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The Jenner Institute is based within the Nuffield Department of Medicine, University of Oxford, and operates out of the Old Road Campus Research Building, in Headington, Oxford.
R21/Matrix-M malaria vaccine drives diverse immune responses in pre-exposed adults: insights from a phase IIb controlled human malaria infection trial.
INTRODUCTION: 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.
Vaccine-induced responses to R21/Matrix-M - an analysis of samples from a phase 1b age de-escalation, dose-escalation trial.
IntroductionThe pre-erythrocytic malaria vaccine R21 vaccine adjuvanted with Matrix-M reported good efficacy (75%) in an ongoing phase 3 trial and was recommended World Health Organization for use in children 5-36 months. Vaccine-induced antibodies against NANP are associated with protection, however, various factors such as age, pre-existing immunity, and vaccine dose have been shown to influence vaccine responses.MethodsSamples from adults (n =18), children (n = 17), and infants (n = 51) vaccinated with R21/Matrix-M in a phase I trial were assayed for vaccine-specific antibody responses. We measured antibodies (quantity) by MSD and ELISA; and function (quality) by complement (C1q) fixation assay, inhibition of sporozoite invasion (ISI) assay, and avidity assay. Pre-existing malaria antibody exposure was assessed using an anti-3D7 Plasmodium falciparum crude parasite lysate ELISA.ResultsVaccine-induced CSP antibodies (against full-length R21, NANP, and C terminus), exhibited complement fixation and inhibition of sporozoites. These were significantly lower in adults compared to children and infants. Additionally, children had a higher rate of decay of vaccine-induced antibodies compared to adults 2 years post-vaccination. Furthermore, a higher Matrix-M adjuvant dose resulted in significantly higher C1q fixation, and ISI than the low adjuvant dose in infants. Importantly, functional measures ISI and C1q-fixation were positively associated with the vaccine-induced antibodies overall, but avidity was not. Interestingly, in adults, previous malaria exposure was negatively associated with ISI but positively correlated with avidity and C1q fixation. At baseline, all the study participants were seropositive for anti-HBsAg IgG above the WHO-required protective threshold of 10 mIU/mL, and titers significantly increased post-vaccination.DiscussionR21/Matrix-M was immunogenic across all age groups, with age and vaccine dose significantly affecting antibody magnitude and function. These findings emphasize the importance of evaluating the right adjuvant and vaccine dose for clinical development progression. This could thus inform the development of next-generation malaria vaccines. However, additional crucial factors need further exploration.
Validity of Clinical Severity Scores for Respiratory Syncytial Virus: A Systematic Review.
BackgroundRespiratory syncytial virus (RSV) is a widespread respiratory pathogen, and RSV-related acute lower respiratory tract infections are the most common cause of respiratory hospitalization in children <2 years of age. Over the last 2 decades, a number of severity scores have been proposed to quantify disease severity for RSV in children, yet there remains no overall consensus on the most clinically useful score.MethodsWe conducted a systematic review of English-language publications in peer-reviewed journals published since January 2000 assessing the validity of severity scores for children (≤24 months of age) with RSV and/or bronchiolitis, and identified the most promising scores. For included articles, (1) validity data were extracted, (2) quality of reporting was assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis checklist (TRIPOD), and (3) quality was assessed using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). To guide the assessment of the validity data, standardized cutoffs were employed, and an explicit definition of what we required to determine a score was sufficiently validated.ResultsOur searches identified 8541 results, of which 1779 were excluded as duplicates. After title and abstract screening, 6670 references were excluded. Following full-text screening and snowballing, 32 articles, including 31 scores, were included. The most frequently assessed scores were the modified Tal score and the Wang Bronchiolitis Severity Score; none of the scores were found to be sufficiently validated according to our definition. The reporting and/or design of all the included studies was poor. The best validated score was the Bronchiolitis Score of Sant Joan de Déu, and a number of other promising scores were identified.ConclusionsNo scores were found to be sufficiently validated. Further work is warranted to validate the existing scores, ideally in much larger datasets.
