439 results found
Kundu R, Sam Narean J, Wang L, et al., 2022, Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts, Nature Communications, ISSN: 2041-1723
Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p=0.0139), and nucleocapsid-specific (p=0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n=26), when compared with those who convert to PCR-positive (n=26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.
Elliott P, Bodinier B, Eales O, et al., 2021, Rapid increase in Omicron infections in England during December 2021: REACT-1 study
Background: The highest-ever recorded numbers of daily severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in England has been observed during December 2021 and have coincided with a rapid rise in the highly transmissible Omicron variant despite high levels of vaccination in the population. Although additional COVID-19 measures have beenintroduced in England and internationally to contain the epidemic, there remains uncertainty about the spread and severity of Omicron infections among the general population.Methods: The REal-time Assessment of Community Transmission–1 (REACT-1) study has been monitoring the prevalence of SARS-CoV-2 infection in England since May 2020.REACT-1 obtains self-administered throat and nose swabs from a random sample of the population of England at ages 5 years and over. Swabs are tested for SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) and samples testing positive are sent for viral genome sequencing. To date 16 rounds have been completed, each including~100,000 or more participants with data collected over a period of 2 to 3 weeks per month.Socio-demographic, lifestyle and clinical information (including previous history of COVID-19 and symptoms prior to swabbing) is collected by online or telephone questionnaire. Here we report results from round 14 (9-27 September 2021), round 15 (19 October - 05 November2021) and round 16 (23 November - 14 December 2021) for a total of 297,728 participants with a valid RT-PCR test result, of whom 259,225 (87.1%) consented for linkage to their NHS records including detailed information on vaccination (vaccination status, date). We usedthese data to estimate community prevalence and trends by age and region, to evaluate vaccine effectiveness against infection in children ages 12 to 17 years, and effect of a third (booster) dose in adults, and to monitor the emergence of the Omicron variant in England.Results: We observed a high overall prevalen
Takele Y, Mulaw, Adem, et al., 2021, Immunological factors, but not clinical features, predict visceral leishmaniasis relapse in patients co-infected with HIV, Cell Reports Medicine, ISSN: 2666-3791
Visceral leishmaniasis (VL) has emerged as a clinically important opportunistic infection in HIV patients, as VL/HIV co-infected patients suffer from frequent VL relapse. Here, we follow cohorts of VL patients with or without HIV in Ethiopia. By the end of the study 78.1% of VL/HIV, but none of the VL patients, experience VL relapse. Despite clinically defined cure, VL/HIV patients maintain higher parasite loads, lower BMI, hepatosplenomegaly and pancytopenia. We identify three immunological markers associated with VL relapse in VL/HIV patients: i) failure to restore antigen-specific production of IFNg, ii) persistently lower CD4+ T cell counts, and iii) higher expression of PD1 on CD4+ and CD8+ T cells. We show that these three markers, that can be measured in primary hospital settings in Ethiopia, combine well in predicting VL relapse. The use of our prediction model has the potential to improve disease management and patient care.
Katsuya H, Cook LBM, Rowan AG, et al., 2021, Erratum to: Clonality of HIV-1- and HTLV-1-Infected Cells in Naturally Coinfected Individuals., J Infect Dis
Short C-E, Quinlan R, Preda V, et al., 2021, Vaginal microbiota, genital inflammation and extracellular matrix remodelling collagenase: MMP-9 in pregnant women with HIV, a potential preterm birth mechanism warranting further exploration, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-14, ISSN: 2235-2988
Background: Pregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria. Material and Methods: Cervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, cART exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored. Results: CVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1b, IL-8, IL-12 and TNF-a in both trimesters compared to HUPW (p≤0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1b(r=0.61), IL-8(r=0.57) and TNF-a(r=0.64), p<
Houston H, Hakki S, Pillay TD, et al., 2021, Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts., Eur Respir J
INTRODUCTION: The success of case isolation and contact tracing for the control of SARS-CoV-2 transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS) - fever; cough; loss or change in smell or taste - could improve case definitions and accelerate case identification in SARS-CoV-2 contacts. METHODS: Two prospective longitudinal London-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and AUC-ROC. Improvements in sensitivity and time-to-detection were compared to penalties in terms of specificity and number-needed-to-test. RESULTS: Of 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion "≥1 of the CS, or ≥2 of the EP" identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than "≥1 of the CS", with only modest reduction in specificity (5.7%). CONCLUSIONS: Broadening symptom criteria to include individuals with at least 2 of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time-to-detection, providing greater opportunities to prevent SARS-CoV-2 transmission.
