Nonpathologic Infection of Macaques by an Attenuated Mycobacterial Vaccine Is Not Reactivated in the Setting of HIV Co-Infection
2017; Elsevier BV; Volume: 187; Issue: 12 Linguagem: Inglês
10.1016/j.ajpath.2017.08.014
ISSN1525-2191
AutoresTaylor W. Foreman, Ashley V. Veatch, Denae N. LoBato, Peter J. Didier, Lara Doyle‐Meyers, Kasi Russell‐Lodrigue, Andrew A. Lackner, Konstantin G. Kousoulas, Shabaana A. Khader, Deepak Kaushal, Smriti Mehra,
Tópico(s)Mycobacterium research and diagnosis
ResumoFailure to replace Bacille Calmette-Guerin vaccines with efficacious anti-tuberculosis (TB) vaccines have prompted outside-the-box thinking, including pulmonary vaccination to elicit local immunity. Inhalational MtbΔsigH, a stress-response–attenuated strain, protected against lethal TB in macaques. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV co-infection. Macaques were aerosol-vaccinated with ΔsigH and subsequently challenged with SIVmac239. Bronchoalveolar lavage and tissues were sampled for mycobacterial persistence, pathology, and immune correlates. Only 35% and 3.5% of lung samples were positive for live bacilli and granulomas, respectively. Our results therefore suggest that the nonpathologic infection of macaque lungs by ΔsigH was not reactivated by simian immunodeficiency virus, despite high viral levels and massive ablation of pulmonary CD4+ T cells. Protective pulmonary responses were retained, including vaccine-induced bronchus-associated lymphoid tissue and CD8+ effector memory T cells. Despite acute simian immunodeficiency virus infection, all animals remained asymptomatic of pulmonary TB. These findings highlight the efficacy of mucosal vaccination via this attenuated strain and will guide its further development to potentially combat TB in HIV-endemic areas. Our results also suggest that a lack of pulmonary pathology is a key correlate of the safety of live mycobacterial vaccines. Failure to replace Bacille Calmette-Guerin vaccines with efficacious anti-tuberculosis (TB) vaccines have prompted outside-the-box thinking, including pulmonary vaccination to elicit local immunity. Inhalational MtbΔsigH, a stress-response–attenuated strain, protected against lethal TB in macaques. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV co-infection. Macaques were aerosol-vaccinated with ΔsigH and subsequently challenged with SIVmac239. Bronchoalveolar lavage and tissues were sampled for mycobacterial persistence, pathology, and immune correlates. Only 35% and 3.5% of lung samples were positive for live bacilli and granulomas, respectively. Our results therefore suggest that the nonpathologic infection of macaque lungs by ΔsigH was not reactivated by simian immunodeficiency virus, despite high viral levels and massive ablation of pulmonary CD4+ T cells. Protective pulmonary responses were retained, including vaccine-induced bronchus-associated lymphoid tissue and CD8+ effector memory T cells. Despite acute simian immunodeficiency virus infection, all animals remained asymptomatic of pulmonary TB. These findings highlight the efficacy of mucosal vaccination via this attenuated strain and will guide its further development to potentially combat TB in HIV-endemic areas. Our results also suggest that a lack of pulmonary pathology is a key correlate of the safety of live mycobacterial vaccines. Mucosal vaccination is being considered as a viable alternative to the systemic route,1Tonnis W.F. Kersten G.F. Frijlink H.W. Hinrichs W.L. de Boer A.H. Amorij J.P. Pulmonary vaccine delivery: a realistic approach?.J Aerosol Med Pulm Drug Deliv. 2012; 25: 249-260Crossref PubMed Scopus (43) Google Scholar especially for lung pathogens like Mycobacterium tuberculosis (Mtb). 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Bucsan A.N. Didier P.J. Doyle-Meyers L.A. Russell-Lodrigue K.E. Roy C.J. Blanchard J. Kuroda M.J. Lackner A.A. Chan J. Khader S.A. Jacobs Jr., W.R. Kaushal D. CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.Proc Natl Acad Sci U S A. 2016; 113: E5636-E5644Crossref PubMed Scopus (87) Google Scholar, 24Mehra S. Golden N.A. Dutta N.K. Midkiff C.C. Alvarez X. Doyle L.A. Asher M. Russell-Lodrigue K. Monjure C. Roy C.J. Blanchard J.L. Didier P.J. Veazey R.S. Lackner A.A. Kaushal D. 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Blanchard J.L. Khader S.A. Lackner A.A. Sherman D.R. Kaushal D. The DosR regulon modulates adaptive immunity and is essential for M. tuberculosis persistence.Am J Respir Crit Care Med. 2015; 191: 1185-1196Crossref PubMed Scopus (114) Google Scholar Blood collected in EDTA tubes (Sarstedt AG & Co., Nümbrecht, Germany) was used for whole blood flow cytometry using the panels as described earlier.5Kaushal D. Foreman T.W. Gautam U.S. Alvarez X. Adekambi T. Rangel-Moreno J. Golden N.A. Johnson A.M. Phillips B.L. Ahsan M.H. Russell-Lodrigue K.E. Doyle L.A. Roy C.J. Didier P.J. Blanchard J.L. Rengarajan J. Lackner A.A. Khader S.A. Mehra S. Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis.Nat Commun. 2015; 6: 8533Crossref PubMed Scopus (142) Google Scholar, 25Mehra S. Foreman T.W. Didier P.J. Ahsan M.H. Hudock T.A. Kissee R. Golden N.A. Gautam U.S. Johnson A.M. Alvarez X. Russell-Lodrigue K.E. Doyle L.A. Roy C.J. Niu T. Blanchard J.L. Khader S.A. Lackner A.A. Sherman D.R. Kaushal D. The DosR regulon modulates adaptive immunity and is essential for M. tuberculosis persistence.Am J Respir Crit Care Med. 2015; 191: 1185-1196Crossref PubMed Scopus (114) Google Scholar, 27Phillips B.L. Mehra S. Ahsan M.H. Selman M. Khader S.A. Kaushal D. LAG3 expression in active Mycobacterium tuberculosis infections.Am J Pathol. 2015; 185: 820-833Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar BAL samples were obtained, as previously described, before vaccination and again at 3, 7, 11, and 14 weeks24Mehra S. Golden N.A. Dutta N.K. Midkiff C.C. Alvarez X. Doyle L.A. Asher M. Russell-Lodrigue K. Monjure C. Roy C.J. Blanchard J.L. Didier P.J. Veazey R.S. Lackner A.A. Kaushal D. Reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus.J Med Primatol. 2011; 40: 233-243Crossref PubMed Scopus (85) Google Scholar, 25Mehra S. Foreman T.W. Didier P.J. Ahsan M.H. Hudock T.A. Kissee R. Golden N.A. Gautam U.S. Johnson A.M. Alvarez X. Russell-Lodrigue K.E. Doyle L.A. Roy C.J. Niu T. Blanchard J.L. Khader S.A. Lackner A.A. Sherman D.R. Kaushal D. The DosR regulon modulates
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