Underreporting and Misclassification of Respiratory Syncytial Virus-Coded Hospitalization Among Adults in Denmark Between 2015-2016 and 2017-2018.
BackgroundLow awareness and lack of routine testing for respiratory syncytial virus (RSV) infections among adults has led to underreporting in hospital records. This study aimed to assess the underreporting and misclassification of RSV infections among adults hospitalized with an respiratory tract infection (RTI)-coded hospitalization.MethodsThis study is an observational cohort study of RSV-associated hospitalizations among Danish adults (≥18 years old) conducted, between 2015 to 2018. Data were extracted from the Danish National Patient Registry (DNPR) and the Danish Microbiology Database. We identified RSV-positive hospitalizations by linking RTI-coded hospitalizations with a positive RSV test.ResultsUsing hospital admission registries, we identified 440 RSV-coded hospitalizations, of whom 420 (95%) had a positive RSV test registered. By linking patients with RTI-coded hospital admissions to RSV test result, we found 570 additional episodes of RSV-positive hospitalizations without an RSV-coded diagnosis.ConclusionsOur study of national register data showed that RSV is underreported among Danish adults. The study showed that the reliability of hospitalization data to estimate the burden of RSV among adults is questionable and are sensitive to changes in practice over time, even with complete nationwide healthcare data. Healthcare data can be useful to observe seasonality but to estimate the disease burden, prospective surveillance is recommended.
Airway and Blood Monocyte Transcriptomic Profiling Reveals an Antiviral Phenotype in Infants With Severe Respiratory Syncytial Virus Infection.
BackgroundRespiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection.MethodsTracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14+) were sorted and analyzed by RNA sequencing for transcriptomic profiling.ResultsPeripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation.ConclusionsWe found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease.
Respiratory viral detection in children hospitalized with pneumonia during periods of major population disruptions in Nepal, 2014-2018.
BackgroundRespiratory viruses commonly cause pneumonia in children. We aimed to identify respiratory viral nucleic acids in the nasopharynx of children admitted with pneumonia from 2014 to 2018, a period including a major earthquake (April 2015), PCV10 introduction (August 2015), and a fuel shortage (October 2015 to March 2016).MethodsChildren 2 months to 14 years admitted to Patan Hospital between March 2014 and February 2018 with a clinical diagnosis of pneumonia had nasopharyngeal swabs collected and tested with a multiplex panel for the presence of genetic material from 23 respiratory pathogens.ResultsOf 1343 children with pneumonia, 974 (72.5%) had the nucleic acids of at least one respiratory virus in the nasopharynx. The median age of children with any viral genetic material detected was lower than those without (1.18, IQR: 0.59-2.39 years; versus 2.01 years, IQR: 0.81-4.34 years; p<0.001). Commonly detected viral nucleic acids included those of RSV (21.0%), rhino/enterovirus (30.8%), and parainfluenza (7.4%). The odds of detecting any respiratory viral genetic material in children with pneumonia increased by 1.88 (95% confidence interval: 1.15, 3.06) in the year after the earthquake, when there were several aftershocks and a fuel crisis, relative to other periods and accounting for other potential confounding factors.ConclusionsThese findings highlight the importance of viral diagnostics in pediatric pneumonia and suggest that public health measures addressing environmental conditions during disasters might help reduce respiratory infections.
Age differences in immunity to human seasonal coronaviruses and the immunogenicity of ChAdOx1 nCoV-19 (AZD1222).
