Sequential intranasal booster triggers class switching from intramuscularly primed IgG to mucosal IgA against SARS-CoV-2
Yifan Lin, … , Zheng Zhang, Hua Peng
Yifan Lin, … , Zheng Zhang, Hua Peng
Published January 14, 2025
Citation Information: J Clin Invest. 2025;135(5):e175233. https://doi.org/10.1172/JCI175233.
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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 3

IN sequential immunization protects against COVID-19–like disease.

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IN sequential immunization protects against COVID-19–like disease. (A) K...
(A) K18-hACE2 transgene mice (n = 10) were IM immunized with 10 μg IPRF or PBS on days 0 and boosted with 10 μg IPRF via IM or IN Mice were challenged with SARS-CoV-2 (Wuhan/WIV04/2019) on day 16 after boost. Five mice from each group were euthanized 2 days after challenge, while for the remaining 5 mice in each group, oral swabs were collected on days 1 and 4, then mice were euthanized 4 days after challenge. The lung tissues were collected for histological assessment 4 days after infection. Viral RNA copies in the lung and nasal turbinate tissue of each mouse were determined by qRT-PCR and plotted as log10 copies per mL. (B) Weight loss of PBS, IM+IM, or IM+IN mice was recorded from days 1-to-4 after infection. The dotted lines represent the no change of weight. (C and D) Infectious virus titers in lung and nasal turbinate tissues were measured on days 2 and 4 after infection. (E) Viral titers from oropharyngeal swabs were assessed on day 1 and 4 after infection. The dotted lines represent the measurement values obtained from the ddH2O wells. (F) Representative H&E staining results from uninfected, PBS, IM+IM, or IM+IN mice. Scale bar: 100μm. The data are presented as mean ± SEM. P values were determined by 1-way ANOVA with Tukey’s multiple comparisons test. **P < 0.01, ***P < 0.001, ****P < 0.0001.