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The mucosal immune response plays a crucial role in the prevention of respiratory viruses. Given the risk of recurrent SARS-CoV-2 infections in the population, the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount. In the current study, we developed a protein-based intranasal vaccine comprising the XBB.1.5 receptor binding domain (RBD)-derived trimeric recombinant protein (RBD XBB.1.5 -HR) and an MF59-like oil-in-water adjuvant. Intranasal administration of RBD XBB.1.5 -HR vaccine elicited robust and sustained humoral immune responses in mice and rats, resulting in high levels of neutralizing antibodies against XBB-lineage subvariants, with protection lasting for at least six months. The intranasal RBD XBB.1.5 -HR vaccine generated potent mucosal immune responses, characterized by the inductions of tissue-resident T (T RM ) cells, local cellular immunity, germinal center, and memory B cell responses in the respiratory tract. The combination of intramuscular and intranasal delivery of the RBD XBB.1.5 -HR vaccine demonstrated exceptional systemic and mucosal protective immunity. Furthermore, intranasal delivery of RBD XBB.1.5 -HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination, as evidenced by the induction of superior systemic and extra mucosal immune response. Importantly, the intranasal RBD XBB.1.5 -HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo. These findings identify the intranasal RBD XBB.1.5 -HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection., Competing Interests: Competing interests This work was supported by the WestVac Biopharma Co. Ltd. Jingyun Yang, Jiong Li, L.Y., Z.W., W.W., G.S., Jinliang Yang, Z.Z., G.L., and X.W. are also working at the WestVac Biopharma Co. Ltd. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Multiple vaccine platforms have been employed to develop the nasal SARS-CoV-2 vaccines in preclinical studies, and the dominating pipelines are viral vectored as protein-based vaccines. Among them, several viral vectored-based vaccines have entered clinical development. Nevertheless, some unsatisfactory results were reported in these clinical studies. In the face of such urgent situations, it is imperative to rapidly develop the next-generation intranasal COVID-19 vaccine utilizing other technologies. Nanobased intranasal vaccines have emerged as an approach against respiratory infectious diseases. Harnessing the power of nanotechnology, these vaccines offer a noninvasive yet potent defense against pathogens, including the threat of COVID-19. The improvements made in vaccine mucosal delivery technologies based on nanoparticles, such as lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles etc., not only provide stability and controlled release but also enhance mucosal adhesion, effectively overcoming the limitations of conventional vaccines. Hence, in this review, we overview the evaluation of intranasal vaccine and highlight the current barriers. Next, the modern delivery systems based on nanoplatforms are summarized. The challenges in clinical application of nanoplatform based intranasal vaccine are finally discussed.

The coronavirus disease 2019 (COVID‐19) pandemic can hardly end with the emergence of different variants over time. In the past 2 years, several variants of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), such as the Delta and Omicron variants, have emerged with higher transmissibility, immune evasion and drug resistance, leading to higher morbidity and mortality in the population. The prevalent variants of concern (VOCs) share several mutations on the spike that can affect virus characteristics, including transmissibility, antigenicity, and immune evasion. Increasing evidence has demonstrated that the neutralization capacity of sera from COVID‐19 convalescent or vaccinated individuals is decreased against SARS‐CoV‐2 variants. Moreover, the vaccine effectiveness of current COVID‐19 vaccines against SARS‐CoV‐2 VOCs is not as high as that against wild‐type SARS‐CoV‐2. Therefore, more attention might be paid to how the mutations impact vaccine effectiveness. In this review, we summarized the current studies on the mutations of the SARS‐CoV‐2 spike, particularly of the receptor binding domain, to elaborate on how the mutations impact the infectivity, transmissibility and immune evasion of the virus. The effects of mutations in the SARS‐CoV‐2 spike on the current therapeutics were highlighted, and potential strategies for future vaccine development were suggested. [ABSTRACT FROM AUTHOR]

The recently emerged Omicron (B.1.1.529) variant has rapidly surpassed Delta to become the predominant circulating SARS-CoV-2 variant, given the higher transmissibility rate and immune escape ability, resulting in breakthrough infections in vaccinated individuals. A new generation of SARS-CoV-2 vaccines targeting the Omicron variant are urgently needed. Here, we developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of RBD derived from the Delta variant (containing L452R and T478K) and HR1 and HR2 in SARS-CoV-2 S2 subunit in a tandem manner, which can self-assemble into a trimer. In multiple animal models, vaccination of RBD-HR/trimer formulated with MF59-like oil-in-water adjuvant elicited sustained humoral immune response with high levels of broad-spectrum neutralizing antibodies against Omicron variants, also inducing a strong T cell immune response in vivo. In addition, our RBD-HR/trimer vaccine showed a strong boosting effect against Omicron variants after two doses of mRNA vaccines, featuring its capacity to be used in a prime-boost regimen. In mice and non-human primates, RBD-HR/trimer vaccination could confer a complete protection against live virus challenge of Omicron and Delta variants. The results qualified RBD-HR/trimer vaccine as a promising next-generation vaccine candidate for prevention of SARS-CoV-2, which deserved further evaluation in clinical trials. The SARS-CoV-2 Omicron variant has quickly become the predominant circulating variant, due to the high transmissibility and immune escape. Here, the authors develop a trimeric protein vaccine candidate and show a sustained humoral immune response, and protection from challenge (Omicron and Delta) in various animal models. [ABSTRACT FROM AUTHOR]