Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies

Abstract

Designing and manufacturing safe and effective vaccines is a crucial challenge for human health worldwide. Research on adjuvant-based subunit vaccines is increasingly being explored to meet clinical needs. Nevertheless, the adaptive immune responses of subunit vaccines are still unfavorable, which may partially be attributed to the immune cascade obstacles and unsatisfactory vaccine design. An extended understanding of the crosstalk between vaccine delivery strategies and immunological mechanisms could provide scientific insight to optimize antigen delivery and improve vaccination efficacy. In this review, we summarized the advanced subunit vaccine delivery technologies from the perspective of vaccine cascade obstacles after administration. The engineered subunit vaccines with lymph node and specific cell targeting ability, antigen cross-presentation, T cell activation properties, and tailorable antigen release patterns may achieve effective immune protection with high precision, efficiency, and stability. We hope this review can provide rational design principles and inspire the exploitation of future subunit vaccines.

Keywords: Antigen cross-presentation; Antigen release kinetics; B cell modulation; Dendritic cell subset targeting; Lymph node targeting; Subunit vaccine; T cell activation; Vaccine design.

Graphical abstract

Figure 1

Schematic illustration of the immune cascade process of subunit vaccines.

Figure 2

Vaccine delivery strategies for lymph node targeting. Intranodal injection ensures antigens and adjuvants to directly inject into the lymph node for manipulating immunity in situ. Diffusion-based lymph node targeting and large particles-based cell recruitment were often used to realize lymph node delivery. Active targeting strategies based on endogenous albumins and high endothelial venule-targeted antibody modification also provide new ideas to produce marked accumulation in lymph nodes.

Figure 3

Targeting dendritic cell (DC) subsets and their effects on the humoral response polarization. (A) Xcr1, Clec9a, and DEC-205 are the main receptors for cDC1 targeting, while DCs-inhibitory factor 2 and toll-like receptor (TLR) 5 can be used for cDC2 targeting. Targeting CD11c can deliver antigens to the cDC1s and cDC2s. (B) The antigen delivery to cDC1s or cDC2s causes antigenic peptide presentation to major histocompatibility complex (MHC) class II. The cDC1s secrete IL-12 to drive Th1 polarization, while cDC2s secrete cytokines such as IL-10 and IL-33 to evoke Th2 polarization. (C) Th cells secrete interferon-γ to promote the secretion of IgG2a antibody or IL-4 to facilitate the secretion of IgG1 antibody in the germinal center. Th cells can also induce the affinity maturation of antigen-specific B cells and promote the formation of plasma cells by IL-21 secretion, thus producing high-affinity antibodies. Reprinted with the permission from Ref. 43. Copyright © 2019 Frontiers Media S.A.

Figure 4

B cells exert multifunctional immune effects: antigen presentation, antibody secretion, cytokine secretion, tumor cell lysis, and tertiary lymphoid structure (TLS) formation. B cell activation can be achieved by particle size optimization, glycosylation, multivalent antigen display, pathogen-associated molecular patterns (PAMP) presentation, and CD40 ligation.

Figure 5

The illustration of antigen presentation process in DCs. MHC-II presents exogenous antigens to activate CD4⁺ T cells, while endogenous antigens combine with MHC-I to activate CD8⁺ T cells. In addition, exogenous antigens can escape from the endosome to be presented by MHC-I, which is called cross-presentation. The antigen cross-presentation of DCs is divided into the cytosol and vacuolar pathways. The antigen cross-presentation can be achieved by alkalization of the endosome, endoplasmic reticulum-targeted delivery, proton sponge effect, physical stress from generated CO₂, photochemical internalization, or morphological transformation to mechanically puncture endosome.

Figure 6

Key immune cascade steps in immune process and strategies for vaccine design.