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Dive into the research topics where Fenella D. Halstead is active.

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Featured researches published by Fenella D. Halstead.


Nature Communications | 2013

Protective CD8 + T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation

Katie Ewer; Geraldine A. O'Hara; Christopher J. A. Duncan; Katharine A. Collins; Susanne H. Sheehy; Arturo Reyes-Sandoval; Anna L. Goodman; Nick J. Edwards; Sean C. Elias; Fenella D. Halstead; Rhea J. Longley; Rosalind Rowland; Ian D. Poulton; Simon J. Draper; Andrew M. Blagborough; Eleanor Berrie; Sarah Moyle; Nicola Williams; Loredana Siani; Antonella Folgori; Stefano Colloca; Robert E. Sinden; Alison M. Lawrie; Riccardo Cortese; Sarah C. Gilbert; Alfredo Nicosia; Adrian V. S. Hill

Induction of antigen-specific CD8+ T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8+ T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/106 peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8+ T cells, but not antibodies, correlates with sterile protection and delay in time to patency (Pcorrected=0.005). Vaccine-induced CD8+ T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells.


The Journal of Infectious Diseases | 2012

Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector

Geraldine A. O'Hara; Christopher J. A. Duncan; Katie Ewer; Katharine A. Collins; Sean C. Elias; Fenella D. Halstead; Anna L. Goodman; Nick J. Edwards; Arturo Reyes-Sandoval; Prudence Bird; Rosalind Rowland; Susanne H. Sheehy; Ian D. Poulton; Claire Hutchings; Stephen Todryk; Laura Andrews; Antonella Folgori; Eleanor Berrie; Sarah Moyle; Alfredo Nicosia; Stefano Colloca; Riccardo Cortese; Loredana Siani; Alison M. Lawrie; Sarah C. Gilbert; Adrian V. S. Hill

Background. Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8+ T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses. Methods. From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen–specific CD8+ and CD4+ T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 1010 viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination. Conclusions. The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use. Clinical Trials Registration. NCT00890019.


Molecular Therapy | 2012

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans

Susanne H. Sheehy; Christopher J. A. Duncan; Sean C. Elias; Prateek Choudhary; Sumi Biswas; Fenella D. Halstead; Katharine A. Collins; Nick J. Edwards; Alexander D. Douglas; Nicholas A. Anagnostou; Katie Ewer; Tom Havelock; Tabitha Mahungu; Carly M. Bliss; Kazutoyo Miura; Ian D. Poulton; Patrick J. Lillie; Richard D. Antrobus; Eleanor Berrie; Sarah Moyle; Katherine Gantlett; Stefano Colloca; Riccardo Cortese; Carole A. Long; Robert E. Sinden; Sarah C. Gilbert; Alison M. Lawrie; Tom Doherty; Saul N. Faust; Alfredo Nicosia

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.


Molecular Therapy | 2011

Phase Ia clinical evaluation of the Plasmodium falciparum blood-stage antigen MSP1 in ChAd63 and MVA vaccine vectors.

Susanne H. Sheehy; Christopher J. A. Duncan; Sean C. Elias; Katharine A. Collins; Katie Ewer; Alexandra J. Spencer; Andrew R. Williams; Fenella D. Halstead; Samuel E. Moretz; Kazutoyo Miura; Christian Epp; Matthew D. J. Dicks; Ian D. Poulton; Alison M. Lawrie; Eleanor Berrie; Sarah Moyle; Carole A. Long; Stefano Colloca; Riccardo Cortese; Sarah C. Gilbert; Alfredo Nicosia; Adrian V. S. Hill; Simon J. Draper

