Multifaceted Effects of Antigen Valency on B Cell Response Composition and Differentiation In Vivo

Abstract

How antigen valency affects B cells in vivo during immune responses is not well understood. Here, using HIV immunogens with defined valencies ranging from 1 to 60, we investigated the role of antigen valency during different phases of B cell responses in vivo . Highly multimerized immunogens preferentially rapidly activated cognate B cells, with little affinity discrimination. This led to strong early induction of the transcription factors IRF4 (interferon regulatory factor 4) and Bcl6, driving both early extrafollicular plasma cell and germinal center responses, in a CD4 + T-cell-dependent manner, involving B cells with a broad range of affinities. Low-valency antigens induced smaller effector B cell responses, with preferential recruitment of high-affinity B cells. Thus, antigen valency has multifaceted effects on B cell responses and can dictate affinity thresholds and competitive landscapes for B cells in vivo , with implications for vaccine design.

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates

“…First, the quantity of the polyclonal antibody response may surpass a threshold that overcomes resistance to neutralization of antigenically distinct virus variants. Second, repetitive, ordered display of antigen on a selfassembling nanoparticle has been shown to drive an expanded germinal center reaction with resultant increases in B cell receptor mutation, affinity maturation and plasma cell differentiation (6)(7)(8). Lastly, the adjuvant, ALFQ, may drive some of the breadth through CD4 T cell activation (49,50), especially given the high Th1 response elicited by the co-formulation.…”

“…Self-assembling protein nanoparticle vaccines offer the advantage of multivalent antigen presentation, a property previously shown to augment immunogenicity over monovalent immunogens (6)(7)(8). Ferritin is a naturally occurring, ubiquitous, iron-carrying protein that selfoligomerizes into a 24-unit spherical particle (9).…”

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

“…One strategy that has garnered increasing interest is multivalent antigen display. Presenting immunogens in a repetitive array on submicron particles have been shown to enhance critical immunological processes such as lymph node trafficking and B cell activation, leading to significantly increased neutralizing responses 16 – 18 . However, compared to the successes of particulate antigen display for RSV, HPV, and influenza 19 – 21 , the improvements to HIV-1 Env immunogenicity have been relatively modest 22 .…”

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

“…In animal studies, stalk immunogens have been shown to elicit heterosubtypic humoral immunity that is broadly protective against unmatched Group 1 and Group 2 IAV challenges, including against avian H5N1 and H7N9 strains [ 86 , 167 , 168 , 169 , 170 ]. For most of these immunogens, structure-guided design was applied to array the trimeric stalk-only domains on a self-associating nanoparticle display [ 168 , 169 , 171 ], an antibody-titer enhancing principle that increases antigen immunogenicity through a combination of elevated BCR crosslinking, increased deposition on antigen-presenting follicular dendritic cells, and enhanced recruitment of B cell clones to GCs [ 174 , 175 ]. Enhanced germline activation through a repetitive antigen array may be particularly important for eliciting Pan-Group 1 and Pan-Group 1/Group 2 immunity in humans, as these stalk bnAbs tend to arise from low-affinity germline BCRs [ 85 , 86 , 169 , 176 , 177 ].…”