Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages

Thomas, Alan W.; Slierendregt, B. L.; Mons, Barend; Druilhe, Pierre

doi:10.1590/s0074-02761994000600023

Cited by 6 publications

(2 citation statements)

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“…In the face of increasing resistance of Plasmodium parasites to anti-malarial (prophylactic) drugs, development of an effective malaria vaccine is generally considered a public health priority [2]. Feasibility of a successful malaria vaccine has been demonstrated by immunization with irradiated sporozoites and subsequent malaria infection in rodent, non-human primate and human models [3-5]. Furthermore, natural long-term exposure to the parasite is associated with an age-related decrease in the incidence, prevalence and density of infection [6].…”

Section: Introductionmentioning

confidence: 99%

Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques

Hamid

Remarque

Hassan

et al. 2011

Malar J

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BackgroundA DNA prime, poxvirus (COPAK) boost vaccination regime with four antigens, i.e. a combination of two Plasmodium knowlesi sporozoite (csp/ssp2) and two blood stage (ama1/msp142) genes, leads to self-limited parasitaemia in 60% of rhesus monkeys and survival from an otherwise lethal infection with P. knowlesi. In the present study, the role of the blood stage antigens in protection was studied in depth, focusing on antibody formation against the blood stage antigens and the functionality thereof.MethodsRhesus macaques were immunized with the four-component vaccine and subsequently challenged i.v. with 100 P. knowlesi sporozoites. During immunization and challenge, antibody titres against the two blood stage antigens were determined, as well as the in vitro growth inhibition capacity of those antibodies. Antigen reversal experiments were performed to determine the relative contribution of antibodies against each of the two blood stage antigens to the inhibition.ResultsAfter vaccination, PkAMA1 and PkMSP119 antibody titres in vaccinated animals were low, which was reflected in low levels of inhibition by these antibodies as determined by in vitro inhibition assays. Interestingly, after sporozoite challenge antibody titres against blood stage antigens were boosted over 30-fold in both protected and not protected animals. The in vitro inhibition levels increased to high levels (median inhibitions of 59% and 56% at 6 mg/mL total IgG, respectively). As growth inhibition levels were not significantly different between protected and not protected animals, the ability to control infection appeared cannot be explained by GIA levels. Judged by in vitro antigen reversal growth inhibition assays, over 85% of the inhibitory activity of these antibodies was directed against PkAMA1.ConclusionsThis is the first report that demonstrates that a DNA prime/poxvirus boost vaccination regimen induces low levels of malaria parasite growth inhibitory antibodies, which are boosted to high levels upon challenge. No association could, however, be established between the levels of inhibitory capacity in vitro and protection, either after vaccination or after challenge.

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Section: Introductionmentioning

confidence: 99%

Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques

Hamid

Remarque

Hassan

et al. 2011

Malar J

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“…The demonstration of T-cell-mediated protection in mice immunized by this means (10,16), the acquisition of a significant level of protection against homologous Plasmodium falciparum challenge in human volunteers (22), and the induction by liver-stage antigens of a high level of protection against P. falciparum infection in chimpanzees (19,31) all point to a major role for preerythrocytic stage antigens as vaccine candidates.…”

mentioning

confidence: 99%

Evidence for Multiple B- and T-Cell Epitopes inPlasmodium falciparumLiver-Stage Antigen 3

et al. 2009

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Liver-stage antigen 3 (LSA-3) is a new vaccine candidate that can induce protection against Plasmodium falciparum sporozoite challenge. Using a series of long synthetic peptides (LSP) encompassing most of the 210-kDa LSA-3 protein, a study of the antigenicity of this protein was carried out in 203 inhabitants from the villages of Dielmo (n ‫؍‬ 143) and Ndiop (n ‫؍‬ 60) in Senegal (the level of malaria transmission differs in these two villages). Lymphocyte responses to each individual LSA-3 peptide were recorded, some at high prevalences (up to 43%). Antibodies were also detected to each of the 20 peptides, many at high prevalence (up to 84% of responders), and were directed to both nonrepeat and repeat regions. Immune responses to LSA-3 were detectable even in individuals of less than 5 years of age and increased with age and hence exposure to malaria, although they were not directly related to the level of malaria transmission. Thus, several valuable T-and B-cell epitopes were characterized all along the LSA-3 protein, supporting the antigenicity of this P. falciparum vaccine candidate. Finally, antibodies specific for peptide LSP10 located in a nonrepeat region of LSA-3 were found significantly associated with a lower risk of malaria attack over 1 year of daily clinical follow-up in children between the ages of 7 and 15 years, but not in older individuals.Preerythrocytic malaria antigens are critical targets of protective immune responses induced by irradiated sporozoites in humans (9,22). The demonstration of T-cell-mediated protection in mice immunized by this means (10, 16), the acquisition of a significant level of protection against homologous Plasmodium falciparum challenge in human volunteers (22), and the induction by liver-stage antigens of a high level of protection against P. falciparum infection in chimpanzees (19, 31) all point to a major role for preerythrocytic stage antigens as vaccine candidates.Liver-stage antigen 3 (LSA-3) is a novel antigen expressed at the preerythrocytic stages (4). LSA-3 was selected by the differential immune response found between protected and nonprotected volunteers, both similarly immunized with irradiated sporozoites (4, 9). The gene encoding LSA-3 is unusually wellconserved (4), in contrast with many other malaria vaccine candidates (11,19,23). More than 10 dominant T-helper (Th), cytotoxic T-lymphocyte, and B-cell epitopes have already been characterized in , some of them displaying crossreactivity with an homologous antigen in Plasmodium yoelii (2). The protective potential of LSA-3 was demonstrated by a series of experiments in chimpanzees and Aotus monkeys challenged with P. falciparum (4, 21) and in mice challenged by P. yoelii following immunization either by recombinant proteins with adjuvant or by formulations without adjuvant, such as recombinant proteins adsorbed on microparticles or lipopeptides in phosphate-buffered saline (PBS) (4), or DNA-based immunization (29). These convergent results stress the potential of LSA-3 as a prime vaccine candidate.We ...

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Plasmodium vivax infection induces expansion of activated naïve/memory T cells and differentiation into a central memory profile

Silva

Lacerda

Fujiwara

et al. 2013

Microbes and Infection

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Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we characterized the profile of circulating naïve and memory (including central and effector) CD4⁺ T cells responses of individuals naturally infected by Plasmodium vivax. In the current study, we demonstrated that acute P. vivax infection induces a significant increase in the absolute number of both naïve and memory cells, which were responsible for the production of anti-inflammatory (IL-10) and pro-inflammatory (IFN-γ) cytokines. Finally, we described the profile of memory cell subtypes (T(CM)-CD45RO(high)CCR7⁺ and T(EM)-CD45RO(high)CCR7⁻), as well as the pattern of cell migration based on CD62L selectin expression, demonstrating that P. vivax-infected donors presented with a predominantly central memory cell profile. Our results indicate that the expansion of both naïve and memory T cells, responsible for the production of both pro-inflammatory and regulatory cytokines, which might also contribute to the modulation of immune responses during P. vivax infection.

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Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages

Cited by 6 publications

References 0 publications

Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques

Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques

Evidence for Multiple B- and T-Cell Epitopes inPlasmodium falciparumLiver-Stage Antigen 3

Plasmodium vivax infection induces expansion of activated naïve/memory T cells and differentiation into a central memory profile

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