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WHO international standard for anti-rubella: learning from its application
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WHO international standard for anti-rubella: learning from its application Sarah L Kempster, Neil Almond, Wayne Dimech, Liliane Grangeot-Keros, Daniela Huzly, Joseph Icenogle, Haja Sittana El Mubarak, Mick N Mulders, C Micha Nübling
The WHO international standard for anti-rubella was first established in the 1960s when clinical diagnostics were in their infancy. Since the endorsement of the first international standard for anti-rubella IgG (RUBI-1-94), new rubella vaccines have been developed and global coverage of rubella vaccination has increased. Methods used to measure concentrations of anti-rubella IgG have also evolved to rapid, high-throughput binding assays, which have replaced often cumbersome and highly technical functional assays. During this timeframe, the protective concentration of antibody was set at 10 IU/mL by extrapolation of functional assay correlates; however, the subpopulation of antibodies within a polyclonal serum that confer protection remained undefined. Anti-rubella assays have variable formats, including antigens used, such that the same clinical sample tested on different assays can report different values with potentially devastating consequences, such as recommending to terminate pregnancy. WHO convened a meeting of experts in the rubella field to discuss the use of RUBI-1-94 and the potential future role of this international standard. The main conclusions of this meeting questioned the appropriateness of 10 IU/mL as the cutoff for protection and acknowledged the continuing role of RUBI-1-94 as a reference preparation to address analytical sensitivity and assay variation.
Introduction The Measles and Rubella Global Strategic Plan 2012–20 provides a blueprint for countries to work together towards a world without measles, rubella, and congenital rubella syndrome, with a target of rubella elimination in four WHO regions (Americas, Eastern Mediterranean, European, and Western Pacific regions) by 2020.2,3 Monitoring vaccine efficacy requires robust diagnostic assays that measure concentrations of anti-rubella IgG as an indicator of protection against infection or as evidence of previous exposure through infection or vaccination. Accurate comparative measurement of anti-rubella antibodies is supported through the physical reference standard (WHO international standard), established by the WHO Expert Committee on Biological Standardization (WHO-ECBS). WHO and other guidelines state that the protective concentration of anti-rubella antibodies in serum is 10 IU/mL.4 Since the endorsement of the first international standard for anti-rubella IgG (RUBI-1-94), new rubella vaccines have been developed and global coverage of rubella vaccination reached about 52% in 2017.1 Developments in design and application of tests measuring concentrations of anti-rubella antibodies have led to question whether the WHO international standard for anti-rubella remains appropriate and suitable as a universal calibrator for measurement of serological responses and, moreover, whether the limit of 10 IU/mL still represents the lower limit of protective immunity capable of preventing congenital rubella syndrome. These concerns raise the question as to whether RUBI-1-94 should continue to be used for assay calibration and, therefore, establishing the cutoff for these serological assays.
