Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara

Webster, Daniel P.; Dunachie, Susanna; Vuola, Jenni M.; Berthoud, Tamara; Keating, Sheila M.; Laidlaw, Stephen M.; McConkey, Samuel; Poulton, Ian; Andrews, Laura; Andersen, Rikke Fredslund; Bejon, Philip; Butcher, G. A.; Sinden, Robert E.; Skinner, Michael A.; Gilbert, Sarah C.; Hill, Adrian V. S.

doi:10.1073/pnas.0406381102

Cited by 229 publications

(227 citation statements)

References 43 publications

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“…Host survival requires that the immune response is sufficient to control parasitemia, but does not cause excessive immunopathology [3]. A protective role for IFN-g-secreting effector T cells is well established and has been exploited in numerous vaccination approaches [4][5][6]. Indeed, in one particular study volunteers were immunized with low doses of Plasmodium-infected RBC (iRBC), and they produced T-cell IFN-g responses against blood-stage Ag that were associated with protection from challenge in the absence of Ab responses [7].…”

Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-c, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-c cultured ELISPOT, were low and unstable over time, despite CD4 1 T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-b, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-c measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.

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Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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“…Although the mouse in general and our approach specifically may have limitations as a preclinical model, the results still may have relevance for understanding why subunit vaccines that evoke sterilizing immunity against human malaria have been difficult to obtain. For example, accumulating data from human clinical trials show that current prime-boost immunizations generate Plasmodium-specific T cell responses in the range of 0.1% of PBL at the peak after boosting and Ͻ0.01% at memory stages (20,(33)(34)(35)(36). These frequencies are 10-fold and 100-fold lower than required to protect mice from Plasmodium infection and consist mainly of CD4 T cells, which may explain why these vaccines delay the onset but rarely prevent blood-stage parasitemia (20,36).…”

Section: Discussionmentioning

confidence: 99%

“…For example, accumulating data from human clinical trials show that current prime-boost immunizations generate Plasmodium-specific T cell responses in the range of 0.1% of PBL at the peak after boosting and Ͻ0.01% at memory stages (20,(33)(34)(35)(36). These frequencies are 10-fold and 100-fold lower than required to protect mice from Plasmodium infection and consist mainly of CD4 T cells, which may explain why these vaccines delay the onset but rarely prevent blood-stage parasitemia (20,36). Clearly, delayed onset of blood-stage parasitemia indicates partial protection by these vaccines, and such partial protection could have real benefits in malaria-endemic areas.…”

Section: Discussionmentioning

confidence: 99%

“…Immunity in rodents can last for 6-12 months (3,4,7,13), but in several studies also seems to wane with time (7,(14)(15)(16). Although irradiated sporozoite vaccines also protect humans (17)(18)(19), current subunit vaccinations limit liver-stage infection but rarely prevent blood-stage parasitemia (20). Importantly, it remains unknown whether sterilizing long-term immunity to Plasmodium infection can be achieved through subunit vaccines that predominantly evoke memory CD8 T cell responses and, if so, precisely what memory T cell parameters will be required.…”

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confidence: 99%

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Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria

Schmidt

Podyminogin

Butler

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Infection of mice with sporozoites of Plasmodium berghei or Plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. Unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. Thus, mice may be used better as models to dissect basic parameters required for immunity to Plasmodium-infection than as preclinical vaccine models. In turn, this basic information may aid in the rational design of malaria vaccines. Here, we describe a model of circumsporozoite-specific memory CD8 T cell generation that protects mice against multiple P. berghei sporozoite challenges for at least 19 months. Using this model we defined a threshold frequency of memory CD8 T cells in the blood that predicts long-term sterilizing immunity against liver-stage infection. Importantly, the number of Plasmodium-specific memory CD8 T cells required for immunity greatly exceeds the number required for resistance to other pathogens. In addition, this model allowed us to identify readily individual immunized mice that exceed or fall below the protective threshold before infection, information that should greatly facilitate studies to dissect basic mechanisms of protective CD8 T cell memory against liver-stage Plasmodium infection. Furthermore, the extremely large threshold in memory CD8 T cell frequencies required for long-term protection in mice may have important implications for development of effective malaria vaccines.

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“…ME-TRAP, a heterologous prime-boost vaccine encoding the TRAP antigen and a string of T-cell epitopes from various preerythrocytic antigens, offered 10 per cent efficacy against infection in Gambian adults in a Phase II trial [46]. However, protection from P. falciparum infection owing to ME-TRAP is associated with high levels of interferon-g secreting T-cells [47], rather than IgG antibody titres, which were not explicitly included in our model. One limitation of our current model is the assumption that non-antibody mechanisms of protection such as cell-mediated immunity can be described by a constant factor r 0 .…”

Section: Discussionmentioning

confidence: 99%

Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

et al. 2010

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Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semiimmune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccineinduced antibody titres, then single-component CSP or TRAP antibody-mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome.

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Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara

Cited by 229 publications

References 43 publications

Multiple functions of human T cells generated by experimental malaria challenge

Multiple functions of human T cells generated by experimental malaria challenge

Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria

Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

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