22 research outputs found
Developing a new anti-sporozoite malaria vaccine
No full textMalaria is one of the leading infectious causes of morbidity and mortality. There was an estimated 241 million malaria cases and 627,000 deaths in 2020 across 85 malaria endemic countries. When compared with data from recent years, this suggests that global progress has stalled, and that malaria mortality is increasing. There is an urgent need to develop new tools to combat this.
Significant progress has been made in malaria vaccine development, with the first malaria vaccine, RTS,S/AS01, achieving prequalification this year (2022). However, the current production capacity of RTS,S/AS01 may not, at least initially, meet the needs of the target population. At the same time, the WHO goal of developing a malaria vaccine with protective efficacy of ≥75% against clinical malaria, for at-risk groups in malaria-endemic areas, over at least 2 years, has not yet been met.
R21 is produced by using recombinant HBsAg particles expressing the central repeat and the C-terminus of the Plasmodium falciparum circumsporozoite protein. R21 was initially developed at the University of Oxford and is now manufactured by the Serum Institute of India Pvt. Ltd (SIIPL). R21 is combined with an adjuvant, Matrix-M, manufactured by Novavax AB, to produce the vaccine candidate R21/Matrix-M which targets P. falciparum malaria.
In this thesis, I describe the clinical development assessing safety, immunogenicity and efficacy of the R21/Matrix-M malaria vaccine candidate across a phase I/IIa clinical trial in UK adults (chapter 3); a phase Ib clinical trial in Kenya in adults, young children and infants (chapter 4); and a phase IIb clinical trial in infants in Burkina Faso (chapter 5). I evaluate the composition of the gut microbiome of infants living in malaria endemic areas (the target population for R21/Matrix-M) to assess if this is affected by any specific participant factors. I also assess if the baseline gut microbiome suggests any correlation with antibody responses generated by R21/Matrix-M, and if any association exists between the gut microbiome composition and the total number of malaria episodes experienced at 12 months following vaccinations (chapter 6).
The clinical development phases of R21/Matrix-M have demonstrated that the vaccine is safe, immunogenic and protective against malaria. Importantly, efficacy of ≥75% against clinical malaria was noted over 2 years in the target population of African infants, in the phase IIb trial, where vaccinations were administered prior to or at the start of the malaria season. The composition of the gut microbiome varied significantly according to age of the infant but had no impact on the antibody responses to the R21/Matrix-M malaria vaccine or the number of malaria episodes experienced by an infant.
In my conclusions in this thesis, I have reflected on some of the key issues beyond the science that affect deployment and implementation of a successful malaria vaccine. In order to make strides in eliminating malaria in sub-Saharan Africa, it is necessary for there to be cooperation amongst multiple stakeholders; developments in manufacturing and delivery of vaccines; and grassroots participation in vaccine programmes.
The results from these trials have led to a phase III trial across five African sites, in East and West Africa, evaluating the safety and efficacy of R21/Matrix-M in areas of differing malaria transmission in a larger number of infants and children. The aim is licensure of a safe, inexpensive vaccine, with high efficacy, that will significantly reduce the malaria disease burden
R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18–45 years: an open-label, partially blinded, phase 1–2a controlled human malaria infection study
No full textBackground: R21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis B surface antigen. Following favourable safety and immunogenicity in a phase 1 study, we aimed to assess the efficacy of R21 administered with Matrix-M (R21/MM) against clinical malaria in adults from the UK who were malaria naive in a controlled human malaria infection study. Methods: in this open-label, partially blinded, phase 1–2A controlled human malaria infection study undertaken in Oxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM. A standard three-dose regimen (groups 1 and 6) was compared with a reduced (fractional) third dose (groups 2 and 5) of R21/MM, concomitant administration with viral vectors ChAd63-MVA expressing ME-TRAP (group 3), and a two-dose R21/MM regimen (group 7). Controlled Human Malaria Infection (CHMI) was delivered by mosquito bite at Imperial College London, London, UK, 3–4 weeks after final vaccination (or 18 months after final vaccination for group 6) alongside unvaccinated controls (groups 4A and 4B). The primary outcome measures were to assess safety of the vaccines in healthy malaria-naive volunteers and the efficacy (occurrence of blood-stage malaria infection) of the different vaccine regimens compared with non-vaccinated controls after CHMI. The trial was registered with ClinicalTrials.gov (NCT02905019). Findings: 66 volunteers were enrolled with 59 undergoing subsequent CHMI. All vaccination schedules were well tolerated. The highest level of protection against CHMI was observed in participants receiving the standard three-dose regimen of R21/MM (group 1, nine of 11 volunteers protected) with protection maintained in three of five volunteers re-challenged by CHMI 7·5 months later. Protection against malaria was also seen in group 2, group 3, and group 5 compared with unvaccinated control participants. Total IgG antibody responses to the NANP repeat region of circumsporozoite protein peaked after the third dose of R21/MM in all volunteers and were well maintained to 90 days after challenge. Reducing the third dose did not affect protection or antibody concentrations. Interpretation: our study shows that R21/MM elicits high-level efficacy against clinical malaria in a controlled human infection model of malaria in adults who are malaria naive. These data supported the evaluation of R21/MM in field efficacy trials in the target population of young children in malaria-endemic areas. Funding: EU Horizon 2020, the UK Medical Research Council, the European Commission, the UK National Institute of Health Research, the Imperial NIHR Clinical Research Facility, the Oxford NIHR Biomedical Research Centre, and the Wellcome Trust.</p
Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.
No full textStalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy.info:eu-repo/semantics/publishe
Safety and immunogenicity of varied doses of R21/Matrix-M™ vaccine at three years follow-up: A phase 1b age de-escalation, dose-escalation trial in adults, children, and infants in Kilifi-Kenya
No full textBackgroundFalciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021 following the advice of the World Health Organisation (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization and WHO Malaria Policy Advisory Group (MPAG). It has since been pre-qualified in 2022 by the WHO. R21 is similar to RTS, S/AS01, and recently licensed in Nigeria, Ghana and Burkina Faso following Phase 3 trial results.MethodsWe conducted a Phase 1b age de-escalation, dose escalation bridging study after a change in the manufacturing process for R21. We recruited healthy adults and children and used a three dose primary vaccination series with a booster dose at 1-2 years. Variable doses of R21 and adjuvant (Matrix-M ™) were administered at 10µgR21/50 µg Matrix-M™, 5µgR21/25µg Matrix-M™ and 5µgR21/50µg Matrix-M™ to 20 adults, 20 children, and 51 infants.ResultsSelf-limiting adverse events were reported relating to the injection site and mild systemic symptoms. Two serious adverse events were reported, neither linked to vaccination. High levels of IgG antibodies to the circumsporozoite antigen were induced, and geometric mean titres in infants, the target group, were 1.1 (0.9 to 1.3) EU/mL at day 0, 10175 (7724 to 13404) EU/mL at day 84 and (following a booster dose at day 421) 6792 (5310 to 8687) EU/mL at day 456.ConclusionR21/Matrix-M™ is safe, and immunogenic when given at varied doses with the peak immune response seen in infants 28 days after a three dose primary vaccination series given four weeks apart. Antibody responses were restored 28 days after a 4 th dose given one year post a three dose primary series in the young children and infants.RegistrationClinicaltrials.gov (NCT03580824; 9 th of July 2018; Pan African Clinical Trials Registry (PACTR202105682956280; 17 th May 2021)
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Technological impact on the art of moviemaking: deploying new and convergent media to redefine a model for Pakistan’s cinema
No full textThis thesis examines the decline in Pakistani cinema during the last two decades. It examines the history of the cinema and exposes some possible, previously ignored, causes for that decline. This research led the author to ask “Can new and convergent media be helpful in reviving the Pakistani cinema?” The thesis introduces the ideas of established and emergent cinema, building on the work of Williams (1977) in discussing the ideas of dominant, residual and emergent culture. The exploration reveals two gaps in the film industry: first, the lack of training in the making of films; and, second, the change in possible production methods allowed by new and emergent technologies. The thesis addresses both of these gaps by suggesting new production paradigms which incorporate the new technology and by examining two scripts to develop methodologies for teaching. The scripts are produced into films as the practice section of the research. The first film, creative element 1, is developed using some of the new tehnologies, students as crew and the available resources of an educational establishment to test the methodologies that have been derived. The outcomes of the creative element 1 laid the foundation of the second film, creative element 2. It is shot on mobile phones and distributed from Pakistan through Vimeo with a negligible budget. The social networks helped to arrange equipment and locations and allowed extreme freedom to the filmmaker
DataSheet_3_Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.docx
No full textProtection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.</p
DataSheet_2_Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.zip
No full textProtection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.</p
DataSheet_1_Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.zip
No full textProtection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.</p
R21/Matrix-M malaria vaccine drives diverse immune responses in pre-exposed adults: insights from a phase IIb controlled human malaria infection trial