Background Rubella was first recognised as a distinct disease in 1815,5 with the association between maternal infection during
pregnancy and birth defects established in 1941.6 Rubella virus was subsequently isolated in culture in 19627,8 shortly before a severe rubella epidemic in the USA in 1964 that resulted in 2100 neonatal deaths, 11 250 therapeutic or spontaneous abortions, and 20 000 cases of congenital rubella syndrome.9 Antirubella γ-globulin was developed as a therapeutic treatment, before the availability of a vaccine, and was shown to provide protection when administered up to 3 days after experimental intranasal challenge.10,11 In 1965, WHO-ECBS recognised the need for an antirubella standard to estimate the potency of anti-rubella γ-globulin preparations and to standardise anti-rubella measurements. Two candidate standards were assessed in a worldwide collaborative study involving eight expert laboratories. In-vitro neutralisation assays were done in each laboratory to determine the anti-rubella titre of each preparation. A freeze-dried pool of human convalescent serum samples was selected to be established by WHOECBS.12 In 1968, a replacement standard was needed because of a loss of potency of the original preparation. In the second international collaborative study, five labora tories participated, and haemagglutination inhibition assays (HAI) as well as neutralisation assays were included in the analysis since HAI had become widely used because of their speed and simple methodology. The second international standard for anti-rubella IgG serum was established by WHO-ECBS in 1971. From the 1970s, enzyme immunoassays were increasingly used for anti-rubella IgG detection and eventually replaced other methods in most clinical serodiagnostic laboratories. By the time the third international collaborative study was done, in 1994, eight of 11 participants reported results obtained by enzyme immunoassays with other laboratories using HAIs or serum radial haemolysis. No laboratories participating in this third study used in-vitro neutralisation assays, and
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
Lancet Infect Dis 2019 Published Online September 6, 2019 http://dx.doi.org/10.1016/ S1473-3099(19)30274-9 National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK (S L Kempster PhD, N Almond PhD); National Serology Reference Laboratory, Fitzroy, VIC 3065, Australia (W Dimech MBA); Paul Brousse Hospital, Villejuif 94800, France (L Grangeot-Keros PhD); University Medical Center Freiburg, Freiburg 79104, Germany (D Huzly MD); Centers for Disease Control and Prevention, Division of Viral Diseases, GA 30329–4027, USA (J Icenogle PhD); The Food and Drug Administration, Silver Spring, MD 20993–0002, USA (H S El Mubarak PhD); WHO, Geneva 1211, Switzerland (M N Mulders PhD, C M Nübling PhD); and Paul-Ehrlich-Institute, Langen 63225, Germany (M N Mulders, C M Nübling) Correspondence to: Dr Sarah L Kempster, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire EN6 3QG, UK [email protected]
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Personal View
although samples of the second international standard from 1968 were included in the study, the association had weakened between the new replacement WHO international standard (RUB-I-94) and neutralisation data from earlier studies. To prevent confusion, this new reference preparation was designated the 1st international standard for anti-rubella IgG. A cutoff value of 10 IU/mL has been assigned as the protective titre for testing concentrations of anti-rubella IgG.4 This cutoff was derived from expressing protective neutralising titres of therapeutic immunoglobulin treatments and antibody titres following wild-type virus infection relative to reference materials, which also incorporated epidemiological and anecdotal evidence.4 The relevance of this cutoff nowadays is uncertain, especially in countries with high rates of rubella vaccination where concentrations of anti-rubella IgG in the general population is low13 and results of less than 10 IU/mL are reported for a large proportion of vaccine recipients.14 Furthermore, enzyme immunoassays com monly used in diagnostic laboratories have different designs (ie, using different rubella antigens or signal detection chemistries) and these assays have been shown to report discrepant quantitative test results despite use of RUBI-1-94 as a common calibrator. Several clinical studies have shown inconsistent measurement of anti-rubella IgG antibodies, particularly in the crucial 5–30 IU/mL range in which a clinical decision to vaccinate or terminate pregnancy can be made.15–18 Variability in measurement highlights that the international standard is not a commutable standard when used to calibrate enzyme immunoassays of different design. Not only does assay design contribute to variability but anti-rubella IgG response is polyclonal and antibodies change as the immune response matures. Therefore, assays are detecting and quantifying multiple different antibodies in vaccinated populations, whereas the international standard is a pooled polyclonal antibody preparation developed when vaccination coverage was much lower. If quantitative measurements of anti-rubella IgG antibodies cannot be reliably compared, particularly at low concentrations that might be clinically actionable, then the international standard might not be appropiate to calibrate enzyme immunoassays. Within the clinical diagnostic community, some propose that clinically validated, robust qualitative tests be introduced to replace quantitative assays. Sensitivity and specificity of qualitative assays can be optimised, as has been achieved with anti-HIV and anti-HCV assays. Immunoblot-detecting antibodies to rubella-specific E1 antigens might be considered a potential reference method for confirmation of protective immunity.19,20 Within Europe, panels of anti-rubella negative serum samples are available from commercial suppliers. These tools might assist in-vitro diagnostic manufacturers and clinical diagnostic laboratories in assessing sensitivity and specificity of diagnostic assays. 2
From a clinical perspective, if a single reference antibody preparation is unable to provide robust calibration of different enzyme immunoassays for the measurement of antibodies, then additional materials are needed to validate the performance of diagnostic assays. The US Centers for Disease Control and Prevention uses a panel of 100 well characterised anti-rubella IgG sera, including positive, negative, and equivocally reactivity samples.21 However, continued availability of a well characterised common reference preparation for anti-rubella, such as RUBI-1-94, might be important for other tasks—eg, to assess analytical sensitivity of an assay or for calibrating secondary standards to assess batch-to-batch variation.
