AddaVax, AddaS03, and Alum Effectively Enhance Cross-Reactive and Cross-Neutralizing Antibody Responses Against SARS-CoV-2 Induced by the Inactivated NDV-HXP-S Vaccine in Mice

<b>Background/Objectives</b>: We previously developed a low-cost vaccine based on Newcastle disease virus expressing a stabilized pre-fusion spike of SARS-CoV-2 (NDV-HXP-S), which has shown safety and immunogenicity in pre-clinical and clinical studies. Due to the emergence of immune-evasive variants and the need to protect vulnerable populations, we evaluated adjuvanted NDV-HXP-S vaccine formulations to enhance and broaden immune responses. <b>Methods</b>: We tested the antibody responses of mice immunized intramuscularly with an inactivated NDV-HXP-S vaccine adjuvanted with AddaVax, AddaS03, Alhydrogel adjuvant 2% (Alum), or Quil-A. <b>Results</b>: AddaVax, AddaS03, and Alum induced the strongest IgG responses to the ancestral spike protein, boosted cross-reactive antibodies against both S1 and S2 subunits, and elicited high cross-neutralizing titers. <b>Conclusions</b>: The present results highlight the critical role of adjuvant selection in shaping both the magnitude and breadth of the immune response induced by the NDV-HXP-S vaccine. AddaVax, AddaS03, and Alum stand out as promising candidates to enhance NDV-HXP-S vaccine immunogenicity, with potential applications in booster strategies against SARS-CoV-2, enabling dose sparing and reducing costs.