Liverpool School Of Tropical Medicine Research Articles

Protocol for a prospective cohort study of open tibia fractures in Malawi with a nested implementation of open fracture guidelines

Background: Road traffic injury (RTI) is the largest cause of death amongst 15–39-year-old people worldwide, and the burden of injuries such as open tibia fractures are rapidly increasing in Malawi. This study aims to investigate disability and economic outcomes of people with open tibia fractures in Malawi and improve these with locally delivered implementation of open fracture guidelines. Methods: This is a prospective cohort study describing function, quality of life and economic burden of open tibia fractures in Malawi. In total, 160 participants will be recruited across six centres and will be followed-up with face-to-face interviews at six weeks, three months, six months and one year following injury. The primary outcome will be function at one year measured by the short musculoskeletal functional assessment (SMFA) score. Secondary outcomes will include quality of life measured by EuroQol EQ-5D-3L, catastrophic loss of income and implementation outcomes (acceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability) at one year. A nested pilot pre-post implementation study of an interventional bundle for all open fractures will be developed based on other implementation studies from low- and middle-income countries (LMICs). Regression analysis will be used to model and investigate associations between SMFA score and fracture severity, infection and the pre- and post-training course period. Outcome: This prospective cohort study will report patient reported outcomes from open tibia fractures in low-resource settings. Subsequent detailed evaluation of both the clinical and implementation components of the study will promote sustainability of improved open fractures management in the study sites and further scale-up of open fracture management guidelines. Ethics: Ethics approval has been obtained from the Liverpool School of Tropical Medicine and College of Medicine Research and Ethics committee.

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol.

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation. For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113).

Protocol for a prospective cohort study of open tibia fractures in Malawi with a nested implementation of open fracture guidelines.

Background: Road traffic injury (RTI) is the largest cause of death amongst 15-39-year-old people worldwide, and the burden of injuries such as open tibia fractures are rapidly increasing in Malawi. This study aims to investigate disability and economic outcomes of people with open tibia fractures in Malawi and improve these with locally delivered implementation of open fracture guidelines. Methods: This is a prospective cohort study describing function, quality of life and economic burden of open tibia fractures in Malawi. In total, 160 participants will be recruited across six centres and will be followed-up with face-to-face interviews at six weeks, three months, six months and one year following injury. The primary outcome will be function at one year measured by the short musculoskeletal functional assessment (SMFA) score. Secondary outcomes will include quality of life measured by EuroQol EQ-5D-3L, catastrophic loss of income and implementation outcomes (acceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability) at one year. A nested pilot pre-post implementation study of an interventional bundle for all open fractures will be developed based on other implementation studies from low- and middle-income countries (LMICs). Regression analysis will be used to model and investigate associations between SMFA score and fracture severity, infection and the pre- and post-training course period. Outcome: This prospective cohort study will report patient reported outcomes from open tibia fractures in low-resource settings. Subsequent detailed evaluation of both the clinical and implementation components of the study will promote sustainability of improved open fractures management in the study sites and further scale-up of open fracture management guidelines. Ethics: Ethics approval has been obtained from the Liverpool School of Tropical Medicine and College of Medicine Research and Ethics committee.

Towards Intermittent Preventive Therapy in Pregnancy with Dihydroartemisinin-Piperaquine?

Malaria is a major cause of adverse pregnancy outcomes in sub-Saharan Africa, but resistance to sulfadoxine-pyrimethamine, the only antimalarial recommended by the World Health Organisation for intermittent preventive therapy, is threatening the gains made in the last two decades. In this issue, Mlugu and colleagues present the results of a trial of dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine. The results are impressive but raise the question why they differ so much from three previous trials.

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Building supply chain capacity for neglected tropical diseases: experience from the Ascend West and Central Africa programme.

The Ascend West and Central Africa programme, funded by the UK Foreign, Commonwealth and Development Office (FCDO) is supporting integrated preventative chemotherapy for up to five neglected tropical diseases (NTDs), including intestinal worms, lymphatic filariasis, river blindness, trachoma and schistosomiasis. The programme is implemented across 13 countries by a consortium of four leading international development partners: Sightsavers, Liverpool School of Tropical Medicine, Schistosomiasis Control Initiative Foundation and Mott Macdonald. This paper presents messages learnt from country assessments that took place prior to the global outbreak of coronavirus disease 2019 (COVID-19). These messages remain relevant post-COVID-19, with greater priority being given to the challenges for national NTD programmes in continuing to deliver mass drug administration (MDA) during the pandemic. Stakeholder coordination from the earliest stages of the pandemic has occurred at two levels: in the first mile with global partners of the NTD Supply Chain Forum and in the last mile with implementing partners in each country. This has been instrumental to manage delayed MDA, including the impact delays have on the shipment of NTD donated drugs and the distribution of stock held in country. The Ascend West and Central Africa programme is supporting countries with the resumption of MDA through a risk assessment and mitigation action (RAMA) process.

