Two-Component Nanoparticle Vaccine Displaying Glycosylated Spike S1 Domain Induces Neutralizing Antibody Response against SARS-CoV-2 Variants

van Oosten, Linda; Altenburg, Jort J.; Fougeroux, Cyrielle; Geertsema, Corinne; van den End, Fred; Evers, Wendy A. C.; Westphal, Adrie H.; Lindhoud, Simon; van den Berg, Willy; Swarts, Daan C.; Deurhof, Laurens; Suhrbier, Andreas; Le, Thuy T.; Torres Morales, Shessy; Myeni, Sebenzile K.; Kikkert, Marjolein; Sander, Adam F.; de Jongh, Willem Adriaan; Dagil, Robert; Nielsen, Morten A.; Salanti, Ali; Søgaard, Max; Keijzer, Timo M. P.; Weijers, Dolf; Eppink, Michel H. M.; Wijffels, René H.; van Oers, Monique M.; Martens, Dirk E.; Pijlman, Gorben P.

Vaccines pave the way out of the SARS-CoV-2 pandemic. Besides mRNA and adenoviral vector vaccines, effective protein-based vaccines are needed for immunization against current and emerging variants. We have developed a virus-like particle (VLP)-based vaccine using the baculovirus-insect cell expression system, a robust production platform known for its scalability, low cost, and safety. Baculoviruses were constructed encoding SARS-CoV-2 spike proteins: full-length S, stabilized secreted S, or the S1 domain. Since subunit S only partially protected mice from SARS-CoV-2 challenge, we produced S1 for conjugation to bacteriophage AP205 VLP nanoparticles using tag/catcher technology. The S1 yield in an insect-cell bioreactor was ∼11 mg/liter, and authentic protein folding, efficient glycosylation, partial trimerization, and ACE2 receptor binding was confirmed. Prime-boost immunization of mice with 0.5 μg S1-VLPs showed potent neutralizing antibody responses against Wuhan and UK/B.1.1.7 SARS-CoV-2 variants. This two-component nanoparticle vaccine can now be further developed to help alleviate the burden of COVID-19.