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Vaccination with Plasmodium vivax Duffy-binding protein inhibits parasite growth during controlled human malaria infection.
There are no licensed vaccines against Plasmodium vivax. We conducted two phase 1/2a clinical trials to assess two vaccines targeting P. vivax Duffy-binding protein region II (PvDBPII). Recombinant viral vaccines using chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors as well as a protein and adjuvant formulation (PvDBPII/Matrix-M) were tested in both a standard and a delayed dosing regimen. Volunteers underwent controlled human malaria infection (CHMI) after their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparisons of parasite multiplication rates in the blood. PvDBPII/Matrix-M, given in a delayed dosing regimen, elicited the highest antibody responses and reduced the mean parasite multiplication rate after CHMI by 51% (n = 6) compared with unvaccinated controls (n = 13), whereas no other vaccine or regimen affected parasite growth. Both viral-vectored and protein vaccines were well tolerated and elicited expected, short-lived adverse events. Together, these results support further clinical evaluation of the PvDBPII/Matrix-M P. vivax vaccine.
Superior antibody immunogenicity of a viral-vectored RH5 blood-stage malaria vaccine in Tanzanian infants as compared to adults.
BACKGROUND: RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown. METHODS: A phase 1b, single-center, dose-escalation, age-de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania (NCT03435874). Between 12th April and 25th October 2018, 63 healthy adults (18-35 years), young children (1-6 years), and infants (6-11 months) received a priming dose of viral-vectored ChAd63 RH5 or rabies control vaccine. Sixty participants were boosted with modified vaccinia virus Ankara (MVA) RH5 or rabies control vaccine 8 weeks later and completed 6 months of follow-up post priming. Primary outcomes were the number of solicited and unsolicited adverse events post vaccination and the number of serious adverse events over the study period. Secondary outcomes included measures of the anti-RH5 immune response. FINDINGS: Vaccinations were well tolerated, with profiles comparable across groups. No serious adverse events were reported. Vaccination induced RH5-specific cellular and humoral responses. Higher anti-RH5 serum immunoglobulin G (IgG) responses were observed post boost in young children and infants compared to adults. Vaccine-induced antibodies showed growth inhibition activity (GIA) in vitro against P. falciparum blood-stage parasites; their highest levels were observed in infants. CONCLUSIONS: The ChAd63-MVA RH5 vaccine shows acceptable safety and reactogenicity and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in RH5-vaccinated infants are the highest reported to date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines to protect against clinical malaria in young African infants. FUNDING: Medical Research Council, London, UK.
Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial.
BACKGROUND: A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. METHODS: We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. FINDINGS: Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]). INTERPRETATION: The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. FUNDING: The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; 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.
Repeat controlled human malaria infection of healthy UK adults with blood-stage Plasmodium falciparum: Safety and parasite growth dynamics.
UNLABELLED: In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth in vivo) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03906474, NCT02927145.
Immunogenic recombinant Mayaro virus-like particles present natively assembled glycoprotein.
Virus-like particles (VLPs) are an established vaccine platform and can be strong immunogens capable of eliciting both humoral and cellular immune responses against a range of pathogens. Here, we show by cryo-electron microscopy that VLPs of Mayaro virus, which contain envelope glycoproteins E1-E2 and capsid, exhibit an architecture that closely resembles native virus. In contrast to monomeric and soluble envelope 2 (E2) glycoprotein, both VLPs as well as the adenovirus and modified vaccinia virus Ankara (MVA) vaccine platforms expressing the equivalent envelope glycoproteins E1-E2, and capsid induced highly neutralising antibodies after immunisation. The levels of neutralising antibodies elicited by the viral-vectored vaccines of structural proteins and VLPs increased significantly upon boosting. Immunisation of Mayaro virus VLPs in mice with or without an adjuvant (poly:IC) yielded similar levels of neutralising antibodies suggesting that the VLPs may be used for immunisation without the need for an adjuvant. A single or two doses of non-adjuvanted 5 µg of MAYV VLP vaccination provided significant protection against viremia and MAYV-induced foot swelling in the C57BL/6 mouse challenge model. MAYV VLPs represent a non-infectious vaccine candidate, which may constitute a complementary option for future immunisation strategies against this important emerging alphavirus.
Population-based, first-tier genomic newborn screening in the maternity ward.
The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation.
