Publications by authors named "Thushan De Silva"

Background: Live attenuated influenza vaccines (LAIVs) alter nasopharyngeal microbiota in adults. It is poorly understood why LAIV immunogenicity varies across populations, but it could be linked to the microbiome. We aimed to investigate the interactions between intranasal immunisation with LAIV and nasopharyngeal microbiota composition in children from The Gambia.

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Exposure to Group A Streptococcus leads to a broad spectrum of disease and sequelae, as the bacterium employs a wide range of virulence factors to facilitate colonization of the host, propagation and onward transmission, disrupting both innate and adaptive immune responses. The protease SpyCEP has a crucial role in contributing to bacterial immune evasion by impairing neutrophil recruitment and killing of bacteria through the cleavage of interleukin-8 (IL-8). Given this critical function, SpyCEP represents a key vaccine antigen and quantifying functional anti-SpyCEP antibodies represents not only an important marker of vaccine efficacy, but also a tool to dissect the natural immune response.

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Whilst SARS-CoV-2 mRNA vaccines generate high neutralising antibodies (nAb) in most individuals, haematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell (CAR-T) recipients respond poorly. HSCT/CAR-T treatment ablates existing immune memory, with recipients requiring revaccination analogous to being vaccine naive. An optimal revaccination strategy for this cohort has not been defined.

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Multiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24-59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017-18.

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  • Spastic paraplegia 47 (SPG47) results from mutations in the AP4B1 gene, leading to symptoms like progressive spastic paraplegia, developmental delays, intellectual disability, and epilepsy.
  • Researchers used a gene therapy approach with a viral vector (AAV9/hAP4B1) to deliver the correct AP4B1 gene into a mouse model, successfully correcting multiple disease symptoms and restoring protein levels.
  • Preclinical safety studies in non-human primates showed no major side effects, setting the stage for potential clinical trials to treat SPG47 patients.
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Intrapartum azithromycin prophylaxis has shown the potential to reduce maternal infections but showed no effect on neonatal sepsis and mortality. Antibiotic exposure early in life may affect gut microbiota development, leading to undesired consequences. Therefore, we here assessed the impact of 2 g oral intrapartum azithromycin on gut microbiota development from birth to the age of 3 years, by 16S-rRNA gene profiling of rectal samples from 127 healthy Gambian infants selected from a double-blind randomized placebo-controlled clinical trial (PregnAnZI-2).

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Introduction: Health care workers (HCWs) have been at increased risk of infection during the SARS-CoV-2 pandemic and as essential workers have been prioritised for vaccination. Due to increased exposure HCW are considered a predictor of what might happen in the general population, particularly working age adults. This study aims to summarise effect of vaccination in this 'at risk' cohort.

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  • The UK Health Security Agency reported a surge in scarlet fever and invasive diseases caused by Group A Streptococcus (StrepA) at the end of 2022 and early 2023, leading to a study of 341 throat and skin isolates collected in Sheffield.
  • The study found that most common types in throat isolates were types 1, 12, and 22, while skin isolates included types 1, 12, 76, and 49, showing a mix of lineages different from previous years (2016-2017).
  • Analysis indicated that only 51% of throat isolates produce a capsule, compared to 78% of skin isolates, and a significant number of throat isolates exhibited high
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Background: Streptococcus pyogenes-related skin infections are increasingly implicated in the development of rheumatic heart disease (RHD) in lower-resourced settings, where they are often associated with scabies. The true prevalence of S. pyogenes-related pyoderma may be underestimated by bacterial culture.

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Background: Streptococcus pyogenes causes more than 500 000 deaths per year globally, which occur disproportionately in low-income and middle-income countries. The roles of S pyogenes skin and pharyngeal carriage in transmission are unclear. We aimed to investigate the clinical epidemiology and household transmission dynamics of both S pyogenes asymptomatic carriage and infection in a high-burden setting.

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Background: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies.

Methods: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies.

