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Evaluation of a novel malaria anti-sporozoite vaccine candidate, R21 in Matrix-M adjuvant, in the UK and Burkina Faso: two phase 1, first-in-human trials.

BACKGROUND: Malaria remains a substantial public health burden among young children in sub-Saharan Africa and a highly efficacious vaccine eliciting a durable immune response would be a useful tool for controlling malaria. R21 is a malaria vaccine comprising nanoparticles, formed from a circumsporozoite protein and hepatitis B surface antigen (HBsAg) fusion protein, without any unfused HBsAg, and is administered with the saponin-based Matrix-M adjuvant. This study aimed to assess the safety and immunogenicity of the malaria vaccine candidate, R21, administered with or without adjuvant Matrix-M in adults naïve to malaria infection and in healthy adults from malaria endemic areas. METHODS: In this Article we report two phase 1, first-in-human trials. The first trial was a phase 1a open-label study in the UK evaluating the safety and immunogenicity of R21 administered either alone, or with 50 μg of Matrix-M. The second trial was a phase 1b randomised controlled trial in Burkina Faso. Adults had to be aged 18-50 years for enrolment in the phase 1a trial, and 18-45 years in the phase 1b trial. The phase 1a trial doses were 2 μg, 10 μg, and 50 μg R21/Matrix-M, and 50 μg R21 only. The phase 1b trial doses were 10 μg R21/Matrix-M and saline placebo. Matrix-M was always dosed at 50 μg. Phase 1b implemented block randomisation by randomisation into study groups by an independent statistician based at the University of Oxford using a randomisation code list with allocation concealment using opaque sealed envelopes. The primary objective of the phase 1a trial was to assess the safety and tolerability of R21 with and without Matrix-M. The primary objective of the phase 1b trial was to assess the safety and tolerability of R21 with Matrix-M. Both trials are registered with ClinicalTrials.gov, NCT02572388 for phase 1a and NCT02925403 for phase 1b, and are completed. FINDINGS: Between Oct 1, 2015, and Jan 3, 2017, 31 individuals were enrolled in the phase 1a study. Six individuals were assigned to receive 2 μg R21/Matrix-M, 11 to 10 μg R21/Matrix-M, ten to 50 μg R21/Matrix-M, and four to 50 μg R21 only. Between Aug 26, 2016, and Sept 28, 2017, 13 individuals were enrolled in the phase 1b study. Eight individuals were assigned to receive 10 μg R21/Matrix-M, and five to placebo. Vaccinations were well tolerated, and most local and systemic adverse events were mild. There were no serious adverse events deemed related to vaccination. Two serious adverse events occurred. The first in the 10 μg R21/Matrix-M group was worsening of previously undisclosed or undiagnosed palindromic rheumatism and was deemed unlikely to be related to vaccination and the second in the 2 μg R21/Matrix-M was hospital admission for an unplanned excision of a pre-existing Bartholin's cyst, also unrelated to vaccination. In the phase 1a study, a total of 21 adverse events were recorded in the 2 μg R21/Matrix-M group, 103 in the 10 μg R21/Matrix-M group, 94 in the 50 μg R21/Matrix-M group, and 21 in the 50 μg R21 alone group. In the phase 1b study, twelve adverse events were recorded in the 10 μg R21/Matrix-M group and 0 in the placebo group. INTERPRETATION: R21 with Matrix-M adjuvant has an acceptable safety profile. These data have formed the basis for efficacy testing of this vaccine. FUNDING: The European Commission Framework 7 and The European & Developing Countries Clinical Trials Partnership.

Corrigendum to "Naturally acquired immune responses to alpha-gal in malaria endemic settings and pre-clinical efficacy testing with R21/MM" [Vaccine 68 (2025) 127897].

Naturally acquired immune responses to alpha-gal in malaria endemic settings and pre-clinical efficacy testing with R21/MM.