Spitting cobras keep constant venom viscosity

Sometimes a bite just isn't good enough. Turning your teeth on a predator won't always be sufficient warning to back off, so some species throw in a dash of venom to get the message across. But one group of snakes take their toxic warning a stage further. They don't wait until a threat is within fang reach; spitting cobras eject their venom, sometimes over several metres, aiming at their victim's face and eyes. To ensure that their venom hits the spot, spitters have evolved specialised fangs that eject the venom forward at high pressure, but Arie van der Meijden and Ignazio Avella from the Research Center in Biodiversity and Genetic Resources (CIBIO), Porto, Portugal, wondered whether the snakes’ alternative lifestyle may also have affected the venom itself. Previous research had suggested that the venom of spitters might be a specialised fluid – known as a non-Newtonian fluid – which becomes less viscous as it flows through the fine channel connecting the venom gland to the fangs before increasing in viscosity as the venom sprays out to extend the range of the jet. But no one had thoroughly tested the theory on a variety of venoms, so Avella travelled to the Liverpool School of Tropical Medicine (LSTM), UK, home to some of the most venomous species on the planet.‘LSTM houses one of the richest collections of venomous snakes in Europe. Nicholas Casewell and Robert Harrison, the heads of LSTM's Centre for Snakebite Research and Interventions, allowed us to analyse the venoms of 13 different cobra species including spitters and non-spitters. I don't know of many other places that would be able to provide such a nice sample!’ exclaims Avella. During Avella's visit, Paul Rowley and Edouard Crittenden carefully collected venom samples by gently holding each snake behind the head and allowing it to bite a Parafilm-covered Petri dish, to catch the venom as it flowed from the fangs. ‘It doesn't matter how many venomous snakes you have dealt with, when a cobra raises its head and inflates its hood at you, it always sends a shiver down your spine’, Avella chuckles. Then he transported the lethal samples – ranging from 0.13 g from a Naja atra to 1.4 g from a Naja nigricollis – to Edgar Barajas-Ledesma and Chris Holland at the University of Sheffield, UK, where they took tiny droplets of each venom to measure the fluid's viscosity and how that altered as the liquids flowed.However, when the team compared the cobra venoms, they were surprised that the viscosity of the spitters’ venom didn't alter at different flow speeds and was remarkably similar to the viscosity of the venom collected from non-spitting snakes. ‘When our measurements disproved something that we considered a given based on previous studies, it was both surprising and exhilarating’, says Van der Meijden. In addition, Barajas-Ledesma calculated the impact of venom viscosity and fang shape on the fluid pressure inside the fang and found that the pressure in the non-spitting Naja nivea fangs was higher than the pressure in the spitting N. nigricollis fangs. However, Barajas-Ledesma adds ‘Spitting and non-spitting cobras still use the same pressure as a firehose to eject their venom, so perhaps it's not so surprising they need it to flow as consistently as possible’.Given that spitting cobras only do so for defence, Van der Meijden is puzzled as to why more of the fearsome serpents haven't opted for this fangs-off approach to self-defence. He suspects that spitters may have evolved the strategy to keep fast-moving predators at bay, especially out in the open.

Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0\u20132-month-old low birth weight infants in India\u2014the \u201cProSPoNS\u201d Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial

BackgroundProgress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising.MethodsA phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites.DiscussionThis adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low–middle-income countries.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019

Demonstrating the sustainability of capacity strengthening amidst COVID-19.

The global disruptions caused by the coronavirus disease 2019 crisis posed a threat to the momentum the vector control team at the Liverpool School of Tropical Medicine (LSTM) and the Programme National de Lutte contre la Tryaponosomiase Humaine Africaine (PNLTHA) had built in their efforts to control tsetse fly populations in the Democratic Republic of Congo. But despite the pandemic and global lockdown, field activities did continue and the same impressive results in tsetse fly reduction were observed and the team followed this by completing a round of ‘tiny target’ deployment without any external presence. Such a success was possible due to the investment in vector control capacity strengthening undertaken by the LSTM and PNLTHA.

