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

• Published in: npj vaccines 2019-05, Vol.4 (1), p.21-21, Article 21
• Main Authors: Darrah, Patricia A., DiFazio, Robert M., Maiello, Pauline, Gideon, Hannah P., Myers, Amy J., Rodgers, Mark A., Hackney, Joshua A., Lindenstrom, Thomas, Evans, Thomas, Scanga, Charles A., Prikhodko, Victor, Andersen, Peter, Lin, Philana Ling, Laddy, Dominick, Roederer, Mario, Seder, Robert A., Flynn, JoAnne L.
• Format: Article
• Language: English
• Subjects: 631/250; 631/326; 692/699; Adenoviruses; Antigens; Biomedical and Life Sciences; Biomedicine; Cytokines; Infections; Infectious Diseases; Medical Microbiology; Proteins; Public Health; Tuberculosis; Vaccine; Vaccines; Virology
• ISSN: 2059-0105; 2059-0105
• DOI: 10.1038/s41541-019-0113-9

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 AS01 E 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/AS01 E 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. Tuberculosis vaccination: Multi-platform/route BCG boosting in rhesus macaques BCG is the only clinically-approved tuberculosis (TB) vaccine but has highly variable protection against pulmonary manifestations of the disease. JoAnne Flynn and colleagues at the University of Pittsburgh investigate whether heterologous boosting can improve the efficacy of BCG vaccination in a highly susceptible rhesus macaque model. The boosting is performed using a variety of vaccination routes (intramuscular, aerosol) and platforms including multiple Mycobacterium tuberculosis (Mtb) protein subunits in adjuvant and/or expressed in adenovirus vectors. The various platforms and routes are designed to enhance immune responses thought to be involve