Vaccine-induced time- and age-dependent mucosal immunity to gastrointestinal parasite infection

Abstract

Individuals vary broadly in their response to vaccination and subsequent challenge infection, with poor vaccine responders causing persistence of both infection and transmission in populations. Yet despite having substantial economic and societal impact, the immune mechanisms that underlie such variability, especially in infected tissues, remain poorly understood. Here, to characterise how antihelminthic immunity at the mucosal site of infection developed in vaccinated lambs, we inserted gastric cannulae into the abomasa of three-month- and six-month-old lambs and longitudinally analysed their local immune response during subsequent challenge infection. The vaccine induced broad changes in pre-challenge abomasal immune profiles and reduced parasite burden and egg output post-challenge, regardless of age. However, age affected how vaccinated lambs responded to infection across multiple immune pathways: adaptive immune pathways were typically age-dependent. Identification of age-dependent and age-independent protective immune pathways may help refine the formulation of vaccines, and indicate specificities of pathogen-specific immunity more generally.

Fig. 1. Vaccine- and age-mediated control of T. circumcincta infection.

a Worm burdens and (b) total egg output in 3 month-old lambs with vaccination (3mo-Vax), 3 month-old lambs with adjuvant only (3mo-Ctrl), 6 month-old lambs with vaccination (6mo-Vax), and 6 month-old lambs with adjuvant only (6mo-Ctrl). Immunisation with the prototype vaccine led to a median 73.7% reduction (P_vacc = 0.002, GLM) in worm counts and 50% reduction (P_vacc = 0.026, GLM) in cumulative egg output.

Fig. 2. Temporal dynamics of the expression of immune pathways that predict either post-mortem worm burden or cFEC identified by supervised machine learning ElasticNet.

Heat map indicates the pathway enrichment reported as negative ${log}_{10}^{\mathrm{P-value}}$, where the dark red denotes stronger enrichment within each pathway. Each concentric circle represents one of six time-points at which abomasal biopsies were taken after challenge infection. Worm burdens predicted by these pathways were measured at D49 post challenge.

Fig. 3. Association between immune pathway gene expression and parasite infection post vaccination.

Heat map of correlation coefficients between (a), worm burdens or (b), cFEC and gene expression in the selected pathways before challenge (D0), seven (D7) and 21 (D21) days post challenge in vaccinated and control lambs. Colours represent negative (red) and positive (blue) Pearson correlation coefficients for each comparison. The immune pathways were clustered using k-means according to their correlation patterns over time in the vaccinated group.

Fig. 4. Gene expression within immune pathways significantly affected by immunisation, age, or both.

a Heat map of gene expression over time within the four treatments (3mo-Vax, 3mo-Ctrl, 6mo-Vax, and 6mo-Ctrl). High to low scaled expression is denoted with blue to white hues. b Heat map of a generalised mixed model t value statistic (number of standard deviations from the mean) indicating the effect of age, vaccination, and the interaction between age and vaccination on the expression of each pathway. Purple indicates a dampening effect on the expression of the pathway while yellow indicates increased expression of that pathway relative to the global average. Pathways included are those presented in Fig. 2. The full list of gene expression is available in Supplementary Fig. 6.