5, 2017). If this is not the case, it must be assumed that it is a non-compliant application that is outside the intended purpose of the manufacturer. As a result of this significant change to the matrix, the diagnostic test loses its CE marking. At the same time, this constitutes "in-house manufacture of an in vitro diagnostic (IVD)". Under the so-called "in-house privilege", such an IVD can only be used in compliance with medical device law if the requirements of Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) are met by the laboratory - as the responsible operator. Article 5 (5) IVDR is applicable for in-house production.

Accordingly, a laboratory that uses a test for the determination of anti-measles IgG that is not specified in the manufacturer's test description for the use of an eluate from DBS on FPK as a matrix must carry out a corresponding validation. The results of an anti-measles IgG determination from serum or from the eluate of DBS on FPK are compared on the basis of the same test samples. The qualitative and quantitative correlation of the results must be proven for both matrices in the corresponding validation documents.

Quality management of the laboratory: A laboratory that carries out a test for the determination of anti-measles IgG from the eluate from DBS for FPK must - like all laboratories that carry out laboratory diagnostic tests in human medicine - work in accordance with the guidelines of the German Medical Association for the quality assurance of laboratory medical tests (RiLiBÄK), i.e. internal quality controls must be carried out and external quality controls (e.g. interlaboratory tests) must be participated in.

Acceptance procedure (preanalytics): Not only does a test validated for the corresponding matrix contribute to a technically sound test result, but sample collection and pre-analysis also have a significant influence on the test result. It must therefore be ensured that samples are taken under qualified supervision or by medical professionals.

Conclusion:
The Joint Diagnostics Commission of the DVV and GfV concludes that the determination of anti-measles IgG from the eluate of dried blood drops on a filter paper card (DBS on FPK) can be equivalent to an anti-measles IgG test from serum with subsequent analysis in a suitable test system.

It must be ensured that (i) the corresponding results of a validation study for the test system used are available in accordance with the requirements of Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) and (ii) the collection of the samples and the dispatch of the filter card is carried out and/or supervised by a medical practice.

It should be noted that the detection of IgG antibodies against the measles virus after a single vaccination does not simultaneously provide proof of successful immunization against mumps or rubella (e.g. after using an MMR vaccine).

This information is limited to technical and diagnostic aspects and does not affect legal aspects of the IfSG/MasernschutzG.

Status: 16.01.2024

Representative:
PD Dr. Nadine Lübke
Prof. Dr. Annette Mankertz
Prof. Dr. Marcus Panning
Prof. Dr. Holger Rabenau
Prof. Dr. Heinz Zeichhardt

Click here for the statement in PDF format.

References

[1] The Standing Committee on Vaccination (STIKO) recommends the measles vaccination as an MMR combination vaccination with a total of two vaccine doses for all children. The first MMR vaccination should be given at the age of 11-14 months. The second vaccination should be given at the earliest 4 weeks after the first vaccination at the age of 15-23 months.

Adults are recommended a single MMR vaccination as a standard vaccination if they were born after 1970 and their vaccination status is unclear or if they received no or only one vaccination in childhood. A double measles vaccination is also recommended by the STIKO for people born after 1970 in special occupational areas. This includes staff in medical facilities, care facilities, community facilities and in technical, vocational and higher education institutions.

[2] Reinhardt B, Taylor R, Dawkins C, Banks T, Watson N, Sundaram A, Ewing D, Danko JR. The use of dried blood spot cards to assess serologic responses of individuals vaccinated against measles, hepatitis A, tetanus, influenza and varicella zoster. PLoS One. 2022 Mar 24;17(3):e0265813. doi: 10.1371/journal.pone.0265813. PMID: 35324972; PMCID: PMC8947131.

[3] https://cdn.who.int/media/docs/default-source/immunization/vpd_surveillance/lab_networks/measles_rubella/manual/updated-annexes-(as-on-2-aug-2021)/annex-a4-dbs-protocols-v1-7_jan_2020_jr002df531-4890-467f-82be-0827e6db8f81.pdf?sfvrsn=4c6c8662_9″