BackgroundChAdOx1 nCoV-19 (AZD1222) vaccine was widely deployed to protect against severe COVID-19 in adults, but the relationship between pre-existing immunity to human seasonal coronaviruses (HCoVs) and vaccine-induced SARS-CoV-2 (SCoV2) response across age groups remains unclear.MethodsWe analysed SCoV2 and HCoVs antibody profiles in UK volunteers (aged 6-≥70), assessing antibody levels, avidity, and FcγR binding after receiving one or two doses of ChAdOx1 nCoV-19. Adult cohorts from trials in Brazil and Kenya were also included to evaluate geographical impacts on baseline HCoVs and SCoV2 induced response.FindingsIn the UK cohort, younger individuals had higher SCoV2 IgG, avidity, FcγR binding and cross-reactivity, particularly towards OC43 and HKU1. The greatest differences were seen after the first dose of ChAdOx1 nCoV-19, but these effects diminished after the second dose. Although baseline HCoVs IgG varied geographically, similar trends were observed across adult cohorts with younger adults showing higher SCoV2 IgG compared to older adults (UK and Brazil).InterpretationThese findings contribute to a better understanding of the immunogenicity of ChAdOx1-based vaccines in various age groups. Determining whether this applies across other vaccines using same platform is essential for evaluating the viability of one-dose regimens in outbreak responses.FundingThe clinical trials COV002, COV003, COV004, and COV006 were made possible by funding from Astra Zeneca, the NIHR and the University of Oxford, UK Department of Health and Social Care, through the UK National Institute for Health and Care Research, the Wellcome Trust (220991), and Innovate UK (project 971614).
Diagnosis of Plasmodium falciparum malaria at very low parasitaemias using a commercially available LAMP assay and RDT.
BackgroundMalaria is the most common tropical infection in the UK. Current guidelines suggest that testing on 3 consecutive days is required following an initial negative result. This study aimed to see whether newer diagnostics (loop-mediated amplification assay [LAMP]) had sufficient sensitivity to support a change in diagnostic practice.MethodsBlood samples from 11 participants who had undergone controlled human malaria infection (CHMI) with Plasmodium falciparum malaria were assessed from day 6 (C+6) for malaria positivity using the Carestart Malaria rapid diagnostic test (RDT) and from C+4 using the Alethia Malaria LAMP assay. Quantitative polymerase chain reaction had been performed twice daily during CHMI follow-up. A retrospective analysis of samples submitted to the Sheffield Teaching Hospitals for malaria testing over a 5-y period was conducted, evaluating the combination of the Carestart RDT alongside blood film analysis, as per UK guidelines.ResultsIn CHMI samples, LAMP was positive for all parasitaemias >1000 parasites/ml, whereas RDTs were less reliable (59% positive for parasitaemias >1000 parasites/ml). The combination of RDT and blood films for clinical samples diagnosed most infections, but only a minority of negative samples had subsequent tests.ConclusionsLAMP has higher sensitivity than current UK recommended methods, with a potential to review the requirement for additional days of testing in the majority of patients.
Longitudinal kinetics of the viral infection biomarker 3'-deoxy-3',4'-didehydro-cytidine in SARS-CoV-2, influenza A virus and RSV human challenge models.
3'-deoxy-3',4'-didehydro-cytidine (ddhC) is a recently discovered host biomarker for viral infections, though its temporal kinetics remain unclear. This study tests the hypothesis that ddhC is an acute phase reactant, rising shortly after viral infection and subsequently falling to baseline. We leveraged the precise monitoring facilitated by human challenge studies to investigate healthy participants inoculated with SARS-CoV-2, influenza A virus (H3N2), or respiratory syncytial virus (RSV). Using targeted liquid chromatography-tandem mass spectrometry, we quantified ddhC concentrations in serial plasma samples collected pre- and post-inoculation. In SARS-CoV-2 and H3N2 influenza A virus infection, but not RSV, ddhC levels peaked at 3-7 days post inoculation and declined to baseline by days 10-14. This pattern was also observed in asymptomatic or paucisymptomatic participants. A comparison of ddhC concentrations with matched timepoint whole blood gene expression revealed a correlation with interferon-related genes, including viperin and CMPK2-enzymes implicated in its upstream biosynthesis. Our results suggest that ddhC is a biomarker of the acute phase of viral infection, with potential to guide early interventions that reduce antimicrobial resistance and strengthen pandemic preparedness. Future work should explore ddhC dynamics in natural and experimental infections across varying severities and assess its utility in diverse populations and healthcare settings.
