The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses

Kagina, Benjamin M.; Tameris, Michèle; Geldenhuys, Hennie; Hatherill, Mark; Abel, Brian; Hussey, Gregory; Scriba, Thomas J.; Mahomed, Hassan; Sadoff, Jerald C.; Hanekom, Willem A.; Mansoor, Nazma; Hughes, Jane; Kock, Marwou de; Whatney, Wendy; Africa, Hadn; Krohn, Colleen; Veldsman, Ashley; Kany, Angelique Luabeya Kany; Douoguih, Macaya; Pau, Maria Grazia; Hendriks, Jenny; McClain, Bruce; Benko, Jacqueline G.; Snowden, Margaret Ann; Hokey, David A.

doi:10.1016/j.vaccine.2014.09.001

Cited by 45 publications

(39 citation statements)

References 28 publications

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“…Further, these participants generated a polyfunctional cytokine response (Supplementary Fig. S2) consistent with prior immunogenicity studies of AERAS-402212324. We note that BCG vaccination resulted in minimal induction of antigen-specific CD8 responses (Figs 1 and 2) as previously reported29.…”

Section: Resultssupporting

confidence: 86%

“…ICS was also performed on day 98. ICS and IFN-γ ELISPOT assays were performed as described previously2427 using synthetic peptide pools with 15-mers overlapping by 11 amino acids (aa) from each antigen contained within AERAS-402. For the CD8 ELISPOT assay (CD8/others), CD8 + T cells were negatively selected from peripheral blood mononuclear cells (PBMC) using a combination of CD4 and CD56 magnetic beads.…”

Section: Resultsmentioning

confidence: 99%

“…While the AERAS-402 vaccine after BCG prime is broadly immunogenic212324, the observation that vaccine-elicited CD8 + T cells were in many instances not capable of recognizing an Mtb-infected cell raises the possibility that enumeration of vaccine-induced polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying cells infected with Mtb. At present, correlates of protective immunity for Mtb are poorly understood, and yet desperately needed to guide improved vaccine design.…”

Section: Discussionmentioning

confidence: 99%

“…Prior work has established that AERAS-402 boosting of BCG vaccination elicits high-frequency, polyfunctional CD4 + and CD8 + T cells in adults and infants21232425. To further study human cellular immune responses to AERAS-402 and define the capacity of vaccine-induced CD8 + T cells to recognize Mtb-infected cells, we performed a phase I double-blind, randomized, placebo-controlled trial.…”

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confidence: 99%

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Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine

Nyendak

Swarbrick

Duncan

et al. 2016

Sci Rep

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The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4+ and CD8+ T cell responses. However, analysis of the vaccine-induced CD8+ T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine

Nyendak

Swarbrick

Duncan

et al. 2016

Sci Rep

Self Cite

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“…common human serotypes such as AdHV-26, which is being tested as a vaccine carrier for HIV-1 [92], or HAdV-35, a CD46 binder, which is being explored for prevention of mycobacterium tuberculosis infections [93]. Others are testing Ad vectors from non-human primates for a variety of infectious agents including Plasmodium falciparum [94], HIV-1 [74], Ebola virus [95], or hepatitis C virus [15 ].…”

Section: Vaccine Carriers Based On Ad Vectorsmentioning

confidence: 99%

Viral vectors as vaccine carriers

Ertl

2016

Current Opinion in Virology

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An Update on Tuberculosis Vaccines

Subbian

2021

Methods in Molecular Biology

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading cause of mortality and morbidity due to a single infectious agent. Aerosol infection with Mtb can result in a range of responses from elimination, active, incipient, subclinical, and latent Mtb infections (LTBI), depending on the host's immune response and the dose and nature of infecting bacilli. Currently, BCG is the only vaccine approved to prevent TB. Although BCG confers protection against severe forms of childhood TB, its use in adults and those with comorbid conditions, such as HIV infection, is questionable. Novel vaccines, including recombinant BCG (rBCG), were developed to improve BCG's efficacy and use as an alternative to BCG in a vulnerable population. The first-generation rBCG vaccines had different Mtb antigens and were tested as a prime, prime-boost, or immunotherapeutic intervention. The novel vaccines target one or more of the following requirements, namely prevention of infection (POI), prevention of disease (POD), prevention of recurrence (POR), and therapeutic vaccines to treat a TB disease. Several vaccine candidates currently in development are classified into four primary categories: live attenuated whole-cell vaccine, inactivated whole-cell vaccine, adjuvanted protein subunit vaccine, and viral-vectored vaccine. Each vaccine's immunogenicity, safety, and efficacy are tested in preclinical animal models and further validated through various phases of clinical trials. This chapter summarizes the various TB vaccine candidates under different clinical trial stages and promises better protection against TB.

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The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses

Cited by 45 publications

References 28 publications

Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine

Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine

Viral vectors as vaccine carriers

An Update on Tuberculosis Vaccines

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