Pushing the boundaries: future directions in the management of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival. These therapies - with distinct mechanisms, routes of administration, dosing schedules, side effect profiles, and financial costs - have dramatically altered the clinical phenotypes of this condition and have presented fresh challenges for patient care. In this review article we discuss potential strategies to maximise clinical outcomes through early diagnosis and treatment, optimised dosing, use of therapeutic combinations and state-of-the-art physiotherapy techniques, and the development of innovative therapies targeting alternative mechanisms.
Treatments for RYR1-related disorders.
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To analyse the benefits and harms of pharmacological or other interventions (e.g. special diet, exercise programme) compared with placebo or standard care for RYR1-related disorders, including both permanent myopathies and intermittent (episodic) presentations (exertional myalgia and rhabdomyolysis), with the aim to improve motor and respiratory function and/or to reduce the frequency of episodes, respectively. Secondary objectives To assess whether the interventions, compared with placebo or standard of care, change the outcome of RYR1-related diseases. To assess whether the interventions, compared with placebo or usual care, change the expression of the disease state in patients with RYR1-related diseases. To identify a set of standardised outcome tools to be used in future studies.
LAP1 Interactome Profiling Provides New Insights into LAP1's Physiological Functions.
The nuclear envelope (NE), a protective membrane bordering the nucleus, is composed of highly specialized proteins that are indispensable for normal cellular activity. Lamina-associated polypeptide 1 (LAP1) is a NE protein whose functions are just beginning to be unveiled. The fact that mutations causing LAP1 deficiency are extremely rare and pathogenic is indicative of its paramount importance to preserving human health, anticipating that LAP1 might have a multifaceted role in the cell. Mapping the LAP1 protein interactome is, thus, imperative to achieve an integrated view of its potential biological properties. To this end, we employed in silico- and mass spectrometry-based approaches to identify candidate LAP1-interacting proteins, whose functional attributes were subsequently characterized using bioinformatics tools. Our results reveal the complex and multifunctional network of protein-protein interactions associated to LAP1, evidencing a strong interconnection between LAP1 and cellular processes as diverse as chromatin and cytoskeleton organization, DNA repair, RNA processing and translation, as well as protein biogenesis and turnover, among others. Novel interactions between LAP1 and DNA repair proteins were additionally validated, strengthening the previously proposed involvement of LAP1 in the maintenance of genomic stability. Overall, this study reaffirms the biological relevance of LAP1 and the need to deepen our knowledge about this NE protein, providing new insights about its potential functional partners that will help guiding future research towards a mechanistic understanding of LAP1's functioning.
Improving Childhood Immunization Service Delivery in Cameroon: A Synthesis of Caregiver Experiences and Recommendations.
BACKGROUND/OBJECTIVES: A "people-centered" approach is one of the core principles of the Immunization Agenda (IA) 2030 and emphasizes the need for services to be organized around the needs and expectations of individuals and the community. A better understanding of the immunization experience from the client's perspective is key to guiding the design of policies and interventions aimed at improving immunization delivery and coverage. This study provides a synthesis of the immunization experiences of children's caregivers in Cameroon, highlighting potential barriers for timely and complete immunization. METHODS: A descriptive cross-sectional study was conducted, targeting caregivers of children brought to selected health facilities for immunization in all ten regions of Cameroon. Using structured questionnaires, data were collected from caregivers and analyzed using STATA version 13. RESULTS: In total, 1230 caregivers were interviewed in 265 health facilities. The median age of participants was 27 years and the median number of children per caregiver was two children. Most (87%) of the study participants reported to be satisfied with immunization service delivery. The median waiting time for vaccination was 1 h 48 min, with regional median waiting times ranging from 18 min in the South region to 4 h 6 min in the North region. About a quarter (24%) of surveyed participants reported to have presented to a health facility for immunization services and were turned away without achieving the purpose for which they came at least once. About half (48%) of the caregivers had never heard about planned vaccination activities in their communities. CONCLUSION: While most caregivers appeared to be satisfied with immunization service delivery in Cameroon, our study highlights some notable caregiver concerns (long waiting times, unproductive immunization visits and inadequate information about outreach activities) which, if addressed, may go a long way to enhance the immunization experience of caregivers in Cameroon, build trust in immunization services and thus improve vaccination uptake.
Facilitators and barriers affecting the implementation of e-health for chronic respiratory diseases in remote settings: a qualitative evidence synthesis.
