Synthetic TLR4 agonists enhance functional antibodies and CD4+ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen

Susan L Baldwin; Will Roeffen; Susheel K Singh; Regis W Tiendrebeogo; Michael Christiansen; Elyse Beebe; Darrick Carter; Christopher B Fox; Randall F Howard; Steven G Reed; Robert Sauerwein; Michael Theisen

doi:10.1016/j.vaccine.2016.03.016

Synthetic TLR4 agonists enhance functional antibodies and CD4⁺ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen

Susan L Baldwin, Will Roeffen, Susheel K Singh, Regis W Tiendrebeogo, Michael Christiansen, Elyse Beebe, Darrick Carter, Christopher B Fox, Randall F Howard, Steven G Reed, Robert Sauerwein, Michael Theisen

22 Citationer (Scopus)

Abstract

A subunit vaccine targeting both transmission and pathogenic asexual blood stages of Plasmodium falciparum, i.e., a multi-stage vaccine, could be a powerful tool to combat malaria. Here, we report production and characterization of the recombinant protein GMZ2.6C, which contains a fragment of the sexual-stage protein Pfs48/45-6C genetically fused to GMZ2, an asexual vaccine antigen in advanced clinical development. To select the most suitable vaccine formulation for downstream clinical studies, GMZ2.6C was tested with various immune modulators in different adjuvant formulations (stable emulsions, liposomes, and alum) in C57BL/6 mice. Some, but not all, formulations containing either the synthetic TLR4 agonist GLA or SLA elicited the highest parasite-specific antibody titers, the greatest IFN-γ responses in CD4+ TH1 cells, and the highest percentage of multifunctional CD4+ T cells expressing IFN-γ and TNF in response to GMZ2.6C. Both of these agonists have good safety records in humans.

Originalsprog	Engelsk
Tidsskrift	Vaccine
Vol/bind	34
Udgave nummer	19
Sider (fra-til)	2207-2215
Antal sider	9
ISSN	0264-410X
DOI	https://doi.org/10.1016/j.vaccine.2016.03.016
Status	Udgivet - 27 apr. 2016

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Adgang til dokumentet

10.1016/j.vaccine.2016.03.016

Citationsformater

Baldwin, S. L., Roeffen, W., Singh, S. K., Tiendrebeogo, R. W., Christiansen, M., Beebe, E., Carter, D., Fox, C. B., Howard, R. F., Reed, S. G., Sauerwein, R., & Theisen, M. (2016). Synthetic TLR4 agonists enhance functional antibodies and CD4⁺ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen. Vaccine, 34(19), 2207-2215. https://doi.org/10.1016/j.vaccine.2016.03.016

Baldwin, SL, Roeffen, W, Singh, SK , Tiendrebeogo, RW, Christiansen, M, Beebe, E, Carter, D, Fox, CB, Howard, RF, Reed, SG, Sauerwein, R & Theisen, M 2016, 'Synthetic TLR4 agonists enhance functional antibodies and CD4⁺ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen', Vaccine, bind 34, nr. 19, s. 2207-2215. https://doi.org/10.1016/j.vaccine.2016.03.016

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title = "Synthetic TLR4 agonists enhance functional antibodies and CD4+ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen",

abstract = "A subunit vaccine targeting both transmission and pathogenic asexual blood stages of Plasmodium falciparum, i.e., a multi-stage vaccine, could be a powerful tool to combat malaria. Here, we report production and characterization of the recombinant protein GMZ2.6C, which contains a fragment of the sexual-stage protein Pfs48/45-6C genetically fused to GMZ2, an asexual vaccine antigen in advanced clinical development. To select the most suitable vaccine formulation for downstream clinical studies, GMZ2.6C was tested with various immune modulators in different adjuvant formulations (stable emulsions, liposomes, and alum) in C57BL/6 mice. Some, but not all, formulations containing either the synthetic TLR4 agonist GLA or SLA elicited the highest parasite-specific antibody titers, the greatest IFN-γ responses in CD4+ TH1 cells, and the highest percentage of multifunctional CD4+ T cells expressing IFN-γ and TNF in response to GMZ2.6C. Both of these agonists have good safety records in humans.",

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AU - Baldwin, Susan L

AU - Roeffen, Will

AU - Singh, Susheel K

AU - Tiendrebeogo, Regis W

AU - Christiansen, Michael

AU - Beebe, Elyse

AU - Carter, Darrick

AU - Fox, Christopher B

AU - Howard, Randall F

AU - Reed, Steven G

AU - Sauerwein, Robert

AU - Theisen, Michael

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N2 - A subunit vaccine targeting both transmission and pathogenic asexual blood stages of Plasmodium falciparum, i.e., a multi-stage vaccine, could be a powerful tool to combat malaria. Here, we report production and characterization of the recombinant protein GMZ2.6C, which contains a fragment of the sexual-stage protein Pfs48/45-6C genetically fused to GMZ2, an asexual vaccine antigen in advanced clinical development. To select the most suitable vaccine formulation for downstream clinical studies, GMZ2.6C was tested with various immune modulators in different adjuvant formulations (stable emulsions, liposomes, and alum) in C57BL/6 mice. Some, but not all, formulations containing either the synthetic TLR4 agonist GLA or SLA elicited the highest parasite-specific antibody titers, the greatest IFN-γ responses in CD4+ TH1 cells, and the highest percentage of multifunctional CD4+ T cells expressing IFN-γ and TNF in response to GMZ2.6C. Both of these agonists have good safety records in humans.

AB - A subunit vaccine targeting both transmission and pathogenic asexual blood stages of Plasmodium falciparum, i.e., a multi-stage vaccine, could be a powerful tool to combat malaria. Here, we report production and characterization of the recombinant protein GMZ2.6C, which contains a fragment of the sexual-stage protein Pfs48/45-6C genetically fused to GMZ2, an asexual vaccine antigen in advanced clinical development. To select the most suitable vaccine formulation for downstream clinical studies, GMZ2.6C was tested with various immune modulators in different adjuvant formulations (stable emulsions, liposomes, and alum) in C57BL/6 mice. Some, but not all, formulations containing either the synthetic TLR4 agonist GLA or SLA elicited the highest parasite-specific antibody titers, the greatest IFN-γ responses in CD4+ TH1 cells, and the highest percentage of multifunctional CD4+ T cells expressing IFN-γ and TNF in response to GMZ2.6C. Both of these agonists have good safety records in humans.

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