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Oxford Centre for Tropical Medicine and Global Health
Interpretations of Studies on SARS-CoV-2 Vaccination and Post-acute COVID-19 Sequelae.
This article discusses causal interpretations of epidemiologic studies of the effects of vaccination on sequelae after acute severe acute respiratory syndrome coronavirus 2 infection. To date, researchers have tried to answer several different research questions on this topic. While some studies assessed the impact of postinfection vaccination on the presence of or recovery from post-acute coronavirus disease 2019 syndrome, others quantified the association between preinfection vaccination and postacute sequelae conditional on becoming infected. However, the latter analysis does not have a causal interpretation, except under the principal stratification framework-that is, this comparison can only be interpreted as causal for a nondiscernible stratum of the population. As the epidemiology of coronavirus disease 2019 is now nearly entirely dominated by reinfections, including in vaccinated individuals, and possibly caused by different Omicron subvariants, it has become even more important to design studies on the effects of vaccination on postacute sequelae that address precise causal questions and quantify effects corresponding to implementable interventions.
Expanded Access Programme for the use of tecovirimat for the treatment of monkeypox infection: A study protocol for an Expanded Access Programme.
BackgroundMonkeypox is a viral zoonotic disease commonly reported in humans in parts of Central and West Africa. This protocol is for an Expanded Access Programme (EAP) to be implemented in the Central African Republic, where Clade I monkeypox virus diseases is primarily responsible for most monkeypox infections. The objective of the programme is to provide patients with confirmed monkeypox with access to tecovirimat, a novel antiviral targeting orthopoxviruses, and collect data on clinical and virological outcomes of patients to inform future research.MethodsThe study will be conducted at participating hospitals in the Central African Republic. All patients who provide informed consent to enrol in the programme will receive tecovirimat. Patients will remain in hospital for the duration of treatment. Data on clinical signs and symptoms will be collected every day while the patient is hospitalised. Blood, throat and lesion samples will be collected at baseline and then on days 4, 8, 14 and 28. Patient outcomes will be assessed on Day 14 -end of treatment-and at Day 28. Adverse event and serious adverse event data will be collected from the point of consent until Day 28.DiscussionThis EAP is the first protocolised treatment programme in Clade I MPXV. The data generated under this protocol aims to describe the use of tecovirimat for Clade I disease in a monkeypox endemic region of Central Africa. It is hoped that this data can inform the definition of outcome measures used in future research and contribute to the academic literature around the use of tecovirimat for the treatment of monkeypox. The EAP also aims to bolster research capacity in the region in order for robust randomised controlled trials to take place for monkeypox and other diseases.Trial registration{2a & 2b}: ISRCTN43307947.
Investigation of Escherichia coli isolates from pigs and humans for colistin resistance in Lao PDR- a cross-sectional study.
BackgroundIn Laos, colistin is not currently registered for use in humans. This One Health study aimed to estimate the prevalence of meat-producing pigs carrying colistin-resistant Escherichia coli, and investigate if E. coli causing invasive human infections were colistin-resistant.MethodsBetween September 2022 and March 2023, rectal swabs were collected from 895 pigs from abattoirs in 9/17 Lao provinces. Pig rectal swabs and stored E. coli isolates from human blood cultures, submitted to Mahosot Hospital Microbiology laboratory between 2005 and 2022, were screened for colistin resistance on selective chromogenic agar with organism identification confirmed using MALDI-TOF MS. Suspected colistin-resistant isolates underwent colistin susceptibility testing by broth microdilution following European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Isolates with MIC values of ≥2 μg/ml were tested for plasmid-mediated colistin resistance genes (mcr-1, mcr-2, and mcr-3) by multiplex SYBR Green PCR.ResultsA total of 15/620 (2.41%) invasive human E. coli isolates were phenotypically colistin-resistant by broth microdilution (MIC values 4 to 8 μg/ml). The earliest isolate was from 2015 in a patient from Phongsaly province in Northern Laos. A total of 582/895 (65.02%) pig rectal swab samples contained colistin-resistant E. coli. The detected colistin resistance genes were predominantly mcr-1 (57.8%, 346/598), followed by mcr-3 (20.23%,121/598), and 22.24% (133/598) were found to co-harbour mcr-1 and mcr-3. Among the 15 human isolates with colistin MIC values of ≥4 μg/ml, 12/15 were mcr-1.ConclusionsWe found that colistin resistant E. coli is causing invasive infection in humans in Laos despite the fact it is not available for human use. Use in animals seems to be widespread, confirmed by high carriage rates of colistin-resistant E. coli in pigs. It is probable that food-producing animals are the source of colistin-resistant E. coli bloodstream infection in Laos, although these have been infrequent to date. This is a serious public health concern in the region that needs to be addressed by appropriate enforceable legislation.