Malaria sporozoite surface glycan alpha-gal (α-gal), which is absent in humans has been shown to elicit an antibody response that can confer protection against malaria in alpha- gal transferase knock- out mice. In humans, several studies have highlighted association of antibodies to this glycan with protection against malaria in endemic regions. Here, we first assess the anti- α-gal IgG and IgM antibody levels in serum samples obtained from sporozoite challenged malaria naïve UK volunteers, and naturally exposed or infected Kenyan adults and Burkina Faso infants. In UK volunteers, there was no significant increase seen in antibody levels 90 days post challenge. We observe increases in anti- α-gal IgG and IgM antibodies over time only in Burkina Faso infants. In Burkina Faso infants, protection from malaria could be correlated to higher anti- α-gal IgM antibody levels and possibly to anti- α-gal IgG antibody levels. We then evaluate Bovine Serum Albumin (BSA) linked α-gal with highly potent adjuvant Matrix-M (MM) for immunogenicity and efficacy in alpha- gal transferase knock-out (α1,3GT KO) mice. BSA-linked α-gal elicits an IgG and IgM response but failed to protect against the sporozoite challenge. Clinical trials registry: VAC049 (NCT01465048), VAC073 (NCT03580824), VAC076 (NCT03896724).

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Subcutaneous administration of the malaria R21/Matrix M vaccine and immune complex formation with anti-circumsporozoite protein mAb 2A10 elicit protective efficacy in mice.

INTRODUCTION: R21, the most efficacious malaria vaccine to date, has been recommended by the World Health Organization (WHO) for the prevention of malaria in children. The current vaccination schedule requires three intramuscular doses per year. Optimizing vaccine administration strategies, including exploring alternative routes of immunization and novel vaccine formulations, has the potential to reduce the number of required doses to achieve high efficacy. Immune complexes (ICs), formed by combining antigens with their cognate antibodies, have been successfully employed in licensed poultry vaccines for viral diseases and are showing promise in preclinical studies for human viral vaccines. Co-delivery of antigen with immune complexes has been reported to enhance antibody titers in preclinical models. METHODS: Here, we present the first report of the immunogenicity and short- term high protective efficacy of R21/Matrix-M administered via the subcutaneous (SC) route, as well as in a modified formulation as an immune complex (IC) (R21: anti-NANP mAb 2A10) with only two immunizations. We also evaluated co-administration of R21 with pre-formed ICs. RESULTS: R21/MM administered via the SC route is immunogenic and more efficacious (100% in BALB/c mice) than the IM route. R21:2A10 IC/MM is immunogenic and induces sterile protection in BALB/c mice. Co-administration of R21/MM with R21:2A10 IC is immunogenic but less protective than IC/MM alone in BALB/c mice. CONCLUSION: While IC-based vaccination strategies have primarily been explored for viral diseases, this study represents the first application of this approach to a parasitic disease. Our findings provide new insights into the potential of alternative vaccine delivery strategies and immune complex platforms for improving malaria vaccination outcomes.

Emulsion and liposome-based adjuvanted R21 vaccine formulations mediate protection against malaria through distinct immune mechanisms.

Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%-100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different TH1/TH2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design.

Production of a high purity, C-tagged hepatitis B surface antigen fusion protein VLP vaccine for malaria expressed in Pichia pastoris under cGMP conditions.

Virus-like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP-based anti-sporozoite malaria vaccine, under current Clinical Good Manufacturing Practice regulations (cGMP). Previous preclinical studies in BALB/c mice showed that R21 produced almost complete protection against sporozoite challenge with transgenic Plasmodium berghei parasites. Here, we have modified the preclinical production process to enable the production of sufficient quantities of highly pure, clinical-grade material for use in human clinical trials. The R21 construct was re-engineered to include a C-tag to allow affinity-based separation from the major contaminant alcohol oxidase 1 (AOX 1, ~74 kDa). To our knowledge, this is the first use of C-tag technology to purify a VLP vaccine candidate for use in human clinical trials. The R21 vaccine has shown high-level efficacy in an African Phase IIb trial, and multiple clinical trials are underway to assess the safety and efficacy of the vaccine. Our findings support the future use of C-tag platform technologies to enable cGMP-compliant biomanufacturing of high purity yeast-expressed VLP-based vaccines for early phase clinical trials when clinical grade material is required in smaller quantities in a quick time frame.

Virus-like particle vaccines

Vaccines are among the most successful and cost-effective public health tools for preventing infectious diseases and death. Virus-like particles (VLPs) have made impressive progress in the field of vaccinology over the last three decades so that several VLP-based vaccines are commercially available and generating great public health impact, for example, the hepatitis B virus and the human papillomavirus (HPV) vaccines or in advanced clinical trials such as the RTS,S and R21 VLP malaria vaccines. We have growing in-house experience in Oxford of the use of a wide range of VLPs to target malaria and other diseases by vaccination. As VLPs lack genetic material, they have no replication capacity and are considered very safe. Additionally, VLP-based vaccines have significant ability to induce both innate and adaptive immune responses as well as being safe templates with favorable low-cost and large-scale manufacturing available.

