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A proactive immune training strategy to generate anticipatory immunity against viral evasion
Shugang Qin1, Yuqin Teng2, Jinxiu Xin2
1Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China.
Introduction:
RNA viruses rapidly evolve to evade host immunity, posing a significant challenge to conventional vaccines. Natural infection, however, provides a blueprint for broad immunity by training the immune system against a diverse antigenic landscape. This study addresses the problem of creating a vaccine that mimics this complex training process.
Objectives:
We aimed to develop and validate a novel vaccination paradigm, "Proactive Immune Training" (PIT), designed to enhance cross-reactive neutralization breadth against variants within the predicted evolutionary space.
Methods:
Using SARS-CoV-2 as a model, we constructed a 600-mutant mRNA library (m-library) based on 30 predicted high-frequency mutation sites. This library was encapsulated in proprietary lipid nanoparticles (LNPs) to form the PIT vaccine. We then evaluated a sequential prime-boost regimen consisting of a single-antigen (SA) vaccine followed by a PIT boost (SA + PIT) in BALB/c mice, assessing humoral and cellular immunity, and performing deep sequencing of B-cell and T-cell receptor repertoires.
Results:
The SA + PIT regimen induced significantly broader and more potent neutralizing antibodies against a range of SARS-CoV-2 variants compared to conventional regimens. This enhanced protection was mechanistically linked to a profound diversification of the T-cell and B-cell receptor repertoires, a hallmark of superior immune adaptability.
Conclusion:
The PIT strategy successfully guides the immune system to generate a broad and adaptive immunological response. This proactive, training-based paradigm offers a powerful and versatile framework for developing next-generation vaccines against highly variable pathogens.
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