Indication - Vaccine-preventable diseases
Rubella IgG antibody
First added in 2020
To screen for prior exposure to rubella infection or vaccination, particularly in pregnant women
Serum, Plasma, Dried blood spots, Oral fluid
WHO prequalified or recommended products
WHO supporting documents
Manual for the laboratory diagnosis of measles and rubella virus infection https://www.who.int/immunization/monitoring_surveillance/burden/laboratory/Manual_lab_diagnosis_of_measles_rubella_virus_infection_ENG.pdf?ua=1 Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome https://www.who.int/immunization/monitoring_surveillance/burden/laboratory/manual/en/ Surveillance standards for vaccine-preventable diseases, 2nd edition https://apps.who.int/iris/handle/10665/275754 The immunological basis for immunization series. Module 11: rubella. Geneva: World Health Organization; 2008. https://apps.who.int/iris/handle/10665/43922 WHO. Rubella vaccines: WHO position paper. Weekly epidemiol record. 2011;29(86):301–316. https://www.who.int/wer/2011/wer8629.pdf?ua=1
ICD11 code: 1F02
Summary of evidence evaluation
Assessment of the accuracy of different tests is challenging, as there is no independent reference standard. Cited studies may be better viewed as assessing equivalence between different tests rather than accuracy. IgG testing has been shown to be important in vaccination campaigns, both to identify who requires vaccination and to assess the success of campaigns. These include national programmes and institute programmes such as in-hospital staff. There is thus evidence of the clinical utility of the IgG test. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
The elimination of rubella is a global priority and requires a concerted effort to identify outbreaks and stop chains of transmission. The rubella IgG test can help by identifying immunity to rubella and preventing CRS, and is particularly useful for screening pregnant women. IgG testing forms part of the case definition for rubella and is an important decision-making tool that is widely used in vaccination strategies, both to identify whom to vaccinate and to assess the success of individual campaigns. This class of IVDs offer good quality, safety and performance for detecting IgG antibodies to rubella virus. A broad range of products are available at all levels, from small, low-tech laboratories to high-throughput commercial laboratories. Some specific questions remain about the test’s use in very low incidence settings, but these do not negate the overall value of the test for preventing CRS. WHO guidelines suggest that rubella IgG testing could also be useful as an additional serologic method for case classification, although the submission to the EDL 3 did not include any data to support this test purpose.
SAGE IVD recommendation
SAGE IVD recommended the inclusion of the rubella IgG antibody test category in the third EDL: • as a disease-specific IVD for clinical laboratories (EDL 3; Section II.b, Vaccine-preventable diseases); • using an immunoassay format; • to screen for prior exposure to rubella infection or vaccination, particularly in pregnant women. The group further recommended securing the requisite evidence to enable an additional test purpose for the rubella IgG antibody test category of diagnosing acute infection.
Details of submission from 2020
Disease condition and impact on patients Rubella is a contagious infectious disease that affects unvaccinated children and young adults. The virus is easily transmitted by respiratory droplets from an infected individual. Childhood infection is often mild and resolves without complication. But if an unvaccinated woman gets rubella in early pregnancy serious consequences can result, including miscarriage, fetal death, stillbirth and having an infant born with congenital rubella syndrome (CRS). CRS results in a group of devastating birth defects that include blindness, deafness and heart defects. More than 100 000 children are born every year with CRS, mainly in Africa, South-East Asia and the Western Pacific (1, 2). Rubella vaccine is highly effective and safe when used across a population; as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by large outbreaks in recent years in Japan and elsewhere. Countries with high rates of susceptibility to rubella among women of childbearing age are at highest risk for CRS. This risk varies between and within countries based on epidemiological and socioeconomic differences (3). An economic burden study in Romania suggests rubella outbreaks have high costs and considerable impact (4). Does the test meet a medical need? If a person tests positive for IgM, a recent or current infection is detected. While the symptoms may not be severe for that particular person, if they come into contact with others, particularly women in early pregnancy, the outcome can be severe for the fetus and child. Outbreaks can occur in countries where vaccination programmes are not routine, with severe consequences. A rise in vaccine hesitancy means they can also occur in HICs where the disease has previously been eradicated. Steps such as quarantining infected individuals, and testing and vaccinating unvaccinated family members (or those who have not been previously exposed), is critical; no medications or treatments can prevent the disease other than vaccination or exposure. IVD diagnostics are critical to manage and control the spread of the disease. How the test is used The test supports a final diagnosis on its own for screening for past exposure and immunity; absence of IgG indicates no exposure or vaccination. The presence of IgG antibodies to rubella virus indicates a previous exposure either by vaccination or prior rubella infection and suggests immunity (3). Seroconversion of specific rubella antibodies or a significant rise of the IgG titre strongly supports the diagnosis of acute rubella infection (3). The quantitative determination of specific IgG is therefore used to determine the immune status to rubella and distinguish between those who have been exposed in the past and those who may have active infection (3). In countries where records are not well kept, the use of IgG testing can help to identify who has natural immunity and who has immunity gained through vaccination. In eradication efforts, this test is crucial to detecting patients needing the vaccine. In countries where the virus has been rampant, natural immunity can be established to ensure vaccines are reserved for the most vulnerable patients, such as women who intend to become pregnant.
