Intranasal DC-targeting vaccine booster elicits durable and cross-clade protective immunity against sarbecoviruses in mice
Nicholas You Zhi Cheang, Wee Chee Yap, Kirsteen McInnes Tullett, Xinlei Qian, Peck Szee Tan, Kiren Purushotorman, Wan Yi Tan, Shirley Yun Yan Mah, Paul Anthony Macary, Chee Wah Tan, Mireille Hanna Lahoud, Sylvie Alonso
Nicholas You Zhi Cheang, Wee Chee Yap, Kirsteen McInnes Tullett, Xinlei Qian, Peck Szee Tan, Kiren Purushotorman, Wan Yi Tan, Shirley Yun Yan Mah, Paul Anthony Macary, Chee Wah Tan, Mireille Hanna Lahoud, Sylvie Alonso
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Research Article Immunology Infectious disease

Intranasal DC-targeting vaccine booster elicits durable and cross-clade protective immunity against sarbecoviruses in mice

Abstract

Short-lived, clade-specific immune responses with limited mucosal priming are limitations of current COVID-19 mRNA vaccines. We have developed a nasal booster vaccine candidate that induced robust, sustained, cross-clade, systemic, and mucosal protective immunity. Two recombinant Clec9A-specific monoclonal antibodies fused to the receptor binding domain (RBD) from Omicron XBB.1.5 and SARS-CoV-1 were generated. In Comirnaty mRNA–vaccinated mice, boosting with both constructs combined (Clec9AOMNI) induced cross-clade neutralizing antibodies and T cell responses that were greater in magnitude and more sustained compared with bivalent Comirnaty (BC) mRNA vaccine booster. Persistence of RBD-specific follicular helper CD4+ T cells, germinal center B cells, and long-lived plasma cells that facilitated affinity maturation correlated with detection of triple cross-reactive B cells binding the RBDs of ancestral SARS-CoV-2, XBB.1.5, and SARS-CoV-1. Remarkably, intranasal boosting with Clec9AOMNI elicited robust and durable immunity across the upper and lower airways while concurrently boosting the systemic immunity to levels matching or exceeding those from systemic boosting. Correspondingly, Clec9AOMNI nasal booster conferred superior protection against SARS-CoV-2 challenge compared with BC mRNA booster, with undetectable viral titers in the respiratory tract. Hence, Clec9AOMNI is a promising nasal booster vaccine candidate that has the potential to mitigate pandemic threats from emerging sarbecoviruses.

Authors

Nicholas You Zhi Cheang, Wee Chee Yap, Kirsteen McInnes Tullett, Xinlei Qian, Peck Szee Tan, Kiren Purushotorman, Wan Yi Tan, Shirley Yun Yan Mah, Paul Anthony Macary, Chee Wah Tan, Mireille Hanna Lahoud, Sylvie Alonso

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Figure 8

Protective efficacy of Clec9AOMNI nasal booster versus BC mRNA vaccine systemic booster.

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Protective efficacy of Clec9AOMNI nasal booster versus BC mRNA vaccine s...
(A) The 5- to six-week-old BALB/c mice were immunized with original Comirnaty mRNA vaccine as described in Figure 1. At 3 months after the second immunization dose, mice were boosted with either BC mRNA vaccine (0.05 μg; i.m.) or Clec9AOMNI (4 μg Clec9AXBB + 1 μg Clec9ACoV1 adjuvanted with 50 μg poly I:C; i.n.). Mice were challenged with Omicron BA.1 virus (106 PFU; i.n.) at 1 and 6 months after boost. At 2 dpi, lungs were harvested and homogenized. (B) BA.1 viral titers in the lung homogenates were quantified via plaque assay. (C) The 5- to six-week-old BALB/c mice were immunized as described in A. Mice were challenged with MA10 SARS-CoV-2 virus (106 PFU; i.n.) at 1 and 6 months after boost. At 2 dpi, the lung and nasal tissues were harvested and homogenized. (D and E) MA10 viral titers in the lung (D) and nasal (E) tissue homogenates were quantified via plaque assay. Data in B, D, and E are from 1 representative experiment performed twice with similar results; n = 4–5 per group/experiment. Symbols represent individual animals, and data shown are means. Statistical analysis: nonparametric 2-tailed Kruskal-Wallis test with Dunn’s multiple-comparison test. *P < 0.05.