A typhoid fever protein capsular matrix vaccine candidate formulated with Advax-CpG adjuvant induces a robust and durable anti-typhoid Vi polysaccharide antibody response in mice, rabbits and nonhuman primates

Article

作者: Thanawastien, Ann ; Cartee, Robert T ; Petrovsky, Nikolai ; Honda-Okubo, Yoshikazu ; Seung Yang, Jae ; Killeen, Kevin P

Typhax is an investigational typhoid fever vaccine candidate that is comprised of Vi polysaccharide from Salmonella enterica serovar typhi (S. Typhi) non-covalently entrapped in a glutaraldehyde catalyzed, cross-linked α-poly-L-lysine and CRM₁₉₇ protein matrix. A previous Phase 1 trial of an aluminum phosphate adjuvanted Typhax formulation showed it induced Vi IgG after a single dose but that subsequent doses failed to further boost Vi IgG levels. The current study asked whether Advax-CpG adjuvant might instead be able to overcome polysaccharide-induced immune inhibition and improve Typhax immunogenicity. Advax-CpG adjuvanted Typhax elicited high and sustained Vi IgG responses in mice, rabbits and non-human primates (NHP) with levels being boosted by repeated immunization. High Vi antibody responses were lost in CD4 + T cell depleted mice confirming that despite the lack of conjugation of the polysaccharide to the carrier protein, Typhax nevertheless acts in a T cell dependent manner, explaining its ability to induce long-term B cell memory responses to Vi capable of being boosted. In NHP, Advax-CpG adjuvanted Typhax induced up to 100-fold higher Vi IgG levels than the commercial Typhim Vi polysaccharide vaccine. Typhax induced high and sustained serum bactericidal activity against S. Typhi and stimulated robust Vi IgG responses even in animals previously primed with a pure polysaccharide vaccine. Hence Advax-CpG adjuvanted Typhax vaccine is a highly promising candidate to provide robust and durable protection against typhoid fever.

2020-06-01·European Journal of Clinical Microbiology & Infectious Diseases3区 · 医学

Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial

3区 · 医学

Article

作者: Benn, Christine S ; Netea, Mihai G ; van Crevel, Reinout ; Aaby, Peter ; Blok, Bastiaan A ; Arts, Rob J W ; Joosten, Leo A B

AbstractThe Vi polysaccharide typhoid fever vaccine (TFV) provides incomplete protection against typhoid fever. BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investigate whether BCG vaccination increases humoral and cellular response to TFV and whether BCG and TFV modulate nonspecific immune responses. Thirty volunteers were randomized to receive either TFV alone or BCG followed by TFV after 2 weeks. Ex vivo leukocyte responses and anti-Vi IgG antibody titers were measured 2 weeks and 3 months after TFV. BCG administration prior to TFV vaccination did not increase specific humoral or cellular immune responses to Salmonella typhi. TFV vaccination decreased pro-inflammatory responses to non-related stimuli. This effect was counteracted by prior BCG administration, which also led to decreased IL-10 and increased IL-22 responses to non-related stimuli. In an in vitro model of trained immunity TFV led to immunotolerance, which was partially reversed by BCG-induced trained immunity. BCG does not modulate adaptive immune responses to TFV but partially prevents inhibition of innate immune responses induced by TFV. Nonspecific effects of vaccines to unrelated microbial stimuli must be considered in the evaluation of their biological effects (ClinicalTrials.gov NCT02175420).

2019-06-03·Human Vaccines & Immunotherapeutics3区 · 医学

In vitro characterization and preclinical immunogenicity of Typhax, a typhoid fever protein capsular matrix vaccine candidate

3区 · 医学

Article

作者: Thanawastien, Ann ; Mekalanos, John J. ; Killeen, Kevin P. ; Cartee, Robert T. ; Griffin, Thomas J.

Typhax is an investigational typhoid fever vaccine candidate that was GMP manufactured applying Protein Capsular Matrix Vaccine (PCMV) technology. It consists of Vi polysaccharide antigen, derived from S. Typhi, non-covalently entrapped in a glutaraldehyde catalyzed cross-linked α-poly-L-lysine and CRM197 protein matrix. Analysis of Typhax determined the average molecular weight of the vaccine particles was approximately 6 x 10⁶ Daltons, corresponding to particles containing 1-2 molecules of Vi polysaccharide and 10-20 molecules of CRM197 protein. The ratio of the concentration of Vi to CRM197 protein in Typhax is 2.4:1. Preclinical immunogenicity studies in mice demonstrated that Typhax was immunogenic and elicited a significant increase in anti-Vi IgG antibody titers following each immunization. The anti-Vi IgG antibody response elicited by Typhax in rabbits increased as the dose increased from 0.1 µg to 2.5 µg. Further, at the 2.5 and 10 µg dose levels, the anti-Vi IgG antibody titers increased after the second and third immunizations. At the 10 µg dose level, 100% of rabbits seroconverted. In the non-human primate (NHP) study, 100% seroconversion was observed at both 2.5 µg and 10 µg dose levels after the first immunization. A murine in vivo immunopotency study demonstrated that Typhax stored at 4°C was stable for at least 30 months. Collectively, the Typhax in vitro profile, preclinical immunogenicity studies, and rabbit toxicology study indicate that Typhax is a viable typhoid fever vaccine candidate for Phase 1 clinical trial evaluation.

100 项与 Typhoid fever vaccine(BioNet-Asia Co. Ltd.) 相关的药物交易

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