Examining the Immunological Effects of COVID-19 Vaccination in Patients with Conditions Potentially Leading to Diminished Immune Response Capacity – The OCTAVE Trial

SARS-COV-2 vaccines have been shown to be efficacious primarily in healthy volunteer populations and population level studies. Immune responses following SARS-CoV-2 vaccination are less well characterised in potentially immune vulnerable patient groups, including those with immune-mediated inflammatory and chronic diseases (inflammatory arthritis [IA] incorporating rheumatoid arthritis [RA] and psoriatic arthritis [PsA]; ANCA-Associated Vasculitis [AAV]; inflammatory bowel disease [IBD]); hepatic disease (HepD), end stage kidney disease requiring haemodialysis (HD) without or with immunosuppression (HDIS); solid cancers (SC) and haematological malignancies (HM), and those that have undergone haemopoietic stem cell transplant (HSCT). The OCTAVE trial is a multi-centre, multi-disease, prospective cohort that will comprehensively assess SARS-CoV-2 vaccine responses within and between the abovementioned disease cohorts using common analytical platforms in patients recruited across the United Kingdom (UK). The majority of subjects received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca formerly AZD1222) as part of the UK National COVID19 vaccination programme. As of 13 th August 2021; 2,583 patients have been recruited. We report herein the humoral and T cell immune response results from the first 600 participants recruited where serology data are available at baseline, pre-second vaccine dose (boost) and/or 4 weeks post second dose. We also include in the analysis, data obtained from 231 healthy individuals from the PITCH (Protective Immunity from T cells in Healthcare workers) study. Overall, in comparison to PITCH where 100% of tested individuals (n=93) generated anti-Spike antibodies after vaccine doses, 89% of patients within OCTAVE seroconverted 4 weeks after second vaccine dose. By corollary, approximately 11% of patients across all disease cohorts fail to generate antibodies that react to SARS-CoV-2 spike 4 weeks after two vaccines. Failure to generate spike reactive antibodies was found at a higher proportion in some specific patient subgroups, particularly AAV (72.4%), HD-IS (16.7%) and HepD (16.7%). Importantly, all recruited AAV patients had received Rituximab; a targeted B cell depletion therapy. Furthermore, even in those who seroconverted, 40% of patients across disease cohorts generate lower levels of SARS-CoV-2 antibody reactivity compared to healthy subjects after two SARS-CoV-2 vaccines; the functional significance of these findings in providing protection from subsequent SARS-CoV-2 exposure is not currently known. In contrast to the observed serological response, evaluation of the Spike-specific T cell response revealed that across all patient sub-groups (including AAV) a response similar to healthy individuals was generated. Our data argue strongly for further vaccination strategies to optimise humoral immune responses against SARS-CoV-2 in patients with chronic diseases and/or patients on immune suppressive therapies. Trial Registration: The trial is registered on ISRCTN 12821688.Funding: This work was supported by the Medical Research Council COVID-19 Immunity – National Core Study (IMM-NCS) [grant number MC-PC-20031]. Staff at the Cancer Research UK Clinical Trials Unit (CRCTU) are supported by a core funding grant from Cancer Research UK (C22436/A25354). PK and EB are supported by the NIHR Birmingham Biomedical Research Centres at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham Biomedical Research Centres. EB and PK are supported by an NIHR Senior Investigator award. PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z), the U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. The PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, is funded by the UK Department of Health and Social Care with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UKCIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).Declaration of Interest: None to declare. Ethical Approval: This study was approved by the UK Medicines and Healthcare Products Regulatory Agency on the 5th February 2021 and the London and Chelsea Research Ethics Committee (REC Ref:21/HRA/0489) on 12th February 2021, with subsequent amendments approved on 3rd March 2021, 19th April 2021 and 26th April 2021).

Prognostic Indicators and Outcomes of Hospitalised COVID-19 Patients with Neurological Disease: A Systematic Review and Individual Patient Data Meta-Analysis