Clinical presentation and treatment of 2 patients with infection caused by Chromobacterium violaceum in Vietnam.
Chromobacterium violaceum is a rare but severe and often fatal cause of disease in humans. We present 2 clinical cases of sepsis and skin abscesses / cellulitis caused by C. violaceum seen in a referral hospital for infectious diseases in Vietnam. Both patients survived, but appropriate antibiotic treatment was only installed after culture of the organism. We reviewed and summarised the characteristics of C. violaceum infection and treatment.
Eight years into the horizon of aspirational maternal and newborn health pledges: a nationwide cross-sectional exploration of the Burundian EmONC network capacity and budget deficits
Objective The Burundian emergency obstetric and neonatal care (EmONC) programme, which was initiated in 2017 and supported by a specific policy, does not appear to reverse maternal and newborn mortality trends. Our study examined the capacity challenges facing participating EmONC facilities and developed alternative investment proposals to improve their readiness paying particular attention to EmONC professionals, physical infrastructure, and capital equipment. Design Cross-sectional study. Setting Burundian EmONC facilities (n=112). Participants We examined EmONC policy documents, consulted 12 maternal and newborn health experts and 23 stakeholders and policymakers, surveyed all EmONC facilities (n=112), and collected cost data from the Ministry of Health and local suppliers in Burundi. We developed three context-specific EmONC resource benchmark standards by facility type; the Burundian policy norms and the expert minimum and maximum suggested thresholds; and used these alternatives to estimate EmONC resource gaps. We forecasted three corresponding budget estimates needed to address prevailing deficits taking a government perspective for a 5-year EmONC investment strategy. Additionally, we explored relationships between EmONC professionals and selected measures of service delivery using bivariate analyses and graphically. Results The lowest EmONC resource benchmark revealed that 95% of basic EmONC and all comprehensive EmONC facilities lack corresponding sets of human resources and 90% of all facilities need additional physical infrastructure and capital equipment. Assessed against the highest benchmark which proposes the most progressive set of standards for the prevailing workloads, Burundi would require 162 more medical doctors, 1005 midwives and nurses, 132 delivery rooms, 191 delivery tables, 678 and 156 maternity and newborn care beds, and 395 incubators amounting to US$32.9 million additional budget for 5 years. Conclusion We demonstrated that Burundian EmONC facilities face enormous capacity challenges equivalent to US$32.9 million funding gap for 5 years; averagely approximating to 5.96% total health budget increase annually.
Full-length MSP1 is a major target of protective immunity after controlled human malaria infection.
The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1FL) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1FL antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1FL is an important target of functional antibodies that contribute to a protective immune response against malaria.
Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci
AbstractStreptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals’ responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins’ ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts’ polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.
Obesity differs from diabetes mellitus in antibody and T-cell responses post-COVID-19 recovery
Abstract 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. Results: In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T-cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, Ov/Ob was associated with decreased neutralizing antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8 + T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T-cell responses after adjustment for obesity and other confounders. Conclusion: Ov/Ob is associated with lower neutralizing antibody levels and higher T-cell responses to SARS-CoV-2 post-COVID-19 recovery, while antibody or T-cell responses remain unaltered in DM.
Accelerated waning of the humoral response to COVID-19 vaccines in obesity
AbstractObesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.
Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination
Abstract T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established ‘Protective Immunity from T Cells in Healthcare workers’ (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12–21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172–444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55–166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.
CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study
ABSTRACT Serological correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after vaccination (“vaccine breakthrough”) have been described. However, T cell correlates of protection against breakthrough are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. Here, 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK cohort study were enrolled in a nested case-control study. Cases were those who tested SARS-CoV-2 PCR or lateral flow device (LFD) positive after two vaccine doses during the Delta-predominant era ( n = 32), while controls were those who did not report a positive test or undergo anti-nucleocapsid immunoglobulin G (IgG) seroconversion during this period ( n = 247). Previous SARS-CoV-2 infection prior to vaccination was associated with reduced odds of vaccine breakthrough. Using samples from 28 d after the second vaccine dose, before all breakthroughs occurred, we observed future cases had lower ancestral spike (S)- and receptor binding domain-specific IgG titers and S1- and S2-specific T cell interferon gamma (IFNγ) responses compared with controls, although these differences did not persist when individuals were stratified according to previous infection status before vaccination. In a subset of matched infection-naïve cases and controls, vaccine breakthrough cases had lower CD4+ and CD8+ IFNγ and tumor necrosis factor (TNF) responses to Delta S peptides compared with controls. For CD8+ responses, this difference appeared to be driven by reduced responses to Delta compared with ancestral peptides among cases; this reduced response to Delta peptides was not observed in controls. Our findings support a protective role for T cells against Delta breakthrough infection. IMPORTANCE 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). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.
Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis
AbstractGerminal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease
AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.