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Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring., (© 2022. The Author(s).)

Enhancing the germinal center (GC) reaction is a prime objective in vaccine development. Targeting of antigen to MHCII on APCs has previously been shown to increase antibody responses, but the underlying mechanism has been unclear. We have here investigated the GC reaction after targeting antigen to MHCII in (i) a defined model with T and B cells of known specificity using adjuvant-free vaccine proteins, and (ii) an infectious disease model using a DNA vaccine. MHCII-targeting enhanced presentation of peptide: MHCII on APCs, and increased the numbers of GC B cells, T FH , and plasma cells. Antibodies appeared earlier and levels were increased. BCR of GC B cells and serum antibodies had increased avidity for antigen. The improved responses required cross-linking of BCR and MHCII in either cis or trans . The enhanced GC reaction induced by MHCII-targeting of antigen has clear implications for design of more efficient subunit vaccines., Competing Interests: B.B. and G.G. are inventors on (1) patents (B.B.) and (2) patent applications (G.G., B.B.) on the described vaccine molecules, filed by the TTO office of the University of Oslo and Oslo University Hospital, according to institutional rules. (1) Patent applicant: Inven2/Vaccibody AS. Inventors: Bjarne Bogen, Agnete B. Fredriksen, Inger Sandlie. Application number: European patent No. 1599504. Status of Application: granted in EU and the US. Specific aspect of manuscript covered in patent Application: Homodimeric modular constructs targeting antigens to antigen presenting cells. (2) Patent applicant: Inven2. Inventors: Bjarne Bogen, Gunnveig Grødeland, Agnete B. Fredriksen. Application number: WO2017/221072. Status of Application: National Phase from Dec 20, 2018. Specific aspect of manuscript covered in patent Application: A human version of the MHCII-specific targeting moiety. BB is head of the Scientific panel of Vaccibody AS, and holds shares in the company.