The rational design of vaccines

Abstract

This review provides an insight into the various opportunities for vaccine intervention, analysis of strategies for vaccine development, vaccine ability to modulate immune responses and resultant rational vaccine design. In addition, wider aspects are considered, such as biotechnological advances, advances in immunological understanding and host-pathogen interactions. The key question addressed here is, with all our research and understanding, have we reached a new echelon in vaccine development, that of rational design?

FIGURE 1

A historical outline of important developments and achievements in vaccine research. The figure outlines many of the important developments and achievements that have underpinned the development of successful vaccines from 1796. The variolation against Smallpox is believed to originate in China or India, later spreading to the Middle East, Africa, Turkey and Great Britain.

FIGURE 2

Important factors in the rational design of vaccines and the cyclical generation of knowledge. The level of involvement of any of these factors depends on the aetiological agent of disease. For example, the level of protection required in a population (herd immunity) will be different and this could allow theoretical flexibility in vaccine efficacy. The application of molecular biology techniques can be crucial in the identification of new candidate antigens and subsequent determination of vaccine efficacy using adjuvants can feed knowledge back to correlates of protection in terms of immunological markers. This knowledge can then be used in choice of appropriate adjuvants and formulation. The key implication projected by this schematic is that for the greatest challenges in vaccine development the cyclical generation of knowledge provides a strong role for rational design. * Can be protective or therapeutic. ** Including reverse vaccinology and associated technologies.

FIGURE 3

Proposed opportunities for vaccination against TB and HIV. In both cases, the utilization of adjuvants capable of driving the required type of immune response can be used. This can be based on our current understanding of TLR interaction, and studies that manipulate this understanding might also serve to elucidate complex interactions during infection and disease. (a) According to recent models, antigen specific CD4+ T cells, CD8+ T cells,γδ T cells and CD1 restricted T cells, all participate in protection against M. tuberculosis infection in response to antigen presentation by macrophages (MΦ) and dendritic cells (DC), probably also involving crosspriming, where mycobacterial antigens are transferred from infected MΦ to DC. It is unlikely that the induction of IFN-γ or the production of inducible nitric oxide synthase alone is enough to control TB infection, and evidence indicates that there might be another role for CD4+ T cells. The development of pre- and post-exposure vaccines will likely require antigens expressed by M. tuberculosis under pre- and post-exposure conditions, respectively. Interestingly, nonpolymorphic CD1 restricted T cells are thought to have evolved as a result of prolonged interaction with mycobacteria, indicating the extent of the impact of mycobacteria on its mammalian host. (b) For vaccines against HIV, it seems increasingly likely that strategies will depend upon highly conserved epitopes and on vaccine strategies that induce potent immune responses capable of driving cytotoxicity, as well as broadly reactive, highly effective neutralizing antibodies. Target antigens might very probably be different for each of these strategies. Figure adapted, with permission, from Ref. [32].