A multi-valent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice

Abstract

Tuberculosis caused by Mycobacterium tuberculosis is responsible for nearly two million deaths every year globally. A single licensed vaccine derived from Mycobacterium bovis, bacille CalmetteGuerin (BCG) administered perinatally as a prophylactic vaccine has been in use for over 80 years and confers substantial protection against childhood tuberculous meningitis and miliary tuberculosis. However, the BCG vaccine is virtually ineffective against the adult pulmonary form of tuberculosis that is pivotal in the transmission of tuberculosis that has infected almost 33% of the global population. Thus, an effective vaccine to both prevent tuberculosis and reduce its transmission is urgently needed. We have generated a multi-valent, vectored vaccine candidate utilizing the modified virus Ankara (MVA) strain of vaccinia virus to tandemly express five antigens, ESAT6, Ag85A, Ag85B, HSP65 and Mtb39A of Mycobacterium tuberculosis that have been reported to be protective individually in certain animal models together with an immunostimulatory cytokine interleukin 15 (MVA/IL-15/5Mtb). Although, immunological correlates of protection against tuberculosis in humans remain to be established, we demonstrate that our vaccine induced comparable CD4 + T cell and greater CD8 + T cell and antibody responses against Mycobacterium tuberculosis in vaccinated mice in a direct comparison with the BCG vaccine and conferred protection against an aerogenic challenge of M. tuberculosis, thus warranting its further preclinical development.

Highly Persistent and Effective Prime/Boost Regimens against Tuberculosis That Use a Multivalent Modified Vaccine Virus Ankara-Based Tuberculosis Vaccine with Interleukin-15 as a Molecular Adjuvant

“…In an earlier report, we described the creation and characterization of a multivalent MVA vectored vaccine which expresses five M. tuberculosis antigens as well as the immunostimulatory cytokine IL-15 (21). We demonstrated that this multivalent MVA vaccine induced robust antituberculosis protective responses and conferred protection against an aerogenic M. tuberculosis challenge.…”

“…MVA recombinant virus expressing ESAT6, Ag85A, Ag85B, HSP65, Mtb39A, and IL-15 was constructed as described previously (21). The E6-85 fusion protein is encoded by the ESAT6 gene fused to the region of the Ag85B gene corresponding to the N terminus without the Ag85B signal sequence.…”

“…In humans, immunization with the MVA85A vaccine induced high levels of antigen-specific gamma interferon (IFN-␥)-secreting T cells in BCG-naive healthy volunteers and boosted preexisting antimycobacterial immune responses elicited by previous BCG vaccination (2,18). In earlier studies from our laboratory, we showed that a novel recombinant MVA vaccine which coexpressed five TB antigens and interleukin-15 (IL-15) (incorporated as a molecular adjuvant) induced robust antituberculosis immune responses in mice (19,21). IL-15 is a promising adjuvant because it plays a role in a wide range of relevant biological activities, including the activation and proliferation of CD8 T cells and NK T cells, the maintenance of CD8 memory cells, and the differentiation and maturation of B cells (24).…”

Development of a Murine Mycobacterial Growth Inhibition Assay for Evaluating Vaccines againstMycobacterium tuberculosis

“…The ⌬secA2 gene deletion mutant was isolated by electroporating the pMB179 suicide vector containing a ⌬secA2 allele and a sacB marker into M. tuberculosis H37Rv and then counterselecting on Middlebrook 7H11 plates containing 38 mM (NH 4 ) 2 SO 4 and 3% sucrose (3). The MVA-4TB vaccine was generated by cloning four M. tuberculosis genes (antigen 85A, antigen 85B, ESAT6, and HSP65) as well as the interleukin-15 (IL-15) gene into a modified vaccinia virus Ankara (MVA) vector (27).…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…It plays critical roles in the activation, proliferation and differentiation of CD8 + T-cells and NK-cells. SC vaccination of mice with a multi-valent TB vaccine with IL-15 induced comparable CD4 + T cell and greater CD8+T cell and antibody responses against Mycobacterium tuberculosis compared with the standard BCG vaccine [342]. Insertion of IL-15 in a recombinant TB virus make it an effective vaccine for generation of consistent anti-TB responses in mice and equal protection as BCG vaccine against M. tuberculosis challenge after heterologous prime/boost regimen (priming with a fusion TB antigen adjuvanted with dimethyldiotacylammonium bromide/monophosphoryl lipid A and boosting with the recombinant TB virus) [343].…”