Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination

Abstract

Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higheraffinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency.vaccination kinetics | antigen retention | humoral response | computational immunology | germinal center formation S ubunit vaccines based on recombinant protein antigens combined with adjuvants can safely elicit protective humoral immune responses in humans, and they have become a cornerstone of modern public health (1, 2). Recent advances in structure-based vaccine design (3, 4) and progress in the development of adjuvants that are safe and effective for prophylactic vaccines (5) have helped drive the field. However, several challenges remain: A number of protein vaccines, such as candidate vaccines against HIV and malaria, have tended to elicit short-lived immunity (6, 7). In HIV, broadly neutralizing antibodies (BNAbs) isolated from infected patients are generally characterized by high degrees of somatic hypermutation (SHM) (8), but methods to generate such highly mutated antibodies by vaccination remain unknown. SHM occurs in germinal centers (GCs) within lymphoid organs, and data from animal models demonstrate a critical role for follicular helper T cells in the induction of GCs and promotion of affinity maturation (9, 10). To date, methods to promote Tfh generation and long-lived germinal centers during vaccination remain unclear (11-15). Much attention has focused on the use of adjuvants to promote affinity maturation, but it remains unclear if adjuvants alone can provide the necessary immunological driving forces for promoting extensive affinity maturation (16).During acute infections, which often provoke robust germinal center responses and durable humoral immunity, microorganism replication typically occurs over the course of one to several weeks (17-19). During this time, recognition of molecular danger signals contained within the pathogen sustains stimulation of the innate immune system, and a continuous supply of antigen is provided to the adaptive immune system. In contrast to these patterns of antigen and inflammatory cues during infection, typical subunit vaccines...

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches

“…Third, extended antigen availability, preferably with increased dose kinetics, mimics conditions found in natural infection and is therefore the scenario for which GCs are naturally optimized. Encouraging data in support of these ideas were obtained in mice (Hu et al., 2015, Tam et al., 2016). …”

Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer

“…A third mechanism by which B cells with neutralizing specificities could be favored may be minimizing presentation of non-neutralizing epitopes. To this end, designs to stabilize Env trimers (de Taeye et al, 2015; Guenaga et al, 2016) or protect the immunogen via slow release mechanisms (Hu et al, 2015; Tam et al, 2016) are of interest. One potential metric for assessing the relative neutralizing and non-neutralizing Ab responses is the BG505-specific:V3-specific IgG ratio.…”

mRNA vaccines — a new era in vaccinology

“…These kinetics of mRNA–LNP expression may be favourable for inducing immune responses. A recent study demonstrated that sustained antigen availability during vaccination was a driver of high antibody titres and germinal centre (GC) B cell and T follicular helper (T FH ) cell responses 84 . This process was potentially a contributing factor to the potency of recently described nucleoside-modified mRNA–LNP vaccines delivered by the intramuscular and intradermal routes 20,22,85 .…”