62 results on '"Poulton I"'
Search Results
2. Safety and immunogenicity of a replication deficient simian adenoviral vectored chikungunya vaccine: A phase I, first-in-human, dose escalation trial
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Folegatti, PM, Harrison, K, Lopez, KR, Tilley, MW, Lopez-Camacho, C, Kim, YC, Preciado-Llanes, L, Rossi, SL, Poulton, I, Jenkin, D, Datoo, M, Themistocleous, Y, Lawrie, A, Roberts, R, Ewer, K, Berrie, E, Hill, A, and Reyes-Sandoval, A
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- 2020
3. Safety of recombinant fowlpox strain FP9 and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers
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Webster, D.P., Dunachie, S., McConkey, S., Poulton, I., Moore, A.C., Walther, M., Laidlaw, S.M., Peto, T., Skinner, M.A., Gilbert, S.C., and Hill, A.V.S.
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- 2006
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4. 682P Results from ADVANCE: A phase I/II open-label non-randomised safety and efficacy study of the viral vectored ChAdOx1-MVA 5T4 (VTP-800) vaccine in combination with PD-1 checkpoint blockade in metastatic prostate cancer
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Tuthill, M., primary, Cappuccini, F., additional, Carter, L., additional, Pollock, E., additional, Poulton, I., additional, Verrill, C., additional, Evans, T., additional, Gillessen, S., additional, Attard, G., additional, Protheroe, A., additional, Hamdy, F., additional, Hill, A.V.S., additional, and Redchenko, I., additional
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- 2020
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5. Efficacy of the novel Plasmodium falciparum blood-stage vaccine RH5.1/AS01B in a phase I/IIA clinical trial
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Minassian, A, Silk, S, Poulton, I, Mitton, C, Payne, R, Rawlinson, T, Barrett, J, Baker, M, Ramon, R, Lopez, F, Edwards, N, Ellis, K, Nielsen, C, Quinkert, D, Barfod, L, Miura, K, Diouf, A, Folegatti, P, Silman, D, Datoo, M, Smith, R, Berrie, E, Morelle, D, Lievens, M, Noe, A, Diggs, C, Soisson, L, Ashfield, R, Long, C, Nugent, F, Lawrie, A, and Draper, S
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- 2019
6. Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured onthe AGE1.CR.pIX Avian Cell Line
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Folegatti, P, Bellamy, D, Flaxman, A, Mair, C, Ellis, C, Ramon, R, Lopez, F, Mitton, C, Baker, M, Poulton, I, Lawrie, A, Roberts, R, Minassian, A, Ewer, K, Evans, T, Hill, A, and Gilbert, S
- Abstract
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines.
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- 2019
7. A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults
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Minhinnick, A, Satti, I, Harris, SC, Wilkie, MEM, Sheehan, S, Stockdale, L, Lopez-Ramon, R, Poulton, I, Lawrie, AM, Vermaak, SJ, Le Vert, A, Del Campo, J, Hill, F, Moss, P, McShane, H, and Manjaly Thomas, Z-R
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Adult ,Male ,Enzyme-Linked Immunospot Assay ,Enzyme-Linked Immunosorbent Assay ,Article ,Young Adult ,Immunology and Microbiology(all) ,Vaccines, DNA ,Tuberculosis ,Humans ,Tuberculosis Vaccines ,Immunity, Cellular ,MVA85A ,IMX313 ,Public Health, Environmental and Occupational Health ,Middle Aged ,Immunogenicity ,Antibodies, Bacterial ,veterinary(all) ,Infectious Diseases ,Immunoglobulin G ,BCG Vaccine ,Cytokines ,Molecular Medicine ,Female ,Vaccine - Abstract
Introduction There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. Methods In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. Results The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN- ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. Conclusion MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85AIMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited.
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- 2016
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8. Safety and immunogenicity of the novel plasmodium falciparum blood-stage vaccine chad63-mva rh5 in a phase ia clinical trial
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Payne, R, Silk, S, Elias, S, Miura, K, Diouf, A, Alanine, D, Jin, J, Labbe, G, Brian, I, Poulton, I, Griffiths, O, Edwards, N, Berrie, E, Siani, L, Douglas, A, Roberts, R, Vekemans, J, Nugent, F, Hill, A, Long, C, Lawrie, A, and Draper, S
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- 2017
9. A monovalent chimpanzee adenovirus Ebola vaccine — preliminary report
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Rampling, T, Ewer, K, Bowyer, G, Wright, D, Imoukhuede, EB, Payne, R, Hartnell, F, Gibani, M, Bliss, C, Minhinnick, A, Wilkie, M, Venkatraman, N, Poulton, I, Lella, N, Roberts, R, Sierra-Davidson, K, Krähling, V, Berrie, E, Roman, F, De Ryck, I, Nicosia, A, Sullivan, NJ, Stanley, DA, Ledgerwood, JE, Schwartz, RM, Siani, L, Colloca, S, Folgori, A, Di Marco, S, Cortese, R, Becker, S, Graham, BS, Koup, RA, Levine, MM, Moorthy, V, Pollard, AJ, Draper, SJ, Ballou, WR, Lawrie, A, Gilbert, SC, and Hill, AV
- Abstract
Background The West African outbreak of Ebola virus disease has caused more than 8500 deaths. A vaccine could contribute to outbreak control in the region. We assessed a monovalent formulation of a chimpanzee adenovirus 3 (ChAd3)-vectored vaccine encoding the surface glycoprotein of Zaire ebolavirus (EBOV), matched to the outbreak strain. Methods After expedited regulatory and ethics approvals, 60 healthy adult volunteers in Oxford, United Kingdom, received a single dose of the ChAd3 vaccine at one of three dose levels: 1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles (with 20 participants per group). Safety was assessed over the next 4 weeks. Antibodies were measured on enzyme-linked immunosorbent assay (ELISA) and T-cell responses on enzyme-linked immunospot (ELISpot) and flow-cytometry assays. Results No safety concerns were identified at any of the dose levels studied. Fever developed in 2 of the 59 participants who were evaluated. Prolonged activated partial-thromboplastin times and transient hyperbilirubinemia were observed in 4 and 8 participants, respectively. Geometric mean antibody responses on ELISA were highest (469 units; range, 58 to 4051; 68% response rate) at 4 weeks in the high-dose group, which had a 100% response rate for T cells on ELISpot, peaking at day 14 (median, 693 spot-forming cells per million peripheral-blood mononuclear cells). Flow cytometry revealed more CD4+ than CD8+ T-cell responses. At the vaccine doses tested, both antibody and T-cell responses were detected but at levels lower than those induced in macaques protected by the same vaccine. Conclusions The ChAd3 monovalent vaccine against EBOV was immunogenic at the doses tested. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875 .).
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- 2016
10. CD4 T cell response to MVA85A vaccination against Mycobacterium tuberculosis in healthy HIV-infected adults
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Beveridge, N, Minassian, A, Rowland, R, Poulton, I, Satti, I, Harris, S, Poyntz, H, Hamill, M, Griffiths, K, Sander, C, Ambrozak, D, Price, D, Hill, B, Casazza, J, Douek, D, Koup, R, Roederer, M, Winston, A, Ross, J, Sherrad, J, Rooney, G, Williams, N, Lawrie, A, Fletcher, H, and Pathan, A
- Published
- 2016
11. ChAd63-MVA-vectored blood-stage Malaria vaccines targeting MSP1 and AMA1: Assessment of efficacy against mosquito bite challenge in humans
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Sheehy, S, Duncan, C, Elias, S, Choudhary, P, Biswas, S, Halstead, F, Collins, K, Edwards, N, Douglas, A, Anagnostou, N, Ewer, K, Havelock, T, Mahungu, T, Bliss, C, Miura, K, Poulton, I, Lillie, P, Antrobus, R, Berrie, E, Moyle, S, Gantlett, K, Colloca, S, Cortese, R, Long, C, and Sinden, R
- Abstract
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 (MSP1AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1ME-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 MSP1AMA1 - 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. © The American Society of Gene and Cell Therapy.
