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
View: Text | PDF
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

×

Figure 6

RBD-specific IgA+ B cells predominantly class switch from IgG+ B cells following IN sequential immunization.

Options: View larger image (or click on image) Download as PowerPoint
RBD-specific IgA+ B cells predominantly class switch from IgG+ B cells f...
(A) Splenocytes from C57BL/6J (n = 10) mice receiving 2 doses of IM vaccination were collected and sorted for the IgG+ and IgM+ B cells and CD4+ T cells, which were then adoptively transferred into Rag-1 mice (n = 8). A day later, the mice were intranasally administrated 10 μg IPRF. The dotted lines represent the endpoint of these ELISA tests. (B) RBD-specific IgA antibody response in sera of immunized Rag-1 mice was evaluated 14 days after vaccination by ELISA. (C) ELISPOT assay measured IgA+ B cells from splenocytes cocultured with RBD protein. (D and E) C57BL/6J mice (n = 30) received 10 μg IPRF via IM at day 0, followed by IN immunization with 10 μg IPRF on day 14 after prime. Nasal draining mandibular lymph nodes (DLN), nasal-associated lymphoid tissue (NALT), nasal turbinate (NT), and mediastinal lymph node (MLN) were harvested on days 0, 1, 3, 5, and 7 (each timepoint, n=6), and lymphocytes were collected. ELISPOT assessed IgG+ (D) or IgA+ (E) B cells from these lymphocytes. The data are presented as mean ± SEM. P values were determined by 1-way ANOVA with Tukey’s multiple comparisons test. *P < 0.05, ***P < 0.001, ****P < 0.0001. Individual data points are represented and pooled from 2 independent experiments.