Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

Hobbs, Charlotte V.; Anderson, Charles A.; Neal, Jillian; Sahu, Tejram; Conteh, Solomon; Voza, Tatiana; Langhorne, Jean; Borkowsky, William; Duffy, Patrick E.

doi:10.1093/infdis/jiw482

Cited by 9 publications

(22 citation statements)

References 49 publications

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“…In our Sporozoite Neutralization Assay, all mice were protected following the inoculation of sporozoites with sera from mice immunized with PbAGT8-OE-CVac parasites, indicative of a strong anti-sporozoite antibody response. This finding contrasts with another study using WT-CVac regimen with live P. yoelii sporozoite immunization under trimethoprim-sulfamethoxazole prophylaxis, in which no anti-sporozoite antibody response was observed 25 . However, in this CVac protocol with P. yoelii, antiserum-treated sporozoites were i.v.…”

Section: Discussioncontrasting

confidence: 93%

“…Immunization of mice with PbATG8-OE-CVac parasites results in a significantly higher population of the antigen-experienced CD8 + T cells during priming that remains comparatively stable, even 3 months after immunization. Interestingly, PbATG8-OE-CVac parasites generate a protective CD8 + T cell-mediated cellular response against liver-stage that is minimally dependent on IFN-γ, unlike many other whole sporozoite vaccines that trigger IFN-γ for protection, such as RAS 35 , WT-CVac with chloroquine or trimethoprim-sulfamethoxazole 9,25,35,36 and GAP 40 .…”

Section: Discussionmentioning

confidence: 99%

“…-OE-CVacimmunized mice, 500 μg of rat anti-CD8 (clone 2.43; BioXCell, West Lebanon, NH), rat anti-CD4 (clone GK 1.5, BioXCell) monoclonal antibodies or isotype control (LTF-2, BioXCell) were i.p. injected into immunized mice one day prior to and on the day of the challenge 25 .…”

Section: In Vivo T-cell Depletion For Selective T-cell Depletion Fromentioning

confidence: 99%

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Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection

Sahu

Gehrke

Flores-García

et al. 2020

Preprint

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Genetically-attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Though CVac with WT sporozoites confers better immunity, the overhanging threat of drug resistance limits its use as a vaccine. Here, we demonstrate that a liver stage-specific mutant of Plasmodium berghei when used as a vaccine under a CVac regimen provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+T-cell response through an IFN-gamma;-independent mechanism and is associated with a stable population of antigen-experienced CD8+T cells. Jointly, our findings support the benefit of liver stage mutants as vaccines over WT, under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.

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Section: Discussioncontrasting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection

Sahu

Gehrke

Flores-García

et al. 2020

Preprint

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“…7 Our model of CVac, described in the following text, has been extensively explored immunologically and pharmacokinetically with P. yoelii and the immunization regimen used. 7,8 Of note, P. berghei was not used for reinfection regimens that use TMP-SMX as some strains of P. berghei possess antifolate resistance. 1 In brief, mice were injected three times with 10,000 P. yoelii 17XNL SPZs at 14-to 21-day intervals.…”

Section: Methodsmentioning

confidence: 99%

Determinants of Malaria Protective Immunity in Mice Immunized with Live Sporozoites during Trimethoprim–Sulfamethoxazole Prophylaxis

Hobbs

Sahu

Neal

et al. 2021

The American Journal of Tropical Medicine and Hygiene

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HIV and malaria geographically overlap. Trimethoprim–sulfamethoxazole (TMP-SMX) is a drug widely used in HIV-exposed uninfected and infected children in malaria-endemic areas, and is known to have antimalarial effects. Further study in terms of antimalarial impact and effect on development of malaria-specific immunity is therefore essential. Using rodent malaria models, we previously showed that repeated Plasmodium exposure during TMP-SMX administration, or chemoprophylaxis vaccination (CVac), induces CD8 T-cell–dependent preerythrocytic immunity. However, humoral immune responses have been shown to be important in models of preerythrocytic immunity. Herein, we demonstrate that antibody-mediated responses contribute to protective immunity induced by CVac immune sera using TMP-SMX in models of homologous, but not heterologous, parasite species. Clinical studies must account for potential anti-Plasmodium antibody induced during TMP-SMX prophylaxis.

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“…Peak rainfall varies from year to year, but occurs typically in March/April and October/November. 10 Malaria is meso- to holoendemic with year-round transmission and highest intensity after the rainy seasons or in communities adjacent to lakes and other mosquito breeding sites. 11…”

Section: Methodsmentioning

confidence: 99%

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

Kasule

Gabriel

Anok

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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Abstract.Trimethoprim–sulfamethoxazole (TMP–SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3–12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP–SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP–SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for Plasmodium falciparum with some, but not all, of the reported antifolate resistance mutations reported in Uganda. With TMP–SMX prophylaxis, suboptimal adherence is concerning. Sulfamethoxazole levels below IC50s required to overcome malaria parasites with multiple antifolate resistance mutations may be significant. Further study of TMP–SMX in this context is needed.

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Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

Cited by 9 publications

References 49 publications

Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection

Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection

Determinants of Malaria Protective Immunity in Mice Immunized with Live Sporozoites during Trimethoprim–Sulfamethoxazole Prophylaxis

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

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