Public health relevance
Prevalence and socioeconomic impact WHO recommends that all countries that have not yet introduced rubella vaccines should consider doing so using existing, well-established measles immunization programmes. To date, four WHO regions have established goals to eliminate this preventable cause of birth defects. In 2015, the WHO Region of the Americas became the first in the world to be declared free of endemic transmission of rubella. The number of countries using rubella vaccines in their national programme continues to steadily increase. As of December 2018, 168 out of 194 countries had introduced rubella vaccines and global coverage was estimated at 69%. Reported rubella cases declined 97%, from 670 894 cases in 102 countries in 2000 to 14 621 cases in 151 countries in 2018 (5, 6). CRS rates are highest in the WHO African and South-East Asia regions, where vaccination coverage is lowest. In April 2012, the Measles Initiative – now known as the Measles & Rubella Initiative – launched its Global Measles and Rubella Strategic Plan for 2012–2020 (7). The plan articulates a series of global goals, which include achieving measles and rubella elimination in at least five WHO regions. Based on the 2018 Global Vaccine Action Plan Assessment Report by SAGE Immunization, rubella control is lagging (8), with 26 countries still to introduce the vaccine, while two regions (Africa and Eastern Mediterranean) have not yet set rubella elimination or control targets. SAGE Immunization recommends incorporating rubella vaccination into immunization programmes as quickly as possible to ensure additional gains in controlling rubella.
WHO or other clinical guidelines relevant to the test
WHO surveillance standards recommend using IgG alongside IgM testing for evaluating pregnant women exposed to rubella (9). WHO offers governments and communities technical support to improve routine immunization programmes and hold targeted vaccination campaigns. The WHO GMRLN supports the diagnosis of rubella and CRS cases and the tracking of rubella virus spread. EIAs are the most commonly used and widely available diagnostic test for rubella IgM and IgG antibodies; they are sensitive and relatively easy to perform.
Evidence for diagnostic accuracy
No systematic reviews of IgG test accuracy were found. Clinical accuracy in pre-pregnancy and perinatal screening: Enders et al. (10) evaluated six assays on samples from 1090 women visiting antenatal care. Sensitivity varied from 78% to more than 90%, and specificity of all assays was 100%. Clinical accuracy in routine screening and diagnosis of acute infection: Dimech et al. (11) discuss the clinical accuracy of diagnostic assays on rubella patients and include routine screening and patients with acute infection. A total of 321 samples were evaluated (48 positive and 273 negative). The sensitivities compared with HIA ranged from 98.9% to 99.9%, and the specificity ranged from 77.1% to 95.8%.
Evidence for clinical usefulness and impact
Systematic reviews on the utility of rubella screening and infection are sparse; but one by Thompson et al. (12) concluded that serological surveys among women of childbearing age provide critical information with an impact on transmission. The review also highlights the gaps and need for more serological data to be able to eradicate rubella. This supports the importance of using diagnostic assays for future eradication of the disease. Another systematic review by Lopez et al. (13) highlights the importance of establishing a CRS surveillance programme that includes IgG testing to determine the proportion of women who are not immune. No studies were found showing the utility of rubella IgG testing for diagnosing acute infection.
