Designing spatial and temporal control of vaccine responses

Abstract

Vaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Material platforms, such as nanoparticles, hydrogels and microneedles, can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Materials-based vaccination strategies can augment the immune response by improving innate immune cell activation, creating local inflammatory niches, targeting lymph node delivery and controlling the time frame of vaccine delivery, with the goal of inducing enhanced memory immunity to protect against future infections. In this Review, we highlight the biological mechanisms underlying strong humoral and cell-mediated immune responses and explore materials design strategies to manipulate and control these mechanisms.

Keywords: Biomaterials - vaccines; Biomedical engineering; Chemical engineering; Vaccines.

Fig. 1. Timeline of vaccine advances and vaccine immune response.

a | Timeline of major events in drug delivery and vaccine development. b | Following administration of a vaccine, interactions between cells and vaccine components lead to a strong and lasting response. At the site of administration, innate immune cells, such as neutrophils and antigen-presenting cells (APCs), first encounter the antigen and adjuvant. The antigen component of the vaccine is endocytosed and broken down by APCs before being presented on the APC surface major histocompatibility complex (MHC) molecules. As innate immune cells become activated, they release cytokines that attract other immune cells from the bloodstream to the site of administration. Soluble vaccine components and activated cells enter the lymphatics and travel to local lymph nodes. c | Maturation and development of a potent adaptive response continues in lymph nodes downstream of the vaccination site (draining lymph nodes). Early in the vaccine response, lymph node-resident phagocytic cells and migratory innate cells arriving from peripheral tissues present antigen and produce inflammatory signals to activate T cells. As the immune response develops, sites of B cell development, called germinal centres, form in the B cell zones of the lymph nodes. d | Immediately following vaccine administration, local innate cells release cytokines into the circulation to enable a coordinated response. These signals are crucial in triggering cell infiltration to the injection site. Following vaccination, plasma cells secrete antigen-specific antibodies, which travel through the circulatory system to tissues, where they respond immediately upon pathogen exposure. Memory T cells also use the circulatory system to inspect the body for foreign invaders. HBV, hepatitis B virus; MPL, monophosphoryl lipid A; siRNA, small interfering RNA;TLR, Toll-like receptor.

Fig. 2. Vaccine delivery from a chemical perspective.

Subunit vaccines are composed of antigens and adjuvants with a range of molecular weights and diverse physical and chemical properties, which affect delivery vehicle selection, encapsulation efficiencies, cargo stability, potential for co-delivery of multiple compounds and delivery characteristics. a | Molecular adjuvants, such as Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) agonists, include highly charged nucleic acids, amphiphilic lipids and small molecules with varying hydrophobicity. Nucleic acid adjuvants have similar charge densities, but can have different molecular weight; for example, cyclic dinucleotides (675 Da) and poly(inosinic:cytidylic acid) (pIC) (up to 5 MDa). b | Subunit antigens include small proteins, such as the SARS-CoV-2 spike protein’s receptor-binding domain with a hydrodynamic size of less than 3 nm, and multivalent protein nanoparticle constructs with hydrodynamic sizes of up to 50 nm (ref.). CDNs, cyclic dinucleotides; CpG, cytosine–phosphate–guanine oligodeoxynucleotide; LPS, lipopolysaccharide; MDP, muramyl dipeptide; MPL, monophosphoryl lipid A; Pam2CSK4, a synthetic diacylated lipopeptide.

Fig. 3. Materials enhance innate immune cell activation.

a | Biomaterials, such as nanoparticles, microparticles and scaffolds, can be used as vehicles for the controlled delivery of antigens and adjuvants, and interact with the immune system in a spatio-temporally controlled manner. These biomaterials can be designed to enhance innate immune cell activation. Protein antigens and adjuvants, such as pathogen-associated molecular pattern (PAMP) molecules, can be co-delivered to improve antigen-presenting cell (APC) recognition and uptake of vaccine components. Nanosized particles can further improve endocytosis by APCs. Self-adjuvanted scaffolds can create a local depot to improve innate cell infiltration, resulting in increased antigen uptake by APCs. Improved antigen processing and APC activation can increase cytokine and chemokine production to improve humoral and cell-mediated adaptive immune responses. b | Nanoparticle strategies can be based on various materials and cargo encapsulation mechanisms. For example, highly charged species such as nucleic acid-derived adjuvants (for example, poly(inosinic:cytidylic acid) (pIC) or cytosine–phosphate–guanine oligodeoxynucleotide (CpG)) can be encapsulated by complexation with polyelectrolytes of opposite charge^,, whereas hydrophobic cargo, such as monophosphoryl lipid A (MPL) or Pam2CSK4 (a synthetic diacylated lipopeptide), can be encapsulated in degradable hydrophobic particles or liposomes. Traditional adjuvants, such as alum particles, typically adsorb proteins and/or other adjuvants in an uncontrolled albeit multivalent fashion, and peptide assembly motifs can be leveraged for precise multivalent display of antigens and/or adjuvants on nanoparticle constructs. MHC, major histocompatibility complex; PRR, pattern-recognition receptor.