Recommendations agreed by WHO-ECBS WHO convened a consultation on June 30, 2017, bringing together parties with an interest in rubella virus serology: WHO collaborating centres in the field of in-vitro diagnostic standardisation, clinicians, regulators, and invitro diagnostic manufacturers. The main discussion point was the existing and future role of RUBI-1-94 in the standardisation and calibration of anti-rubella assays and in defining the immunity threshold. As a result of this consultation, recommendations were drafted and subsequently discussed at the meeting of WHO-ECBS in October 2017.22 The following recommendations were proposed by WHO-ECBS. First, WHO-ECBS agreed that RUBI-1-94 should continue to be made available as a well characterised reference material. Manufacturers, regulators, and assay users should be made aware of this lack of commutability and other limitations in the instructions for use. Second, stakeholders in the diagnostic field (eg, diagnostic expert committees, vaccine efficacy evaluators, and regulators) should be encouraged to reconsider the appropriateness of quantitative anti-rubella measurement for the determination of immune status and use of 10 IU/mL as a cutoff point for assessing immune protection. Existing evidence should be summarised and further studies in this field, if necessary, encouraged. Dependant on the conclusions of these considerations, revision of guidelines and regulatory requirements should be done. Finally, to establish the protection status of individuals, anti-rubella determination using highspecificity qualitative assays should be considered as an alternative approach to antibody quantitation. WHO-ECBS proposed that the outcomes of the consultation and final WHO-ECBS conclusions should be disseminated to technical and relevant clinical audiences. This publication is one attempt to follow this proposal. Calibration and standardisation of anti-rubella IgG assays have raised general questions regarding standard isation of serological assays: these challenges are not unique to rubella. Greater understanding is needed of the power and limitations of quantitative serological assays to measure polyclonal antibody samples. Raising awareness in the clinical diagnostic community will support accurate interpretation of data from serological
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
Personal View
assays and will inform clinical management for patients’ benefit.
9
Contributors SLK wrote the manuscript. NA and CMN contributed to the manuscript preparation and editing. JI contributed to the development of the ideas and conclusions of this manuscript and reviewed the manuscript for content. WD, LG-K, DH, JI, HSElM, and MNM commented on the manuscript.
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Declaration of interests We declare no competing interests. Acknowledgments We thank further participants of the consultation who contributed to these recommendations: K E Brown (Public Health England, London, UK), P Minor (National Institute for Biological Standards and Control, Hertfordshire, UK), S Nicholson (The Doherty Institute, Melbourne, VIC 3000, Australia), S Santibanez (Robert Koch-Institute, Berlin 13302, Germany), H Zeichhardt (Charité–University Medicine Berlin, Berlin, Germany), G Bouchard (bioMérieux Craponne, Craponne 69290, France), R Bollhagen (Roche Diagnostics GmbH, Mannheim 68305, Germany), J Serra (Biokit SA, Barcelona 08186, Spain), A Vockel (Abbott GmbH & Co KG, Wiesbaden 65205, Germany), M Ben Mamou (Vaccine-preventable Diseases and Immunization, WHO, DK-2100 Copenhagen, Denmark), and R Meurant (WHO Headquarters, Geneva, Switzerland). The findings and conclusions in this Personal View are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. References 1 WHO. Global and regional immunization profile. 2018. http://www.who.int/immunization/monitoring_surveillance/data/ gs_gloprofile.pdf?ua=1 (accessed Jan 19, 2018). 2 WHO. Global measles and rubella strategic plan: 2012–2020. https://apps.who.int/iris/bitstream/ handle/10665/44855/9789241503396_eng.pdf;sequence=1 (accessed Jan 30, 2018). 3 Orenstein WA, Hinman A, Nkowane B, Olive JM, Reingold A. Measles and rubella global strategic plan 2012–2020 midterm review. Vaccine 2018; 36: A1–34. 4 Skendzel LP. Rubella immunity. Defining the level of protective antibody. Am J Clin Pathol 1996; 106: 170–74. 5 Maton WG. Some account of a rash liable to be mistaken for scarlatina. Med Transact Coll 1815; 5: 149–65. 6 Gregg NM. Congenital cataract following German measles in the mother. Trans Ophtalmol Soc Aust 1941; 3: 35–46. 7 Parkman PD, Buescher EL, Artenstein MS. Recovery of rubella virus from army recruits. Proc Soc Exp Biol Med 1962; 111: 225–30. 8 Weller TH, Neva FA. Propagation in tissue culture of cytopathic agents from patients with rubella-like illness. Proc Soc Exp Biol Med 1962; 111: 215–25.
