A novel nanoparticle vaccine, based on S1-CTD, elicits robust protective immune responses against porcine deltacoronavirus.

Porcine deltacoronavirus (PDCoV), an emerging swine pathogen causing severe enteric disease in piglets, poses cross-species transmission risks, including humans. The C-terminal domain (CTD) of its spike protein harbors a key receptor-binding region with antigenic specificity and cross-protective potential. Here, we developed a novel nanoparticle-based CTD vaccine (CTDnps) by conjugating PDCoV S1-CTD to bacteriophage AP205 capsids, leveraging subunit vaccine advantages in safety, scalability, and affordability, to address urgent needs for PDCoV control. Compared to the CTD monomer, the CTDnps vaccine induced a markedly faster antigen-specific IgG response and greater neutralizing antibody (NAb) titers in mice. In immunized sows, the CTDnps vaccine elicited sustained IgG and secretory IgA (sIgA) responses, with serum NAbs persisting up to 60 days post-farrowing at titers exceeding 1:64. Passive transfer of maternal antibodies to newborn piglets significantly reduced viral loads and clinical signs upon PDCoV challenge, whereas histopathological and immunohistochemical analyses confirmed reduced viral presence and intestinal damage in the CTDnps-vaccinated group. Furthermore, CTDnps enhanced dendritic cell antigen uptake and upregulated expression of major histocompatibility complex II and co-stimulatory molecules (CD80 and CD86) to activate humoral and cellular immunity. We concluded that the PDCoV S1-CTD nanoparticle vaccine has much potential for robust and prolonged PDCoV prevention. Finally, the formed nanoparticle platform has potentially broad applications for developing multivalent vaccines against diverse coronaviruses. IMPORTANCE: Although porcine deltacoronavirus (PDCoV) poses a potential threat to public health, effective vaccines against PDCoV remain lacking. Here, we developed a novel nanoparticle-based C-terminal domain vaccine (CTDnps) targeting the conserved S1-CTD domain of the PDCoV spike protein. Unlike traditional subunit vaccines, CTDnps displayed AP205 capsids to enhance antigen presentation, induced rapid and robust neutralizing antibodies in sows, and conferred passive immunity to piglets via maternal antibody transfer. Mechanistically, CTDnps promoted dendritic cell activation and cellular immunity by upregulating major histocompatibility complex II and co-stimulatory molecules, a feature absent in monomeric CTD vaccines. We not only established CTDnps as a potent PDCoV intervention, but also pioneered a scalable, fast platform adaptable to emerging or multivalent coronavirus vaccines. This study provided actionable strategies to mitigate PDCoV outbreaks and broader coronavirus threats.