Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

perior to CT. 97 Similarly, Kayamuro et al. 98 tested 26 interleukins as adjuvants in intranasal immunizations of mice with influenza HA and noted that IL-1 family members (IL-1α, IL-1β, IL-18, IL-33) were effective in increasing IgG and IgA levels in serum and saliva, nasal wash, faecal extract and vaginal wash, respectively. The authors also found that upon viral challenge, all mice immunized with HA and cytokine adjuvants were alive after 7 days while within the same time frame, 86% of those receiving HA only had perished, and none mock vaccinated with PBS were alive. There were also no signs of severe inflammation or tissue damage in the nasal cavities. 98 It is interesting to note that there is some evidence for a role of glutamine in favouring intestinal IgA production. 99 Several studies describe the induction of mucosal immunity after parenteral administration of adjuvants. Heine et al.- 100 used E. coli double mutant LT R192G/L211A (dmLT) for improving immune response to Shigella antigens IpaB and IpaD delivered intradermally using microneedles. Mice were immunized 3 times at 2 week intervals leading to quick infiltration of neutrophils, macrophages, dendritic and Langerhans cells, as well as CD4 + and CD8 + T cells. IgG levels in serum were elevated but contrary to observations made with control intranasal immunizations, no IgA was detected in serum or stools. Intranasal delivery also led to antibody IgG and IgA secreting cells in lung, spleen and bone marrow while intradermal injection only led to IgG secreting in spleen and bone marrow. Interestingly, intradermal vaccination provided up to 70% and 50% protection against lethal pulmonary challenge with S. flexneri and S. sonnei, respectively (50% and 20% without dmLT adjuvant) while intranasal vaccine delivery provided 100% protection. Only antigen-specific IgG was present in lung mucosal fluid after intradermal immunization while both IgG and IgA were detected after intranasal delivery. 100 Frederick et al. 101 compared the effect of CpG and dmLT in combination with MHC class II CD4 + T cell peptide antigen 2W1S after intramuscular and intradermal ear immunization in mice. dmLT was superior to CpG for expanding and maintaining antigen-specific CD4 + T cells in lymph nodes and spleen and at inducing intestinal homing integrin α4β7 in spleen and mesenteric lymph nodes. Small and large intestine lamina propria also had greater number of antigenspecific CD4 + T cells. Intramuscular and intradermal immunization in the flank gave similar results indicating that adjuvant and not route of administration determines T cell migration to intestine tissue. While CpG leads to a Th1 CD4 + T cell bias, dmLT results in both Th1 and Th17 responses. 101 In brief, adjuvants play a major role in stimulating immune responses, especially with inactivated or subunit vaccines. Although several proven single component and combination of adjuvants are available for parenteral immunization, mucosal adjuvants are harder to develop. Following toxicity problems in the clinic with E. coli LT, detoxified versions of LT and CT, as well as cytokines, are being explored in clinical trials. Intradermal immunization adjuvanted with dmLT seems to trigger IgG and antigen-specific CD4 + T cells in intestines but not IgA (while the latter is present after intranasal delivery in serum and stool samples).