Research Article: CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial

Date Published: May 23, 2019

Publisher: Public Library of Science

Author(s): Tereza Masonou, David A. Hokey, Timothy Lahey, Alice Halliday, Luis C. Berrocal-Almanza, Wendy F. Wieland-Alter, Robert D. Arbeit, Ajit Lalvani, C. Fordham von Reyn, Angelo A. Izzo.

http://doi.org/10.1371/journal.pone.0217091

Abstract

DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo.

We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining.

DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses.

DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters.

ClinicalTrials.gov NCT02063555.

Partial Text

Tuberculosis (TB) is the leading infectious cause of death in the world and has been targeted for eradication by 2030 [1]. An improved vaccine strategy against TB will be essential for the success of this effort. The only currently licensed vaccine for TB prevention is Mycobacterium bovis bacillus Calmette-Guérin (BCG). Although newer analyses indicate that BCG is highly effective against pulmonary tuberculosis when given at birth, local side effects are common, and efficacy decreases after 15–20 years [2]. Thus, TB vaccine development includes both new priming vaccines to replace BCG and vaccines to boost BCG. Development has been challenging since a new vaccine must be safe in HIV and be effective in both persons with and without latent TB [3]. Modelling studies indicate that a booster vaccine with a 10-year protective duration and 40% efficacy targeted at adolescents/adults will have a greater impact on TB epidemiology than an improved BCG prime [4].

In a Phase 1 trial we found that three doses of whole cell inactivated DAR-901 immunization elicited polyfunctional Th1-type CD4+ T cell responses to the non-tuberculous mycobacterial vaccine antigen but not to Mtb lysate. DAR-901-specific responder cells exhibited predominantly an effector memory phenotype. DAR-901 represents the same inactivated non-tuberculous mycobacterial strain as SRL172 which was associated with protection from TB in an earlier Phase 3 randomized placebo-controlled double-blind clinical trial[11]. SRL172 induced IFNγ responses to the vaccine antigen and antibody to Mtb LAM but CD4+ T cell specific cytokine responses were not assessed [6,13].

DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172, a vaccine that was shown to prevent TB and to be safe and effective in a Phase 3 trial, has the potential to be an effective booster for BCG in adults and children living in tuberculosis-endemic countries. The present study has shown that DAR-901 induces low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These observations suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for a candidate TB vaccine booster. A broader interrogation of immune response should be included in future clinical trials of candidate TB vaccine boosters.

 

Source:

http://doi.org/10.1371/journal.pone.0217091

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments