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.
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.
Tuberculosis (TB) is the leading infectious cause of death in the world and has been targeted for eradication by 2030 . 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 . 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 . 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 .
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. 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.