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National Institute for Communicable Disease Center. Rubella surveillance. Bethesda, MD: US Department of Health, Education, and Welfare, 1969. Neumann-Haefelin D, Neumann-Haefelin C, Petersen EE, Luthardt T, Hass R. [Passive immunization against rubella: studies on the effectiveness of rubella-immunoglobulin after intranasal infection with rubella vaccination virus]. Dtsch Med Wochenschr 1975; 100: 177–81 (in German). McDonald JC. Gamma-globulin for prevention of rubella in pregnancy. Br Med J 1963; 2: 416–18. Rawls WE, Melnick JL, Bradstreet CM, et al. WHO collaborative study on the sero-epidemiology of rubella. Bull World Health Organ 1967; 37: 79–88. Dimech W, Grangeot-Keros L, Vauloup-Fellous C. Standardization of assays that detect anti-rubella virus IgG antibodies. Clin Microbiol Rev 2016; 29: 163–74. Dimech W, Arachchi N, Cai J, Sahin T, Wilson K. Investigation into low-level anti-rubella virus IgG results reported by commercial immunoassays. Clin Vaccine Immunol 2013; 20: 255–61. Dimech W, Bettoli A, Eckert D, et al. Multicenter evaluation of five commercial rubella virus immunoglobulin G kits which report in international units per milliliter. J Clin Microbiol 1992; 30: 633–41. Dimech W, Panagiotopoulos L, Francis B, et al. Evaluation of eight anti-rubella virus immunoglobulin g immunoassays that report results in international units per milliliter. J Clin Microbiol 2008; 46: 1955–60. Francis BH, Thomas AK, McCarty CA. The impact of rubella immunization on the serological status of women of childbearing age: a retrospective longitudinal study in Melbourne, Australia. Am J Public Health 2003; 93: 1274–76. Bouthry E, Furione M, Huzly D, et al. Assessing immunity to rubella virus: a plea for standardization of IgG (immuno)assays. J Clin Microbiol 2016; 54: 1720–25. Huzly D, Hanselmann I, Neumann-Haefelin D, Panning M. Performance of 14 rubella IgG immunoassays on samples with low positive or negative haemagglutination inhibition results. J Clin Virol 2016; 74: 13–18. Picone O, Bouthry E, Bejaoui-Olhmann Y, et al. Determination of rubella virus-specific humoral and cell-mediated immunity in pregnant women with negative or equivocal rubella-specific IgG in routine screening. J Clin Virol 2019; 112: 27–33. Vauloup-Fellous C. Standardization of rubella immunoassays. J Clin Virol 2018; 102: 34–38. WHO. WHO Expert Committee on Biological Standardization: sixty-eigth report. 2018 http://apps.who.int/iris/bitstream/hand le/10665/272807/9789241210201-eng.pdf?ua=1&ua=1 (accessed Aug 9, 2019).