Chadeau M, Wang H, Eales O, et al., 2021, Randomised community surveys of SARS-CoV-2 infection and vaccine effectiveness in England: REACT-1 study., The Lancet Respiratory Medicine, ISSN: 2213-2600
Background: England experienced a third wave of the COVID-19 epidemic from end May 2021 coinciding with the rapid spread of Delta variant despite high levels of vaccination among adults. Vaccination rates (single-dose) are lower among children aged 16-17 and 12-15 years whose vaccination in England commenced in August and September respectively. Methods: The REACT-1 study involves a series of random cross-sectional surveys in the general population of England aged 5 years and over. Using RT-PCR swab-positivity data from (N=100,527) participants with valid swabs in round 14 (9 to 27 September 2021), we estimated community-based prevalence of SARS-CoV-2 and vaccine effectiveness against infection by combining data with round 13 (24 June to 12 July 2021, N=172,862).Findings: During September 2021 we estimated a mean RT-PCR positivity rate of 0.83% (0.76%, 0.89%) with a reproduction number R overall of 1.03 (0.94, 1.14). Among the 475 sequenced positive swabs, all were Delta variant; 22 (4.63%) included the Y145H mutation in the spike protein associated with the AY.4 sub-lineage, and there was one E484K mutation. Age, region, key worker status, and household size jointly contributed to the risk of swab-positivity. The highest weighted prevalence was observed among children aged 5-12 years at 2.32% (1.96%, 2.73%) and 13-17 years at 2.55% (2.11%, 3.08%). The epidemic grew in those aged 5-11 years with R of 1.42, but decreased in those aged 18-54. At ages 18-64 years, the adjusted vaccine effectiveness against infection was 62.8% (49.3%, 72.7%) after two doses compared to unvaccinated people, for all vaccines combined, and 44.8% (22.5%, 60.7%) and 71.3% (56.6%, 81.0%) for AstraZeneca and Pfizer-BioNTech, respectively. At ages >18 years, weighted prevalence of swab-positivity was 0.35% (0.31%, 0.40%) if second dose was <3 months before their swab but 0.55% (0.50%, 0.61%) for those who received their second dose 3-6 months prior, compared to 1.76% (1.60%, 1.95%) among
Chadeau-Hyam M, Eales O, Bodinier B, et al., 2021, REACT-1 round 15 final report: Increased breakthrough SARS-CoV-2 infections among adults who had received two doses of vaccine, but booster doses and first doses in children are providing important protection
Background: It has been nearly a year since the first vaccinations against SARS-CoV-2were delivered in England. The third wave of COVID-19 in England began in May 2021 asthe Delta variant began to outcompete and largely replace other strains. The REal-timeAssessment of Community Transmission-1 (REACT-1) series of community surveys forSARS-CoV-2 infection has provided insights into transmission dynamics since May 2020.Round 15 of the REACT-1 study was carried out from 19 October to 5 November 2021.Methods: We estimated prevalence of SARS-CoV2 infection and used multiple logisticregression to analyse associations between SARS-CoV-2 infection in England anddemographic and other risk factors, based on RT-PCR results from self-administered throatand nose swabs in over 100,000 participants. We estimated (single-dose) vaccineeffectiveness among children aged 12 to 17 years, and among adults comparedswab-positivity in people who had received a third (booster) dose with those who hadreceived two vaccine doses. We used splines to analyse time trends in swab-positivity.Results: During mid-October to early-November 2021, weighted prevalence was 1.57%(1.48%, 1.66%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14).Weighted prevalence increased between rounds 14 and 15 across most age groups(including older ages, 65 years and over) and regions, with average reproduction numberacross rounds of R=1.09 (1.08, 1.11). During round 15, there was a fall in prevalence from amaximum around 20-21 October, with an R of 0.76 (0.70, 0.83), reflecting falls in prevalenceat ages 17 years and below and 18 to 54 years. School-aged children had the highestweighted prevalence of infection: 4.95% (4.39%, 5.58%) in those aged 5 to 12 years and5.21% (4.61%, 5.87%) in those aged 13 to 17 years. In multiple logistic regression, age, sex,key worker status and presence of one or more children in the home were associated withswab positivity. There was evidence of heterogeneity between rounds in
Chadeau-Hyam M, Eales O, Bodinier B, et al., 2021, REACT-1 round 15 interim report: Exponential rise in prevalence of SARS-CoV-2 infection in England from end September 2021 followed by dip during October 2021
