<i>Plasmodium yoelii</i> Can Ablate Vaccine-Induced Long-Term Protection in Mice

Wykes, Michelle N.; Zhou, Yonghong; Liu, Xue Q.; Good, Michael F.

doi:10.4049/jimmunol.175.4.2510

Cited by 84 publications

(134 citation statements)

References 45 publications

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“…In this study, we showed that mBC levels increased significantly postimmunization at the time points assessed and that these responses correlated with longer-term serum IgG levels, similar to that seen with the AMA1 protein vaccine in a phase Ia clinical trial (63). Although the direct role for these cells in immediate and long-term immunity to malaria remains unclear (27,28,67), their evaluation in blood-stage malaria vaccine clinical trials is becoming more routine (63,68,69). Such studies should shed more light on the role that these cells play in the maintenance and boostability of vaccine-induced IgG responses and how these cells are modulated by chronic malaria infection.…”

Section: Discussionmentioning

confidence: 71%

“…Studies of naturally acquired immunity and experimental immunization in humans and animal models have painted a complex picture (14), with protection associated with Abs against merozoite Ags (15), specific IgG isotypes (16), T cells against blood-stage parasites (17)(18)(19)(20), innate effector cell types (21)(22)(23), serum cytokines (21,24), and regulatory T cells (25). Numerous other studies described the immunomodulatory effects of parasite exposure on T and B lymphocyte populations (26)(27)(28). It is perhaps not surprising that single-modality vaccine platforms, aiming to induce a single type of immune response, have failed to impact on the blood-stage growth rates of P. falciparum in clinical trials.…”

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confidence: 99%

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Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

Draper

Biswas

Spencer

et al. 2010

The Journal of Immunology

109

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Protein-in-adjuvant formulations and viral-vectored vaccines encoding blood-stage malaria Ags have shown efficacy in rodent malaria models and in vitro assays against Plasmodium falciparum. Abs and CD4+ T cell responses are associated with protective efficacy against blood-stage malaria, whereas CD8+ T cells against some classical blood-stage Ags can also have a protective effect against liver-stage parasites. No subunit vaccine strategy alone has generated demonstrable high-level efficacy against blood-stage infection in clinical trials. The induction of high-level Ab responses, as well as potent T and B cell effector and memory populations, is likely to be essential to achieve immediate and sustained protective efficacy in humans. This study describes in detail the immunogenicity of vaccines against P. falciparum apical membrane Ag 1 in rhesus macaques (Macaca mulatta), including the chimpanzee adenovirus 63 (AdCh63), the poxvirus modified vaccinia virus Ankara (MVA), and protein vaccines formulated in Alhydrogel or CoVaccine HT adjuvants. AdCh63-MVA heterologous prime-boost immunization induces strong and long-lasting multifunctional CD8+ and CD4+ T cell responses that exhibit a central memory-like phenotype. Three-shot (AdCh63-MVA-protein) or two-shot (AdCh63-protein) regimens induce memory B cells and high-titer functional IgG responses that inhibit the growth of two divergent strains of P. falciparum in vitro. Prior immunization with adenoviral vectors of alternative human or simian serotype does not affect the immunogenicity of the AdCh63 apical membrane Ag 1 vaccine. These data encourage the further clinical development and coadministration of protein and viral vector vaccine platforms in an attempt to induce broad cellular and humoral immune responses against blood-stage malaria Ags in humans.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

Draper

Biswas

Spencer

et al. 2010

The Journal of Immunology

109

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“…iRBCs have been shown to cause apoptosis of B cells, T cells, macrophages, and endothelial cells in human in vitro studies and in animal malaria models (10,15,16,33,48,55,56), and a recent study found that the majority of CD8 ϩ splenic DCs harvested from Plasmodium chabaudi-infected mice were apoptotic (45). Apoptosis of DC subsets could interfere with developing antimalarial immune responses, and further studies are required to establish the physiological relevance of our observation and elucidate the mechanism.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

et al. 2007

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Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36-and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both innate and adaptive immune responses and play a critical role in the initiation of primary T-cell responses. To function effectively as antigen-presenting cells, they undergo a process of maturation, characterized by increased expression of costimulator, major histocompatibility complex and adhesion molecules, and secretion of proinflammatory cytokines (reviewed in reference 35). DC maturation is usually activated by pathogens through ligation of pattern recognition receptors, such as Toll-like receptors, but may also be initiated by inflammatory cytokines and endogenous signals of cellular damage (reviewed in references 29 and 34).It has been suggested that modulation of DC function by the malaria parasite Plasmodium falciparum contributes to both the delayed acquisition of antimalarial immunity as well as immunosuppression associated with acute malaria infection. Urban et al. (50,52) showed that red blood cells infected with P. falciparum (iRBCs) at 100 iRBCs per DC inhibit maturation of human monocyte-derived DCs and interfere with their ability to activate T-cell responses. Interaction between the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surfaces of iRBCs, and the DC scavenger receptor...

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“…Kinyanjui et al (38) showed that IgG responses in Kenyan children following (41) showed that human B cell memory and long-lived Ab levels expand gradually with repeated infections. In mice, although some studies have shown normal development of memory B cell responses during Plasmodium infection (22,42), others have shown defects in memory B cell generation or maintenance (43,44). Crompton and colleagues (45) also have suggested that P. falciparum drives short-lived plasma cell responses, which may explain why Ab levels are not maintained in the absence of repeated exposures, and because memory B cell and plasma cell responses are regulated independently of each other, the presence of memory B cells may not be required to maintain serum Ab levels.…”

Section: Discussionmentioning

confidence: 99%

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

Wilmore

Maue

Lefebvre

et al. 2013

The Journal of Immunology

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High rates of coinfection occur in malaria endemic regions, leading to more severe disease outcomes. Understanding how coinfecting pathogens influence the immune system is important in the development of treatment strategies that reduce morbidity and mortality. Using the Plasmodium chabaudi mouse model of malaria and immunization with model Ags that are either T-dependent (4-hydroxy-3-nitrophenyl [NP]-OVA) or T-independent (NP-Ficoll), we analyzed the effects of acute malaria on the development of humoral immunity to secondary Ags. Total Ig and IgG1 NP–specific Ab responses to NP-OVA were significantly decreased in the P. chabaudi–infected group compared with the uninfected group, whereas NP-specific IgG2c Ab was significantly increased in the P. chabaudi–infected group. In contrast, following injection with T-independent NP-Ficoll, the P. chabaudi–infected group had significantly increased NP-specific total Ig, IgM, and IgG2c Ab titers compared with controls. Treatment with anti–IFN-γ led to an abrogation of the NP-specific IgG2c Ab induced by P. chabaudi infection but did not affect other NP-specific Ab isotypes or titers. IFN-γ depletion also increased the percentage of plasma cells in both P. chabaudi–infected and uninfected groups but decreased the percentage of B cells with a germinal center (GC) phenotype. Using immunofluorescent microscopy, we were able to detect NP+ GCs in the spleens of noninfected mice, but there were no detectible NP+ GCs in mice infected with P. chabaudi. These data suggest that during P. chabaudi infection, there is a shift toward an extrafollicular Ab response that could be responsible for decreased Ab responses to secondary T-dependent Ags.

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Plasmodium yoelii Can Ablate Vaccine-Induced Long-Term Protection in Mice

Cited by 84 publications

References 45 publications

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

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