Current Status and Challenges of Vaccine Development for Seasonal Human Coronaviruses.

Seasonal human coronaviruses (HCoVs), including HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, circulate globally in an epidemic pattern and account for a substantial proportion of common cold cases, particularly in infants, the elderly, and immunocompromised individuals. Although clinical manifestations are typically mild, these HCoVs exhibit ongoing antigenic drift and have demonstrated the potential to cause severe diseases in certain populations, underscoring the importance of developing targeted and broad-spectrum vaccines. This review systematically examines the pathogenesis, epidemiology, genomic architecture, and major antigenic determinants of seasonal HCoVs, highlighting key differences in receptor usage and the roles of structural proteins in modulating viral tropism and host immunity. We summarize recent advances across various vaccine platforms, including inactivated, DNA, mRNA, subunit, viral-vectored, and virus-like particle (VLP) approaches, in the development of seasonal HCoV vaccines. We specifically summarize preclinical and clinical findings demonstrating variable cross-reactivity between SARS-CoV-2 and seasonal HCoV vaccines. Evidence indicates that cross-reactive humoral and cellular immune responses following SARS-CoV-2 infection or vaccination predominantly target conserved epitopes of structural proteins, supporting strategies that incorporate conserved regions to achieve broad-spectrum protection. Finally, we discuss current challenges in pathogenesis research and vaccine development for seasonal HCoVs. We propose future directions for the development of innovative pan-coronavirus vaccines that integrate both humoral and cellular antigens, aiming to protect vulnerable populations and mitigate future zoonotic spillover threats.