Efficacy trials of antibody-inducing protein-in-adjuvant vaccines targeting the blood-stage Plasmodium falciparum malaria parasite have so far shown disappointing results. The induction of cell-mediated responses in conjunction with antibody responses is thought to be one alternative strategy that could achieve protective efficacy in humans. Here, we prepared chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient vectors encoding the well-studied P. falciparum blood-stage malaria antigen merozoite surface protein 1 (MSP1). A phase Ia clinical trial was conducted in healthy adults of a ChAd63-MVA MSP1 heterologous prime-boost immunization regime. The vaccine was safe and generally well tolerated. Fewer systemic adverse events (AEs) were observed following ChAd63 MSP1 than MVA MSP1 administration. Exceptionally strong T-cell responses were induced, and these displayed a mixed of CD4(+) and CD8(+) phenotype. Substantial MSP1-specific serum immunoglobulin G (IgG) antibody responses were also induced, which were capable of recognizing native parasite antigen, but these did not reach titers sufficient to neutralize P. falciparum parasites in vitro. This viral vectored vaccine regime is thus a leading approach for the induction of strong cellular and humoral immunogenicity against difficult disease targets in humans. Further studies are required to assess whether this strategy can achieve protective efficacy against blood-stage malaria infection.


PLOS ONE | 2012

Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.

Susanne H. Sheehy; Christopher J. A. Duncan; Sean C. Elias; Sumi Biswas; Katharine A. Collins; Geraldine A. O'Hara; Fenella D. Halstead; Katie Ewer; Tabitha Mahungu; Alexandra J. Spencer; Kazutoyo Miura; Ian D. Poulton; Matthew D. J. Dicks; Nick J. Edwards; Eleanor Berrie; Sarah Moyle; Stefano Colloca; Riccardo Cortese; Katherine Gantlett; Carole A. Long; Alison M. Lawrie; Sarah C. Gilbert; Tom Doherty; Alfredo Nicosia; Adrian V. S. Hill; Simon J. Draper

Background Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question. Methodology We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4+/CD8+ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro. Conclusions ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection. Trial Registration ClinicalTrials.gov NCT01095055


PLOS ONE | 2011

Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

Christopher J. A. Duncan; Susanne H. Sheehy; Katie Ewer; Alexander D. Douglas; Katharine A. Collins; Fenella D. Halstead; Sean C. Elias; Patrick J. Lillie; Kelly M. Rausch; Joan Aebig; Kazutoyo Miura; Nick J. Edwards; Ian D. Poulton; Angela Hunt-Cooke; David Porter; Fiona M. Thompson; Ros Rowland; Simon J. Draper; Sarah C. Gilbert; Michael P. Fay; Carole A. Long; Daming Zhu; Yimin Wu; Laura B. Martin; Charles Anderson; Alison M. Lawrie; Adrian V. S. Hill; Ruth D. Ellis

Background Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. Methods In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. Results A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = −0.93 [95% CI: −1.0, −0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = −0.93 [95% CI: −0.99, −0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5–9], control group median 9 days [range 7–9]). Conclusions Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. Trial Registration ClinicalTrials.gov [NCT00984763]


PLOS ONE | 2014

Assessment of Humoral Immune Responses to Blood-Stage Malaria Antigens following ChAd63-MVA Immunization, Controlled Human Malaria Infection and Natural Exposure

Sumi Biswas; Prateek Choudhary; Sean C. Elias; Kazutoyo Miura; Kathryn H. Milne; Simone C. de Cassan; Katharine A. Collins; Fenella D. Halstead; Carly M. Bliss; Katie Ewer; Faith Osier; Susanne H. Hodgson; Christopher J. A. Duncan; Geraldine O’Hara; Carole A. Long; Adrian V. S. Hill; Simon J. Draper

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite – MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors – ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.


The Journal of Infectious Diseases | 2016

Demonstration of the blood-stage plasmodium falciparum controlled human malaria infection model to assess efficacy of the p. falciparum apical membrane antigen 1 Vaccine, FMP2.1/AS01

Ruth O. Payne; Kathryn H. Milne; Sean C. Elias; Nick J. Edwards; Alexander D. Douglas; Rebecca E. Brown; Sarah E. Silk; Sumi Biswas; Kazutoyo Miura; Rachel Roberts; Tommy Rampling; Navin Venkatraman; Susanne H. Hodgson; Geneviève M. Labbé; Fenella D. Halstead; Ian D. Poulton; Fay L. Nugent; H. de Graaf; Priya Sukhtankar; Nicola Williams; Christian F. Ockenhouse; April K. Kathcart; A N Qabar; Norman C. Waters; L A Soisson; A J Birkett; Graham S. Cooke; Saul N. Faust; C Woods; Karen Ivinson

BACKGROUND Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. METHODS Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. RESULTS FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. CONCLUSIONS FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. CLINICAL TRIALS REGISTRATION NCT02044198.


