Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection against Bovine Tuberculosis

Abstract

Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.More than 50 million cattle are infected with Mycobacterium bovis, resulting in economic losses of approximately $3 billion annually (34). Over the last two decades, in Great Britain, failure of the (tuberculin) test-and-slaughter strategy has resulted in a dramatic rise in the incidence of tuberculosis (TB) in cattle (19). The urgent need for new and improved cattle vaccines and diagnostic reagents has been acknowledged by the British government, and development of a cattle vaccine is a research priority. As cattle can be considered a large-animal model for human TB vaccination, experiments with cattle will

Cytokine responses of Holstein and Sahiwal zebu derived monocytes after mycobacterial infection

“…Further, vaccination experiments in non-human primates have associated a distinctive cytokine profile including IL-6 with protection (Reed et al 2009), whilst a recent mouse study has emphasized its role in the establishment of local innate responses after TB subunit vaccination (Hall et al 2010). IL-6 also promotes murine and (to a lesser degree) human TH17 cell differentiation (de Jong et al 2010), a T-cell subset recently linked to protection against tuberculosis (Khader et al 2007;Vordermeier et al 2009).…”

Interleukin-17A as a Biomarker for Bovine Tuberculosis

“…Significant IL-17 responses are elicited by M. tuberculosis infection of mice (42) and humans (43,44), as well as M. bovis infection of cattle (7,11). With M. tuberculosis infection of mice, early expression of IL-17 in response to vaccination is required for the rapid accumulation of protective memory cells in the lungs (45).…”

“…While TSTs are the mainstays for bovine TB antemortem testing, blood-based tests are attractive, as they require only a single visit to the farm, provide the opportunity for immediate repeat testing, and yield results that are less subjective than those of TSTs. Additional biomarkers have recently emerged as potential candidates for use in blood-based TB tests for humans (reviewed by Walzl et al [5] and Salgame et al [6]) and cattle, including interleukin-1␤ (IL-1␤), IL-2, tumor necrosis factor alpha (TNF-␣), nitric oxide, IL-17, and IFN-␥-induced protein 10 (IP-10) (7)(8)(9)(10)(11)(12)(13). Of these, IL-17 is particularly appealing as a biomarker for bovine TB, as IL-17A mRNA responses determined using real-time quantitative PCR (RT-qPCR) may be predictive of both vaccine efficacy (11,14,15) and lesion severity (7) when measured after vaccination and infection, respectively.…”

Current status of new tuberculosis vaccine in children

“…48 With the support from Aeras, the OxfordEmergent Tuberculosis Consortium developed this virally vectored TB vaccine. As a heterologous boost for BCG, MVA85A moderately improved BCG-induced protective efficacy against M. tuberculosis challenge in animal models, [49][50][51][52] which was predominantly attributable to better induction of CD4 and CD8 T cell responses, as well as antigen-specific Th1 and Th17 cells responsible for protection against M. tuberculosis. 53 Several clinical trials have demonstrated that MVA85A appears to be safe and well tolerated.…”