Anti‐rubella <scp>IgG</scp> serum levels predict risk for <scp>SARS</scp>‐<scp>CoV</scp>‐2 breakthrough infections
Authors: Moritz M. Hollstein, Sascha Dierks, Michael P. Schön, Uwe Groß, Karin Thiele, Andreas Leha, Andreas E. Zautner, Andreas Fischer, Luise Erpenbeck, Moritz Schnelle
Journal: Allergy (2024)

SARS-CoV-2 breakthrough infections among vaccinated individuals are common.1 The identification of people at risk for such breakthrough infections remains challenging.2 In this regard, age and preexisting comorbidities have been shown to significantly influence the risk for SARS-CoV-2 breakthrough infections.3 Immunological factors have long been recognized to play a central role in the prevention of viral infections; however, we were unable to predict SARS-CoV-2 breakthrough infections in the extensively studied CoV-ADAPT cohort using a machine learning approach based on SARS-CoV-2-specific, longitudinal, immunological data from different time points prior to infection.4 Recently, low anti-rubella IgG titers were shown to be associated with low SARS-CoV-2 anti-RBD IgG responses following vaccination with BNT162b2.5 Hence, the aim of this study was to investigate whether lower anti-rubella IgG serum levels predispose for SARS-CoV-2 breakthrough infections and add predictive value. This study was carried out using serum material from the well-defined CoV-ADAPT cohort.4, 6, 7 The inclusion criteria were described previously.6 Anti-rubella IgG levels were measured in a total of 234 samples—collected from 134 participants prior to a potential SARS-CoV-2 breakthrough infection (Table S1)—from T1 (<2 weeks before the second SARS-CoV-2 vaccination) and T3 (3–7 months after the second vaccination) using the Rubella IgG assay (Abbott Laboratories, Abbott Park, USA) on the Architect i2000SR (Abbott Laboratories). Measurements were then linked to the respective breakthrough status at later stages between T3 and T4 (3–7 months after the third vaccination). Details regarding the study design (Figure S1) and statistical analyses can be found in the Supplementary Material—Data S1. The CoV-ADAPT study was approved by the local ethics committee (21/5/21) and was registered with the German Clinical Trials Register (DRKS00026029). All participants provided written informed consent. At T1, 52 samples belonged to individuals with later SARS-CoV-2 breakthrough infection versus 63 without. At T3, these numbers were 50 versus 69, respectively. It must be noted that breakthrough infections were not subclassified according to the SARS-CoV-2 variants of concern; however, as previously reported, infections in the CoV-ADAPT cohort could predominantly be attributed to the omicron variants BA.1 and BA.2.4 The measurements demonstrated significantly lower anti-rubella IgG levels in subjects who experienced a SARS-CoV-2 breakthrough infection afterwards as compared to those who remained infection-free at both investigated time points T1 (mean ± SD: 45 ± 47 vs. 65 ± 59 IU/mL; p = .019) and T3 (49 ± 53 vs. 61 ± 46 IU/mL; p = .013) (Figure 1). Separate analyses for the different vaccination regimes can be found in Figure S2. In the next step, we assessed whether SARS-CoV-2 breakthrough infections could be predicted based on the prior anti-rubella IgGs. Indeed, the odds of breakthrough infections predicted from a logistic regression model using the anti-rubella IgG levels at T1 and T3 were significantly lower with increasing anti-rubella IgGs at both T1 (OR: 0.75; p = .019) and T3 (OR: 0.77; p = .037) (Figure 2A,B). Thus, individuals with lower anti-rubella IgG serum levels have an increased risk and are more susceptible to later SARS-CoV-2 breakthrough infections. In fact, anti-rubella IgGs could be shown to add relevant information for predicting such infections. These results extend an earlier observation of an association between low anti-rubella IgG levels and weak humoral immune responses following SARS-CoV-2 vaccination to a possible functional relationship.5 Our findings have several important clinical implications. Assessment of the anti-rubella IgG serum levels may help to identify individuals in need for an additional SARS-CoV-2 vaccination. It may even be speculated that they serve as a broader indicator of vaccine efficacy against infections beyond SARS-CoV-2. As rubella vaccinations are usually administered at a young age only, they may be a good surrogate for a general responsiveness of the immune system. Our data suggest that vaccination response patterns show clinically relevant differences in otherwise healthy individuals and ultimately determine the vaccination success. Therefore, finding an easy-to-obtain parameter indicating anti-viral and/or anti-bacterial vaccine efficacy would be a considerable asset to the public health system, and it is conceivable that anti-rubella IgG has great potential in this regard. This could contribute to the larger goal of personalized prevention strategies. M.M.H., L.E. and M.S. designed the study with input from S.D., M.P.S., U.G., A.E.Z. and A.F. S.D. and K.T. carried out the measurements and collected data. A.L. performed statistical analyses. S.D., A.L. and M.S. extracted and compiled data. M.M.H., S.D., M.P.S., U.G., K.T., A.L., A.E.Z., A.F., L.E. and M.S. discussed and interpreted data. M.M.H., S.D., L.E. and M.S. drafted the manuscript. All authors jointly discussed, reviewed and approved the final version of the manuscript. This work was supported by the German Research Foundation Deutsche Forschungsgemeinschaft (DFG), grant number ER723/3-1 (to LE) as well as the TRR332 (to LE). Open Access funding enabled and organized by Projekt DEAL. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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