Abstract
The development of effective vaccines continues to be a key goal for public health bodies, governments, funding bodies and pharmaceutical companies. With new vaccines such as Shingrix targeting Shingles and Bexsero for Meningitis B, licensed in recent years, today’s population can be protected from more infectious diseases than ever before. Despite this, we are yet to license vaccines for some of the deadliest endemic diseases affecting children, such as malaria. In addition, the threat of epidemics caused by emerging pathogens is very real as exemplified by the 2014–2016 Ebola outbreak. Most licensed vaccines provide efficacy through humoral immunity and correlates of protection often quantify neutralising antibody titre. The role of T-cells in vaccine efficacy is less well understood and more complex to quantify. Defining T-cell responses which afford protection also remains a challenge, although more sophisticated assays for assessing cell-mediated immunity with the potential for higher throughput and scalability are now available and warrant review. Here we discuss the benefits of multiparameter cytokine analysis and omics approaches compared with flow cytometric and ELISpot assays. We also review technical challenges unique to clinical trial studies, including assay validation across laboratories and availability of sample type. Measuring T-cell immunogenicity alongside humoral responses provides information on the breadth of immune responses induced by vaccination. Accurately enumerating and phenotyping T-cell immunogenicity to vaccination is key for the determination of immune correlates of protection. However, identifying such T-cell parameters remains challenging without a clear understanding of the immunological mechanisms by which a T-cell-mediated response induces protection.
Highlights
The implementation of routine vaccination programmes across the globe in the last 70 years has been a major factor in mortality reduction associated with infectious disease
The most widely used ELISpot in vaccine studies is the IFN-γ assay. Advantages of this assay include: It is high throughput, robust and economical, it can be standardised and validated, it can be adapted to use in pre-clinical i.e. mouse or non-human primate (NHP) studies and in human trials, both cells and supernatant can be recovered for further analysis, data is obtained from single cells, fine epitope mapping can be performed, and data analysis is straightforward [39,42]
Given that so many vaccines are efficacious at the pre-clinical stage, but show lower than expected efficacy in clinical trials, are there new methods which could be utilised at the pre-clinical stage and in early clinical trials to inform about better potential efficacy at the later clinical stage? Limitations at the pre-clinical stage include differences in the markers used in flow cytometry to assess memory
Summary
The implementation of routine vaccination programmes across the globe in the last 70 years has been a major factor in mortality reduction associated with infectious disease. T-cell-mediated surrogates of protection, where a certain quantifiable parameter correlates with protective efficacy through an unknown protective response, would aid progress of T-cell vaccines, such as those for HIV [10] and TB [11], toward licensure Identifying such parameters remains challenging without a clear understanding of the immunological mechanisms by which a. One way to identify and better understand the cell-mediated immune response to vaccination and pinpoint responses that correlate with efficacy is to use novel methods to assess immunogenicity in pre-clinical studies and to transfer these assays into clinical trials. Such methods can utilise a system’s biology approach, using ‘omics’ rather than focusing on single cytokine responses [11]. We discuss the technical challenges in the assessment of vaccine-induced T-cell immunogenicity from preliminary pre-clinical studies to late stage clinical trials: from mouse to man
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