No full textIntroduction: The recently licenced R21/Matrix-M vaccine induces a protective antibody response. In this study, we examined vaccine-induced responses in semi-immune adults in a controlled human malaria infection (CHMI) Phase IIb clinical trial. Methods: Plasma and peripheral blood mononuclear cells from healthy adult volunteers living in coastal Kenya were analysed following vaccination with R21/Matrix-M (n = 19) and CHMI challenge with Plasmodium falciparum (PfSPZ NF54) sporozoites (n = 17). Humoral immunity was evaluated by quantifying antigen specific antibody subtypes and subclasses via ELISA, alongside functional antibody properties including avidity and complement fixation elicited by vaccination and challenge. Antigen-specific memory B cells were characterised using FluoroSpot assays to detect concurrent secretion of multiple antibody isotypes and the frequency and phenotypes of circulating Tfh (cTfh) cells were assessed using multiparametric flow cytometry. Results: Vaccination increased antibody titres across IgA, IgM, and IgG isotypes and IgG1 and IgG3 subclasses but not IgG2 or IgG4 subclasses, targeting different vaccine antigens (full-length R21, NANP, and C-terminus), indicating a broad and heterogeneous response. The responses were maintained over time and, importantly, they demonstrated complement-fixing capabilities. IgG+ and IgA+ antigen-specific memory B cells were boosted but were short-lived for IgA. We observed an increase in total CXCR5+/PD1+ cTfh cells following vaccination and challenge with the predominant Th2/Th17 population. Discussion: We provide insights into the diverse immune responses induced by R21/Matrix-M vaccination and their potential contribution to protection against malaria. These findings highlight the potential of the R21/Matrix-M vaccination and protection in adults with varying levels of prior malaria exposure
Data for: A Phase 1b, open-label, age de-escalation, dose-escalation study to evaluate the safety and immunogenicity of different doses of a candidate malaria vaccine; adjuvanted R21(R21/MM) in adults, young children and infants in Kilifi, Kenya
No full text In the era of anti-malaria drug resistance and resistance to insecticide treated bed nets, there is an urgent need for a highly efficacious vaccine. We evaluated a candidate malaria vaccine incorporating the antigen R21 (part of the P. falciparum circumsporozoite malaria antigen co-expressed with hepatitis B antigen plus an adjuvant to boost the immune responses (Matrix-M). R21c/Matrix-M showed promising safety and immunogenicity data in preclinical and early phase trials in Oxford. We conducted an open label, age de-escalation, dose escalation study in 20 healthy adults (18-45 years), 20 young children aged 1-5 years and 51 infants aged 5- <12 months. Each participant was screened to ensure they were in good health based on clinical assessment and laboratory results. Participants had a blood test to ensure suitability prior to vaccination. For each participant, there was a total of 31 visits to the clinic and at home, 15 of which were associated with blood sampling (38 visits for those in the booster phase). Participants recieved 3 vaccinations 4 weeks apart. Blood tests and clinical assessments were conducted to screen out participants with health conditions that may have impacted participants or study outcomes. Bloods were taken at screening and a day prior to enrolment. Blood were also taken prior to each vaccination and on days 2 and 7 post vaccination at the clinic for the primary series ( 3 doses). Home visits were conducted on days 1, 3, 4, 5, and 6 to identify solicited adverse events. Bloods for immunology were taken prior to vaccination, and throughout the study to assess the immune response to R21/Matrix-M. In addition, we invited participants to receive a booster vaccine at 9-25 months after receipt of the 3rd vaccine of R21/Matrix-M and took bloods in clinic 28 days after boosting with field workers supporting participants or their parents/guardians to do this over the phone. During the booster vaccination visit (4th dose_, the participants/Parents/guardians were guided through the measurement of body temperature, assessment of the vaccination site (for redness, swelling and erythema) and documentation of the results on the diary card. They were then issued with a thermometer, vaccination ruler, a copy of the diary card and a pen to facilitate the completion of the remote safety assessments. </p