Screening of viral-vectored P. falciparum pre-erythrocytic candidate vaccine antigens using chimeric rodent parasites.

To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in establishment of hepatocyte infection. For preclinical evaluation of immunogenicity of these proteins in mice, chimeric P. berghei sporozoites were created that express the P. falciparum proteins in sporozoites as an additional copy gene under control of the uis4 gene promoter. All fourteen chimeric parasites produced sporozoites but sporozoites of eight lines failed to establish a liver infection, indicating a negative impact of these P. falciparum proteins on sporozoite infectivity. Immunogenicity of the other six proteins (SPELD, ETRAMP10.3, SIAP2, SPATR, HT, RPL3) was analyzed by immunization of inbred BALB/c and outbred CD-1 mice with viral-vectored (ChAd63 or ChAdOx1, MVA) vaccines, followed by challenge with chimeric sporozoites. Protective immunogenicity was determined by analyzing parasite liver load and prepatent period of blood stage infection after challenge. Of the six proteins only SPELD immunized mice showed partial protection. We discuss both the low protective immunogenicity of these proteins in the chimeric rodent malaria challenge model and the negative effect on P. berghei sporozoite infectivity of several P. falciparum proteins expressed in the chimeric sporozoites.

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.

BACKGROUND: Stalled 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. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Efficacy of a low dose candidate malaria vaccine, R21 in adjuvant Matrix-M™, with seasonal administration to children in Burkina Faso

Phase I assessments of first-in-human administration of a novel malaria anti-sporozoite vaccine candidate, R21 in matrix-M adjuvant, in UK and Burkinabe volunteers

ABSTRACT Background Improvements in malaria control have stalled recently and new tools are needed. The R21 vaccine is comprised of the malaria circumsporozoite protein fused to hepatitis B surface antigen (HBsAg). It forms particles that lack the excess HBsAg in the frequently tested malaria vaccine candidate, RTS,S/AS01 B . Methods We conducted an open-label, first-in-human, Phase Ia study evaluating safety and immunogenicity of R21 administered alone and with the saponin-based adjuvant, Matrix-M ™ (MM). Twenty-eight healthy adults received three doses of R21 given intramuscularly 4 weeks apart. We subsequently conducted a Phase Ib randomised, controlled trial in West African adults. Findings Vaccinations were well tolerated, and the majority of local and systemic adverse events were mild. Reactogenicity was significantly lower in Burkinabe than UK vaccinees (p<0.0001). Antibody responses increased significantly 28 days after the 2 nd vaccination in UK volunteers. Antibody responses to R21 in all dose groups (2μg, 10μg and 50μg) were comparable to those of 50μg RTS,S/AS01 B in malaria-naïve adults at 28 days after final vaccination. The 10μg dose induced more durable responses, with 2-fold higher NANP-specific IgG titres at 6 months compared with the 2μg and 50μg dose groups. R21 also boosted baseline humoral responses in Burkinabe adults with well-maintained responses suggesting natural boosting. Interpretation R21 adjuvanted with MM is safe and has comparable immunogenicity to RTS,S/AS01 B , even when administered at a five-fold lower 10μg dose in UK and African populations. This forms the basis for efficacy testing of this vaccine which could prove to be particularly cost-effective to manufacture and deploy.

SAFETY AND IMMUNOGENICITY OF WITH NOVEL MALARIA VACCINE CANDIDATE, R21 ADJUVANTED WITH MATRIX M1

SAFETY, IMMUNOGENICITY AND DURABILITY OF A NOVEL MALARIA VACCINE CANDIDATE, R21 ADJUVANTED WITH AS01B

Author Correction: Spatial fibroblast niches define Crohn's fistulae.