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- 2016
12. Demonstration of the blood-stage controlled human malaria infection model to assess efficacy of the Plasmodium falciparum AMA1 vaccine FMP2.1/AS01
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Payne, R, Milne, K, Elias, S, Edwards, N, Douglas, A, Brown, R, Silk, S, Biswas, S, Miura, K, Roberts, R, Rampling, T, Venkatraman, N, Hodgson, S, Labbé, G, Halstead, F, Poulton, I, Nugent, F, de Graaf, H, Sukhtankar, P, Williams, N, Ockenhouse, C, Kathcart, A, Qabar, A, Waters, N, Soisson, L, Birkett, A, Cooke, G, Faust, S, Woods, C, Ivinson, K, McCarthy, J, Diggs, C, Vekemans, J, Long, C, Hill, A, Lawrie, A, Dutta, S, and Draper, S
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parasitic diseases - Abstract
Mosquito-bite controlled human malaria infection (CHMI) models have been widely used to assess efficacy of pre-erythrocytic vaccine candidates in small proof-of-concept Phase IIa clinical trials. Efficacy testing of blood-stage vaccines, however, has generally relied on larger-scale Phase IIb field trials in endemic populations. We report the use of a blood-stage Plasmodium falciparum CHMI model to assess blood-stage vaccine candidates using impact on the parasite multiplication rate (PMR) as the primary efficacy endpoint. Fifteen healthy UK adult volunteers were vaccinated with FMP2.1, a protein vaccine, based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1), and formulated in AS01. Twelve vaccinees, and fifteen infectivity controls, subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time PCR, and PMR was modelled from these data. The FMP2.1/AS01 vaccine elicited anti-AMA1 T cell and serum antibody responses. Purified IgG showed functional growth inhibition 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. 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 malaria vaccine candidates. NCT02044198.
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- 2016
13. Safety and high level efficacy of the combination malaria vaccine regimen of RTS,S/AS01B with ChAd-MVA vectored vaccines expressing ME-TRAP
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Rampling, T, Ewer, K, Bowyer, G, Bliss, C, Edwards, N, Wright, D, Payne, R, Venkatraman, N, Snudden, C, Poulton, I, Roberts, R, Sinden, R, Gerry, S, Lawrie, A, Gilbert, S, and Hill, A
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parasitic diseases - Abstract
Background: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining two distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to CSP (RTS,S/AS01B) and the other inducing potent T-cell responses to TRAP using viral vectors. Method: 37 healthy malaria-naïve adults were vaccinated with either ChAd63-MVA expressing ME-TRAP and 3 doses of RTS,S/AS01B (Group 1, n=20) or 3 doses of RTS,S/AS01B alone (Group 2, n=17). CHMI was delivered by mosquito bites in 33 vaccinated subjects at week 12 after first vaccination, and 6 unvaccinated controls. Results: No SUSAR or SAEs related to vaccination were reported. Protective vaccine efficacy was observed in 14/17 (82.4%) subjects in Group 1 and 12/16 (75%) subjects in Group 2. All control subjects were diagnosed with blood stage malaria. Both vaccination regimens were immunogenic. 14 protected subjects underwent repeat CHMI 6 months after initial CHMI; 7/8 (87.5%) Group 1 subjects and 5/6 (83.3%) Group 2 subjects remained protected. Conclusion: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.
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- 2016
14. Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors
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Sheehy, S, Duncan, C, Elias, S, Biswas, S, Collins, K, O'Hara, G, Halstead, F, Ewer, K, Mahungu, T, Spencer, A, Miura, K, Poulton, I, Dicks, M, Edwards, N, Berrie, E, Moyle, S, Colloca, S, Cortese, R, Gantlett, K, Long, C, Lawrie, A, Gilbert, S, Doherty, T, Nicosia, A, Hill, A, Draper, S, Sheehy, Sh, Duncan, Cj, Elias, Sc, Biswas, S, Collins, Ka, O'Hara, Ga, Halstead, Fd, Ewer, Kj, Mahungu, T, Spencer, Aj, Miura, K, Poulton, Id, Dicks, Md, Edwards, Nj, Berrie, E, Moyle, S, Colloca, S, Cortese, R, Gantlett, K, Long, Ca, Lawrie, Am, Gilbert, Sc, Doherty, T, Nicosia, Alfredo, Hill, Av, and Draper, Sj
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Male ,ADJUVANT VACCINES ,Enzyme-Linked Immunospot Assay ,T-Lymphocytes ,VIRUS ANKARA ,Antibodies, Protozoan ,lcsh:Medicine ,Protozoology ,Malaria, Falciparum ,lcsh:Science ,Vaccination ,Middle Aged ,Infectious Diseases ,Medicine ,Female ,Research Article ,Adult ,RHESUS-MACAQUES ,Adolescent ,Clinical Research Design ,Genetic Vectors ,Plasmodium falciparum ,MALARIA VACCINE ,Antigens, Protozoan ,Vaccinia virus ,NATURAL IMMUNE-RESPONSES ,Microbiology ,complex mixtures ,PARASITE GROWTH ,Interferon-gamma ,Young Adult ,Malaria Vaccines ,parasitic diseases ,Parasitic Diseases ,Animals ,Humans ,Biology ,Life Cycle Stages ,MEROZOITE SURFACE PROTEIN-1 ,lcsh:R ,Immunity ,Tropical Diseases (Non-Neglected) ,IN-VITRO ,Antibodies, Neutralizing ,Malaria ,PRIME-BOOST IMMUNIZATION ,Adenoviruses, Simian ,Parastic Protozoans ,Immunization ,Clinical Immunology ,lcsh:Q ,APICAL MEMBRANE ANTIGEN-1 - Abstract
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.
- Published
- 2012
15. Comparison of the safety and immunogenicity of a candidate TB vaccine, MVA85A, given by the intramuscular or intradermal route in BCG-vaccinated adults
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Harris, S, Meyer, J, Satti, I, Kostov, M, Rowland, R, Poulton, I, Poyntz, H, Tanner, R, Lillie, P, Lawrie, A, Hill, A, and Mcshane, H
- Published
- 2011
16. Evaluating the effect of BCG vaccination on a whole-blood mycobacterial growth inhibition assay (BACTEC MGIT)
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Tanner, R, Fletcher, H, Meyer, J, Wallis, R, Harris, S, Marsay, L, Poulton, I, and Mcshane, H
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- 2011
17. SAFETY, IMMUNOGENICITY AND IMPACT ON PARASITE MULTIPLICATION RATES OF THE CANDIDATE BLOOD-STAGE VACCINE AMA1-C1/ALHYDROGEL WITH THE NOVEL ADJUVANT CPG 7909 AGAINST BLOOD-STAGE MALARIA CHALLENGE IN HEALTHY MALARIA-NAIVE VOLUNTEERS
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Duncan, C, Sheehy, S, Ewer, K, Douglas, A, Halstead, F, Edwards, N, Collins, K, Lillie, P, Poulton, I, Hunt-Cooke, A, Lawrie, A, Draper, S, Gilbert, S, Fay, M, Miura, K, Long, C, Wu, Y, Hill, A, and Ellis, R
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- 2010
18. HETEROLOGOUS PRIME-BOOST VACCINATION WITH ADCH63 AND MVA EXPRESSING MSP1 CAN INDUCE PROTECTIVE EFFICACY AGAINST SPOROZOITE CHALLENGE IN VOLUNTEERS
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Sheehy, S, Duncan, C, Elias, S, Collins, K, Ewer, K, Edwards, N, Blagborough, A, Sinden, R, Murphy, J, Correa, S, Hunt-Cooke, A, Meyer, J, Lillie, P, Colloca, S, Cortese, R, Nicosia, A, Poulton, I, Long, C, Gilbert, S, Lawrie, A, Hill, A, and Draper, S
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- 2010
19. Evaluation of a Human BCG Challenge Model to Assess Antimycobacterial Immunity Induced by BCG and a Candidate Tuberculosis Vaccine, MVA85A, Alone and in Combination
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Harris, S. A., primary, Meyer, J., additional, Satti, I., additional, Marsay, L., additional, Poulton, I. D., additional, Tanner, R., additional, Minassian, A. M., additional, Fletcher, H. A., additional, and McShane, H., additional
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- 2013
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20. A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults
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Minassian, A. M., primary, Rowland, R., additional, Beveridge, N. E. R., additional, Poulton, I. D., additional, Satti, I., additional, Harris, S., additional, Poyntz, H., additional, Hamill, M., additional, Griffiths, K., additional, Sander, C. R., additional, Ambrozak, D. R., additional, Price, D. A., additional, Hill, B. J., additional, Casazza, J. P., additional, Douek, D. C., additional, Koup, R. A., additional, Roederer, M., additional, Winston, A., additional, Ross, J., additional, Sherrard, J., additional, Rooney, G., additional, Williams, N., additional, Lawrie, A. M., additional, Fletcher, H. A., additional, Pathan, A. A., additional, and McShane, H., additional
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- 2011
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21. 152. DEVELOPMENT OF A VAGINALLY APPLIED, NON-HORMONAL CONTRACEPTIVE: THE CONTRACEPTIVE EFFICACY AND IMPACT ON BONE TURNOVER OF PEGLA, A LONG-ACTING LIF ANTAGONIST
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Menkhorst, E. M., primary, Zhang, J. G., additional, Morgan, P. O., additional, Poulton, I. J., additional, Metcalf, D., additional, Salamonsen, L. A., additional, Sims, N. A., additional, Nicola, N. A., additional, and Dimitriadis, E., additional
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- 2010
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22. A DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccine Encoding Thrombospondin-Related Adhesion Protein but Not Circumsporozoite Protein Partially Protects Healthy Malaria-Naive Adults against Plasmodium falciparum Sporozoite Challenge
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Dunachie, S. J., primary, Walther, M., additional, Epstein, J. E., additional, Keating, S., additional, Berthoud, T., additional, Andrews, L., additional, Andersen, R. F., additional, Bejon, P., additional, Goonetilleke, N., additional, Poulton, I., additional, Webster, D. P., additional, Butcher, G., additional, Watkins, K., additional, Sinden, R. E., additional, Levine, G. L., additional, Richie, T. L., additional, Schneider, J., additional, Kaslow, D., additional, Gilbert, S. C., additional, Carucci, D. J., additional, and Hill, A. V. S., additional
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- 2006
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23. The Search for a Malaria Vaccine: Clinical Trials of DNA-MVA and other Prime-Boost Approaches
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Dunachie, SJ, primary, Webster, DP, additional, Walther, M, additional, McConkey, SJ, additional, Moorthy, VS, additional, Vuola, J, additional, Reece, WHH, additional, Butcher, G, additional, Anderson, R, additional, Watkins, K, additional, Hannan, CM, additional, Everaere, S, additional, Poulton, I, additional, Bejon, P, additional, Schneider, J, additional, Peto, T, additional, Sinden, R, additional, Berthoud, T, additional, Gilbert, SC, additional, and Hill, AVS, additional
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- 2003
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24. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals.
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Sander CR, Pathan AA, Beveridge NE, Poulton I, Minassian A, Alder N, Van Wijgerden J, Hill AV, Gleeson FV, Davies RJ, Pasvol G, McShane H, Sander, Clare R, Pathan, Ansar A, Beveridge, Natalie E R, Poulton, Ian, Minassian, Angela, Alder, Nicola, Van Wijgerden, Johan, and Hill, Adrian V S
- Abstract
Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care.Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI.Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS.Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination.Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183). [ABSTRACT FROM AUTHOR]- Published
- 2009
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25. A DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccine Encoding Thrombospondin-Related Adhesion Protein but Not Circumsporozoite Protein Partially Protects Healthy Malaria-Naive Adults against Plasmodium falciparumSporozoite Challenge
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Dunachie, S. J., Walther, M., Epstein, J. E., Keating, S., Berthoud, T., Andrews, L., Andersen, R. F., Bejon, P., Goonetilleke, N., Poulton, I., Webster, D. P., Butcher, G., Watkins, K., Sinden, R. E., Levine, G. L., Richie, T. L., Schneider, J., Kaslow, D., Gilbert, S. C., Carucci, D. J., and Hill, A. V. S.
- Abstract
ABSTRACTThe safety, immunogenicity, and efficacy of DNA and modified vaccinia virus Ankara (MVA) prime-boost regimes were assessed by using either thrombospondin-related adhesion protein (TRAP) with a multiple-epitope string ME (ME-TRAP) or the circumsporozoite protein (CS) of Plasmodium falciparum. Sixteen healthy subjects who never had malaria (malaria-naive subjects) received two priming vaccinations with DNA, followed by one boosting immunization with MVA, with either ME-TRAP or CS as the antigen. Immunogenicity was assessed by ex vivo gamma interferon (IFN-γ) enzyme-linked immunospot assay (ELISPOT) and antibody assay. Two weeks after the final vaccination, the subjects underwent P. falciparumsporozoite challenge, with six unvaccinated controls. The vaccines were well tolerated and immunogenic, with the DDM-ME TRAP regimen producing stronger ex vivo IFN-γ ELISPOT responses than DDM-CS. One of eight subjects receiving the DDM-ME TRAP regimen was completely protected against malaria challenge, with this group as a whole showing significant delay to parasitemia compared to controls (P= 0.045). The peak ex vivo IFN-γ ELISPOT response in this group correlated strongly with the number of days to parasitemia (P= 0.033). No protection was observed in the DDM-CS group. Prime-boost vaccination with DNA and MVA encoding ME-TRAP but not CS resulted in partial protection against P. falciparumsporozoite challenge in the present study.
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- 2006
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26. CD4 T cell response to MVA85A vaccination against Mycobacterium tuberculosis in healthy HIV-infected adults
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Beveridge, N., Minassian, A., Rowland, R., Poulton, I., Satti, I., Harris, S., Poyntz, H., Hamill, M., Griffiths, K., Sander, C., Ambrozak, D., David Price, Hill, B., Casazza, J., Douek, D., Koup, R., Roederer, M., Winston, A., Ross, J., Sherrad, J., Rooney, G., Williams, N., Lawrie, A., Fletcher, H., Pathan, A., and Mcshane, H.
27. Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trial.