Immunology | 2014

Analysis of human B-cell responses following ChAd63-MVA MSP1 and AMA1 immunization and controlled malaria infection.

Sean C. Elias; Prateek Choudhary; Simone C. de Cassan; Sumi Biswas; Katharine A. Collins; Fenella D. Halstead; Carly M. Bliss; Katie Ewer; Susanne H. Hodgson; Christopher J. A. Duncan; Adrian V. S. Hill; Simon J. Draper

Acquisition of non‐sterilizing natural immunity to Plasmodium falciparum malaria has been shown in low transmission areas following multiple exposures. However, conflicting data from endemic areas suggest that the parasite may interfere with the induction of effective B‐cell responses. To date, the impact of blood‐stage parasite exposure on antigen‐specific B cells has not been reported following controlled human malaria infection (CHMI). Here we analysed human B‐cell responses in a series of Phase I/IIa clinical trials, which include CHMI, using candidate virus‐vectored vaccines encoding two blood‐stage antigens: merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1). Previously vaccinated volunteers show boosting of pre‐existing antigen‐specific memory B‐cell (mBC) responses following CHMI. In contrast, unvaccinated malaria‐naive control volunteers developed an mBC response against MSP1 but not AMA1. Serum IgG correlated with the mBC response after booster vaccination but this relationship was less well maintained following CHMI. A significant reduction in peripheral MSP1‐specific mBC was observed at the point of diagnosis of blood‐stage infection. This was coincident with a reduction in peripheral blood B‐cell subsets expressing CXCR3 and elevated serum levels of interferon‐γ and CXCL9, suggesting migration away from the periphery. These CHMI data confirm that mBC and antibody responses can be induced and boosted by blood‐stage parasite exposure, in support of epidemiological studies on low‐level parasite exposure.


Journal of Immunology | 2013

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

Sean C. Elias; Katharine A. Collins; Fenella D. Halstead; Prateek Choudhary; Carly M. Bliss; Katie Ewer; Susanne H. Sheehy; Christopher J. A. Duncan; Sumi Biswas; Adrian V. S. Hill; Simon J. Draper

Overcoming antigenic variation is one of the major challenges in the development of an effective vaccine against Plasmodium falciparum, a causative agent of human malaria. Inclusion of multiple Ag variants in subunit vaccine candidates is one strategy that has aimed to overcome this problem for the leading blood-stage malaria vaccine targets, that is, merozoite surface protein 1 (MSP1) and apical membrane Ag 1 (AMA1). However, previous studies, utilizing malaria Ags, have concluded that inclusion of multiple allelic variants, encoding altered peptide ligands, in such a vaccine may be detrimental to both the priming and in vivo restimulation of Ag-experienced T cells. In this study, we analyze the T cell responses to two alleles of MSP1 and AMA1 induced by vaccination of malaria-naive adult volunteers with bivalent viral-vectored vaccine candidates. We show a significant bias to the 3D7/MAD20 allele compared with the Wellcome allele for the 33 kDa region of MSP1, but not for the 19 kDa fragment or the AMA1 Ag. Although this bias could be caused by “immune interference” at priming, the data do not support a significant role for “immune antagonism” during memory T cell restimulation, despite observation of the latter at a minimal epitope level in vitro. A lack of class I HLA epitopes in the Wellcome allele that are recognized by vaccinated volunteers may in fact contribute to the observed bias. We also show that controlled infection with 3D7 strain P. falciparum parasites neither boosts existing 3D7-specific T cell responses nor appears to “immune divert” cellular responses toward the Wellcome allele.

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