Background: Neurological COVID-19 disease has been reported widely, but often without using standard case definitions or detailed diagnostic work up. Several meta-analyses, based on such reports, describe the neurological diagnoses but give little information on outcomes and risk factors.Methods: We conducted an individual patient data meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute, and extracted aggregate data from published reports. We analysed features associated with poor outcome (moderate to severe sequelae or death, 3-6, on the modified Rankin scale) using multivariable models. Findings: We identified 381 studies (31 unpublished) describing 4443 patients with COVID-19 and neurological disease: 83 of these provided IPD for 1979 (45%) patients. Encephalopathy (978 [49%]) and cerebrovascular events (506 [26%]), were the most common diagnoses in the IPD database and aggregate data. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41] overall), and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-Dimer. Overall, 30-day mortality was 30% (27-32). The hazard of death was reduced for patients in the WHO European region, but increased in low- and lower-middle-income countries. Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission. Funding This study was funded by the UK Medical Research Council’s Global Effort on COVID-19 Programme (MR/V033441/1); UK National Institute for Health Research (NIHR)-funded Global Health Research Group on Acute Brain Infections (17/63/110); and the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907), at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (Grant Nos. IS-HPU-1112-10117 and NIHR200907).Declaration of Interests: BS reports a grant from UKRI/DHSC Global Effort on COVID-19 Research (Medical Research Council) and non-financial support from UK National Institute for Health Research Global Health Research Group on Brain Infections. SL and TS are supported by a grant from the EU Zika Preparedness Latin American Network consortium (ZikaPLAN). ZikaPLAN has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 734584. LCG reports non-financial support from Pfizer, non-financial support from Gilead. LB reports grants from GlaxoSmithKline, Research England and Wellcome Trust. AMBM reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq/Brazil, and São Paulo Research Foundation FAPESP/Brazil. AP reports personal fees from ZAMBON, UCB , BIOMARIN, and ABBvie pharma. TS was an adviser to the GlaxoSmithKline Ebola Vaccine programme, chaired a Siemens Diagnostics clinical advisory board, and advises the WHO Brain Health Unit Forum on Neurology and COVID-19; TS has also previously filed a patent for a test for bacterial meningitis based on a blood test (GB 1606537.7, April 14, 2016), and has grants from the UK Medical Research Council and National Institute for Health Research. All other authors declare no conflict of interest

Simian Varicella Virus: Molecular Virology and Mechanisms of Pathogenesis.

Simian varicella virus (SVV) was first isolated in 1966 from African green monkeys (Cercopithecus aethiops) imported from Nairobi, Kenya, to the Liverpool School of Tropical Medicine in the United Kingdom (UK) (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967). SVV infection caused severe disease that resulted in a 56% case fatality rate (CFR) in the imported animals within 48h of the appearance of a varicella-like rash (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967; Hemme et al., Am J Trop Med Hyg 94:1095-1099, 2016). The deceased animals presented with fever, widespread vesicular rash, and multiple hemorrhagic foci throughout the lungs, liver, and spleen (Clarkson et al., Arch Gesamte Virusforsch 22:219-234, 1967). This outbreak was quickly followed by a second outbreak in 47 patas monkeys (Erythrocebus patas) imported from Chad and Nigeria by Glaxo Laboratories (London, England, UK), which quickly spread within the facility (McCarthy et al., Lancet 2:856-857, 1968).

Sustained T Cell Immunity, Protection and Boosting Using Extended Dosing Intervals of BNT162b2 mRNA Vaccine

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. In a study of 503 healthcare workers, we show that after priming following the first vaccine there is a marked decline in SARS-CoV-2 neutralizing antibody (NAb) levels, but, in contrast, a sustained T cell response to spike protein. This divergent immune profile was accompanied by robust protection from infection over this period from the circulating alpha (B.1.1.7) variant. Importantly, following the second vaccine dose, NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by a clear enrichment of CD4+ T cells expressing IL2. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol and that antiviral T cell responses are a potential mechanism of protection.Trial Registration Details: PITCH is a sub-study of the SIREN study which is registered with ISRCTN, number ISRCTN11041050,Funding Information: This work was funded by the UK Department of Health and Social Care as part of the PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).EB and PK are NIHR Senior Investigators and PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). RPP is funded by a Career Re-entry Fellowship (204721/Z/16/Z). CJAD is funded by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z) and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. DGW is supported by an NIHR Advanced Fellowship in Liverpool. LT and MC are supported by U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. Declaration of Interests: AJP is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in policy decisions on COVID-19 vaccines. He is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. AJP is chief investigator on clinical trials of Oxford University’s COVID-19 vaccine funded by NIHR. Oxford University has entered a joint COVID-19 vaccine development partnership with AstraZeneca. Ethics Approval Statement: PITCH is a sub-study of the SIREN study which was approved by the Berkshire Research Ethics Committee, Health Research 250 Authority (IRAS ID 284460, REC reference 20/SC/0230), with PITCH recognised as a sub-study on 2 December 2020. SIREN is registered with ISRCTN (Trial ID:252 ISRCTN11041050). Some participants were recruited under aligned study protocols. In Birmingham participants were recruited under the Determining the immune response to SARS-CoV-2 infection in convalescent health care workers (COCO) study (IRAS ID: 282525). In Liverpool some participants were recruited under the “Human immune responses to acute virus infections” Study (16/NW/0170), approved by North West - Liverpool Central Research Ethics Committee on 8 March 2016, and amended on 14th September 2020 and 4th May 2021. In Oxford, participants were recruited under the GI Biobank Study 16/YH/0247, approved by the research ethics committee (REC) at Yorkshire & The Humber - Sheffield Research Ethics Committee on 29 July 2016, which has been amended for this purpose on 8 June 2020. In Sheffield, participants were recruited under the Observational Biobanking study STHObs (18/YH/0441), which was amended for this study on 10 September 2020. The study was conducted in compliance with all relevant ethical regulations for work with human participants, and according to the principles of the Declaration of Helsinki (2008) and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Written informed consent was obtained for all patients enrolled in the study.

