Lewis George K, Ciupe Stanca, Sajadi Mohammad
Division of Vaccine Research, Institute of Human Virology, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
Department of Mathematics, Virginia Polytechnic Institute and State University, 225 Stanger Street, Blacksburg, 24060, VA, United States.
Curr HIV Res. 2025 Jul 23. doi: 10.2174/011570162X366336250707084941.
Achieving durable antibody-mediated protection remains critical in vaccine develop-ment, particularly for viral diseases like COVID-19 and HIV. We discuss factors influencing an-tibody durability, highlighting the role of long-lived plasma cells (LLPCs) in the bone marrow, which are essential for sustained antibody production over many years. The frequencies and prop-erties of bone marrow LLPC are critical determinants of the broad spectrum of antibody durability for different vaccines. Vaccines for diseases like measles and mumps elicit long-lasting antibod-ies; those for COVID-19 and HIV do not. High epitope densities in the vaccine are known to favor antibody durability, but we discuss three underappreciated variables that also play a role in long-lived antibody responses. First, in addition to high epitope densities, we discuss the im-portance of CD21 as a critical determinant of antibody durability. CD21 is a B cell antigen recep-tor (BCR) complex component. It significantly affects BCR signaling strength in a way essential for generating LLPC in the bone marrow. Second, all antibody-secreting cells (ASC) are not cre-ated equal. There is a four-log range of antibody secretion rates, and we propose epigenetic im-printing of different rates on ASC, including LLPC, as a factor in antibody durability. Third, antibody durability afforded by bone marrow LLPC is independent of continuous antigenic stim-ulation. By contrast, tissue-resident T-bet+CD21low ASC also persists in secondary lymphoid tissues and continuously produces antibodies depending on persisting antigen and the tissue mi-croenvironment. We discuss these variables in the context of making an HIV vaccine that elicits broadly neutralizing antibodies against HIV that persist at protective levels without continuous vaccination over many years.
在疫苗研发中，实现持久的抗体介导保护仍然至关重要，尤其是对于像新冠病毒和艾滋病毒这样的病毒性疾病。我们讨论了影响抗体持久性的因素，强调了骨髓中长寿浆细胞（LLPCs）的作用，它们对于多年来持续产生抗体至关重要。骨髓LLPC的频率和特性是不同疫苗抗体持久性广泛谱的关键决定因素。麻疹和腮腺炎等疾病的疫苗能引发持久的抗体；而新冠病毒和艾滋病毒的疫苗则不能。已知疫苗中的高表位密度有利于抗体持久性，但我们讨论了三个未被充分认识的变量，它们在长寿抗体反应中也起作用。首先，除了高表位密度外，我们讨论了CD21作为抗体持久性关键决定因素的重要性。CD21是B细胞抗原受体（BCR）复合物的一个组成部分。它以一种对在骨髓中产生LLPC至关重要的方式显著影响BCR信号强度。其次，并非所有分泌抗体的细胞（ASC）都是相同的。抗体分泌率有四个对数范围，我们提出不同分泌率在包括LLPC在内的ASC上的表观遗传印记是抗体持久性的一个因素。第三，骨髓LLPC提供的抗体持久性与持续的抗原刺激无关。相比之下，组织驻留的T-bet+CD21low ASC也存在于二级淋巴组织中，并根据持续存在的抗原和组织微环境持续产生抗体。我们在研发一种能引发针对艾滋病毒的广泛中和抗体的艾滋病毒疫苗的背景下讨论这些变量，这些抗体在多年不进行持续接种的情况下仍能维持在保护水平。
