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Viral replicative capacity, antigen availability via hematogenous spread, and high TFH:TFR ratios drive induction of potent neutralizing antibody responses


Eldi, P and Chaudhri, G and Nutt, SL and Newsome, TP and Karupiah, G, Viral replicative capacity, antigen availability via hematogenous spread, and high TFH:TFR ratios drive induction of potent neutralizing antibody responses, Journal of Virology, 93, (6) pp. 1-17. ISSN 0022-538X (2019) [Refereed Article]

Copyright Statement

Copyright 2019 American Society for Microbiology

DOI: doi:10.1128/JVI.01795-18


Live viral vaccines elicit protective, long-lived humoral immunity, but the underlying mechanisms through which this occurs are not fully elucidated. Generation of affinity matured, long-lived protective antibody responses involve close interactions between T follicular helper (TFH) cells, germinal center (GC) B cells, and T follicular regulatory (TFR) cells. We postulated that escalating concentrations of antigens from replicating viruses or live vaccines, spread through the hematogenous route, are essential for the induction and maintenance of long-lived protective antibody responses. Using replicating and poorly replicating or nonreplicating orthopox and influenza A viruses, we show that the magnitude of TFH cell, GC B cell, and neutralizing antibody responses is directly related to virus replicative capacity. Further, we have identified that both lymphoid and circulating TFH:TFR cell ratios during the peak GC response can be used as an early predictor of protective, long-lived antibody response induction. Finally, administration of poorly or nonreplicating viruses to allow hematogenous spread generates significantly stronger TFH:TFR ratios and robust TFH, GC B cell and neutralizing antibody responses.

Importance: Neutralizing antibody response is the best-known correlate of long-term protective immunity for most of the currently licensed clinically effective viral vaccines. However, the host immune and viral factors that are critical for the induction of robust and durable antiviral humoral immune responses are not well understood. Our study provides insight into the dynamics of key cellular mediators of germinal center reaction during live virus infections and the influence of viral replicative capacity on the magnitude of antiviral antibody response and effector function. The significance of our study lies in two key findings. First, the systemic spread of even poorly replicating or nonreplicating viruses to mimic the spread of antigens from replicating viruses due to escalating antigen concentration is fundamental to the induction of durable antibody responses. Second, the TFH:TFR ratio may be used as an early predictor of protective antiviral humoral immune responses long before memory responses are generated.

Item Details

Item Type:Refereed Article
Keywords:vaccination, neutralising antibody, viral infection, long-lived antibody responses
Research Division:Biomedical and Clinical Sciences
Research Group:Immunology
Research Field:Humoural immunology and immunochemistry
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Karupiah, G (Associate Professor Guna Karupiah)
ID Code:131548
Year Published:2019
Web of Science® Times Cited:2
Deposited By:Medicine
Deposited On:2019-03-22
Last Modified:2020-08-12

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