A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa

Abstract

Background: Tuberculosis (TB) remains the leading cause of infectious disease-related death. Recently, a trial of BCG revaccination and vaccination with H4:IC31, a recombinant protein vaccine, in South African adolescents (Aeras C-040-404) showed efficacy in preventing sustained QuantiFERON (QFT) conversion, a proxy for Mycobacterium tuberculosis (M.tb) infection. A phase 1b trial of 84 South African adolescents was conducted, concurrent with Aeras C-040-404, to assess the safety and immunogenicity of H4:IC31, H56:IC31 and BCG revaccination, and to identify and optimize immune assays for identification of candidate correlates of protection in efficacy trials. Methods: Two doses of H4:IC31 and H56:IC31 vaccines were administered intramuscularly (IM) 56 days apart, and a single dose of BCG (2À8 £ 10 5 CFU) was administered intradermally (ID). T-cell and antibody responses were measured using intracellular cytokine staining and binding antibody assays, respectively. Binding antibodies and CD4+/CD8+ T-cell responses to H4-and H56-matched antigens were measured in samples from all participants. The study was designed to characterize safety and immunogenicity and was not powered for group comparisons. (Clinicaltrials.gov NCT02378207). Findings: In total, 481 adolescents (mean age 13¢9 years) were screened; 84 were enrolled (54% female). The vaccines were generally safe and well-tolerated, with no reported severe adverse events related to the study vaccines. H4:IC31 and H56:IC31 elicited CD4+ T cells recognizing vaccine-matched antigens and H4-and H56specific IgG binding antibodies. The highest vaccine-induced CD4+ T-cell response rates were for those recognizing Ag85B in the H4:IC31 and H56:IC31 vaccinated groups. BCG revaccination elicited robust, polyfunctional BCG

Developing New Anti-Tuberculosis Vaccines: Focus on Adjuvants

“…In a subsequent trial, Nemes and co-workers attempted to compare the protection ability of the H4:IC31 vaccine with BCG revaccination (NCT02075203) [ 28 ]. This trial confirmed that the immune responses that the vaccine elicited were CD4+ polyfunctional T-cells, which was in agreement with previous preclinical models and phase I trials [ 28 , 30 ]. Although the immune responses were promising, the clinical trial endpoint was not met with success and the vaccine did not show a desired efficacy in TB prevention [ 28 ].…”

Rescuing ESAT-6 Specific CD4 T Cells From Terminal Differentiation Is Critical for Long-Term Control of Murine Mtb Infection

“…Together these studies highlight that adjuvanted protein vaccines have an advantage over BCG in inducing sustainable protection ( 54 ), which might be associated to induction of less differentiated CD4 T cell subsets with increased proliferative potential (e.g. IL-2 + TNFα + ) seen in both mice ( 16 ) and humans ( 55 , 56 ).…”

The Case for Why Africa Should Host COVID-19 Candidate Vaccine Trials

“…Africa has a long history of, and considerable experience in, hosting and conducting vaccine trials [32], including phase 1 vaccine trials on a range of major diseases across the continent [33][34][35][36][37]. African scientists are also making valuable contributions to COVID-19 vaccine development [38][39][40][41].…”