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Jenkin D, Wright D, Folegatti PM, Platt A, Poulton I, Lawrie A, Tran N, Boyd A, Turner C, Gitonga JN, Karanja HK, Mugo D, Ewer KJ, Bowden TA, Gilbert SC, Charleston B, Kaleebu P, Hill AVS, and Warimwe GM
- Subjects
- Humans, Adult, Male, Female, Animals, Antibodies, Neutralizing, Glycoproteins, United Kingdom, Immunogenicity, Vaccine, Antibodies, Viral, Double-Blind Method, Rift Valley Fever prevention & control, Viral Vaccines
- Abstract
Background: Rift Valley fever is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We aimed to evaluate the safety and immunogenicity of a non-replicating simian adenovirus-vectored Rift Valley fever (ChAdOx1 RVF) vaccine in humans., Methods: We conducted a phase 1, first-in-human, open-label, dose-escalation trial in healthy adults aged 18-50 years at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Participants were required to have no serious comorbidities or previous history of receiving an adenovirus-based vaccine before enrolment. Participants were non-randomly allocated to receive a single ChAdOx1 RVF dose of either 5 × 10
9 virus particles (vp), 2·5 × 1010 vp, or 5 × 1010 vp administered intramuscularly into the deltoid of their non-dominant arm; enrolment was sequential and administration was staggered to allow for safety to be assessed before progression to the next dose. Primary outcome measures were assessment of adverse events and secondary outcome measures were Rift Valley fever neutralising antibody titres, Rift Valley fever GnGc-binding antibody titres (ELISA), and cellular response (ELISpot), analysed in all participants who received a vaccine. This trial is registered with ClinicalTrials.gov (NCT04754776)., Findings: Between June 11, 2021, and Jan 13, 2022, 15 volunteers received a single dose of either 5 × 109 vp (n=3), 2·5 × 1010 vp (n=6), or 5 × 1010 vp (n=6) ChAdOx1 RVF. Nine participants were female and six were male. 14 (93%) of 15 participants reported solicited local adverse reactions; injection-site pain was the most frequent (13 [87%] of 15). Ten (67%) of 15 participants (from the 2·5 × 1010 vp and 5 × 1010 vp groups only) reported systemic symptoms, which were mostly mild in intensity, the most common being headache (nine [60%] of 15) and fatigue (seven [47%]). All unsolicited adverse events reported within 28 days were either mild or moderate in severity; gastrointestinal symptoms were the most common reaction (at least possibly related to vaccination), occurring in four (27%) of 15 participants. Transient decreases in total white cell, lymphocyte, or neutrophil counts occurred at day 2 in some participants in the intermediate-dose and high-dose groups. Lymphopenia graded as severe occurred in two participants in the 5 × 1010 vp group at a single timepoint, but resolved at the subsequent follow-up visit. No serious adverse events occurred. Rift Valley fever neutralising antibodies were detectable across all dose groups, with all participants in the 5 × 1010 vp dose group having high neutralising antibody titres that peaked at day 28 after vaccination and persisted through the 3-month follow-up. High titres of binding IgG targeting Gc glycoprotein were detected whereas those targeting Gn were comparatively low. IFNγ cellular responses against Rift Valley fever Gn and Gc glycoproteins were observed in all participants except one in the 5 × 1010 vp dose group. These IFNγ responses peaked at 2 weeks after vaccination, were highest in the 5 × 1010 vp dose group, and tended to be more frequent against the Gn glycoprotein., Interpretation: ChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use., Funding: UK Department of Health and Social Care through the UK Vaccines Network, Oak Foundation, and the Wellcome Trust., Translation: For the Swahili translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests PMF receives funding from the Brazilian Government (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for PhD work and consulting fees from Vaccitech, a company developing ChAdOx1 vectored vaccines. KJE is named as a contributor to a patent relating to ChAdOx1 MERS. TAB receives funding from the Medical Research Council UK. SCG is named as an inventor on the patent covering ChAdOx1 use as a vaccine vector and holds stock in Vaccitech. AVSH has received royalties from the COVID-19 vectored ChAdOx1 vaccine to both himself and his institution, and is named as an inventor on the patent covering ChAdOx1 use as a vaccine vector. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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28. Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial.
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Madhavan M, Ritchie AJ, Aboagye J, Jenkin D, Provstgaad-Morys S, Tarbet I, Woods D, Davies S, Baker M, Platt A, Flaxman A, Smith H, Belij-Rammerstorfer S, Wilkins D, Kelly EJ, Villafana T, Green JA, Poulton I, Lambe T, Hill AVS, Ewer KJ, and Douglas AD
- Subjects
- Adult, Humans, Adenoviridae genetics, Antibodies, Viral, BNT162 Vaccine, ChAdOx1 nCoV-19, COVID-19 Vaccines adverse effects, SARS-CoV-2, Vaccination adverse effects, mRNA Vaccines, COVID-19 prevention & control, Viral Vaccines
- Abstract
Background: Intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens. A number of intranasal SARS-CoV-2 vaccine candidates have achieved protection in pre-clinical challenge models, including ChAdOx1 nCoV-19 (AZD1222, University of Oxford / AstraZeneca)., Methods: We performed a single-centre open-label Phase I clinical trial of intranasal vaccination with ChAdOx1 nCoV-19 in healthy adults, using the existing formulation produced for intramuscular administration. Thirty SARS-CoV-2 vaccine-naïve participants were allocated to receive 5 × 10
9 viral particles (VP, n=6), 2 × 1010 VP (n=12), or 5 × 1010 VP (n=12). Fourteen received second intranasal doses 28 days later. A further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46. To investigate intranasal ChAdOx1 nCoV-19 as a booster, six participants who had previously received two intramuscular doses of ChAdOx1 nCoV-19 and six who had received two intramuscular doses of BNT162b2 (Pfizer / BioNTech) were given a single intranasal dose of 5 × 1010 VP of ChAdOx1 nCoV-19. Objectives were to assess safety (primary) and mucosal antibody responses (secondary)., Findings: Reactogenicity was mild or moderate. Antigen-specific mucosal antibody responses to intranasal vaccination were detectable in a minority of participants, rarely exceeding levels seen after SARS-CoV-2 infection. Systemic responses to intranasal vaccination were typically weaker than after intramuscular vaccination with ChAdOx1 nCoV-19. Antigen-specific mucosal antibody was detectable in participants who received an intramuscular mRNA vaccine after intranasal vaccination. Seven participants developed symptomatic SARS-CoV-2 infection., Interpretation: This formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response., Funding: AstraZeneca., Competing Interests: Declaration of interests Oxford University has entered into a partnership with AstraZeneca to develop ChAdOx1 nCoV-19. AJR and KE may receive royalties arising from the University of Oxford/AstraZeneca COVID-19 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was previously a consultant to Vaccitech on an unrelated project. AVSH is a cofounder of and former consultant to Vaccitech is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467), and may receive royalties arising for the University of Oxford/AstraZeneca COVID-19 vaccine. DW, EJK, TV, and JAG are current employees of AstraZeneca and hold or may hold AstraZeneca stock. ADD reports grants and personal fees from AstraZeneca outside of the submitted work, is a named inventor on patent applications relating the chimpanzee adenovirus platform technology and manufacturing, and may receive royalties arising from the University of Oxford/AstraZeneca COVID-19 vaccine. All other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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29. Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial.