BACKGROUND: Chronic respiratory diseases are important causes of disability and mortality globally. Their incidence may be higher in remote locations where healthcare is limited and risk factors, such as smoking and indoor air pollution, are more prevalent. E-health could overcome some healthcare access obstacles in remote locations, but its utilisation has been limited. An improved understanding of barriers and facilitators to the implementation of e-health in remote locations could aid enhanced application of these approaches. METHODS: We performed a qualitative evidence synthesis to explore factors affecting the successful implementation of e-health interventions in remote locations for patients with chronic respiratory diseases. We searched PubMed, CINAHL, Embase, Web of Science and PsycINFO databases for qualitative and mixed-methods studies. Studies were assessed by two researchers, and 41 studies were included in the synthesis. Quality was assessed via the CASP-tool. Findings were coded with Atlas.ti software and categorised based on an adapted Digital Health Equity Framework. RESULTS: Nineteen themes were identified across five levels (individual, interpersonal, community, society and technology), with associated facilitators and barriers for implementation. An important facilitator of e-health was its role as a tool to overcome obstacles of distance and to increase access to care and patients' self-efficacy. Potential barriers included the reduction of in-person interactions and an increased burden of work for healthcare providers. Good quality, usability, adaptability and efficacy of e-health interventions were important for implementation to be successful, as were adaptation to the local setting - including culture and language -and involvement of relevant stakeholders throughout the process. CONCLUSIONS: Several factors affecting the implementation of e-health in remote and rural locations for patients with chronic respiratory disease were identified. Intervention objectives, target population, geographical location, local culture, and available resources should be carefully considered when designing an e-health intervention. These findings can be used to inform the successful design and implementation of future e-health interventions.
Regulatory workshop on standardisation of clinical procedures, endpoints and data robustness of human challenge studies - A stakeholder meeting report.
Inno4Vac, a public-private partnership funded by the IMI2/EU/EFPIA Joint Undertaking (IMI2 JU), brings together academic institutions, SMEs, and pharmaceutical companies to accelerate and de-risk vaccine development. The project has made significant strides in the selection and production of challenge agents for influenza, respiratory syncytial virus (RSV), and toxigenic Clostridioides difficile for controlled human infection model studies (CHIMs). A regulatory workshop held on March 20, 2024, addressed the standardisation of clinical procedures, ethical considerations, endpoints, and data integrity, highlighting the ongoing initiatives related to these CHIMs. Key discussions focused on refining trial protocols to balance statistical power with participant burden, overseen by a data safety monitoring board. The meeting emphasised the importance of harmonizing CHIM protocols to ensure robust, reproducible, and transparent research. Mandatory trial registration and adherence to the Findable, Accessible, Interoperable, and Reusable (FAIR) data principles were recommended to enhance data reuse and scientific value. This report consolidates efforts to standardise CHIM protocols, essential for accelerating therapeutic innovations and advancing global health research.
Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.
Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.
Phase I/IIa study to assess the safety, immunogenicity and efficacy of ChAdOx1-MVA vectored vaccines expressing a novel liver-stage malaria dual antigen LS2 by sporozoite challenge in malaria-naïve adults
Background Induction of CD8+ T-cells using viral vectors is a promising strategy in developing effective vaccines against pre-erythrocytic malaria. A recent comparative assessment of candidate antigens using this approach in a mouse model had identified Liver Stage Antigen 1 (LSA1) and Liver Stage Associated Protein 2 (LSAP2) as more protective than TRAP and CSP antigens, which have been the dominant focus of clinical testing. We proposed that combining these within a novel dual antigenic insert (LS2), encoded alongside an orthologous immunogenic domain from invariant chain in ChAdOx1, and the F11 promoter in MVA, could translate to protective clinical efficacy against malaria. Methods We conducted a non-randomised, open-label, dose escalation phase I/IIa study in UK adults, vaccinating a small lead-in group with ChAdOx1 LS2 5x109 vp (group 1; n = 3) and subsequently a heterologous prime–boost group with ChAdOx1 LS2 2.5x1010 vp and MVA LS2 2x108 pfu (group 2; n =10). Group 2 volunteers and 6 unvaccinated controls underwent Controlled Human Malaria Infection (CHMI) delivered by mosquito bite and standardized follow-up. Results Vaccination with ChAdOx1 LS2 (both low and full doses) and MVA LS2 were generally well tolerated with solicited symptoms observed similar to previous vectored vaccines and no Severe Adverse Events (SAEs). Immunogenicity of the prime-boost schedule as measured by IFN-γ ELISpot was high showing median response of 4473 SFC/10^6 PBMC at the pertinent pre-challenge timepoint, covering a broad range of potential determinants. All vaccinated volunteers became infected with malaria during CHMI with a median time to diagnosis of 13 days compared to 13.25 days in controls. Conclusions Though this study further indicates ChAd/MVA as a safe, highly effective platform for driving CD8+ responses specific to liver-stage malaria antigens, the promise of LSA1 and LSAP2 as potential candidates shown preclinically has not translated to protection from infection in humans. Clinical Trial Registration ClinicalTrials.gov (Ref: NCT03203421), date of registration, 3rd July 2017.
