BackgroundHeterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI).MethodologyWe conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.ResultsChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC).ConclusionsChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.Trial RegistrationPactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430
To induce a deployable level of efficacy, a successful malaria vaccine would likely benefit from both potent cellular and humoral immunity. These requirements are met by a heterologous prime-boost immunization strategy employing a chimpanzee adenovirus vector followed by modified vaccinia Ankara (MVA), both encoding the pre-erythrocytic malaria antigen ME-thrombospondin-related adhesive protein (TRAP), with high immunogenicity and significant efficacy in UK adults. We undertook two phase 1b open-label studies in adults in Kenya and The Gambia in areas of similar seasonal malaria transmission dynamics and have previously reported safety and basic immunogenicity data. We now report flow cytometry and additional interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) data characterizing pre-existing and induced cellular immunity as well as anti-TRAP IgG responses. T-cell responses induced by vaccination averaged 1,254 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMC) across both trials and flow cytometry revealed cytokine production from both CD4(+) and CD8(+) T cells with the frequency of CD8(+) IFN-γ-secreting monofunctional T cells (previously shown to associate with vaccine efficacy) particularly high in Kenyan adults. Immunization with ChAd63 and MVA ME-TRAP induced strong cellular and humoral immune responses in adults living in two malaria-endemic regions of Africa. This prime-boost approach targeting the pre-erythrocytic stage of the malaria life-cycle is now being assessed for efficacy in a target population.
Placental malaria (PM), a frequent infection of pregnancy, provides an ideal opportunity to investigate the impact on immune development of exposure of the foetal immune system to foreign Ag. We investigated the effect of PM on the regulatory phenotype and function of cord blood cells from healthy Gambian newborns and peripheral blood cells from their mothers, and analyzed for effects on the balance between regulatory and effector responses. Using the gold standard for classifying PM we further distinguished between resolved infection and acute or chronic PM active at the time of delivery. We show that exposure to malarial Ag in utero results in the expansion of malaria-specific FOXP31 Treg and more generalized FOXP3 1 CD4 1 Treg in chronic and resolved PM, alongside increased Th1 pro-inflammatory responses (IFN-c, TNF-a, IFN-c:IL-10) in resolved PM infection only. These observations demonstrate a clear effect of exposure to malarial Ag in foetal life on the immune environment at birth, with a regulatory response dominating in the newborns with ongoing chronic PM, while those with resolved infection produce both regulatory and inflammatory responses. The findings might explain some of the adverse effects on the health of babies born to women with PM.
Malaria remains a significant global health burden and a vaccine would make a substantial contribution to malaria control. Chimpanzee Adenovirus 63 Modified Vaccinia Ankara Multiple epitope thrombospondin adhesion protein (ME-TRAP) and vaccination has shown significant efficacy against malaria sporozoite challenge in malaria-naive European volunteers and against malaria infection in Kenyan adults. Infants are the target age group for malaria vaccination; however, no studies have yet assessed T-cell responses in children and infants. We enrolled 138 Gambian and Burkinabe children in four different age-groups: 2–6 years old in The Gambia; 5–17 months old in Burkina Faso; 5–12 months old, and also 10 weeks old, in The Gambia; and evaluated the safety and immunogenicity of Chimpanzee Adenovirus 63 Modified Vaccinia Ankara ME-TRAP heterologous prime-boost immunization. The vaccines were well tolerated in all age groups with no vaccine-related serious adverse events. T-cell responses to vaccination peaked 7 days after boosting with Modified Vaccinia Ankara, with T-cell responses highest in 10 week-old infants. Heterologous prime-boost immunization with Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara ME-TRAP was well tolerated in infants and children, inducing strong T-cell responses. We identify an approach that induces potent T-cell responses in infants, which may be useful for preventing other infectious diseases requiring cellular immunity.
T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases IntroductionKaposi sarcoma-associated herpesvirus (KSHV) is a lymphotropic human herpesvirus with oncogenic potential. KSHV infects endothelial and B cells where it can cause malignancies of these cell types, namely, Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), respectively, 1 and it is associated with the B-cell pathology multicentric Castleman disease (MCD). The HIV epidemic has made these diseases significantly more prevalent, with KS being the most frequently reported HIV-associated malignancy.An important finding from studying KS patients either with HIV, or those immunosuppressed after solid organ transplantation, is that this malignancy can resolve on restoration of immune function through the administration of highly active antiretroviral therapy (HAART) 2 or relaxation of immunosuppression, 3 respectively. These findings and the increased incidence of PEL and MCD in HIV patients 4 suggest that T-cell immunity is critical for control of KSHV infection and disease. Potential immune targets in KS include the latent antigens, namely, the genome maintenance protein LANA that is expressed in all infected cells and malignancies, the viral cyclin vCyclin, the antiapoptotic multifunctional protein vFLIP, and Kaposin. PELs and infected cells in MCD also express at least 2 other proteins, the viral IL-6 and the immunomodulatory and antiapoptotic protein vIRF3.Relatively low T-cell responses to LANA and Kaposin have been described in healthy immunocompetent donors; 5,6 however, most studies have been undertaken using donors with a disrupted immune system or in disease settings, focusing on responses to LANA and Kaposin. Thus, HIV-infected patients on HAART who control KSHV have been found to make T-cell responses to LANA, MCD patients make responses comparable to HIV patients on HAART, but patients with KS disease have very weak or no detectable responses. [7][8][9][10][11] The administration of HAART to HIVassociated KS patients has been associated with the detection and increase in KSHV-specific responses over time. 2,12 Little is known, however, about the size of responses made to the potential tumor antigens vFLIP or vCyclin in healthy donors or patients with disease.How T-cell control is exercised over KSHV-associated malignancies is unclear, particularly in view of the immune evasion mechanisms used by the virus. Thus, LANA encodes an extensive acidic repeat sequence that inhibits efficient synthesis and proteasomal degradation of itself. 13 This strategy, also used by the Epstein-Barr virus (EBV) homolog EBNA1, 14 limits the supply of peptides for presentation to CD8 ϩ T cells. 15 KSHV-specific T-cell killing of infected endothelial cells has not been tested; however, such in vitro infected cells transiently express K5 16 that functions to down-regulate surface HLA class I and other costimulatory molecules. No studies have been performed on the ability of T cells to recognize KSHV-infected cells fro...
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