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Jenkin D, Ritchie AJ, Aboagye J, Fedosyuk S, Thorley L, Provstgaad-Morys S, Sanders H, Bellamy D, Makinson R, Xiang ZQ, Bolam E, Tarrant R, Ramos Lopez F, Platt A, Poulton I, Green C, Ertl HCJ, Ewer KJ, and Douglas AD
- Subjects
- Adult, Antibodies, Neutralizing, Antibodies, Viral, Humans, Adenoviruses, Simian genetics, Rabies prevention & control, Rabies Vaccines adverse effects
- Abstract
Background: Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults., Methods: We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 10
9 viral particles), middle (2·5 × 1010 viral particles), and high doses (5 x 1010 viral particles) of ChAdOx2 RabG and were followed up to day 56 after vaccination. The primary objective was to assess safety. The secondary objective was to assess immunogenicity with the internationally standardised rabies virus neutralising antibody assay. In an optional follow-up phase 1 year after enrolment, we measured antibody maintenance then administered a licensed rabies vaccine (to simulate post-exposure prophylaxis) and measured recall responses. The trial is registered with ClinicalTrials.gov, NCT04162600, and is now closed to new participants., Findings: Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0-54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7-18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0-486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL., Interpretation: In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation., Funding: UK Medical Research Council and Engineering and Physical Sciences Research Council., Competing Interests: Declaration of interests AJR might receive royalties arising from the University of Oxford— AstraZeneca COVID-19 vaccine, which also uses the chimpanzee adenovirus technology platform. SF has received payment from Merck for a presentation at the ISPE Virtual Annual Conference, and is a contributor to intellectual property assigned to Oxford University Innovation relating to the ChAdOx1 nCoV-19 vaccine and might receive a proportion of proceeds from out-licensing of the property. CG has received a personal honorarium from the Duke Human Vaccine Institute ISAB and is director of Vaxxers. HCJE reports funding from the Wellcome Trust; grants from the US Department of Defense, Virion Therapeutics, Corona Discovery Fund, and Commonwealth of Pennsylvania, USA; research funding from Virion Therapeutics; consulting fees from Takeda, Biogen, RegenXBio; support for attending meetings or travel from Society for Immunotherapy of Cancer; support from Virion Therapeutics for travel to the Genetic Vaccine Development for Infectious Diseases Summit, Boston, MA, USA; has patents filed (US Patent 11291716 adenoviral vectors encoding hepatitis B viral antigens fused to herpes virus glycoprotein D and methods of using the same; and US Patent 11207402 constructs for enhancing immune responses); and has stock options in Ring Therapeutics. ADD reports grant funding from the Medical Research Council, Engineering and Physical Sciences Research Council, and the Wellcome Trust; might receive income arising from licensing of intellectual property related to ChAdOx2 RabG or other adenovirus-vectored vaccines; has received consultancy fees from AstraZeneca, relating to another adenovirus-vectored vaccine; and is a named inventor on patent applications relating to chimpanzee adenovirus platform technology. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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30. A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial.
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Folegatti PM, Harrison K, Preciado-Llanes L, Lopez FR, Bittaye M, Kim YC, Flaxman A, Bellamy D, Makinson R, Sheridan J, Azar SR, Campos RK, Tilley M, Tran N, Jenkin D, Poulton I, Lawrie A, Roberts R, Berrie E, Rossi SL, Hill A, Ewer KJ, and Reyes-Sandoval A
- Subjects
- Adolescent, Adult, Chikungunya Fever prevention & control, Chikungunya Fever virology, Chikungunya virus classification, Chikungunya virus physiology, Cytokines immunology, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Fatigue chemically induced, Female, Headache chemically induced, Humans, Immunoglobulin G immunology, Injections, Intramuscular, Male, Middle Aged, T-Lymphocytes immunology, T-Lymphocytes metabolism, Vaccination methods, Viral Vaccines administration & dosage, Viral Vaccines adverse effects, Young Adult, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Chikungunya Fever immunology, Chikungunya virus immunology, Viral Vaccines immunology
- Abstract
Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18-50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT
50 seroconversion after a single dose., (© 2021. The Author(s).)- Published
- 2021
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31. Author Correction: Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.
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Barrett JR, Belij-Rammerstorfer S, Dold C, Ewer KJ, Folegatti PM, Gilbride C, Halkerston R, Hill J, Jenkin D, Stockdale L, Verheul MK, Aley PK, Angus B, Bellamy D, Berrie E, Bibi S, Bittaye M, Carroll MW, Cavell B, Clutterbuck EA, Edwards N, Flaxman A, Fuskova M, Gorringe A, Hallis B, Kerridge S, Lawrie AM, Linder A, Liu X, Madhavan M, Makinson R, Mellors J, Minassian A, Moore M, Mujadidi Y, Plested E, Poulton I, Ramasamy MN, Robinson H, Rollier CS, Song R, Snape MD, Tarrant R, Taylor S, Thomas KM, Voysey M, Watson MEE, Wright D, Douglas AD, Green CM, Hill AVS, Lambe T, Gilbert S, and Pollard AJ
- Published
- 2021
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32. Author Correction: T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.
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Ewer KJ, Barrett JR, Belij-Rammerstorfer S, Sharpe H, Makinson R, Morter R, Flaxman A, Wright D, Bellamy D, Bittaye M, Dold C, Provine NM, Aboagye J, Fowler J, Silk SE, Alderson J, Aley PK, Angus B, Berrie E, Bibi S, Cicconi P, Clutterbuck EA, Chelysheva I, Folegatti PM, Fuskova M, Green CM, Jenkin D, Kerridge S, Lawrie A, Minassian AM, Moore M, Mujadidi Y, Plested E, Poulton I, Ramasamy MN, Robinson H, Song R, Snape MD, Tarrant R, Voysey M, Watson MEE, Douglas AD, Hill AVS, Gilbert SC, Pollard AJ, and Lambe T
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- 2021
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33. Safety and Immunogenicity of Adenovirus and Poxvirus Vectored Vaccines against a Mycobacterium Avium Complex Subspecies.
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Folegatti PM, Flaxman A, Jenkin D, Makinson R, Kingham-Page L, Bellamy D, Ramos Lopez F, Sheridan J, Poulton I, Aboagye J, Tran N, Mitton C, Roberts R, Lawrie AM, Hill AVS, Ewer KJ, and Gilbert S
- Abstract
Heterologous prime-boost strategies are known to substantially increase immune responses in viral vectored vaccines. Here we report on safety and immunogenicity of the poxvirus Modified Vaccinia Ankara (MVA) vectored vaccine expressing four Mycobacterium avium subspecies paratuberculosis antigens as a single dose or as a booster vaccine following a simian adenovirus (ChAdOx2) prime. We demonstrate that a heterologous prime-boost schedule is well tolerated and induced T-cell immune responses.
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- 2021
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34. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.
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Barrett JR, Belij-Rammerstorfer S, Dold C, Ewer KJ, Folegatti PM, Gilbride C, Halkerston R, Hill J, Jenkin D, Stockdale L, Verheul MK, Aley PK, Angus B, Bellamy D, Berrie E, Bibi S, Bittaye M, Carroll MW, Cavell B, Clutterbuck EA, Edwards N, Flaxman A, Fuskova M, Gorringe A, Hallis B, Kerridge S, Lawrie AM, Linder A, Liu X, Madhavan M, Makinson R, Mellors J, Minassian A, Moore M, Mujadidi Y, Plested E, Poulton I, Ramasamy MN, Robinson H, Rollier CS, Song R, Snape MD, Tarrant R, Taylor S, Thomas KM, Voysey M, Watson MEE, Wright D, Douglas AD, Green CM, Hill AVS, Lambe T, Gilbert S, and Pollard AJ
- Subjects
- Adolescent, Adult, Antibodies, Neutralizing immunology, ChAdOx1 nCoV-19, Dose-Response Relationship, Drug, Genetic Vectors immunology, Humans, Middle Aged, Spike Glycoprotein, Coronavirus immunology, Time Factors, Young Adult, Antibody Formation immunology, COVID-19 immunology, COVID-19 Vaccines immunology, Immunization, Secondary, SARS-CoV-2 immunology
- Abstract
More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.
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- 2021
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35. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.
