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Oxford University doctors and scientists are performing the second phase of clinical studies of an experimental Ebola vaccine regimen. The study is part of the EBOVAC2 project, a collaborative programme involving the University of Oxford, French Institute of Health and Medical Research (INSERM) as project coordinator, London School of Hygiene & Tropical Medicine, Le Centre Muraz, Inserm Transfert (IT) and the Janssen Pharmaceutical Companies of Johnson & Johnson.
Risdiplam in Presymptomatic Spinal Muscular Atrophy.
BACKGROUND: Risdiplam, an oral pre-messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear. METHODS: We conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth. RESULTS: A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious. CONCLUSIONS: Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam. (Funded by F. Hoffmann-La Roche; RAINBOWFISH ClinicalTrials.gov number, NCT03779334.).
Synthesis, Biophysical and Biological Evaluation of Splice-Switching Oligonucleotides with Multiple LNA-Phosphothiotriester Backbones.
Polyanionic antisense oligonucleotides hold great promise as RNA targeting drugs but issues with bioavailability hinder their development. Uncharged phosphorus-based backbones are promising alternatives but robust methods to produce them are limited. We report the synthesis and properties of oligonucleotides containing charge-neutral LNA alkyl phosphothiotriester backbones combined with 2'-O-methyl phosphorothioate nucleotides for therapeutic applications. The nature of the triester alkyl group dictates the success of solid-phase synthesis; tertiary alkyl groups are lost during the P(III) oxidation step, whereas primary alkyl groups are partially cleaved during deprotection. In contrast, oligonucleotides containing secondary phosphothiotriester linkages are stable, and large numbers of triesters can be incorporated. The modified oligonucleotides have excellent duplex stability with complementary RNA and exhibit strong nuclease resistance. To expand synthetic flexibility, oligonucleotides containing multiple internal alkynyl phosphothiotriesters can be conjugated to lipids, carbohydrates, or small molecules through CuAAC click chemistry. Oligonucleotides containing LNA-THP phosphothiotriesters exhibit high levels of pre-mRNA splice switching in eukaryotic cells.
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: Final results of a phase 2, single-blind, randomised controlled trial (COV006).
BACKGROUND: Paediatric COVID-19 vaccination programmes were initiated in response to the coronavirus pandemic declared by the World Health Organisation (WHO) in 2020. Ten COVID-19 vaccines received WHO Emergency Use Listing, however, only five were approved for use in children. ChAdOx1 nCoV-19 (AZD1222) was approved in adults in a two-dose regimen. We previously reported interim findings of a phase 2 study of ChAdOx1 nCoV-19 in children with immunogenicity, comparable with adults. Final results after 12 month follow-up are reported. METHODS: Single-blind, randomised controlled trial across four UK centres, recruiting 261 children and adolescents (aged 6-17 years). Participants received either two doses of ChAdOx1 nCoV-19 or Bexsero vaccine (controls). The primary outcome was safety (adverse events for 28 days following vaccination and serious adverse events throughout), and secondary outcome was immunogenicity (measured by SARS-CoV-2 anti-spike enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISpot)). FINDINGS: Five serious adverse events and four adverse events of special interest were reported. None were related to study vaccinations, and there were no deaths. Geometric mean titres (GMTs) from an anti-spike (Wuhan) ELISA in participants aged 6-11 years were 1 EU/ml (95% CI 1-2) at baseline versus 796 EU (95% CI 161-3948, n =4) at D364. In participants aged 12-17 years, GMTs were 1 EU/ml (95% CI 1-2, n=3) at baseline versus 1432 EU/ml (95% CI 2337-6083; n=6) at D364 (2 dose regimen at 112-day interval), compared to 3 EU/ml (95% CI 0-62) at baseline versus 392 EU/ml (95% CI 24, 6493; n=3) at D364 (2 dose regimen at a 28-day interval). INTERPRETATION: A two-dose regimen of ChAdOx1 nCoV-19 was immunogenic and safe in the trial population. No vaccine-related serious adverse events were reported. Immune responses persisted to 12 months in participants who did not experience breakthrough infection, This trial was registered with ISRCTN, trial number 15638344. FUNDING: The study was funded by the Department of Health and Social Care, through the National Institute for Health Research, and AstraZeneca.
Evaluation of 1st WHO anti-malaria reference reagent for competition ELISA harmonisation and development of ADAMSEL analytical platform.
This study focuses on harmonising the competition ELISA (cELISA) assay for Plasmodium falciparum (P. falciparum), using the 1st WHO reference reagent for anti-malaria (P. falciparum) human reference serum (10/198). Antibody-mediated immune responses against the Apical Membrane Antigen 1 (AMA1) play a significant role in protection against malaria. However, the sequence diversity of AMA1 and cross-reactivity among variants pose challenges in assessing antibody responses. To address this, the cELISA assay was selected to examine cross-reactive antibody responses against different variants. The harmonisation process for cELISA was performed in three laboratories. The 10/198 served as an internal standard for the calculation of IgG concentrations in the cELISA using ADAMSEL software. Additionally, a novel semi-automated analytical tool was developed in the R-statistics environment. This tool is freely available for download and streamlines generating results while minimising human error. This study demonstrated the effectiveness of the 1st WHO reference reagent as a standard for cELISA. Additionally, the ADAMSEL software and R-platform tool provide a user-friendly and accessible tool for the analysis of cELISA data. Its automation capabilities improve efficiency and ensure global accessibility at no cost, benefitting laboratories with limited resources.
Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines.
Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA-lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2-specific T cells and inform the optimization of mRNA vaccination regimens.
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines.
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
Safety and efficacy of the blood-stage malaria vaccine RH5.1/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled, phase 2b trial in children.
BACKGROUND: Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a blood-stage P falciparum malaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. We therefore assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children. METHODS: In this double-blind, randomised, controlled, phase 2b trial, RH5.1/Matrix-M was given to children aged 5-17 months in Nanoro, Burkina Faso, a seasonal malaria transmission setting. Children received either three intramuscular vaccinations with 10 μg RH5.1 protein with 50 μg Matrix-M adjuvant or three doses of rabies control vaccine, Rabivax-S, given either in a delayed third-dose (0, 1, and 5 month) regimen (first cohort) or a 0, 1, and 2 month regimen (second cohort). Vaccinations were completed part way through the malaria season. Children were randomly assigned 2:1 within each cohort to receive RH5.1/Matrix-M or Rabivax-S. Participants were assigned according to a random allocation list generated by an independent statistician using block randomisation with variable block sizes. Participants, their families, and the study teams were masked to group allocation; only pharmacists who prepared the vaccines were unmasked. Vaccine safety, immunogenicity, and efficacy were evaluated. The coprimary outcomes assessed were: first, the safety and reactogenicity of RH5.1/Matrix-M; and second, the protective efficacy of RH5.1/Matrix-M against clinical malaria (measured as time to first episode of clinical malaria, using a Cox regression model) from 14 days to 6 months after the third vaccination in the per-protocol sample. This ongoing trial is registered with ClinicalTrials.gov (NCT05790889). FINDINGS: From April 6 to 13 and July 3 to 7, 2023, 412 children aged 5-17 months were screened, and 51 were excluded. A total of 361 children were enrolled in this study. In the first cohort, 119 were assigned to the RH5.1/Matrix-M delayed third-dose group, and 62 to the equivalent rabies control group. The second cohort included 120 children in the monthly RH5.1/Matrix-M group and 60 in the equivalent rabies control group. The final vaccination was administered to all groups from Sept 4 to 21, 2023. RH5.1/Matrix-M in both cohorts had a favourable safety profile and was well tolerated. Most adverse events were mild, with the most common being local swelling and fever. No serious adverse events were reported. Comparing the RH5.1/Matrix-M delayed third-dose regimen with the pooled control groups resulted in a vaccine efficacy of 55% (95% CI 20 to 75%; p=0·0071). The same analysis showed a vaccine efficacy of 40% (-3 to 65%; p=0·066) when comparing the monthly regimen with the pooled control groups. Participants vaccinated with RH5.1/Matrix-M in both cohorts showed high concentrations of anti-RH5.1 serum IgG antibodies 14 days after the third vaccination, and the purified IgG showed high levels of in vitro growth inhibition activity against P falciparum; these responses were higher in patients who received the RH5.1/Matrix-M vaccine delayed third-dose regimen, as opposed to monthly regimen (growth inhibition activity 79·0% [SD 14·3] vs 74·2% [SD 15·9]; p=0·016). INTERPRETATION: RH5.1/Matrix-M appears safe and highly immunogenic in African children and shows promising efficacy against clinical malaria when given in a delayed third-dose regimen. This trial is ongoing to further monitor efficacy over time. FUNDING: The European and Developing Countries Clinical Trials Partnership, the UK Medical Research Council, the National Institute for Health and Care Research Oxford Biomedical Research Centre, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the US Agency for International Development, and the Wellcome Trust.
Novel and optimized diagnostics for pediatric TB in endemic countries: NOD-pedFEND study protocol.
BACKGROUND: Pediatric tuberculosis is a major global public health challenge, with reliable diagnosis being a main obstacle to identifying and treating affected children. New and improved diagnostics, ideally on non-sputum samples, are urgently required, especially in the most vulnerable group of children under five years of age. Studies to date have been limited by small sample sizes and few bacteriologically-confirmed cases. Here, we describe the study protocol of the NIH-funded NOD-pedFEND study, which will be one of the largest diagnostic studies to date of children at greatest risk of tuberculosis. METHODS: In this prospective observational cohort study, we aim to evaluate existing and novel diagnostic assays, including pathogen- and host-based tests and combinations of tests. A consecutive cohort of children under five years of age with signs and symptoms of tuberculosis is enrolled in Uganda and Peru. All children undergo an extensive baseline workup with signs- and symptoms recording, microbiological reference tests, chest X-ray and tuberculin skin test for rigorous classification according to internationally recognized microbiological, composite reference and strict standards. An array of samples is collected for investigational tests. Follow-up visits are conducted at 2 weeks, 2 months and 6 months. A small cohort of healthy controls is enrolled to evaluate the specificity of selected diagnostics. The study has been approved by the relevant institutional review boards. DISCUSSION: With this large cohort study of children under five years of age, we aim to make an important contribution to the evaluation of new diagnostics for pediatric tuberculosis. By establishing a comprehensive biorepository, the study will also enable the assessment of novel tests as they become available during and after the study.
Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 lineages circulating in Brazil.
Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity.
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1+ macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β-responsive stromal subsets that up-regulate expression of disease risk-associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: results from COV-BOOST trial.
BACKGROUND: Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines. METHODS: Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enrolled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster. RESULTS: The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules. CONCLUSIONS: A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.