Progress and prospects in antisense oligonucleotide-mediated exon skipping therapies for Duchenne muscular dystrophy.
Recent years have seen enormous progress in the field of advanced therapeutics for the progressive muscle wasting disease Duchenne muscular dystrophy (DMD). In particular, four antisense oligonucleotide (ASO) therapies targeting various DMD-causing mutations have achieved FDA approval, marking major milestones in the treatment of this disease. These compounds are designed to induce alternative splicing events that restore the translation reading frame of the dystrophin gene, leading to the generation of internally-deleted, but mostly functional, pseudodystrophin proteins with the potential to compensate for the genetic loss of dystrophin. However, the efficacy of these compounds is very limited, with delivery remaining a key obstacle to effective therapy. There is therefore an urgent need for improved ASO technologies with better efficacy, and with applicability to a wider range of patient mutations. Here we discuss recent developments in ASO therapies for DMD, and future prospects with a focus on ASO chemical modification and bioconjugation strategies.
Urine-derived stem cells serve as a robust platform for generating native or engineered extracellular vesicles.
BACKGROUND: Mesenchymal stromal cell (MSC) therapy holds great potential yet efficacy and safety concerns with cell therapy persist. The beneficial effects of MSCs are often attributed to their secretome that includes extracellular vesicles (EVs). EVs carry biologically active molecules, protected by a lipid bilayer. However, several barriers hinder large-scale MSC EV production. A serum-free culturing approach is preferred for producing clinical-grade MSC-derived EVs but this can affect both yield and purity. Consequently, new strategies have been explored, including genetically engineering MSCs to alter EV compositions to enhance potency, increase circulation time or mediate targeting. However, efficient transfection of MSCs is challenging. Typical sources of MSC include adipose tissue and bone marrow, which both require invasive extraction procedures. Here, we investigate the use of urine-derived stem cells (USCs) as a non-invasive and inexhaustible source of MSCs for EV production. METHODS: We isolated, expanded, and characterized urine-derived stem cells (USCs) harvested from eight healthy donors at three different time points during the day. We evaluated the number of clones per urination, proliferation capacity and conducted flow cytometry to establish expression of surface markers. EVs were produced in chemically defined media and characterized. PEI/DNA transfection was used to genetically engineer USCs using transposon technology. RESULTS: There were no differences between time points for clone number, doubling time or viability. USCs showed immunophenotypic characteristics of MSCs, such as expression of CD73, CD90 and CD105, with no difference at the assessed time points, however, male donors had reduced CD73 + cells. Expanded USCs were incubated without growth factors or serum for 72 h without a loss in viability and EVs were isolated. USCs were transfected with high efficiency and after 10 days of selection, pure engineered cell cultures were established. CONCLUSIONS: Isolation and expansion of MSCs from urine is non-invasive, robust, and without apparent sex-related differences. The sampling time point did not affect any measured markers or USC isolation potential. USCs offer an attractive production platform for EVs, both native and engineered.
The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children.
Respiratory syncytial virus (RSV) is the leading cause of infant respiratory infections and hospitalizations. To investigate the relationship between the respiratory microbiome and RSV infection, we sequence nasopharyngeal samples from a birth cohort and a pediatric case-control study (Respiratory Syncytial virus Consortium in Europe [RESCEU]). 1,537 samples are collected shortly after birth ("baseline"), during RSV infection and convalescence, and from healthy controls. We find a modest association between baseline microbiota and the severity of consecutive RSV infections. The respiratory microbiota during infection clearly differs between infants with RSV and controls. Haemophilus, Streptococcus, and Moraxella abundance are associated with severe disease and persistence of symptoms, whereas stepwise increasing abundance of Dolosigranulum and Corynebacterium is associated with milder disease and health. We conclude that the neonatal respiratory microbiota is only modestly associated with RSV severity during the first year of life. However, the respiratory microbiota at the time of infection is strongly associated with disease severity and residual symptoms.