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Ewer KJ, Barrett JR, Belij-Rammerstorfer S, Sharpe H, Makinson R, Morter R, Flaxman A, Wright D, Bellamy D, Bittaye M, Dold C, Provine NM, Aboagye J, Fowler J, Silk SE, Alderson J, Aley PK, Angus B, Berrie E, Bibi S, Cicconi P, Clutterbuck EA, Chelysheva I, Folegatti PM, Fuskova M, Green CM, Jenkin D, Kerridge S, Lawrie A, Minassian AM, Moore M, Mujadidi Y, Plested E, Poulton I, Ramasamy MN, Robinson H, Song R, Snape MD, Tarrant R, Voysey M, Watson MEE, Douglas AD, Hill AVS, Gilbert SC, Pollard AJ, and Lambe T
- Subjects
- Adolescent, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, COVID-19 immunology, COVID-19 virology, ChAdOx1 nCoV-19, Dose-Response Relationship, Immunologic, Female, Humans, Immunity, Cellular, Immunity, Humoral, Immunoglobulin A immunology, Immunoglobulin M immunology, Interferon-gamma metabolism, Lymphocyte Activation immunology, Male, Middle Aged, Protein Subunits immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, Vaccination, Young Adult, Antibody Formation immunology, COVID-19 Vaccines immunology, T-Lymphocytes immunology
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed
1 . Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3 . Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4 . Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs.5,6 ). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.- Published
- 2021
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36. Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial.
- Author
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Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A, Mair C, Makinson R, Sheridan J, Rohde C, Halwe S, Jeong Y, Park YS, Kim JO, Song M, Boyd A, Tran N, Silman D, Poulton I, Datoo M, Marshall J, Themistocleous Y, Lawrie A, Roberts R, Berrie E, Becker S, Lambe T, Hill A, Ewer K, and Gilbert S
- Subjects
- Adult, Antibodies, Neutralizing immunology, Antibodies, Viral, Coronavirus Infections prevention & control, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Middle East Respiratory Syndrome Coronavirus genetics, United Kingdom, Vaccines, DNA, Young Adult, Dose-Response Relationship, Immunologic, Immunogenicity, Vaccine, Middle East Respiratory Syndrome Coronavirus immunology, Viral Vaccines administration & dosage
- Abstract
Background: Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans., Methods: This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18-50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 10
9 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578., Findings: Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66-81]) of 124 solicited adverse events were mild, 31 (25% [18-33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11-17·42], p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19-73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58-93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay., Interpretation: ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials., Funding: UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2020
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37. Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial.
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Cappuccini F, Bryant R, Pollock E, Carter L, Verrill C, Hollidge J, Poulton I, Baker M, Mitton C, Baines A, Meier A, Schmidt G, Harrop R, Protheroe A, MacPherson R, Kennish S, Morgan S, Vigano S, Romero PJ, Evans T, Catto J, Hamdy F, Hill AVS, and Redchenko I
- Subjects
- Adult, Biopsy, Cancer Vaccines administration & dosage, Cancer Vaccines genetics, Cancer Vaccines immunology, Cells, Cultured, Enzyme-Linked Immunospot Assay, Genetic Vectors genetics, Humans, Immunization, Secondary, Kallikreins blood, Lymphocytes, Tumor-Infiltrating immunology, Male, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Middle Aged, Neoplasm Staging, Primary Cell Culture, Prostate cytology, Prostate immunology, Prostate pathology, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Prostatic Neoplasms immunology, Vaccination methods, Vaccines, DNA, Cancer Vaccines adverse effects, Immunogenicity, Vaccine, Prostatic Neoplasms therapy, T-Lymphocytes immunology, Vaccination adverse effects
- Abstract
Background: Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity., Methods: In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells., Results: The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ., Conclusions: An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab., Trial Registration: The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063)., Competing Interests: Competing interests: AVSH is a co-founder of and shareholder in Vaccitech Ltd which has supported the Oxford prostate cancer vaccine programme., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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38. Safety and Immunogenicity of a Novel Recombinant Simian Adenovirus ChAdOx2 as a Vectored Vaccine.
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Folegatti PM, Bellamy D, Roberts R, Powlson J, Edwards NJ, Mair CF, Bowyer G, Poulton I, Mitton CH, Green N, Berrie E, Lawrie AM, Hill AVS, Ewer KJ, Hermon-Taylor J, and Gilbert SC
- Abstract
Adenovirus vectored vaccines are a highly effective strategy to induce cellular immune responses which are particularly effective against intracellular pathogens. Recombinant simian adenovirus vectors were developed to circumvent the limitations imposed by the use of human adenoviruses due to widespread seroprevalence of neutralising antibodies. We have constructed a replication deficient simian adenovirus-vectored vaccine (ChAdOx2) expressing 4 genes from the Mycobacterium avium subspecies paratuberculosis ( AhpC , Gsd , p12 and mpa ). Safety and T-cell immunogenicity results of the first clinical use of the ChAdOx2 vector are presented here. The trial was conducted using a 'three-plus-three' dose escalation study design. We demonstrate the vaccine is safe, well tolerated and immunogenic., Competing Interests: J.H.-T. is the Chief Scientific and Medical Officer for HAV Vaccines Ltd. S.C.G. and A.V.S.H. are co-founders of, consultants to and shareholders in Vaccitech plc which is developing adenoviral vectored vaccines.
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- 2019
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39. Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal.
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Venkatraman N, Ndiaye BP, Bowyer G, Wade D, Sridhar S, Wright D, Powlson J, Ndiaye I, Dièye S, Thompson C, Bakhoum M, Morter R, Capone S, Del Sorbo M, Jamieson S, Rampling T, Datoo M, Roberts R, Poulton I, Griffiths O, Ballou WR, Roman F, Lewis DJM, Lawrie A, Imoukhuede E, Gilbert SC, Dieye TN, Ewer KJ, Mboup S, and Hill AVS
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- Adolescent, Adult, Ebola Vaccines administration & dosage, Ebola Vaccines adverse effects, Ebola Vaccines immunology, Ebolavirus immunology, Female, Humans, Immunization Schedule, Immunization, Secondary adverse effects, Immunization, Secondary methods, Male, Middle Aged, Senegal, United Kingdom, Young Adult, Ebola Vaccines pharmacology
- Abstract
Background: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine., Methods: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events., Results: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb., Conclusions: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control., Clinical Trials Registration: NCT02451891; NCT02485912., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2019
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40. Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line.
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Folegatti PM, Bellamy D, Flaxman A, Mair C, Ellis C, Ramon RL, Ramos Lopez F, Mitton C, Baker M, Poulton I, Lawrie A, Roberts R, Minassian A, Ewer KJ, Evans TG, Hill AVS, and Gilbert SC
- Abstract
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines., Competing Interests: T.G.E is the Chief Executive Officer and Board Director for Vaccitech Ltd. C.E. is the Chief Operating Officer for Vaccitech Ltd. AV.S.H and S.C.G scientific co-founders of, advisors to and shareholders in Vaccitech Ltd.
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- 2019
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41. Prime and target immunization protects against liver-stage malaria in mice.