MetE: a promising protective antigen for tuberculosis vaccine development
IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health concern. The existing vaccine, Bacillus Calmette-Guérin (BCG), provides inconsistent protection, highlighting the pressing need for a more effective vaccine. We aimed to identify novel MTB antigens and assess their protective efficacy as TB vaccine candidates.MethodsUsing immunopeptidomics, we identified 64 and 80 unique mycobacterial antigens derived from BCG and MTB, respectively. We prioritised antigens based on HLA allele coverage through an immunoinformatics approach.ResultsThe candidates, hisD, metE, and mmpL12, delivered as DNA vaccines, were evaluated for efficacy in mice using the ex vivo Mycobacterial Growth Inhibition Assay (MGIA) and metE was identified as a promising candidate. In vivo murine MTB challenge experiments confirmed the protective efficacy conferred by metE when formulated as recombinant protein with AS01™ or AddaS03™ adjuvants, compared to the naïve group. The immunogenic profiles of metE formulated in the two different adjuvants differed, with metE-AS01™ inducing antigen-specific IFN-γ, TNF-α, IL-2, IL-17, IgG1 and IgG2a-c, while metE-AddaS03™ induced TNF-α, IL-2, IL-17, IL-4, IgM, IgG1, IgG2b.ConclusionOur findings highlight metE as a promising protective antigen for future TB vaccine development.
Immunogenicity and Safety of ChAdOx1 nCoV-19 (AZD1222) as a Homologous Fourth-Dose Booster: A Substudy of the Phase 3 COV003 Trial in Brazil
Objective: To address that, despite widespread use of ChAdOx1 nCoV-19 (AZD1222) as a COVID-2019 booster, fourth-dose clinical outcomes data are limited. We report immunogenicity and safety for ChAdOx1 nCoV-19 as a homologous fourth-dose booster. Participants and Methods: Participants (aged ≥18 years) who had received 2 doses of ChAdOx1 nCoV-19 in phase 3 COV003 trial in Brazil were offered a third dose after a planned dose interval from 11 to 13 months and a fourth dose after a planned interval from 6 to 15 months (both 5 × 1010 viral particles). All fourth doses were administered to substudy participants between August 18 and October 28, 2022. The data cutoff was December 9, 2022. The primary immunogenicity outcome was noninferiority of ancestral severe acute respiratory syndrome coronavirus (SARS-CoV)-2–neutralizing antibody responses 28 days after dose 4 versus dose 3. Solicited and unsolicited adverse events were recorded 7 and 28 days postdose 4, respectively. Results: 172 participants received a fourth dose (median interval postthird dose, 10.7 months). Ancestral SARS-CoV-2–neutralizing antibody titers postdose 4 were noninferior to those postdose 3; geometric mean fold rise was 1.9 (95% CI, 1.6-2.4; n=112). Immunogenicity results were consistent across all variants analyzed. Local and systemic solicited adverse events were reported in 60.3% (n=35/58) and 43.1% (n=25/58) of participants, respectively. Conclusion: Immune responses after a fourth dose of ChAdOx1 nCoV-19 were noninferior to those after a third dose across SARS-CoV-2 variants. The fourth dose was well tolerated with no emergent safety concerns, supporting the continued development of the ChAdOx1 platform in preparation for future pandemics. Trial Registration: clinicaltrials.gov Identifier: NCT04536051
Pf8: an open dataset of Plasmodium falciparum genome variation in 33,325 worldwide samples
We describe the Pf8 data resource, the latest MalariaGEN release of curated genome variation data on over 33,000 Plasmodium falciparum samples from 99 partner studies and 122 locations over more than 50 years. This release provides open access to raw sequencing data and genotypes at over 12 million genomic positions. For the first time, it includes copy-number variation (CNV) calls in the drug-resistance associated genes gch1 and crt. As in Pf7, CNV calls are provided for mdr1 and plasmepsin2/3, along with calls for deletion in hrp2 and hrp3, genes associated with rapid diagnostic test failures. This data resource additionally features derived datasets, interactive web applications for exploring patterns of drug resistance and variation in over 5,000 genes, an updated Python package providing methods for accessing and analysing the data, and open access analysis notebooks that can be used as starting points for further analyses. In addition, informative example analyses show contrasting profiles of the decline of chloroquine resistance-associated mutations in Africa, and variation in copy number variation across 10 distinct sub-populations. To the best of our knowledge, Pf8 is the largest open data set of genome variation in any eukaryotic species, making it an invaluable foundational resource for understanding evolution, including that of pathogens.
