Unveiling an Immunological Mystery: Deciphering the Durability Divide in Vaccine-Elicited Antibody Responses.

Achieving durable antibody-mediated protection remains critical in vaccine development, particularly for viral diseases like COVID-19 and HIV. We discuss factors influencing antibody 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 properties 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 antibodies; 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 importance of CD21 as a critical determinant of antibody durability. CD21 is a B cell antigen receptor (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 created equal. There is a four-log range of antibody secretion rates, and we propose epigenetic imprinting 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 stimulation. 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 microenvironment. 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.