Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

Mucosal surfaces of human adults comprise about 400 m 2 (200-fold higher than skin area). Therefore they present ample opportunities for both pathogen entry (70% of all infections take place via this route) and also immunization. An ideal mucosal vaccine should lead to appropriate adaptive response without excessive inflammation, tissue damage or other side effects arising from stimulation of wrong target cells such as mucosal epithelial cells for e.g. production of proinflammatory cytokines. Antigen uptake and presentation in intestinal and lung mucosal tissue relies on dendritic cells (DCs) and M cells. The latter comprise a basolateral pocket that facilitates transcytosis of antigens, such as viruses and bacteria, and contact with underlying lymphoid tissue. Antigens are delivered to follicular B cells or mucosal DCs that present such cargo to T cells or transit to mesenteric lymph nodes. 53 The fact that M cells are sparse (~1 in 10 million intestinal epithelial cells) may reflect a mechanism of self-protection against food allergy and inflammatory disease. 54 Mice studies show that M cells differentiation is a highly regulated process. 55 Although increasing M cell number has been achieved with modulators of their proliferation (e.g. RANKL 56 ), targeting of M cells with specific ligands may be a safer approach. An ideal M cell marker would be membrane-bound (to favour internalization of tagged cargo) and also conserved among different humans and preclinical animal models for enabling efficient translation of results. However, finding such universal M cell markers has proven difficult. 57 Research in this field includes work on Lewis A antigen 58 and GP2. [59] [60] [61] Several groups have searched for M cell-specific targeting ligands. Kim et al. 62 screened a human M cell model coculture by phage display with a peptide library. One peptide (Co1; SFHQLPARSPLP) facilitated transcytosis of GFP-Co1 fusions to M cells in mouse intestine and that also led to higher anti-GFP serum IgG and faecal IgA upon oral immunization. 62 Similar data was reported for Co1 fusions to Dengue virus envelope domain EDIII protein. 63 Also, mice that were orally immunized with GPF-OmpH β1α1 peptide fusions (AKIAIVNVSRIFQQLPESET) led to higher IgG and faecal IgA responses towards GFP as compared to GFP alone or GFP-Co1 fusions. 64 Mucosal vaccines can become too diluted in fluids and miss target due to bulk flow while being degraded by proteases so it is critical to appropriately design them to retain ideal biophysical properties. Hydrophilic and un-charged surfaces favour mucus penetration while adhesion to mucus is promoted by hydrophobicity/positive charges (e.g. chitosan, cellulose derivatives). Polyethyleneglycol can also favor adhesion to mucus or diffusion, when ≥10 kDa or ≤2 kDa, respectively. 53 Another example of a peptide found by phage display mediating M cell entry is that of CKS9 (CKSTHPLSC), which was conjugated to swine dysentery bacterial antigen BmpB and loaded into poly (lactic-co-glycolic acid), PLGA particles coated with water-soluble chitosan. Oral immunization of mice with these particles led to increased faecal sIgA and IgG responses. 65 Importantly, PLGA is frequently used as a drug delivery system and regarded as safe. 66 Singh et al. 67 described an ileum-targeted protein delivery system based on commonly used and safe hydroxypropyl methylcellulose phthalate in thiolated form (T-HPMCP) for delivery at pH≥.4, while favouring mucoa