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
3
WHO international standard for anti-rubella: learning from its application Sarah L Kempster, Neil Almond, Wayne Dimech, Liliane Grangeot-Keros, Daniela Huzly, Joseph Icenogle, Haja Sittana El Mubarak, Mick N Mulders, C Micha Nübling
The WHO international standard for anti-rubella was first established in the 1960s when clinical diagnostics were in their infancy. Since the endorsement of the first international standard for anti-rubella IgG (RUBI-1-94), new rubella vaccines have been developed and global coverage of rubella vaccination has increased. Methods used to measure concentrations of anti-rubella IgG have also evolved to rapid, high-throughput binding assays, which have replaced often cumbersome and highly technical functional assays. During this timeframe, the protective concentration of antibody was set at 10 IU/mL by extrapolation of functional assay correlates; however, the subpopulation of antibodies within a polyclonal serum that confer protection remained undefined. Anti-rubella assays have variable formats, including antigens used, such that the same clinical sample tested on different assays can report different values with potentially devastating consequences, such as recommending to terminate pregnancy. WHO convened a meeting of experts in the rubella field to discuss the use of RUBI-1-94 and the potential future role of this international standard. The main conclusions of this meeting questioned the appropriateness of 10 IU/mL as the cutoff for protection and acknowledged the continuing role of RUBI-1-94 as a reference preparation to address analytical sensitivity and assay variation.
Introduction The Measles and Rubella Global Strategic Plan 2012–20 provides a blueprint for countries to work together towards a world without measles, rubella, and congenital rubella syndrome, with a target of rubella elimination in four WHO regions (Americas, Eastern Mediterranean, European, and Western Pacific regions) by 2020.2,3 Monitoring vaccine efficacy requires robust diagnostic assays that measure concentrations of anti-rubella IgG as an indicator of protection against infection or as evidence of previous exposure through infection or vaccination. Accurate comparative measurement of anti-rubella antibodies is supported through the physical reference standard (WHO international standard), established by the WHO Expert Committee on Biological Standardization (WHO-ECBS). WHO and other guidelines state that the protective concentration of anti-rubella antibodies in serum is 10 IU/mL.4 Since the endorsement of the first international standard for anti-rubella IgG (RUBI-1-94), new rubella vaccines have been developed and global coverage of rubella vaccination reached about 52% in 2017.1 Developments in design and application of tests measuring concentrations of anti-rubella antibodies have led to question whether the WHO international standard for anti-rubella remains appropriate and suitable as a universal calibrator for measurement of serological responses and, moreover, whether the limit of 10 IU/mL still represents the lower limit of protective immunity capable of preventing congenital rubella syndrome. These concerns raise the question as to whether RUBI-1-94 should continue to be used for assay calibration and, therefore, establishing the cutoff for these serological assays.
Background Rubella was first recognised as a distinct disease in 1815,5 with the association between maternal infection during
pregnancy and birth defects established in 1941.6 Rubella virus was subsequently isolated in culture in 19627,8 shortly before a severe rubella epidemic in the USA in 1964 that resulted in 2100 neonatal deaths, 11 250 therapeutic or spontaneous abortions, and 20 000 cases of congenital rubella syndrome.9 Antirubella γ-globulin was developed as a therapeutic treatment, before the availability of a vaccine, and was shown to provide protection when administered up to 3 days after experimental intranasal challenge.10,11 In 1965, WHO-ECBS recognised the need for an antirubella standard to estimate the potency of anti-rubella γ-globulin preparations and to standardise anti-rubella measurements. Two candidate standards were assessed in a worldwide collaborative study involving eight expert laboratories. In-vitro neutralisation assays were done in each laboratory to determine the anti-rubella titre of each preparation. A freeze-dried pool of human convalescent serum samples was selected to be established by WHOECBS.12 In 1968, a replacement standard was needed because of a loss of potency of the original preparation. In the second international collaborative study, five labora tories participated, and haemagglutination inhibition assays (HAI) as well as neutralisation assays were included in the analysis since HAI had become widely used because of their speed and simple methodology. The second international standard for anti-rubella IgG serum was established by WHO-ECBS in 1971. From the 1970s, enzyme immunoassays were increasingly used for anti-rubella IgG detection and eventually replaced other methods in most clinical serodiagnostic laboratories. By the time the third international collaborative study was done, in 1994, eight of 11 participants reported results obtained by enzyme immunoassays with other laboratories using HAIs or serum radial haemolysis. No laboratories participating in this third study used in-vitro neutralisation assays, and
