Boosting BCG with proteins or rAd5 does not enhance protection against tuberculosis in rhesus macaques

Patricia A Darrah,Philana Ling Lin,Dominick Laddy,Charles A Scanga,Amy J Myers,Thomas Evans,Joshua A Hackney,Mark A Rodgers,Robert A Seder,Thomas Lindenstrom,Mario Roederer,Hannah P Gideon,Peter Andersen,Pauline Maiello,Robert M Difazio,Joanne L Flynn,Victor Prikhodko

doi:10.1038/s41541-019-0113-9

Abstract

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

Highlights

An estimated one billion people have succumbed to tuberculosis (TB) over the past two centuries.[1]
A major aim of the study was to determine whether specific mycobacterial proteins and adjuvant subunit vaccines administered by standard IM immunization or adenovirus serotype 5 (Ad5)(TB) vaccines administered by AE and IM immunization could enhance immune responses in the blood and lung following ID Bacille Calmette–Guérin (BCG) priming and enhance protection against TB
ID BCG priming with or without IM protein plus adjuvant boosting did not alter the number of the total T cells in the bronchoalveolar lavage (BAL) (Supplementary Fig. 1a, c)

Summary

Introduction

An estimated one billion people have succumbed to tuberculosis (TB) over the past two centuries.[1] Currently, Mycobacterium tuberculosis (Mtb) infection causes ~1.6 million deaths per year. Bacille Calmette–Guérin (BCG) is the only approved vaccine against TB.[2,3] BCG given at birth by intradermal (ID) immunization is effective at protecting infants from the systemic manifestations of TB; it has variable protective efficacy of 0–80% in adolescents and adults from pulmonary infection and disease, which is the major cause of transmission and death.[1,4] vaccine strategies that limit Mtb infection and subsequent disease are urgently needed.[5] Since BCG confers protection in infants against extrapulmonary manifestations of TB and has partial efficacy against pulmonary infection in adolescents and adults,[4] the replacement of BCG in newborns is unlikely. We tested different prime-boost vaccine regimens to determine whether the efficacy of BCG could be enhanced against pulmonary Mtb infection

Objectives

Methods

Results

Conclusion