Recombinant Pichinde viral vector expressing tuberculosis antigens elicits strong T cell responses and protection in mice

Abstract

IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global health threat. The only available vaccine Bacille Calmette-Guérin (BCG) does not prevent adult pulmonary TB. New effective TB vaccines should aim to stimulate robust T cell responses in the lung mucosa to achieve high protective efficacy. We have previously developed a novel viral vaccine vector based on recombinant Pichinde virus (PICV), a non-pathogenic arenavirus with low seroprevalence in humans, and have demonstrated its efficacy to induce strong vaccine immunity with undetectable anti-vector neutralization activity.MethodsUsing this tri-segmented PICV vector (rP18tri), we have generated viral vectored TB vaccines (TBvac-1, TBvac-2, and TBvac-10) encoding several known TB immunogens (Ag85B, EsxH, and ESAT-6/EsxA). A P2A linker sequence was used to allow for the expression of two proteins from one open-reading-frame (ORF) on the viral RNA segments. The immunogenicity of TBvac-2 and TBvac-10 and the protective efficacy of TBvac-1 and TBvac-2 were evaluated in mice.ResultsBoth viral vectored vaccines elicited strong antigen-specific CD4 and CD8 T cells through intramuscular (IM) and intranasal (IN) routes as evaluated by MHC-I and MHC-II tetramer analyses, respectively. The IN inoculation route helped to elicit strong lung T cell responses. The vaccine-induced antigen-specific CD4 T cells are functional, expressing multiple cytokines as detected by intracellular cytokine staining. Finally, immunization with TBvac-1 or TBvac-2, both expressing the same trivalent antigens (Ag85B, EsxH, ESAT6/EsxA), reduced Mtb lung tissue burden and dissemination in an aerosol challenge mouse model.ConclusionsThe novel PICV vector-based TB vaccine candidates can express more than two antigens via the use of P2A linker sequence and elicit strong systemic and lung T cell immunity with protective efficacy. Our study suggests the PICV vector as an attractive vaccine platform for the development of new and effective TB vaccine candidates.

The role of ESAT-6 in tuberculosis immunopathology

“…Notably, immunization with TBvac-1 or TBvac-2, both harboring the same trivalent antigens (Ag85B, EsxH, ESAT6/EsxA), resulted in a notable reduction of Mtb burden and limited lung tissue dissemination in a mouse model subjected to aerosol challenge [34]. Thus, the combination of ESAT-6/EsxA with Ag85B and EsxH enhances the generation of a long-term memory immune response ( 76 ). Thus, with the role of ESAT-6 as a pivotal antigen in TB vaccine design substantiated, and its conjunction with promising viral vectors like PICV established, novel vaccination strategies can be envisioned and developed.…”

Análise Da Distribuição Toxicológica Do Ácido Hipúrico Na População Ocupacional Dos Postos De Combustíveis Do Centro Da Vidade De Altamira-Pará

“…Segundo os pesquisadores Kirk et al (33). A tuberculose é um problema de saúde público pensando nisso os pesquisadores buscam novas vacinas efetivas contra que devem ter como objetivo estimular respostas robustas de células T na mucosa pulmonar para alcançar alta eficácia protetora a um novo vetor de vacina viral baseado no vírus Pichinde recombinante (33).…”