AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates.

Mangalakumari Jeyanathan,Robin Harkness,Tao Zhu,Junqiang Li,Xuefeng Yu,Rong Jiang,Zhongqi Shao,Zhou Xing,Hong Wei Chu

doi:10.1371/journal.pone.0135009

Mangalakumari Jeyanathan, Robin Harkness + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0135009

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Journal: PloS one	Publication Date: Aug 7, 2015
Citations: 53	License type: CC BY 4.0

Affiliation: McMaster University Medical Centre, CanSino (China)

Abstract

Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen–specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.

Highlights

Pulmonary tuberculosis (TB) remains a leading infectious cause of global morbidity and mortality, causing approximately 1.5 million deaths and 9 million new cases each year [1]
Respiratory mucosal AdHu5Ag85A boost immunization is safe in parenteral BCG-primed animals (BCG)-primed rhesus macaques
The safety and efficacy of AdHu5Ag85A delivered via the respiratory mucosal route has been well established and evaluated in a variety of animal models [3,5,21], evaluation of its safety for respiratory mucosal delivery in non-human primates (NHP) is a critical step towards human application

Summary

Introduction

Pulmonary tuberculosis (TB) remains a leading infectious cause of global morbidity and mortality, causing approximately 1.5 million deaths and 9 million new cases each year [1]. It is increasingly realized that in addition to the formulation of candidate vaccines, the new immunization strategy needs to take the route of vaccination into consideration [5,6] This realization is based on recent findings that M.tb has evolved mechanisms to significantly slow down the appearance of T cell immunity in the lung of even the parenteral-BCG vaccinated hosts [7,8,9]. Almost all novel TB vaccine formulations in the TB vaccine pipeline have been or are being evaluated via a parenteral route for human application [2,3,4] In this regard, protein- and replicating mycobacterial organism-based TB vaccines may not be amenable to respiratory mucosal applications due to a limited choice of immune adjuvants and safety concerns. None of these candidates had been evaluated in human clinical trials via the respiratory mucosal route until recently [13]

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