Sequential intranasal booster triggers class switching from intramuscularly primed IgG to mucosal IgA against SARS-CoV-2
Yifan Lin, Xuejiao Liao, Xuezhi Cao, Zhaoyong Zhang, Xiuye Wang, Xiaomeng He, Huiping Liao, Bin Ju, Furong Qi, Hairong Xu, Zhenhua Ren, Yanqun Wang, Zhenxiang Hu, Jiaming Yang, Yang-Xin Fu, Jincun Zhao, Zheng Zhang, Hua Peng
Yifan Lin, Xuejiao Liao, Xuezhi Cao, Zhaoyong Zhang, Xiuye Wang, Xiaomeng He, Huiping Liao, Bin Ju, Furong Qi, Hairong Xu, Zhenhua Ren, Yanqun Wang, Zhenxiang Hu, Jiaming Yang, Yang-Xin Fu, Jincun Zhao, Zheng Zhang, Hua Peng
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Research Article Immunology

Sequential intranasal booster triggers class switching from intramuscularly primed IgG to mucosal IgA against SARS-CoV-2

Abstract

The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, IFN-armed SARS-CoV-2 fusion protein vaccine with IM priming and intranasal (IN) boost sequential immunization. Our study showed that this sequential vaccination strategy of the IM+IN significantly enhanced both upper respiratory and systemic antiviral immunity in a mouse model, characterized by the rapid increase in systemic and mucosal T and B cell responses, particularly the mucosal IgA antibody response. The IN boost triggered a swift secondary immune response, rapidly inducing antigen-specific IgA+ B cells. Further B cell receptor–seq (BCR-seq) analysis indicated that these IgA+ B cells primarily arose through direct class switching from preexisting IgG+ B cells in draining lymph nodes. Notably, our clinical studies revealed that the IN boost after IM vaccination elicited a robust systemic IgA antibody response in humans, as measured in serum. Thus, we believe that our cytokine-armed protein vaccine presents a promising strategy for inducing rapid and potent mucosal protection against respiratory viral infections.

Authors

Yifan Lin, Xuejiao Liao, Xuezhi Cao, Zhaoyong Zhang, Xiuye Wang, Xiaomeng He, Huiping Liao, Bin Ju, Furong Qi, Hairong Xu, Zhenhua Ren, Yanqun Wang, Zhenxiang Hu, Jiaming Yang, Yang-Xin Fu, Jincun Zhao, Zheng Zhang, Hua Peng

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Figure 4

An IN booster induces a rapid and robust secondary immune response upon IM priming.

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An IN booster induces a rapid and robust secondary immune response upon ...
(A) C57BL/6J mice (n = 10) were primed with 10 μg IPRF and boosted via IM or IN routes and subsequently boosted via either route. RBD-specific IgA antibody responses in sera were evaluated 7 days after boost by ELISA. The dotted lines represent the endpoint of these ELISA tests. (B–D) C57BL/6J mice were immunized with 10 μg IPRF or PBS via IM on day 0, followed by IN immunization with 10 μg IPRF on day 14 after prime. DLNs were harvested on days 0, 1, 3, 5, and 7 (each timepoint n = 10). ELISPOT assays assessed T cells, IgG+ or IgA+ B cells from mice DLN lymphocytes. The data are shown as mean ± SEM. P values were determined by 1-way ANOVA with Tukey’s multiple comparisons test. **P < 0.01, ****P < 0.0001. Individual data points are represented and were pooled from 2 or 3 independent experiments.