Rubella Serology: A Renewed Call to Action

To the Editor.—A recent letter to the editor entitled “Anti-Rubella Immunoglobulin G Proficiency Testing Results Suggest Consistent Manufacturer Differences and Opportunity for Harmonization”1 highlights the differences in the reporting of international units per milliliter by rubella immunoglobulin G (IgG) assays. This issue has been identified for about 30 years.2–5 Its history6 and cause7,8 have been well documented. Assays use different antigens, antibodies, and detection systems, and therefore do not detect the same measurand. Unlike inert, homogeneous chemistry markers such as glucose, infectious disease antibodies are heterogeneous, dependent on individual immune systems, the stage of infection, and the infecting agent genotype/serotype.7In 2015, the World Health Organization (WHO) and concerned virologists formed an international expert committee to address this situation, including the US Centers for Disease Control and Prevention and Food and Drug Administration; the German Paul-Ehrlich-Institute; the National Reference Laboratory, Australia; and the United Kingdom National Institute of Biological Standards and Control. Key outcomes9 included published reviews of the history of rubella standardization6 and the standardization of infectious disease assays.7 A panel of 100 rubella IgG–seronegative specimens was prepared by BioMex (Heidelberg, Germany).10 The international standard instructions for use11 had inserted a statement: “IVD manufacturers, regulators and assay users should be made aware of RUBI-1-94 potential lack of commutability when used as a calibrant. This was highlighted by the WHO Expert Committee on Biological Standardization (ECBS) in TRS 68th Report (Section 3.3.4: 2018).”12The expert committee recommended that “stakeholders in the diagnostic field should be encouraged to reconsider both the appropriateness of quantitative anti-rubella measurement for the determination of immune status and the use of 10 IU/ml as a cut-off point for assessing immune protection,”9,12 noting that the initial use of 10 IU/mL as a cutoff arose from an assay manufacturer’s claim in 1988.2 Picone et al13 subsequently demonstrated that individuals with rubella IgG results of less than 10 IU/mL have evidence of protective immunity, concluding that rubella IgG assay manufacturers should establish their own cutoffs. Several other papers have identified variable qualitative results between assays.5,14Little progress has been made since the publication of the WHO Expert Committee on Biological Standardization report in 2018.12 We know that mass vaccination leads to increased numbers of individuals with low-level reactivity.15,16 We know that vaccination hesitancy has led to increased numbers of susceptible individuals having no rubella IgG–specific antibodies,17 and we know that current quantitative assays do not differentiate low-level and negative samples well.5,14,18 There is a serious possibility of sporadic outbreaks of rubella infection, including congenital rubella syndrome, in countries previously rubella free. Without appropriate tools, this situation will be difficult to control.There has been more than 30 years of evidence that standardization of quantitative rubella IgG results has been ineffective. The baton has now been passed from the clinical virologists to regulators and assay manufacturers. It is time that manufacturers of rubella IgG assays be obliged to bring to market qualitative assays that clearly differentiate between the presence and absence of rubella-specific IgG.