Eliciting B cell immunity against infectious diseases using nanovaccines

Abstract

Infectious diseases, including the coronavirus disease 2019 (COVID-19) pandemic that has brought the world to a standstill, are emerging at an unprecedented rate with a substantial impact on public health and global economies. For many life-threatening global infectious diseases, such as human immunodeficiency virus (HIV) infection, malaria and influenza, effective vaccinations are still lacking. There are numerous roadblocks to developing new vaccines, including a limited understanding of immune correlates of protection to these global infections. To induce a reproducible, strong immune response against difficult pathogens, sophisticated nanovaccine technologies are under investigation. In contrast to conventional vaccines, nanovaccines provide improved access to lymph nodes, optimal packing and presentation of antigens, and induction of a persistent immune response. This Review provides a perspective on the global trends in emerging nanoscale vaccines for infectious diseases and describes the biological, experimental and logistical problems associated with their development, and how immunoengineering can be leveraged to overcome these challenges.

Fig. 1 |. How nanovaccines induce high-affinity antibody response.

a, Nanovaccines are carried through the lymphatics into the subcapsular sinuses located between the collagenous capsule and the immune cell-rich cortex region of the lymph node. The nanovaccines can localize on subcapsular macrophages overlying B-cell follicles. Nanovaccines are transported to FDCs in B-cell follicles by the relay of complexes from subcapsular sinus macrophages to migrating B cells, which in turn transfer antigen to FDCs, in a complement- and complement receptor-dependent manner. After encountering vaccine antigens, primed B cells decrease their migration velocity and relocate to the border of B-cell follicles (a C-X-C chemokine receptor type 5 (CXCR5) and CC-chemokine receptor 7 (CCR7)-dependent migration), where they encounter a specific subclass of CD4+ T cells, the T_FH cells, eventually leading to germinal centre reactions. Nanovaccine size may regulate transport mechanisms in the lymph nodes, with ~5-nm nanoparticles entering the B-cell follicle through collagen conduits and >500 nm particles transported by dendritic cells. b, Naïve B cells differentiate into germinal centre B cells (1) or short-lived plasma cells (2) as two possible outcomes of antigen and T-cell encounter. If successfully induced by nanovaccines, the germinal centre could lead to a high-affinity antibody response through a complex iterative process of somatic hypermutation, affinity maturation and selection. c, Multiple distinct B-cell clones seed each germinal centre in a vaccinated individual, and these specialized cells lose clonal diversity at widely disparate rates. Multiple clones can evolve in parallel within the same germinal centre, making it a highly heterogeneous structure, and a fraction of germinal centres become heavily dominated by the substantial expansion of the descendants of a single somatic hypermutation variant arising at or after the onset of germinal centre selection over cells of the same and of different clones. NP, nanoparticles; SCS MΦ, subcapsular sinus macrophage; CSR, class switch recombination.

Fig. 2 |. Immunoengineering approaches to overcome transport barriers to access B-cell follicles and restrictions imposed by the gut microbiome.

a, Glycoengineered nanovaccines, when immunized, enhance antigen trafficking to FDCs in B-cell follicles. The glycoengineered (Glycosylated) nanovaccines elicit a higher number of antigen-specific B cells, and increased germinal centre B cell-T_FH cell interactions and neutralizing antibodies than non-glycoengineered (aGlycosylated) nanovaccines. b, The gut microbiome, either through TLRs or other means, such as metabolites, secondary bile acids and inflammasome regulation, enhances antigen-specific germinal centre and antibody response to influenza vaccines in healthy individuals. Disruption of the gut microbiome through antibiotics or lack of sensing of TLR5, leads to poor vaccine outcomes. Rationally designed nanovaccines using immunomodulatory nanomaterials or co-delivery of TLR agonists may enhance the immune response under altered gut microbiome conditions, leading to a universal response. Immunization image in b reproduced with permission from ref., Springer Nature Ltd.

Fig. 3 |. Overcoming challenges in eliciting bnAbs and ADE.

a, bnAbs require complex somatic hypermutations to acquire improbable mutations for neutralizing activity. Conventional vaccines face this somatic hypermutation roadblock and do not typically elicit bnAbs like an infectious response. Immunoengineered nanovaccines can elicit antibodies that exhibit neutralization activity similar to that of intermediate-stage bnAbs. By rationally combining nanoparticles with structurally engineered immunogens followed by serial immunizations, improbable mutations, akin to infection, may be achievable. b, ADE may impose a challenge in nanovaccine design and elicited immune response. Nanovaccines may induce high-quality, mutated, neutralizing antibodies that would bind to targeted proteins on pathogen surface and inhibit host-pathogen interaction. Nanovaccines may reduce production of non-neutralizing antibodies, which can use their Fab domain to attach to pathogens, without neutralizing them he, and their Fc domain to bind to the corresponding receptors on innate immune cells, actually facilitating infection and/or induction of a cytokine storm through the stimulation of TLRs.