Dear Colleagues, 

The emergence and global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been estimated to have led to the infection of over a half billion people and caused over 6 million deaths. SARS-CoV-2 infection primarily depends on the interaction of its spike protein with the host cell receptor ACE2. SARS-CoV-2 spike protein is a class I fusion transmembrane glycoprotein composed of S1 and S2 subunits. The S1 subunit contains an N-terminal domain (NTD) with unclear function, and a receptor-binding domain (RBD) which binds to ACE2. The S2 subunit includes the fusion peptides Heptad repeat 1 and 2, and it directly mediates viral fusion and host entry after cleavage by host proteases such as TMPRSS2 and furin. These facts clearly demonstrate the critical roles of SARS-CoV-2 spike protein in virus pathogenesis and transmission, making it an important target for developing therapeutics and vaccines. 

SARS-CoV-2 spike-based vaccines have been proven a huge success in eliciting protective humoral and cellular immunity and mitigating the disease. Other spike-targeting therapies including natural products, antiviral peptides, natural lectins, monoclonal neutralizing antibodies, and convalescent plasmas have also been developed, and some of them are effective in clinics. However, mutations do occur within the spike region, leading to improved transmissibility and/or enhanced ability to evade anti-viral therapies of SARS-CoV-2. Since it first began circulating, the WHO has identified five variants of concern: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529). Omicron has further emerged into BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/5 subvariants, which have displayed further immune escape, compromising current vaccine and antibody effectiveness. 

The fact that SARS-CoV-2 continues to evolve ignites concerns about future emerging variants. Improving our understanding the spike protein, including its structural features, pathogenesis, receptor binding patterns, mutations, and immunogenicity, has become a pressing need for better vaccine design and therapeutic strategies. Based on your expertise in this field, we are pleased to invite you to contribute to this Special Issue with original research articles and reviews focusing on, but not limited to, the following aspects: 

• Studies that broaden our current understandings of spike protein’s roles in SARS-CoV-2 pathogenesis.
• Insights into host humoral and cellular responses against spike proteins.
• Novel approaches for spike mutation predictions and mechanisms of immune evasion.
• Exploration of next-generation vaccine, pan-beta coronavirus vaccine, pan-human endemic coronavirus vaccine developments and potential anti-COVID therapies.
• Interdisciplinary technologies or platforms to accelerate the development of new anti-COVID therapies. 

We look forward to receiving your contributions. 

Best regards,
Dr. Hanzhong Ke
Dr. Zhaoqi Yan
Guest Editors

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• SARS-CoV-2
• COVID-19
• spike
• pathogenesis
• variants
• immunogenicity
• vaccines
• therapies