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Little is known about SARS-CoV-2 infection risk in African countries with high levels of infection-driven immunity and low vaccine coverage. We conducted a prospective cohort study of 349 participants from 52 households in The Gambia between March 2021 and June 2022, with routine weekly SARS-CoV-2 RT-PCR and 6-monthly SARS-CoV-2 serology. Attack rates of 45% and 57% were seen during Delta and Omicron BA.

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  • The study focuses on the SARS-CoV-2 nucleocapsid protein (Ncap), which is important for diagnostics and vaccine development since the Covid-19 pandemic started in 2019.
  • Researchers successfully expressed and purified SARS-CoV-2 Ncap proteins in E. coli, specifically using a synthetic gene with a 6His affinity tag to enhance purification.
  • ELISA assays were conducted to compare the immune response of human sera to different Ncap proteins, showing no major differences between tagged and untagged versions, except a slight potential decrease in sensitivity to some Ncap variants.
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Objective: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh.

Methods: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020.

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  • One in ten COVID-19 infections lead to long COVID, characterized by prolonged symptoms, but the underlying mechanisms remain unclear.
  • In a study of 657 individuals, certain inflammatory markers were linked to long COVID symptoms, revealing connections to cardiorespiratory issues, fatigue, anxiety, gastrointestinal problems, cognitive impairments, and potential nerve tissue repair disturbances.
  • Findings suggest that targeting specific inflammatory pathways could offer new therapeutic options for treating different subtypes of long COVID in future clinical trials.*
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Group A Streptococcus (Strep A) bacteria causes a broad spectrum of diseases. The most common manifestations of Strep A infection are sore throat and pus-producing skin infections such as impetigo. Complications of Strep A infection can lead to inflammation in the bones, muscles, joints, and internal organs causing acute rheumatic fever and rheumatic heart disease (RHD).

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Introduction: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve.

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The high burden of disease and the long-lasting sequelae following Streptococcus pyogenes (Strep A) infections make the development of an effective vaccine a global health priority. Streptolysin O (SLO), is a key toxin in the complex pathogenesis of Strep A infection. Antibodies are elicited against SLO after natural exposure and represent a key target for vaccine-induced immunity.

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Previous studies have associated COVID-19 symptoms severity with levels of physical activity. We therefore investigated longitudinal trajectories of COVID-19 symptoms in a cohort of healthcare workers (HCWs) with non-hospitalised COVID-19 and their real-world physical activity. 121 HCWs with a history of COVID-19 infection who had symptoms monitored through at least two research clinic visits, and via smartphone were examined.

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Background: (StrepA) causes a significant burden of disease globally from superficial infections to invasive disease. It is responsible for over 500,000 deaths each year, predominantly in low- and middle-income countries (LMIC). Superficial StrepA infections of the skin and pharynx can lead to rheumatic heart disease, the largest cause of StrepA-related deaths in LMIC.

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Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs).

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Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.

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Background: Genomic surveillance of SARS-CoV-2 is crucial for monitoring the spread of COVID-19 and guiding public health decisions, but the capacity for SARS-CoV-2 testing and sequencing in Africa is low. We integrated SARS-CoV-2 surveillance into an existing influenza surveillance network with the aim of providing insights into SARS-CoV-2 transmission and genomics in Ghana.

Methods: In this molecular epidemiological analysis, which is part of a wider multifaceted prospective observational study, we collected national SARS-CoV-2 test data from 35 sites across 16 regions in Ghana from Sept 1, 2020, to Nov 30, 2021, via the Ghanaian integrated influenza and SARS-CoV-2 surveillance network.

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The prevalence and strength of serological responses mounted toward SARS-CoV-2 proteins other than nucleocapsid (N) and spike (S), which may be of use as additional serological markers, remains underexplored. Using high-content microscopy to assess antibody responses against full-length StrepTagged SARS-CoV-2 proteins, we found that 85% (166/196) of unvaccinated individuals with RT-PCR confirmed SARS-CoV-2 infections and 74% (31/42) of individuals infected after being vaccinated developed detectable IgG against the structural protein M, which is higher than previous estimates. Compared with N antibodies, M IgG displayed a shallower time-dependent decay and greater specificity.

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