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Murine infection models for vaccine development: the malaria example.

ABSTRACT: Vaccines are developed and eventually licensed following consecutive human clinical trials. Malaria is a potential fatal vector-borne infectious disease caused by blood infection of the single-cell eukaryote Plasmodium. Pathogen stage conversion is a hallmark of parasites in general and permits unprecedented vaccine strategies. In the case of malaria, experimental human challenge infections with Plasmodium falciparum sporozoites can be performed under rigorous clinical supervision. This rare opportunity in vaccinology has permitted many small-scale phase II anti-malaria vaccine studies using experimental homologous challenge infections. Demonstration of safety and lasting sterile protection are central endpoints to advance a candidate malaria vaccine approach to phase II field trials. A growing list of antigens as targets for subunit development makes pre-selection and prioritization of vaccine candidates in murine infection models increasingly important. Preclinical assessment in challenge studies with murine Plasmodium species also led to the development of whole organism vaccine approaches. They include live attenuated, metabolically active parasites that educate effector memory T cells to recognize and inactivate developing parasites inside host cells. Here, opportunities from integrating challenge experiments with murine Plasmodium parasites into malaria vaccine development will be discussed.

SUBMITTER: Matuschewski K

PROVIDER: S-EPMC3891699 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Murine infection models for vaccine development: the malaria example.

Matuschewski Kai K

Human vaccines & immunotherapeutics 20121218 3

Vaccines are developed and eventually licensed following consecutive human clinical trials. Malaria is a potential fatal vector-borne infectious disease caused by blood infection of the single-cell eukaryote Plasmodium. Pathogen stage conversion is a hallmark of parasites in general and permits unprecedented vaccine strategies. In the case of malaria, experimental human challenge infections with Plasmodium falciparum sporozoites can be performed under rigorous clinical supervision. This rare opp ...[more]

PMID: 23249712

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Project description:Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines.

Dataset Information

Murine infection models for vaccine development: the malaria example.

Publications

Murine infection models for vaccine development: the malaria example.

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