Evidence for economic impact and/or cost–effectiveness
The cost–effectiveness of the vaccine can translate to IVD value, as treatment for CRS is very costly. A systematic review by Babigumira et al. (14) of 11 cost–benefit analyses, four cost–effectiveness analyses and one cost–utility analysis concluded that CRS treatment is costly, and vaccination programmes are cost-effective. Kanamori et al. (15) discuss the cost–effectiveness of rubella antibody screening among Japanese health care workers. Implementation of a seroprevalence programme (IgG assessment) among 243 new and 2664 previous health care workers was cost-effective and reduced unnecessary vaccination.
Ethical issues, equity and human rights issues
The use of rubella IVDs to ensure eventual rubella eradication is key to reducing inequity globally. The tests can identify individuals requiring the vaccine and support the need for more global access.
1. Disease and epidemiology. In: EMRO/Rubella . Cairo: WHO Regional Office of the Eastern Mediterranean; 2020 (http://www.emro.who.int/health-topics/rubella/disease-and-epidemiology.html, accessed 11 March 2020). 2. More about measles, rubella and congenital rubella syndrome (CRS) worldwide. In: CDC/Global Health . Atlanta: US Centers for Disease Control and Prevention; 2020 (https://www.cdc.gov/globalhealth/measles/facts.htm, accessed 11 March 2020). 3. Lambert N, Strebel P, Orenstein W, Icenogle J, Poland GA. Rubella. Lancet. 2015;385(9984):2297–2307. doi:10.1016/S0140-6736(14)60539-0. 4. Njau J, Janta D, Stanescu A, Pallas SS, Pistol A, et al. Assessment of economic burden of concurrent measles and rubella outbreaks, Romania, 2011–2012. Emerg Infect Dis. 2019;25(6):1101–1109. doi:10.3201/eid2506.180339. 5. Rubella. In: WHO/Newsroom . Geneva: World Health Organization; 2020 (https://www.who.int/news-room/fact-sheets/detail/rubella, accessed 11 March 2020). 6. Lanzieri T, Redd S, Abernathy E, Icenogle J. Chapter 14: Rubella. In: Roush SW, Baldy LM, Kirkconnell Hall MA, editors. Manual for the surveillance of vaccine-preventable diseases. Atlanta: US Centers for Disease Control and Prevention; 2020. 7. Measles & Rubella Initiative . Washington DC: American Red Cross; 2020 (https://measlesrubellainitiative.org/, accessed 11 March 2020). 8. Immunization today and in the next decade: 2018 assessment report of the Global Vaccine Action Plan. Geneva: World Health Organization; 2018 (WHO reference number: WHO/IVB/18.11). 9. Rubella. In: Surveillance standards for vaccine-preventable diseases, 2nd edition. Geneva: World Health Organization; 2018. 10. Enders M, Bartelt U, Knotek F, Bunn K, Strobel S, et al. Performance of the Elecsys Rubella IgG assay in the diagnostic laboratory setting for assessment of immune status. Clin Vaccine Immunol. 2013;20(3):420–426. doi:10.1128/CVI.00688-12. 11. Dimech W, Panagiotopoulos L, Francis B, Laven N, Marler J, et al. Evaluation of eight anti-rubella virus immunoglobulin G immunoassays that report results in international units per milliliter. J Clin Microbiol. 2008;46(6):1955–1960. doi:10.1128/JCM.00231-08. 12. Thompson KM, Odahowski CL. Systematic review of measles and rubella serology studies. Risk Anal. 2016;36(7):1459–1486. doi:10.1111/risa.12430. 13. Lopez AL, Raguindin PF, Silvestre MA, Fabay XC, Vinarao AB, et al. Rubella and congenital rubella syndrome in the Philippines: a systematic review. Int J Pediatr. 2016. doi:10.1155/2016/8158712. 14. Babigumira JB, Morgan I, Levin A. Health economics of rubella: a systematic review to assess the value of rubella vaccination. BMC Public Health. 2013;13:406. doi:10.1186/1471-2458-13-406. 15. Kanamori H, Tokuda K, Ikeda S, Endo S, Ishizawa C, et al. Prevaccination antibody screening and immunization program for healthcare personnel against measles, mumps, rubella, and varicella in a Japanese tertiary care hospital. Tohoku J Exp Med. 2014;234(2):111–116. doi:10.1620/tjem.234.111.