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Gola A, Silman D, Walters AA, Sridhar S, Uderhardt S, Salman AM, Halbroth BR, Bellamy D, Bowyer G, Powlson J, Baker M, Venkatraman N, Poulton I, Berrie E, Roberts R, Lawrie AM, Angus B, Khan SM, Janse CJ, Ewer KJ, Germain RN, Spencer AJ, and Hill AVS
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- Animals, Biomarkers metabolism, CD8-Positive T-Lymphocytes immunology, Genetic Vectors administration & dosage, Hepatocytes immunology, Hepatocytes parasitology, Humans, Injections, Intravenous, Malaria, Falciparum pathology, Mice, Inbred C57BL, Nanoparticles chemistry, Ovalbumin immunology, Plasmodium berghei physiology, Plasmodium falciparum growth & development, Polylactic Acid-Polyglycolic Acid Copolymer chemistry, Sporozoites physiology, Immunization, Life Cycle Stages, Liver parasitology, Malaria, Falciparum immunology, Malaria, Falciparum prevention & control
- Abstract
Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8
+ T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of Plasmodium -specific circulating T cells necessary to confer sterile protection. We describe an alternative "prime and target" vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2018
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42. Safety and immunogenicity of heterologous prime-boost immunization with viral-vectored malaria vaccines adjuvanted with Matrix-M™.
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Venkatraman N, Anagnostou N, Bliss C, Bowyer G, Wright D, Lövgren-Bengtsson K, Roberts R, Poulton I, Lawrie A, Ewer K, and V S Hill A
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- Adenoviridae immunology, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic adverse effects, Adolescent, Adult, Antibodies, Protozoan immunology, Enzyme-Linked Immunospot Assay methods, Epitopes adverse effects, Epitopes immunology, Female, Genetic Vectors adverse effects, Genetic Vectors immunology, Humans, Immunity, Cellular immunology, Immunity, Humoral immunology, Immunoglobulin G immunology, Malaria, Falciparum immunology, Malaria, Falciparum prevention & control, Male, Middle Aged, Protozoan Proteins immunology, T-Lymphocytes immunology, Vaccinia immunology, Young Adult, Immunization, Secondary adverse effects, Immunogenicity, Vaccine immunology, Malaria Vaccines adverse effects, Malaria Vaccines immunology, Nanoparticles adverse effects, Saponins adverse effects, Saponins immunology, Vaccination adverse effects
- Abstract
The use of viral vectors in heterologous prime-boost regimens to induce potent T cell responses in addition to humoral immunity is a promising vaccination strategy in the fight against malaria. We conducted an open-label, first-in-human, controlled Phase I study evaluating the safety and immunogenicity of Matrix-M adjuvanted vaccination with a chimpanzee adenovirus serotype 63 (ChAd63) prime followed by a modified vaccinia Ankara (MVA) boost eight weeks later, both encoding the malaria ME-TRAP antigenic sequence (a multiple epitope string fused to thrombospondin-related adhesion protein). Twenty-two healthy adults were vaccinated intramuscularly with either ChAd63-MVA ME-TRAP alone (n=6) or adjuvanted with 25μg (n=8) or 50μg (n=8) Matrix-M. Vaccinations appeared to be safe and generally well tolerated, with the majority of local and systemic adverse events being mild in nature. The addition of Matrix-M to the vaccine did not increase local reactogenicity; however, systemic adverse events were reported more frequently by volunteers who received adjuvanted vaccine in comparison to the control group. T cell ELISpot responses peaked at 7-days post boost vaccination with MVA ME-TRAP in all three groups. TRAP-specific IgG responses were highest at 28-days post boost with MVA ME-TRAP in all three groups. There were no differences in cellular and humoral immunogenicity at any of the time points between the control group and the adjuvanted groups. We demonstrate that Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity. Clinical Trials Registration NCT01669512., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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43. A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA.
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Ewer K, Rampling T, Venkatraman N, Bowyer G, Wright D, Lambe T, Imoukhuede EB, Payne R, Fehling SK, Strecker T, Biedenkopf N, Krähling V, Tully CM, Edwards NJ, Bentley EM, Samuel D, Labbé G, Jin J, Gibani M, Minhinnick A, Wilkie M, Poulton I, Lella N, Roberts R, Hartnell F, Bliss C, Sierra-Davidson K, Powlson J, Berrie E, Tedder R, Roman F, De Ryck I, Nicosia A, Sullivan NJ, Stanley DA, Mbaya OT, Ledgerwood JE, Schwartz RM, Siani L, Colloca S, Folgori A, Di Marco S, Cortese R, Wright E, Becker S, Graham BS, Koup RA, Levine MM, Volkmann A, Chaplin P, Pollard AJ, Draper SJ, Ballou WR, Lawrie A, Gilbert SC, and Hill AV
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- Adenoviruses, Simian immunology, Adult, Animals, Antibodies, Viral blood, B-Lymphocytes physiology, Cytokines blood, Ebola Vaccines administration & dosage, Female, Hemorrhagic Fever, Ebola immunology, Humans, Immunity, Cellular, Immunization, Secondary, Male, Middle Aged, Pan troglodytes, T-Lymphocytes physiology, Vaccinia, Young Adult, Ebola Vaccines immunology, Ebolavirus immunology, Hemorrhagic Fever, Ebola prevention & control
- Abstract
Background: The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak., Methods: In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels--1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles--with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability., Results: No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001)., Conclusions: The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.).
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- 2016
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44. A human Phase I/IIa malaria challenge trial of a polyprotein malaria vaccine.
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Porter DW, Thompson FM, Berthoud TK, Hutchings CL, Andrews L, Biswas S, Poulton I, Prieur E, Correa S, Rowland R, Lang T, Williams J, Gilbert SC, Sinden RE, Todryk S, and Hill AV
- Subjects
- Adolescent, Adult, Antibodies, Protozoan immunology, Antigens, Protozoan immunology, Humans, Immunization, Secondary, Interferon-gamma biosynthesis, Malaria, Falciparum immunology, Malaria, Falciparum prevention & control, Middle Aged, Treatment Outcome, Vaccination, Vaccines, Subunit administration & dosage, Vaccines, Subunit adverse effects, Vaccines, Subunit immunology, Young Adult, Malaria Vaccines administration & dosage, Malaria Vaccines adverse effects, Malaria Vaccines immunology, Plasmodium falciparum immunology, Polyproteins immunology, Protozoan Proteins immunology
- Abstract
We examined the safety, immunogenicity and efficacy of a prime-boost vaccination regime involving two poxvirus malaria subunit vaccines, FP9-PP and MVA-PP, expressing the same polyprotein consisting of six pre-erythrocytic antigens from Plasmodium falciparum. Following safety assessment of single doses, 15 volunteers received a heterologous prime-boost vaccination regime and underwent malaria sporozoite challenge. The vaccines were safe but interferon-γ ELISPOT responses were low compared to other poxvirus vectors, despite targeting multiple antigens. There was no vaccine efficacy as measured by delay in time to parasitaemia. A number of possible explanations are discussed, including the very large insert size of the polyprotein transgene., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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45. Severe developmental bone phenotype in ClC-7 deficient mice.
