Vaccinology at the beginning of the 21st century

Abstract

Today, the main challenges for vaccinologists include improving vaccines against as yet undefeated pathogens, rapid identification and response to emerging diseases and successful intervention in chronic diseases in which ongoing immune responses are insufficient. Reverse genetics and reverse vaccinology are now used to generate rapidly new vaccine strains and to mine whole genomes in the search for promising antigens. The rational design of adjuvants has become possible as a result of the discovery of the receptors that recognize microbial patterns and lead to dendritic cell activation. Antigen-loaded dendritic cells, DNA in naked, formulated or viral form, and other delivery systems are used to maximize immune responses. Although work on the 'easy' vaccines has already been completed, it is hoped that a combination of conceptual and technical innovation will enable the development of more complex and sophisticated vaccines in the future.

Figure 1

Possible intervention points for vaccine improvement. Schematic view of a pathogen- or vaccine-induced immune response. Vaccines or pathogens cross epithelial barriers and are taken up by antigen-presenting cells such as DCs. Interaction between pattern recognition receptors (PRRs) and their agonists activate DCs, resulting in increased antigen presentation, cytokine production and co-stimulation. CD4⁺ and CD8⁺ T cells recognize antigen presented by DCs and are activated. Cognate interaction between primed CD4⁺ T cells and B cells activates the B cells, resulting in clonal expansion and antibody production. DC activation also leads to inhibition of the regulatory effect of CD4⁺CD25⁺ Treg cells. Fully activated CD8⁺ cells can target tumor cells and pathogen-infected cells. The letters (a–i) indicate processes where improved vaccines can lead to more efficient immune responses: (a) The site of administration influences the type of immune response and enables the usage of lower vaccine doses [19, 20]. (b) Particulate antigen is taken up more easily by macrophages and DCs than soluble antigen [47]. (c) TLR agonists and other immunostimulants binding to PRRs increase the activation of DCs [32, 33, 34, 35, 36•, 37•, 38, 40]. (d) DCs matured and loaded with antigen in vitro are efficient vaccines [41••, 42, 43]. (e) DNA vaccination leads to efficient antigen presentation on MHC class I [48, 49, 50•, 51••, 52, 53]. Crosspresentation of antigen on MHC class I of host DCs is facilitated after vaccination with antigen-loaded DCs undergoing delayed apoptosis [44^•]. (f) Cytokines can be added in protein or DNA form as natural adjuvants [32, 33]. (g) Recruited NK cells can be an early source of Th1-driving cytokines [39^•]. (h) Vaccines can break tolerance when the suppressive effect of CD4⁺CD25⁺ Treg cells is overcome [54^•]. (i) Pre-existing T cells specific for tumor antigens not contained in the vaccine expand after vaccination and predominate in the antitumor response [55•, 56•].