Fig. 4. Enhancing the vaccine response by engineering an inflammatory niche.

a | Biomaterials, such as hydrogels and self-assembled scaffolds, can be designed to create an inflammatory niche, which persists in vivo and encourages innate immune cell engagement. Incorporating adjuvants into the vaccine formulation leads to local immune cell activation and further recruitment of cells from circulation. Encapsulating chemokines in the delivery system can increase cell infiltration into the site of administration. b | Engineering an inflammatory niche requires endogenous cells to migrate into the material. For cells to enter a static network, the pores of the material must be larger than the cells. Nanoporous materials do not allow cell infiltration and can lead to a decrease in humoral immunity compared with microporous structures. c | Physically cross-linked networks with dynamic bonds permit active cell motility through a polymer mesh, even if the mesh size is smaller than the cells. If the pores in the polymer mesh are sufficiently small, passive diffusion and release of molecular cargo can be extremely slow, prolonging local retention of the cargo. Cell motility into the material is enhanced by adjuvant encapsulation. d | Following cell infiltration into the biomaterial niche, antigen-presenting cells (APCs) may become activated by immune stimulants in the material and begin processing antigen locally. Cell phenotypes in the material are determined by the encapsulated adjuvants and chemokines, as well secreted cytokines from the infiltrating cells. APCs may exit the inflammatory niche and migrate to the draining lymph node to mediate the adaptive immune response.

Fig. 5. Strategies for lymph node targeting.

Targeted delivery of antigen and adjuvant to the lymphatic system can be achieved by nanoparticle injection in the subcutaneous, muscular or intradermal space. Nanoparticle properties, such as size, surface chemistry and targeting ligands, impact drainage through the lymphatic system and interactions with antigen-presenting cells (APCs). a | Passive drainage is best achieved with nanocarriers of a hydrodynamic diameter between 20 and 200 nm. Further surface modifications such as PEGylation and anionic surface charge increase diffusion to the lymphatic system. b | Large nanoparticles are actively transported to the lymph nodes by migratory APCs. c | Targeting of specific cell populations within the lymph nodes, for example, subcapsular sinus macrophages, follicular dendritic cells, B cells and T cells, can be achieved through surface modification of the nanoparticles with, for example, antibodies targeting specific cell surface markers. PEG, polyethylene glycol.

Fig. 6. Enhancing the vaccine response by sustained release of vaccines.

Materials can be engineered to control the temporal dynamics of vaccine exposure to the immune system. a | Biomaterials encapsulating antigen and adjuvant can be designed with extended release kinetics after administration. Prolonged release allows the vaccine cargo to enter lymph nodes through the lymphatics and extends activation of antigen-presenting cells (APCs) at the administration site. Activated APCs process antigen and migrate to the draining lymph nodes. Prolonged presence of vaccine components extends germinal centre reactions, which facilitate more rounds of affinity selection and somatic hypermutation, ultimately leading to a higher-quality antibody response. b | Osmotic pump technology enables extended vaccine release, but requires surgical implantation. c | Solid polymer matrices, for example microneedle technologies, can provide sustained delivery of entrapped cargo over several weeks; however, the cargo release rate is highly dependent on the cargo’s molecular size and physico-chemical properties, limiting the type of antigens and adjuvants that can be delivered. d | Depot technologies, such as hydrogels and self-assembled scaffolds, provide tunable cargo release, from days to months. Passive cargo diffusion in hydrogels can be controlled through modulation of the polymer mesh size. Physically entrapped cargo, whereby the cargo is larger than the mesh size, can only be released through network degradation, swelling or dynamic rearrangement. Hydrogels constructed with dynamic or degradable cross-links enable cell infiltration and formation of an inflammatory niche. Self-assembled scaffolds can provide sustained cargo delivery and are inherently macroporous, enabling cell infiltration and rapid formation of an inflammatory niche.