Controlled Infection Immunization Using Delayed Death Drug Treatment Elicits Protective Immune Responses to Blood-Stage Malaria Parasites

Low, Leanne M.; Ssemaganda, Aloysious; Liu, Xue Q.; Ho, Mei‐Fong; Ozberk, Victoria; Fink, James; Sundac, Lana; Alcorn, Kylie; Morrison, Amy C.; O’Callaghan, Kevin; Gerrard, John; Stanisic, Danielle I.; Good, Michael F.

doi:10.1128/iai.00587-18

Cited by 13 publications

(14 citation statements)

References 98 publications

(119 reference statements)

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“…We reviewed 14 publications of interest concerning Pf SPZ challenge by systemic administration in nonimmune healthy participants. 58 , 66 – 78 Laboratory safety data were often absent or insufficiently detailed during the timeframe of interest. When adverse events categorized under investigations or laboratory safety data were provided, aminotransferase elevations above the ULN were noted in nonimmune individuals at a rate of 0–61%.…”

Section: Discussion Of Prior Evidence For Liver Enzyme Elevations In mentioning

confidence: 99%

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations

Chughlay

Akakpo

Odedra

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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. Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum . Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5–5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.

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Section: Discussion Of Prior Evidence For Liver Enzyme Elevations In mentioning

confidence: 99%

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations

Chughlay

Akakpo

Odedra

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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“…In vivo, this has been achieved by creating a persistent subpatent blood-stage infection using a low dose of malaria parasite followed by treatment with anti-malaria drugs, which induces sterile protection against both high-dose homologous and heterologous blood-stage challenge (Pombo et al, 2002;Elliott et al, 2005). In vitro, several approaches have been used to chemically attenuate the blood stage, such as treatment with the parasite DNA-binding drugs centanamycin (CM; Good et al, 2013) and tafuramycin-A (TF-A; Stanisic et al, 2018), or the delayed death-causing drugs doxycycline or azithromycin (Low et al, 2019). The vaccination of in vitro chemically attenuated blood stage has also been reported to induce protective immunity against both homologous and heterologous blood-stage challenges (Good et al, 2013;Raja et al, 2016;Low et al, 2019).…”

Section: Promising Malaria Vaccine: Whole-parasite Blood-stage Vaccinementioning

confidence: 99%

Whole-Killed Blood-Stage Vaccine: Is It Worthwhile to Further Develop It to Control Malaria?

et al. 2021

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Major challenges have been encountered regarding the development of highly efficient subunit malaria vaccines, and so whole-parasite vaccines have regained attention in recent years. The whole-killed blood-stage vaccine (WKV) is advantageous as it can be easily manufactured and efficiently induced protective immunity against a blood-stage challenge, as well as inducing cross-stage protection against both the liver and sexual-stages. However, it necessitates a high dose of parasitized red blood cell (pRBC) lysate for immunization, and this raises concerns regarding its safety and low immunogenicity. Knowledge of the major components of WKV that can induce or evade the host immune response, and the development of appropriate human-compatible adjuvants will greatly help to optimize the WKV. Therefore, we argue that the further development of the WKV is worthwhile to control and potentially eradicate malaria worldwide.

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“…P. chabaudi immunization did not protect against P. yoelii challenge in outbred CD-1 mice (32), whereas partial protection was observed in BALB/c mice, and complete protection in C57BL/6 and CBA mice (33). More recently, this was observed using a different vaccination scheme termed 'controlled infection immunization' where mice were immunized with one species while under doxycycline chemoprophylaxis then challenged with the heterologous species (34). C57BL/6 mice immunized with P. chabaudi or P. yoelii promoted survival following heterologous challenge with the reciprocal parasite (34).…”

Section: Infections In Experimental Animalsmentioning

confidence: 99%

“…More recently, this was observed using a different vaccination scheme termed 'controlled infection immunization' where mice were immunized with one species while under doxycycline chemoprophylaxis then challenged with the heterologous species (34). C57BL/6 mice immunized with P. chabaudi or P. yoelii promoted survival following heterologous challenge with the reciprocal parasite (34). While in BALB/c mice, protection was non-reciprocal; only P. chabaudi immunization could protect against P. yoelii, mirroring the findings from the older study.…”

Section: Infections In Experimental Animalsmentioning

confidence: 99%

The Case for Exploiting Cross-Species Epitopes in Malaria Vaccine Design

Mitran

Yanow

2020

Front. Immunol.

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The infection dynamics between different species of Plasmodium that infect the same human host can both suppress and exacerbate disease. This could arise from inter-parasite interactions, such as competition, from immune regulation, or both. The occurrence of protective, cross-species (heterologous) immunity is an unlikely event, especially considering that strain-transcending immunity within a species is only partial despite lifelong exposure to that species. Here we review the literature in humans and animal models to identify the contexts where heterologous immunity can arise, and which antigens may be involved. From the perspective of vaccine design, understanding the mechanisms by which exposure to an antigen from one species can elicit a protective response to another species offers an alternative strategy to conventional approaches that focus on immunodominant antigens within a single species. The underlying hypothesis is that certain epitopes are conserved across evolution, in sequence or in structure, and shared in antigens from different species. Vaccines that focus on conserved epitopes may overcome the challenges posed by polymorphic immunodominant antigens; but to uncover these epitopes requires approaches that consider the evolutionary history of protein families across species. The key question for vaccinologists will be whether vaccines that express these epitopes can elicit immune responses that are functional and contribute to protection against Plasmodium parasites.

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Controlled Infection Immunization Using Delayed Death Drug Treatment Elicits Protective Immune Responses to Blood-Stage Malaria Parasites

Abstract: Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium. This develops as a result of repeated natural infection, taking several years to develop.

Cited by 13 publications

References 98 publications

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations

Whole-Killed Blood-Stage Vaccine: Is It Worthwhile to Further Develop It to Control Malaria?

The Case for Exploiting Cross-Species Epitopes in Malaria Vaccine Design

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