Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

Oral administration of vaccines is challenging in part due to hyporesponsiveness and tolerance issues. Adjuvants act by enhancing and modulating immune response therefore allowing for lower and less frequent dosing and as such antigen saving, which can prove critically important in case of pandemics. They also hold promise for enhancing responses in children, immunosenescent and immunocompromised patients. Adjuvants stimulate the innate immune system by acting on DCs, macrophages and neutrophils, and also on the adaptive immune system. As discussed above, encapsulation in biodegradable particulate delivery systems and mucosal adjuvants is a promising approach for protection from digestive enzymes. 84 Live attenuated vaccines can harbour multiple antigens that also serve as adjuvants. Inactivated vaccines generally have lower efficacy as these components may lack ideal function. Subunit vaccines also show poor immunogenicity and therefore need an adjuvant to elicit satisfactory responses. 53 For instance, encouraging results have been reported in preclinical studies by grafting epitopes onto appropriate scaffolds (e.g. HIV1 gp41 85, 86 ). Further, immunization with structurally similar regions of different pathogens e.g. Candida albicans adhesin Als3 conferred protection against Staphylococcus aureus via its adhesin ClfA. 87 Similar observations have been made with targeted substitutions within N. meningitidis fHBP (a component of Bexesero vaccine 88 ). These results emphasize the need for discovery of suitable mucosal adjuvants such as bacterial toxins that can induce strong local and systemic immune responses. An example that reached commercialization was an inactivated intranasal virosomal-subunit influenza vaccine supplemented with E. coli ADP-ribosylating heat-labile toxin (LT) as a mucosal adjuvant. Although prelicensure trials including 1218 individuals over 4 winters showed no serious side effects, following introduction of the vaccine 46 cases of Bell's Palsy were recorded over the course of 7 months. This represented an estimated 19-fold relative risk increase, leading to the vaccine being withdrawn from the market. 89 Although LT and also cholera toxin can be detoxified, their use has been limited to animal models and clinical trials. [90] [91] [92] Detoxified versions of bacterial toxins are normally less potent adjuvants than the original molecule. 93 A phase I clinical trial with an intranasal influenza vaccine comprising a mutant detoxified form of LT toxin (LTK63) was well tolerated with the adjuvant dosed at 3, 10 and 30 μg within a cohort of 70 volunteers. 94 However, in phase I clinical trials with intranasal HIV and tuberculosis vaccines adjuvanted LTK63 at a dose of 30 μg, two healthy volunteers showed symptoms of transient Bell's Palsy. These data indicated that nasal delivery of the toxin is not advisable. 95 In that regard, the LT double mutant dmLT (R192G/L211A) was used as an adjuvant in a clinical trial for an oral enterotoxigenic E. coli vaccine and shown to be well tolerated and effective in increasing immune responses among a cohort of 129 Swedish volunteers. 96 Certain cytokines also show potential as mucosal adjuvants. Cholera toxin (CT) can increase levels of IL-1, IL-6 and IL-8 in mucosal epithelial cells. Therefore IL-1α and IL-1β were tested as adjuvants in intranasal immunization of mice with ovalbumin and tetanus toxoid and shown to increase IgG and IgA in vaginal lavages in a manner comparable or su