Strengthening integration of chronic care in Africa: protocol for the qualitative process evaluation of integrated HIV, diabetes and hypertension care in a cluster randomised controlled trial in Tanzania and Uganda

IntroductionIn sub-Saharan Africa, the burden of non-communicable diseases (NCDs), particularly diabetes mellitus (DM) and hypertension, has increased rapidly in recent years, although HIV infection remains a leading cause of death...

Long-term consequences of COVID-19: research needs

Weeks and months after the onset of acute COVID-19, people continue to suffer. Paul Garner, a professor of epidemiology at Liverpool School of Tropical Medicine, UK, wrote on the 95th day after the onset of symptoms that “I am unable to be out of bed for more than three hours at a stretch, my arms and legs are permanently fizzing as if injected with Szechuan peppercorns, I have ringing in the ears, intermittent brain fog, palpitations, and dramatic mood swings.”1 Other people also describe similar complaints.

Antibiotic Resistance Is Associated with Integrative and Conjugative Elements and Genomic Islands in Naturally Circulating Streptococcus pneumoniae Isolates from Adults in Liverpool, UK.

Pneumonia is the sixth largest cause of death in the UK. It is usually caused by Streptococcus pneumoniae, which healthy individuals can carry in their nose without symptoms of disease. Antimicrobial resistance further increases mortality and morbidity associated with pneumococcal infection, although few studies have analysed resistance in naturally circulating pneumococcal isolates in adult populations. Here, we report on the resistome and associated mobile genetic elements within circulating pneumococcus isolated from adult volunteers enrolled in the experimental human pneumococcal colonisation (EHPC) research program at the Liverpool School of Tropical Medicine, UK. Pneumococcal isolates collected from 30 healthy asymptomatic adults who had volunteered to take part in clinical research were screened for antibiotic susceptibility to erythromycin and tetracycline, and whole-genome sequenced. The genetic context of resistance to one or both antibiotics in four isolates was characterised bioinformatically, and any association of the resistance genes with mobile genetic elements was determined. Tetracycline and macrolide resistance genes [tet(M), erm(B), mef(A), msr(D)] were detected on known Tn916-like integrative and conjugative elements, namely Tn6002 and Tn2010, and tet(32) was found for the first time in S. pneumoniae located on a novel 50 kb genomic island. The widespread use of pneumococcal conjugate vaccines impacts on serotype prevalence and transmission within the community. It is therefore important to continue to monitor antimicrobial resistance (AMR) genes present in both vaccine types and non-vaccine types in response to contemporary antimicrobial therapies and characterise the genetic context of acquired resistance genes to continually optimise antibiotic therapies.

A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi - A feasibility study.

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation. As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

Tackling two pandemics: a plea on World Tuberculosis Day

Tackling two pandemics: a plea on World Tuberculosis Day

A call to action for universal health coverage: Why we need to address gender inequities in the neglected tropical diseases community.

The UN’s Sustainable Development Goals (SDGs) and pledge to leave no one behind have raised the importance of ensuring equitable health outcomes and healthcare delivery. Multisectoral approaches to tackling neglected tropical diseases (NTDs), including prevention, diagnosis, treatment, and healthcare, have had a limited focus on gender. Yet, gender roles and relations shape vulnerability to NTDs, access to prevention and treatment, and experience of living with NTDs [1]. Understanding the similarities and differences of disease vulnerability and experience between genders can support NTD actors to deliver equitable prevention, diagnosis, and treatment services. The NTD community, including researchers and practitioners, needs to better understand these dynamics and take action to advance gender equality, meet the NTD roadmap 2020 goals, and contribute towards the SDGs and universal health coverage (UHC). The UHC movement is advocating for clear action to address the gender determinants of health. This viewpoint synthesizes evidence from a discussion paper [2] developed by the UN Development Programme (UNDP) and TDR (Special Programme for Research and Training in Tropical Diseases sponsored by UNICEF, UNDP, World Bank, and WHO) in partnership with the Liverpool School of Tropical Medicine to support governments and nongovernment organizations to understand how to recognize and address gender inequities within NTD programs and improve delivery through gender analysis.

A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation. As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.