Tuberculosis (TB) is a major global health problem with an estimated 8.6 million new cases and 1.3 million deaths in 2012
. Effective vaccination is likely to be necessary for the long-term control of the TB epidemic however Bacille Calmette-Guerin (BCG), the only currently licensed vaccine, provides variable protection against pulmonary disease
. Despite high BCG coverage, the incidence of TB remains high in endemic countries. Research efforts into new TB vaccines have focused largely on two strategies; either to modify BCG or replace it with an attenuated strain of Mycobacterium tuberculosis (M.tb), or to improve the protection provided by BCG through prime-boost regimes, often using viral vectors expressing TB antigens to enhance the pool of circulating memory cells primed by vaccination with BCG
. Twelve novel TB vaccines are currently in clinical trials, including two in Phase 2b efficacy studies
. The results of the first efficacy trial of a novel vaccine, Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) were published in early 2013
Although the efficacy of boosting BCG with MVA85A was not superior to that of BCG alone, the study demonstrated that a trial of a novel TB vaccine is feasible in a high burden setting. Furthermore, the collection of blood samples from all infants during the trial will enable research into the mechanisms of disease risk and response to vaccination in this setting. Previous studies with MVA85A have shown it to be safe and immunogenic in several diverse populations including adults without or with latent TB infection in the UK; healthy, latently infected and HIV-infected adults in Africa and healthy adolescents, children and infants in Africa
[5–8]. The vaccine shows a quantitatively lower immunogenicity in African adults and in younger children and infants in Africa compared to UK adults
. In all trials to date, MVA85A induces antigen-specific Th1 and Th17 cells, believed to be important in protection against tuberculosis
[9–11]. If, as has been suggested
, low T cell responses to vaccination in this trial contributed to the lack of vaccine efficacy, understanding the mechanisms determining the magnitude of the response to vaccination is important to the development of an improved vaccine.
Several studies published in the last five years have demonstrated the power of genomics approaches in understanding the molecular mechanisms of the immune response to vaccination
[13–16]. Work using the yellow fever vaccine, YF-17D, identified a gene expression signature in circulating leukocytes of vaccinated volunteers shortly after vaccination which could predict the magnitude of the subsequent CD8+ T cell response
. Follow-up studies have yielded further mechanistic insight, showing that activation of the nutrient sensor GCN2 in dendritic cells following vaccination leads to increased antigen presentation and the development of a stronger immune response
. Similar approaches have been used by other groups and are beginning to reveal some of the factors contributing to the variability of the human immune response. The data show the importance of innate pathways in determining the magnitude of subsequent adaptive immune responses with a role for the stress response and gut microbiota in particular
. The cellular environment and its modification by vaccines and adjuvants are determined by many factors, underscoring the large variation seen in the immune response to vaccines across individuals and populations.
Understanding the differences in immune responses in different groups is key to developing targeted approaches to vaccination. The immune system changes with age, with a decrease in response to vaccination often noted in the elderly
, though a recent study found no decrease in T cell responses in older adults following a novel MVA-vectored influenza vaccine
. Inflammation, apoptosis and immune senescence have all been linked to lower responses to vaccination in this age group
[16, 21]. As the population of the developed world continues to age, understanding these factors will be important in developing effective vaccination strategies. At the other end of the spectrum are the immature immune systems of infants, which also differ to those of adults
[8, 22]. Although children and infants, particularly in the developing world, are the target population for many vaccines against infectious diseases, the factors underpinning the immune response to vaccination in this population remain poorly characterized. Understanding the immune response to vaccination in infants living in areas with a high burden of disease, and how this differs from the immune response of healthy, young adults living in areas of lower disease prevalence –but in whom early testing of vaccines is usually carried out- is therefore a crucial component in the development and early selection of many of the vaccines in development.
In this study, we have analysed gene expression signatures pre- and post-vaccination in infants from the MVA85A Phase 2b efficacy trial who did not develop TB disease during the trial (non-cases) and correlated these changes to the antigen-specific T cell response to vaccination, as measured by IFN-γ ELISpot to Ag85A peptides, in an effort to understand the variability in response to vaccination in this setting. Finally, we compare these findings with previous work performed in UK adults receiving the same vaccine
, in an effort to characterise some of the differences between these populations.