Preclinical Evaluation of TB/FLU-04L—An Intranasal Influenza Vector-Based Boost Vaccine against Tuberculosis

Abstract

Tuberculosis is a major global threat to human health. Since the widely used BCG vaccine is poorly effective in adults, there is a demand for the development of a new type of boost tuberculosis vaccine. We designed a novel intranasal tuberculosis vaccine candidate, TB/FLU-04L, which is based on an attenuated influenza A virus vector encoding two mycobacterium antigens, Ag85A and ESAT-6. As tuberculosis is an airborne disease, the ability to induce mucosal immunity is one of the potential advantages of influenza vectors. Sequences of ESAT-6 and Ag85A antigens were inserted into the NS1 open reading frame of the influenza A virus to replace the deleted carboxyl part of the NS1 protein. The vector expressing chimeric NS1 protein appeared to be genetically stable and replication-deficient in mice and non-human primates. Intranasal immunization of C57BL/6 mice or cynomolgus macaques with the TB/FLU-04L vaccine candidate induced Mtb-specific Th1 immune response. Single TB/FLU-04L immunization in mice showed commensurate levels of protection in comparison to BCG and significantly increased the protective effect of BCG when applied in a “prime-boost” scheme. Our findings show that intranasal immunization with the TB/FLU-04L vaccine, which carries two mycobacterium antigens, is safe, and induces a protective immune response against virulent M. tuberculosis.

Safety and Protective Efficacy of a Candidate Vector-Based Vaccine for Bovine Tuberculosis

“…Similar studies assessing the safety of recombinant influenza viruses expressing M. tuberculosis’ proteins ESAT-6 and Ag-85 in laboratory animals such as mice and guinea pigs have proved them to be completely safe. They have also demonstrated that animals immunised with recombinant influenza viruses developed a T-cell immune response and a level of protection that was not inferior to those induced by commercial BCG vaccines [ 30 , 31 ].…”

Vaccines against Tuberculosis: Where Are We Now?

“…TB/FLU-04L is another viral vector vaccine based on the replication-deficient influenza virus expressing two M.tb antigens, Ag85A and ESAT-6 [ 6 ]. Preclinical studies in mice showed induction of strong T helper 1 (Th1)-type immune response and reduced regulatory T cells (Treg cell), when administered as booster to BCG [ 71 ]. It is in Phase I clinical trials [ 4 ].…”

The Use of Viral Vectors for Gene Therapy and Vaccination in Tuberculosis

“…When administered as part of a "prime-boost" strategy, a single immunization with TB/FLU-04L vaccine in mice demonstrated comparable levels of protection to BCG. It dramatically improved the protective effect of BCG [77] Neonatal and adult mice were used to test the replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vector producing Mtb antigens Ag85B and TB10.4 (Ag85B-TB10.4). After delivery, it was noted that this vaccine could produce heterogeneous CD4 + , and CD8 + T-cell populations, and lung damage when infected with Mtb was reduced.…”