Abstract
T follicular helper (TFH) cells are powerful regulators of affinity matured long-lived plasma cells. Eliciting protective, long-lasting antibody responses to achieve persistent immunity is the goal of most successful vaccines. Thus, there is potential in manipulating TFH cell responses. Herein, we describe an HIV vaccine development approach exploiting the cytokine activin A to improve antibody responses against recombinant HIV Envelope (Env) trimers in non-human primates. Administration of activin A improved the magnitude of Env-specific antibodies over time and promoted a significant increase in Env-specific plasma cells in the bone marrow. The boost in antibody responses was associated with reduced frequencies of T follicular regulatory (TFR) cells and increased germinal center T follicular helper (GC-TFH) to TFR cell ratios. Overall, these findings suggest that adjuvants inducing activin A production could potentially be incorporated in future rational design vaccine strategies aimed at improving germinal centers, long-lived plasma cells, and sustained antibody responses.
Highlights
Over 30 million people are currently living with HIV, and developing a protective vaccine for HIV is still a global health priority [1]
In line with the importance of T follicular helper (TFH) cells in modulating affinity-matured Ab responses, highly functional blood TFH cells have been found by us and others to correlate with broadly neutralizing Abs (bnAbs) generation in HIV infected people [21, 22]
TFH cells limit the magnitude of germinal center (GC) reactions, and fostering TFH responses might influence the extent of somatic hypermutation as well as the recruitment of rare precursor of neutralizing Abs (nAbs) into the GC [5]
Summary
Over 30 million people are currently living with HIV, and developing a protective vaccine for HIV is still a global health priority [1]. The goal of generating bnAbs by immunization is an unprecedented challenge due to many reasons, including the high level of somatic hypermutation present in most bnAbs and the Activin A’s Regulation of Antibody Responses to HIV immunodominance of non-neutralizing epitopes in HIV envelope trimers [2, 5]. To circumvent these obstacles, multiple approaches aimed at focusing B cell responses on neutralizing epitopes and fostering somatic hypermutation will likely be required [3, 6]. The finding that this protection is lost as nAbs progressively wane over time [7] highlights the need for identifying approaches to improve the longevity of vaccine-elicited nAbs
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