Assessing Metabolic Ageing via DNA Methylation Surrogate Markers: A Multicohort Study in Britain, Ireland and the USA

ABSTRACTMetabolomics and epigenomics have been used to develop ‘ageing clocks’ that assess biological age and identify ‘accelerated ageing’. While metabolites are subject to short‐term variation, DNA methylation (DNAm) may capture longer‐term metabolic changes. We aimed to develop a hybrid DNAm‐metabolic clock using DNAm as metabolite surrogates (‘DNAm‐metabolites’) for age prediction. Within the UK Airwave cohort (n = 820), we developed DNAm metabolites by regressing 594 metabolites on DNAm and selected 177 DNAm metabolites and 193 metabolites to construct ‘DNAm‐metabolic’ and ‘metabolic’ clocks. We evaluated clocks in their age prediction and association with noncommunicable disease risk factors. We additionally validated the DNAm‐metabolic clock for the prediction of age and health outcomes in The Irish Longitudinal Study of Ageing (TILDA, n = 488) and the Health and Retirement Study (HRS, n = 4018). Around 70% of DNAm metabolites showed significant metabolite correlations (Pearson's r: > 0.30, p < 10−4) in the Airwave test set and overall stronger age associations than metabolites. The DNAm‐metabolic clock was enriched for metabolic traits and was associated (p < 0.05) with male sex, heavy drinking, anxiety, depression and trauma. In TILDA and HRS, the DNAm‐metabolic clock predicted age (r = 0.73 and 0.69), disability and gait speed (p < 0.05). In HRS, it additionally predicted time to death, diabetes, cardiovascular disease, frailty and grip strength. DNAm metabolite surrogates may facilitate metabolic studies using only DNAm data. Clocks built from DNAm metabolites provided a novel approach to assess metabolic ageing, potentially enabling early detection of metabolic‐related diseases for personalised medicine.

Designing a computer-assisted diagnosis system for cardiomegaly detection and radiology report generation

Chest X-ray (CXR) is a diagnostic tool for cardiothoracic assessment. They make up 50% of all diagnostic imaging tests. With hundreds of images examined every day, radiologists can suffer from fatigue. This fatigue may reduce diagnostic accuracy and slow down report generation. We describe a prototype computer-assisted diagnosis (CAD) pipeline employing computer vision (CV) and Natural Language Processing (NLP). It was trained and evaluated on the publicly available MIMIC-CXR dataset. We perform image quality assessment, view labelling, and segmentation-based cardiomegaly severity classification. We use the output of the severity classification for large language model-based report generation. Four board-certified radiologists assessed the output accuracy of our CAD pipeline. Across the dataset composed of 377,100 CXR images and 227,827 free-text radiology reports, our system identified 0.18% of cases with mixed-sex mentions, 0.02% of poor quality images ( F 1 = 0.81), and 0.28% of wrongly labelled views (accuracy 99.4%). We assigned views for 4.18% of images which have unlabelled views. Our binary cardiomegaly classification model has 95.2% accuracy. The inter-radiologist agreement on evaluating the generated report’s semantics and correctness for radiologist-MIMIC is 0.62 (strict agreement) and 0.85 (relaxed agreement) similar to the radiologist-CAD agreement of 0.55 (strict) and 0.93 (relaxed). Our work found and corrected several incorrect or missing metadata annotations for the MIMIC-CXR dataset. The performance of our CAD system suggests performance on par with human radiologists. Future improvements revolve around improved text generation and the development of CV tools for other diseases.

LAVASET: Latent Variable Stochastic Ensemble of Trees. An ensemble method for correlated datasets with spatial, spectral, and temporal dependencies

Abstract Motivation Random forests (RFs) can deal with a large number of variables, achieve reasonable prediction scores, and yield highly interpretable feature importance values. As such, RFs are appropriate models for feature selection and further dimension reduction. However, RFs are often not appropriate for correlated datasets due to their mode of selecting individual features for splitting. Addressing correlation relationships in high-dimensional datasets is imperative for reducing the number of variables that are assigned high importance, hence making the dimension reduction most efficient. Here, we propose the LAtent VAriable Stochastic Ensemble of Trees (LAVASET) method that derives latent variables based on the distance characteristics of each feature and aims to incorporate the correlation factor in the splitting step. Results Without compromising on performance in the majority of examples, LAVASET outperforms RF by accurately determining feature importance across all correlated variables and ensuring proper distribution of importance values. LAVASET yields mostly non-inferior prediction accuracies to traditional RFs when tested in simulated and real 1D datasets, as well as more complex and high-dimensional 3D datatypes. Unlike traditional RFs, LAVASET is unaffected by single ‘important’ noisy features (false positives), as it considers the local neighbourhood. LAVASET, therefore, highlights neighbourhoods of features, reflecting real signals that collectively impact the model’s predictive ability. Availability and implementation LAVASET is freely available as a standalone package from https://github.com/melkasapi/LAVASET.