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A Platform Incorporating Trimeric Antigens into Self-Assembling Nanoparticles Reveals SARS-CoV-2-Spike Nanoparticles to Elicit Substantially Higher Neutralizing Responses than Spike Alone

By Baoshan Zhang, Cara W. Chao, Yaroslav Tsybovsky, Olubukola M. Abiona, Geoffrey B. Hutchinson, Juan I. Moliva, Adam S. Olia, Amarendra Pegu, Emily Phung, Guillaume Stewart-Jones, Raffaello Verardi, Lingshu Wang, Shuishu Wang, Anne Werner, Eun Sung Yang, Christina Yap, Tongqing Zhou, John R. Mascola, Nancy J. Sullivan, Barney S. Graham, Kizzmekia S. Corbett, Peter D. Kwong

Posted 12 Jun 2020
bioRxiv DOI: 10.1101/2020.06.11.147496

Antigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when an N- linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer – stabilized in the prefusion conformation and fused with SpyCatcher – could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with the SARS-CoV-2 spike-LuS nanoparticles elicited ~25-fold higher neutralizing responses, weight-per-weight relative to spike alone. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses. ### Competing Interest Statement K.S.C. and B.S.G. are inventors on International Patent Application No. WO/2018/081318 entitled "Prefusion Coronavirus Spike Proteins and Their Use." K.S.C., O.M.A., G.B.H., and B.S.G. are inventors on US Patent Application No. 62/972,886 entitled "2019-nCoV Vaccine".

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