Journal of Vaccine Research 2024, Vol.14, No.5, 217-230 http://medscipublisher.com/index.php/jvr 219 2.3 Challenges encountered in the early development of multi-pathogen vaccines The early development of multi-pathogen vaccines was fraught with challenges. One of the primary hurdles was ensuring that combining antigens from multiple pathogens would not reduce the immune response to any single pathogen, a phenomenon known as immune interference. This was particularly evident in early trials of combination vaccines, where concerns about reduced efficacy led to significant delays in development (Malfertheiner et al., 2018). Another challenge was the increased complexity of manufacturing multi-pathogen vaccines, which required the integration of different types of pathogens, proteins, or genetic material into a single vaccine. This complexity often resulted in stability issues and difficulty in maintaining consistent immune responses across all targeted pathogens. Additionally, safety concerns arose, as combining vaccines increased the potential for adverse reactions or side effects, which necessitated extensive testing and regulatory oversight (Baden et al., 2020). Despite these challenges, the progress in multi-pathogen vaccines has been significant. Modern advances in immunology, molecular biology, and vaccine technologies have addressed many of these early obstacles, paving the way for safer and more effective vaccines. However, the continued development of these vaccines must remain vigilant to both immunological and logistical complexities to ensure their global applicability and success. 3 Biology and Immunological Basis of Multi-Pathogen Vaccines 3.1 Overview of the immune response The immune response is the body's defense mechanism against pathogens, initiated through innate and adaptive immune pathways (Figure 2) (Xu et al., 2020; Xu and Li, 2024). Upon encountering an infectious agent, innate immune cells such as macrophages and dendritic cells identify pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). This leads to the activation of innate immune responses, including the release of cytokines and chemokines, which create an inflammatory environment that helps recruit immune cells to the site of infection. In parallel, antigen-presenting cells (APCs) process and present antigens to T cells, activating the adaptive immune system (Lacaille-Dubois, 2019). Figure 2 In Vitro Transcription Process of mRNA Vaccines and Their Activation Mechanism in Innate Immunity (Adapted from Xu et al., 2020) Image caption: After entering the cytoplasm through endocytosis, mRNA vaccines are recognized by various pattern recognition receptors (PRRs). Toll-like receptors (TLR7 and TLR8) recognize single-stranded RNA (ssRNA), while TLR3, cytoplasmic protein kinase R (PKR), and retinoic acid-inducible gene I (RIG-I) recognize double-stranded RNA (dsRNA). These recognition events activate antigen-presenting cells (APCs), leading to the secretion of type I interferon (IFN) and pro-inflammatory cytokines, which subsequently initiate an immune response (Adapted from Xu et al., 2020)
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