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
Lancet Infect Dis 2019 Published Online September 6, 2019 http://dx.doi.org/10.1016/ S1473-3099(19)30274-9 National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK (S L Kempster PhD, N Almond PhD); National Serology Reference Laboratory, Fitzroy, VIC 3065, Australia (W Dimech MBA); Paul Brousse Hospital, Villejuif 94800, France (L Grangeot-Keros PhD); University Medical Center Freiburg, Freiburg 79104, Germany (D Huzly MD); Centers for Disease Control and Prevention, Division of Viral Diseases, GA 30329–4027, USA (J Icenogle PhD); The Food and Drug Administration, Silver Spring, MD 20993–0002, USA (H S El Mubarak PhD); WHO, Geneva 1211, Switzerland (M N Mulders PhD, C M Nübling PhD); and Paul-Ehrlich-Institute, Langen 63225, Germany (M N Mulders, C M Nübling) Correspondence to: Dr Sarah L Kempster, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire EN6 3QG, UK [email protected]
1
Personal View
although samples of the second international standard from 1968 were included in the study, the association had weakened between the new replacement WHO international standard (RUB-I-94) and neutralisation data from earlier studies. To prevent confusion, this new reference preparation was designated the 1st international standard for anti-rubella IgG. A cutoff value of 10 IU/mL has been assigned as the protective titre for testing concentrations of anti-rubella IgG.4 This cutoff was derived from expressing protective neutralising titres of therapeutic immunoglobulin treatments and antibody titres following wild-type virus infection relative to reference materials, which also incorporated epidemiological and anecdotal evidence.4 The relevance of this cutoff nowadays is uncertain, especially in countries with high rates of rubella vaccination where concentrations of anti-rubella IgG in the general population is low13 and results of less than 10 IU/mL are reported for a large proportion of vaccine recipients.14 Furthermore, enzyme immunoassays com monly used in diagnostic laboratories have different designs (ie, using different rubella antigens or signal detection chemistries) and these assays have been shown to report discrepant quantitative test results despite use of RUBI-1-94 as a common calibrator. Several clinical studies have shown inconsistent measurement of anti-rubella IgG antibodies, particularly in the crucial 5–30 IU/mL range in which a clinical decision to vaccinate or terminate pregnancy can be made.15–18 Variability in measurement highlights that the international standard is not a commutable standard when used to calibrate enzyme immunoassays of different design. Not only does assay design contribute to variability but anti-rubella IgG response is polyclonal and antibodies change as the immune response matures. Therefore, assays are detecting and quantifying multiple different antibodies in vaccinated populations, whereas the international standard is a pooled polyclonal antibody preparation developed when vaccination coverage was much lower. If quantitative measurements of anti-rubella IgG antibodies cannot be reliably compared, particularly at low concentrations that might be clinically actionable, then the international standard might not be appropiate to calibrate enzyme immunoassays. Within the clinical diagnostic community, some propose that clinically validated, robust qualitative tests be introduced to replace quantitative assays. Sensitivity and specificity of qualitative assays can be optimised, as has been achieved with anti-HIV and anti-HCV assays. Immunoblot-detecting antibodies to rubella-specific E1 antigens might be considered a potential reference method for confirmation of protective immunity.19,20 Within Europe, panels of anti-rubella negative serum samples are available from commercial suppliers. These tools might assist in-vitro diagnostic manufacturers and clinical diagnostic laboratories in assessing sensitivity and specificity of diagnostic assays. 2
From a clinical perspective, if a single reference antibody preparation is unable to provide robust calibration of different enzyme immunoassays for the measurement of antibodies, then additional materials are needed to validate the performance of diagnostic assays. The US Centers for Disease Control and Prevention uses a panel of 100 well characterised anti-rubella IgG sera, including positive, negative, and equivocally reactivity samples.21 However, continued availability of a well characterised common reference preparation for anti-rubella, such as RUBI-1-94, might be important for other tasks—eg, to assess analytical sensitivity of an assay or for calibrating secondary standards to assess batch-to-batch variation.