Risk factors of metabolic dysfunction-associated steatotic liver disease in a cohort of patients with chronic hepatitis B.
Background and aimsChronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) commonly co-exist, with conflicting data in prevalence and disease severity. We aimed to investigate these discrepancies.MethodsThis multicentre study included consecutive CHB patients from 19 European centres. A survey on standard of care for MASLD screening in CHB was circulated.Results1709 CHB patients were included; median age: 53 (42-64), males 60.7%, BMI 25.6 (14-63), 57.3% White. MASLD prevalence (1510 consecutive patients) was 42.3%. BMI (OR=1.27, 95% CI:1.19-1.36), ferritin (OR=1.00, 95% CI:1.00-1.00) and type-2-diabetes (T2DM) (OR=2.60, 95% CI:1.12-6.02) were independently associated with MASLD. The prevalence of advanced fibrosis was 18% (255/1420) in the whole cohort, 25.4% (162/639) among CHB with MASLD, and 13.7% in those without MASLD. Independent predictors of advanced fibrosis were MASLD (OR:2.76, 95%CI:1.50-5.05), BMI (OR:1.08, 95%CI:1.02-1.15), ALT (OR:1.01, 95%CI:1.00-1.03), lower PLTs (OR:0.99, 95%CI:0.98-0.99), insulin-treatment (OR:13.88, 95%CI:2.95-65.28) and long-term antivirals (OR:4.86, 95%CI:2.40-9.85). During follow-up (48 months), only patients without MASLD showed significant LSM improvement over time (p<0.001). Among patients with MASLD, FIB-4 and LSM performed moderately at predicting advanced fibrosis (AUROC 0.71 vs 0.70, p=0.38), against histology. As standard of care, 68.4% centres screened all CHB patients for MASLD. 52.6% followed the same treatment indication in those with CHB and MASLD vs CHB only.ConclusionIn this large European cohort, MASLD and fibrosis were highly prevalent among CHB, while MASLD aggravated liver fibrosis. Though screening strategies remain inconsistent, ferritin levels, increased BMI and T2DM may inform on the presence of MASLD. Biomarkers showed modest performance in predicting fibrosis.
Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.
Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.
Core-shell microcapsules compatible with routine injection enable prime/boost immunization against malaria with a single shot
Inadequate booster uptake threatens the success of immunization campaigns as seen with the recently rolled-out R21 malaria vaccine. The ability to administer both prime and boost immunizations with a single injection would therefore save lives and alleviate health care burdens. We present a platform for delayed delivery of the booster dose that is scalable with existing technology, easily injectable, and protective against malaria in vivo. Using chip-based microfluidics, we encapsulated the R21 malaria vaccine in polymer microcapsules that release their content weeks to months postinjection. Coinjecting microcapsules with the priming dose of the R21 vaccine elicited strong antibody responses in a mouse model and provided 85% of the protection of a standard prime/boost schedule. If confirmed in humans, these results would pave the way for rapid deployment of single-shot prime/boost vaccination, an urgently needed global health intervention.