Chapter 43 : Systems Vaccinology: Using Functional Signatures To Design Successful Vaccines

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Analyzing the functional signatures of vaccines aids vaccine development in two ways: (i) by monitoring the efficacy of vaccines as they are refined and (ii) by revealing the mechanisms of vaccine action, such that they can be applied to the development of future vaccines. Vaccines operate by stimulating the innate immune system to develop acquired immune responses. Professional antigen presenting cells such as macrophages and dendritic cells (DCs) are key orchestrators of this process. Simple standardized methods to measure the antibody responses include antibody titers measured through ELISAs (enzyme-linked immunosorbent assay) and hemagglutination inhibition and functional measures of activity such as neutralization and opsonophagocytosis. Functional signatures may not only help in the design of protective vaccines but may also help to limit the deleterious side effects. Recent discoveries have identified alternative ways to stimulate the immune system than using alum by studying the natural adjuvants found in pathogens. The chapter presents a study with an aim to apply systems biological approaches to: (i) obtain novel biological insights about the mechanism of action of YF-17D vaccine and; (ii) to determine whether it was possible to identify molecular signatures early after vaccination, which could predict the later immunogenicity of the vaccine. The systems biological approaches used with YF-17D may be broadly applicable in vaccinology in the identification of molecular signatures of vaccine efficacy.

Citation: Querec T, Pulendran B. 2011. Systems Vaccinology: Using Functional Signatures To Design Successful Vaccines, p 549-557. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch43

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Future correlates of protection may integrate multiple measurements. Using multiple cocorrelates of protection (e.g., A, B, C), immunological protection would increase (dark shading) as any of the individual correlates increased in strength, but the greatest level of protection is achieved when cocorrelates combine. These cocorrelates may be, for example, neutralizing antibody titer, T-cell proliferation, T-cell IFN-γ to IL-10 ratio, or frequency of trifunctional T cells.

Citation: Querec T, Pulendran B. 2011. Systems Vaccinology: Using Functional Signatures To Design Successful Vaccines, p 549-557. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch43
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Innate correlates of YF-17D immunogenicity identified by systems biological approaches. YF-17D stimulates polyvalent functional modules of innate immune activation. For example, YF-17D is sensed by TLRs 2, 7, 8, and 9 (which are expressed on distinct subsets of DCs), as well as by RIG-I and MDA-5, resulting in a balanced Th1/Th2 response. YF-17D also induces robust antiviral responses including PKR, OAS 1, 2, 3, L, TRIM5, and complement cascade components such as C1Qb. In addition, EI-F2AK4, a key player in the integrated stress response, is present in the signatures that predict the CD8 T-cell responses to YF1-7D. Consistent with this, the expression of other genes involved in the integrated stress response (e.g., calreticulin, protein-disulfide isomerase family A, members 4 and 5) also correlate with the magnitude of the CD8 T-cell response. Consistent with the induction of a stress response, YF-17D induces phosphorylation of eiF2α and the formation of stress granules. Finally, YF-17D induces TNFRSF17 (BCMA), a receptor for BlyS/BAFF, known to regulate B-cell responses.

Citation: Querec T, Pulendran B. 2011. Systems Vaccinology: Using Functional Signatures To Design Successful Vaccines, p 549-557. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch43
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Methods to measure antibody correlates of protection

Citation: Querec T, Pulendran B. 2011. Systems Vaccinology: Using Functional Signatures To Design Successful Vaccines, p 549-557. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch43

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