Recommendations agreed by WHO-ECBS WHO convened a consultation on June 30, 2017, bringing together parties with an interest in rubella virus serology: WHO collaborating centres in the field of in-vitro diagnostic standardisation, clinicians, regulators, and invitro diagnostic manufacturers. The main discussion point was the existing and future role of RUBI-1-94 in the standardisation and calibration of anti-rubella assays and in defining the immunity threshold. As a result of this consultation, recommendations were drafted and subsequently discussed at the meeting of WHO-ECBS in October 2017.22 The following recommendations were proposed by WHO-ECBS. First, WHO-ECBS agreed that RUBI-1-94 should continue to be made available as a well characterised reference material. Manufacturers, regulators, and assay users should be made aware of this lack of commutability and other limitations in the instructions for use. Second, stakeholders in the diagnostic field (eg, diagnostic expert committees, vaccine efficacy evaluators, and regulators) should be encouraged to reconsider the appropriateness of quantitative anti-rubella measurement for the determination of immune status and use of 10 IU/mL as a cutoff point for assessing immune protection. Existing evidence should be summarised and further studies in this field, if necessary, encouraged. Dependant on the conclusions of these considerations, revision of guidelines and regulatory requirements should be done. Finally, to establish the protection status of individuals, anti-rubella determination using highspecificity qualitative assays should be considered as an alternative approach to antibody quantitation. WHO-ECBS proposed that the outcomes of the consultation and final WHO-ECBS conclusions should be disseminated to technical and relevant clinical audiences. This publication is one attempt to follow this proposal. Calibration and standardisation of anti-rubella IgG assays have raised general questions regarding standard isation of serological assays: these challenges are not unique to rubella. Greater understanding is needed of the power and limitations of quantitative serological assays to measure polyclonal antibody samples. Raising awareness in the clinical diagnostic community will support accurate interpretation of data from serological
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
Personal View
assays and will inform clinical management for patients’ benefit.
9
Contributors SLK wrote the manuscript. NA and CMN contributed to the manuscript preparation and editing. JI contributed to the development of the ideas and conclusions of this manuscript and reviewed the manuscript for content. WD, LG-K, DH, JI, HSElM, and MNM commented on the manuscript.
10
Declaration of interests We declare no competing interests. Acknowledgments We thank further participants of the consultation who contributed to these recommendations: K E Brown (Public Health England, London, UK), P Minor (National Institute for Biological Standards and Control, Hertfordshire, UK), S Nicholson (The Doherty Institute, Melbourne, VIC 3000, Australia), S Santibanez (Robert Koch-Institute, Berlin 13302, Germany), H Zeichhardt (Charité–University Medicine Berlin, Berlin, Germany), G Bouchard (bioMérieux Craponne, Craponne 69290, France), R Bollhagen (Roche Diagnostics GmbH, Mannheim 68305, Germany), J Serra (Biokit SA, Barcelona 08186, Spain), A Vockel (Abbott GmbH & Co KG, Wiesbaden 65205, Germany), M Ben Mamou (Vaccine-preventable Diseases and Immunization, WHO, DK-2100 Copenhagen, Denmark), and R Meurant (WHO Headquarters, Geneva, Switzerland). The findings and conclusions in this Personal View are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. References 1 WHO. Global and regional immunization profile. 2018. http://www.who.int/immunization/monitoring_surveillance/data/ gs_gloprofile.pdf?ua=1 (accessed Jan 19, 2018). 2 WHO. Global measles and rubella strategic plan: 2012–2020. https://apps.who.int/iris/bitstream/ handle/10665/44855/9789241503396_eng.pdf;sequence=1 (accessed Jan 30, 2018). 3 Orenstein WA, Hinman A, Nkowane B, Olive JM, Reingold A. Measles and rubella global strategic plan 2012–2020 midterm review. Vaccine 2018; 36: A1–34. 4 Skendzel LP. Rubella immunity. Defining the level of protective antibody. Am J Clin Pathol 1996; 106: 170–74. 5 Maton WG. Some account of a rash liable to be mistaken for scarlatina. Med Transact Coll 1815; 5: 149–65. 6 Gregg NM. Congenital cataract following German measles in the mother. Trans Ophtalmol Soc Aust 1941; 3: 35–46. 7 Parkman PD, Buescher EL, Artenstein MS. Recovery of rubella virus from army recruits. Proc Soc Exp Biol Med 1962; 111: 225–30. 8 Weller TH, Neva FA. Propagation in tissue culture of cytopathic agents from patients with rubella-like illness. Proc Soc Exp Biol Med 1962; 111: 215–25.
