Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

Enzymatic degradation and clearance via mucus secretion and bulk movement limit efficiency of oral vaccine delivery to some extent. Some forms of transgenic plant-expressed antigens can protect from gut digestion without inducing tolerance if properly dosed. 69 For instance, transgenic rice expressing Cholera toxin B ('MucoRice-CTB') has shown potential for expression and long-time storage of vaccine antigens in seeds within a storage organelle (protein body) where it remains protected from digestion therefore retaining immunogenicity. After ingestion of rice powder (50 mg/course, 75 μg CTB, total of 6 doses every 2 weeks/mouse), uptake via M cells induces IgG (serum) and sIgA (faeces) while oral administration of similar amounts of recombinant purified CTB did not or barely elicit IgA (there was some incidence of diarrhoea in latter but none in the former 70 ). MucoRice-CTB also provides cross-protection to enterotoxigenic E. coli with lower levels of IgG, faecal sIgA than toward CTB. 71 The technology is currently being evaluated in clinical trials. 72 Oral immunization in regions affected by environmental enteropathy leads to lower vaccine efficacy. Alternative forms of administration such as microneedle transdermal patches could therefore be of interest to bypass this constraint. These target dense network of antigen-presenting cells (APCs) in dermis and epidermis (compared to skeletal muscle) and provide overall similar or increased immunogenicity to intramuscular delivery while showing high stability and dosesparing capabilities. Microneedles are generally regarded as safe in clinical trails, 73 can be simply and painlessly applied in a single dose without requiring special training, vaccine reconstitution and sharp waste. Taking into account that they can be mass-produced for less than US$0.10 per unit, microneedle patches could be economically appealing in low income areas. 74 These can be solid metallic, silicon or polymeric coated with dried vaccine or self-dissolving (e.g. vaccine encapsulated in water-soluble materials that release antigen/ adjuvant in skin). Vaccines can be made available in dry formulations which may comprise stabilizers and adjuvants, thus reducing cold chain needs. These have been applied in preclinical and clinical studies for a variety of pathogen sources such as live attenuated viruses, inactivated viruses, viral subunits, VLPs, bacterial antigens and also DNA vaccine. 73, 74 For instance Moon et al. 75 compared single dose stainless steel microneedle patch and intramuscular injection for the delivery of unadjuvanted human CDC-9 inactivated Rotavirus vaccine in mice. They found that the IgG level induced by a 0.5 μg dose delivered with microneedles was at least as efficient at the 5 μg dose given via intramuscular route 28 days after injection. Also, spleen analysis indicated that both delivery methods seemed equally efficient in inducing a recall response. 75 Another study tested a hollow microneedle injection device to deliver three 5 μg doses of CDC-9 G1P [8] vaccine without adjuvant and compared it with equal intramuscular (IM) injections adjuvanted with aluminium hydroxide in piglets (days 0, 10 and 21). Following challenge with human Wa G1P [8] Rotavirus (day 28), the authors found no signs of reactogenicity at the site of injection and at day 21 IgA and IgG serum mean titres were 19-and 20-fold higher after IM administration compared with microneedle, with no significant differences at day 28 (