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Neutzsky-Wulff AV, Sims NA, Supanchart C, Kornak U, Felsenberg D, Poulton IJ, Martin TJ, Karsdal MA, and Henriksen K
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- Animals, Bone Development genetics, Bone Matrix physiopathology, Bone Resorption genetics, Bone Resorption metabolism, Bone Resorption physiopathology, Cartilage physiopathology, Cell Communication, Cell Differentiation, Cytokines, Homozygote, Mice, Mice, Knockout, Osteoblasts metabolism, Osteoclasts cytology, Osteoclasts metabolism, Osteogenesis, Osteopetrosis genetics, Osteopetrosis metabolism, Bone and Bones physiopathology
- Abstract
Bone development is dependent on the functionality of three essential cell types: chondrocytes, osteoclasts and osteoblasts. If any of these cell types is dysfunctional, a developmental bone phenotype can result. The bone disease osteopetrosis is caused by osteoclast dysfunction or impaired osteoclastogenesis, leading to increased bone mass. In ClC-7 deficient mice, which display severe osteopetrosis, the osteoclast malfunction is due to abrogated acidification of the resorption lacuna. This study sought to investigate the consequences of osteoclast malfunction on bone development, bone structure and bone modeling/remodeling in ClC-7 deficient mice. Bones from wildtype, heterozygous and ClC-7 deficient mice were examined by bone histomorphometry and immunohistochemistry. ClC-7 deficient mice were found to have a severe developmental bone phenotype, characterized by dramatically increased bone mass, a high content of cartilage remnants, impaired longitudinal and radial growth, as well as lack of compact cortical bone development. Indices of bone formation were reduced in ClC-7 deficient mice; however, calcein labeling indicated that mineralization occurred on most trabecular bone surfaces. Osteoid deposition had great regional variance, but an osteopetrorickets phenotype, as observed in oc/oc mice, was not apparent in the ClC-7 deficient mice. A striking finding was the presence of very large abnormal osteoclasts, which filled the bone marrow space within the ClC-7 deficient bones. The development of these giant osteoclasts could be due to altered cell fate of the ClC-7 deficient osteoclasts, caused by increased cellular fusion and/or prolonged osteoclast survival. In summary, malfunctional ClC-7 deficient osteoclasts led to a severe developmental bone phenotype including abnormally large and non-functional osteoclasts. Bone formation paremeters were reduced; however, bone formation and mineralization were found to be heterogenous and continuing., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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46. Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A.
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Whelan KT, Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Hill AV, and McShane H
- Subjects
- Acyltransferases chemistry, Adult, Antigens, Bacterial chemistry, BCG Vaccine chemistry, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry methods, Humans, Interferon-gamma metabolism, Male, Middle Aged, Peptides chemistry, Time Factors, Acyltransferases immunology, Antigens, Bacterial immunology, BCG Vaccine administration & dosage, Dendritic Cells virology, Tuberculosis Vaccines chemistry
- Abstract
Objectives: To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A., Design: Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-gamma) ELISpot assay and flow cytometry., Results and Conclusions: BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNgamma (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated. In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells., Trial Registration: ClinicalTrials.gov NCT00654316 NCT00427830.
- Published
- 2009
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47. Evidence of blood stage efficacy with a virosomal malaria vaccine in a phase IIa clinical trial.
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Thompson FM, Porter DW, Okitsu SL, Westerfeld N, Vogel D, Todryk S, Poulton I, Correa S, Hutchings C, Berthoud T, Dunachie S, Andrews L, Williams JL, Sinden R, Gilbert SC, Pluschke G, Zurbriggen R, and Hill AV
- Subjects
- Animals, Antibodies, Protozoan biosynthesis, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Humans, Malaria Vaccines adverse effects, Plasmodium falciparum immunology, Malaria Vaccines therapeutic use, Malaria, Falciparum immunology
- Abstract
Background: Previous research indicates that a combination vaccine targeting different stages of the malaria life cycle is likely to provide the most effective malaria vaccine. This trial was the first to combine two existing vaccination strategies to produce a vaccine that induces immune responses to both the pre-erythrocytic and blood stages of the P. falciparum life cycle., Methods: This was a Phase I/IIa study of a new combination malaria vaccine FFM ME-TRAP+PEV3A. PEV3A includes peptides from both the pre-erythrocytic circumsporozoite protein and the blood-stage antigen AMA-1. This study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. The participants were healthy, malaria naïve volunteers, from Oxford. The interventions were vaccination with PEV3A alone, or PEV3A+FFM ME-TRAP. The main outcome measure was protection from malaria in a sporozoite challenge model. Other outcomes included measures of parasite specific immune responses induced by either vaccine; and safety, assessed by collection of adverse event data., Results: We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this group. One volunteer, who received PEV3A alone, was diagnosed very late, on day 20 compared to an average of 11.8 days in unvaccinated controls. (ii). Morphologically abnormal parasites were present in the blood of all (n = 24) PEV3A vaccinated volunteers, and in only 2/6 controls (p = 0.001). We describe evidence of vaccine-induced blood stage efficacy for the first time in a sporozoite challenge study.
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- 2008
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48. Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: different boosting intervals and implications for efficacy trials.
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Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Beveridge NE, Whelan KT, Hill AV, and McShane H
- Subjects
- Adult, Antigens, Bacterial, Antigens, Viral chemistry, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Recombinant Proteins chemistry, Treatment Outcome, Tuberculin Test, Vaccination, BCG Vaccine administration & dosage, Immunization, Secondary, Vaccinia virus metabolism
- Abstract
Objectives: To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination., Design: There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naïve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime-MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG., Results: MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination., Conclusions: The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here., Trial Registration: ClinicalTrials.gov NCT00427453 (short boosting interval), NCT00427830 (long boosting interval), NCT00480714 (BCG alone).
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- 2007
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49. Safety, immunogenicity, and efficacy of prime-boost immunization with recombinant poxvirus FP9 and modified vaccinia virus Ankara encoding the full-length Plasmodium falciparum circumsporozoite protein.
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Walther M, Thompson FM, Dunachie S, Keating S, Todryk S, Berthoud T, Andrews L, Andersen RF, Moore A, Gilbert SC, Poulton I, Dubovsky F, Tierney E, Correa S, Huntcooke A, Butcher G, Williams J, Sinden RE, and Hill AV
- Subjects
- Adult, Animals, Antibodies, Protozoan blood, Clinical Trials as Topic, Glycosylphosphatidylinositols physiology, Humans, Immunization, Secondary, Interferon-gamma biosynthesis, Malaria Vaccines adverse effects, Parasitemia prevention & control, Poxviridae genetics, Vaccines, Synthetic adverse effects, Vaccinia virus genetics, Malaria Vaccines immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology, Vaccines, Synthetic immunology
- Abstract
Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first time, these vaccines were administered intramuscularly and at doses of up to 5 x 10(8) PFU. Vaccines containing this antigen proved safe and induced modest immune responses but showed no evidence of efficacy in a sporozoite challenge.
- Published
- 2006
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50. A clinical trial of prime-boost immunisation with the candidate malaria vaccines RTS,S/AS02A and MVA-CS.
- Author
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Dunachie SJ, Walther M, Vuola JM, Webster DP, Keating SM, Berthoud T, Andrews L, Bejon P, Poulton I, Butcher G, Watkins K, Sinden RE, Leach A, Moris P, Tornieporth N, Schneider J, Dubovsky F, Tierney E, Williams J, Heppner DG Jr, Gilbert SC, Cohen J, and Hill AV
- Subjects
- Adolescent, Adult, Antibodies, Protozoan blood, Female, Humans, Interferon-gamma biosynthesis, Malaria immunology, Malaria Vaccines administration & dosage, Malaria Vaccines adverse effects, Male, Middle Aged, T-Lymphocytes immunology, Immunization, Secondary, Malaria prevention & control, Malaria Vaccines immunology, Vaccinia virus immunology
- Abstract
Heterologous prime-boost immunisation with RTS,S/AS02A and the poxvirus MVA-CS was evaluated in 18 healthy malaria-naïve subjects in Oxford. Both priming with RTS,S and boosting MVA-CS, and the reverse, were found to be safe and well tolerated. T cell responses as measured by IFN-gamma ex vivo ELISPOT were induced, but the responses were low to moderate in both groups, with heterologous boosting yielding only small increments in T cell immunogenicity and no increased antibody response. Protection against 3D7 Plasmodium falciparum sporozoite challenge 4 weeks after the final vaccination was equal for both regimens at 33% (95% C.I. 4.3-77.7%), with one subject remaining fully protected on rechallenge at 5 months.
- Published
- 2006
- Full Text
- View/download PDF
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