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National Institute for Communicable Disease Center. Rubella surveillance. Bethesda, MD: US Department of Health, Education, and Welfare, 1969. Neumann-Haefelin D, Neumann-Haefelin C, Petersen EE, Luthardt T, Hass R. [Passive immunization against rubella: studies on the effectiveness of rubella-immunoglobulin after intranasal infection with rubella vaccination virus]. Dtsch Med Wochenschr 1975; 100: 177–81 (in German). McDonald JC. Gamma-globulin for prevention of rubella in pregnancy. Br Med J 1963; 2: 416–18. Rawls WE, Melnick JL, Bradstreet CM, et al. WHO collaborative study on the sero-epidemiology of rubella. Bull World Health Organ 1967; 37: 79–88. Dimech W, Grangeot-Keros L, Vauloup-Fellous C. Standardization of assays that detect anti-rubella virus IgG antibodies. Clin Microbiol Rev 2016; 29: 163–74. Dimech W, Arachchi N, Cai J, Sahin T, Wilson K. Investigation into low-level anti-rubella virus IgG results reported by commercial immunoassays. Clin Vaccine Immunol 2013; 20: 255–61. Dimech W, Bettoli A, Eckert D, et al. Multicenter evaluation of five commercial rubella virus immunoglobulin G kits which report in international units per milliliter. J Clin Microbiol 1992; 30: 633–41. Dimech W, Panagiotopoulos L, Francis B, et al. Evaluation of eight anti-rubella virus immunoglobulin g immunoassays that report results in international units per milliliter. J Clin Microbiol 2008; 46: 1955–60. Francis BH, Thomas AK, McCarty CA. The impact of rubella immunization on the serological status of women of childbearing age: a retrospective longitudinal study in Melbourne, Australia. Am J Public Health 2003; 93: 1274–76. Bouthry E, Furione M, Huzly D, et al. Assessing immunity to rubella virus: a plea for standardization of IgG (immuno)assays. J Clin Microbiol 2016; 54: 1720–25. Huzly D, Hanselmann I, Neumann-Haefelin D, Panning M. Performance of 14 rubella IgG immunoassays on samples with low positive or negative haemagglutination inhibition results. J Clin Virol 2016; 74: 13–18. Picone O, Bouthry E, Bejaoui-Olhmann Y, et al. Determination of rubella virus-specific humoral and cell-mediated immunity in pregnant women with negative or equivocal rubella-specific IgG in routine screening. J Clin Virol 2019; 112: 27–33. Vauloup-Fellous C. Standardization of rubella immunoassays. J Clin Virol 2018; 102: 34–38. WHO. WHO Expert Committee on Biological Standardization: sixty-eigth report. 2018 http://apps.who.int/iris/bitstream/hand le/10665/272807/9789241210201-eng.pdf?ua=1&ua=1 (accessed Aug 9, 2019).
www.thelancet.com/infection Published online September 6, 2019 http://dx.doi.org/10.1016/S1473-3099(19)30274-9
3