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

By J. Moon, Heikyung Suh, Adrienne V. Li, C. Ockenhouse, A. Yadava, D. Irvine. 2012

305 citations recorded by the source corpus.

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 Administration–approved 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 (Tfh), 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.

Subfields: Immunology, Molecular Biology, Public Health, Environmental and Occupational Health

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Citations in the corpus

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, positive): “These data are consistent with previous studies showing that particulate immunogens enhance GC formation and Tfh expansion compared to soluble antigen (Moon et al., 2012).”
T follicular helper cell biology: A decade of discovery and diseases (2019, background): “TLR4, TLR6, TLR7, TLR8, and TLR9 agonists can all enhance Tfh cell and Ab responses to protein antigens compared to alum (Kasturi et al., 2011; Leroux-Roels et al., 2016; Moon et al., 2012), and human vaccines containing TLR4 and TLR9 agonists are now available.”
HIV-1 envelope trimer fusion proteins and their applications (2016, unknown): “Although the improved immunogenicity was less pronounced in rabbits compared to mice, it is consistent with other observations showing the benefits of particulate antigen presentation [12,17,18] (Fig.”