Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand T _fh cells and promote germinal center induction

Abstract

For subunit vaccines, adjuvants play a key role in shaping immunological memory. Nanoparticle (NP) delivery systems for antigens and/or molecular danger signals are promising adjuvants capable of promoting both cellular and humoral immune responses, but in most cases the mechanisms of action of these materials are poorly understood. Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP001, both entrapped in the aqueous core and anchored to the lipid bilayer surfaces. Immunization with these particles and monophosphoryl lipid A (MPLA), a US Food and Drug Administrationapproved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high-avidity antibody responses against VMP001, lasting more than 1 y in mice at 10-fold lower doses than conventional adjuvants. Compared to soluble VMP001 mixed with MPLA, VMP001-NPs promoted broader humoral responses, targeting multiple epitopes of the protein and a more balanced Th1/Th2 cytokine profile from antigen-specific T cells. To begin to understand the underlying mechanisms, we examined components of the B-cell response and found that NPs promoted robust germinal center (GC) formation at low doses of antigen where no GC induction occurred with soluble protein immunization, and that GCs nucleated near depots of NPs accumulating in the draining lymph nodes over time. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells (T fh ), compared to vaccinations with soluble VMP001 or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response.

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

“…Similarly, other studies have shown improved therapeutic outcomes by either conjugating the adjuvant or the antigen onto or into delivery systems, such as poly(lactideco-glycolide) particles and liposomes, but, to our knowledge, this is the first study to show enhanced co-uptake of both adjuvant and antigen by LN-resident APCs after nanoparticle conjugation (14)(15)(16)(17)(18)(19). Furthermore, it has been shown recently that encapsulating antigens or TLR agonists in nanoparticles enhanced humoral responses compared with immunization with soluble antigen or adjuvant (41,42).…”

Vaccine Nanoparticles for Protection Against HIV Infection

“…The average ICMV diameter was approximately 375 nm with each harboring on average 160 gp140 trimers for a mean inter-trimer distance of 33 nm [54]. In this instance, Env trimers were displayed greater than tentimes the amount seen on HIV virions while retaining a native orientation on the nanoparticle system designed for efficient delivery of antigens, stable antigen presentation and induction of germinal centers in vivo [54,[56][57][58]. Immunizations with Env-ICMVs in mice-induced Th1/Th2-balanced Env-specific antibodies, IgG 1 and IgG 2c , expanded the breadth of serum antibodies to recognize peptide sequences of two additional Env regions, V2 and membrane-proximal external region (MPER), and increased their titers, compared with soluble protein formulated with a strong oil-inwater emulsion adjuvant [54].…”

Particle platforms for cancer immunotherapy

“…Multivalent presentation of PAMPs or antigens by particles mimics repetitive presentation by live pathogens, 63,64 leading to enhanced antigenicity through receptor cross-linking and immune-cell activation. Moon et al 65 demonstrated that particle-based antigen presentation achieved a tenfold reduction in the amount of antigen needed to achieve equivalent antibody responses to that presented by conventional adjuvants. Enhanced diversity in antibody production was also observed with particlebased antigen presentation, potentially due to activation of lower-avidity B cells that would not be achieved with lower antigen densities.…”