Background: The third wave of COVID-19 in England coincided with the rapid spread of theDelta variant of SARS-CoV-2 from the end of May 2021. Case incidence data from thenational testing programme (Pillar 2) in England may be affected by changes in testingbehaviour and other biases. Community surveys may provide important contextualinformation to inform policy and the public health response.Methods: We estimated patterns of community prevalence of SARS-CoV-2 infection inEngland using RT-PCR swab-positivity, demographic and other risk factor data from round15 (interim) of the REal-time Assessment of Community Transmission-1 (REACT-1) study(round 15a, carried out from 19 to 29 October 2021). We compared these findings with thosefrom round 14 (9 to 27 September 2021).Results: During mid- to late-October 2021 (round 15a) weighted prevalence was 1.72%(1.61%, 1.84%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14). Theoverall reproduction number (R) from round 14 to round 15a was 1.12 (1.11, 1.14) withincreases in prevalence over this period (September to October) across age groups andregions except Yorkshire and The Humber. However, within round 15a (mid- to late-October)there was evidence of a fall in prevalence with R of 0.76 (0.65, 0.88). The highest weightedprevalence was observed among children aged 5 to 12 years at 5.85% (5.10%, 6.70%) and13 to 17 years at 5.75% (5.02%, 6.57%). At regional level, there was an almost four-foldincrease in weighted prevalence in South West from round 14 at 0.59% (0.43%,0.80%) toround 15a at 2.18% (1.84%, 2.58%), with highest smoothed prevalence at subregional levelalso found in South West in round 15a. Age, sex, key worker status, and presence ofchildren in the home jointly contributed to the risk of swab-positivity. Among the 126sequenced positive swabs obtained up until 23 October, all were Delta variant; 13 (10.3%)were identified as the AY.4.2 sub-lineage.Discussion: We observed the highest overall prevalence of swab-p
Elliott P, Haw D, Wang H, et al., 2021, Exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant, Science, Vol: 374, Pages: 1-11, ISSN: 0036-8075
SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.
Singanayagam A, Hakki S, Dunning J, et al., 2021, Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study, The Lancet Infectious Diseases, ISSN: 1473-3099
BackgroundThe SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.MethodsBetween Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.FindingsThe SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for unin
Chadeau-Hyam M, Wang H, Eales O, et al., 2021, REACT-1 study round 14: High and increasing prevalence of SARS-CoV-2 infection among school-aged children during September 2021 and vaccine effectiveness against infection in England
Background: England experienced a third wave of the COVID-19 epidemic from end May2021 coinciding with the rapid spread of Delta variant. Since then, the population eligible forvaccination against COVID-19 has been extended to include all 12-15-year-olds, and abooster programme has been initiated among adults aged 50 years and over, health careand care home workers, and immunocompromised people. Meanwhile, schoolchildren havereturned to school often with few COVID-19-related precautions in place.Methods: In the REal-time Assessment of Community Transmission-1 (REACT-1) study,throat and nose swabs were sent to non-overlapping random samples of the populationaged 5 years and over in England. We analysed prevalence of SARS-CoV-2 using reversetranscription-polymerase chain reaction (RT-PCR) swab-positivity data from REACT-1 round14 (between 9 and 27 September 2021). We combined results for round 14 with round 13(between 24 June and 12 July 2021) and estimated vaccine effectiveness and prevalence ofswab-positivity among double-vaccinated individuals. Unlike all previous rounds, in round 14,we switched from dry swabs transported by courier on a cold chain to wet swabs usingsaline. Also, at random, 50% of swabs (not chilled until they reached the depot) weretransported by courier and 50% were sent through the priority COVID-19 postal service.Results: We observed stable or rising prevalence (with an R of 1.03 (0.94, 1.14) overall)during round 14 with a weighted prevalence of 0.83% (0.76%, 0.89%). The highest weightedprevalence was found in children aged 5 to 12 years at 2.32% (1.96%, 2.73%) and 13 to 17years at 2.55% (2.11%, 3.08%). All positive virus samples analysed correspond to the Deltavariant or sub-lineages of Delta with one instance of the E484K escape mutation detected.The epidemic was growing in those aged 17 years and under with an R of 1.18 (1.03, 1.34),but decreasing in those aged 18 to 54 years with an R of 0.81 (0.68, 0.97). For allparticipants and all vaccin
Rosadas de Oliveira C, Zetterberg H, Heslegrave A, et al., 2021, Neurofilament light in CSF and plasma is a marker of neuronal damage in HTLV-1-associated myelopathy and correlates with neuroinflammation, Neurology, Neuroimmunology and Neuroinflammation, Vol: 8, Pages: 1-7, ISSN: 2332-7812
Objective: To evaluate the usefulness of cerebrospinal fluid (CSF) and plasma neurofilament light (Nf-L) as a biomarker for HTLV-1-associated myelopathy (HAM). Methods: Nf-L, CXCL10 and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by SIMOA. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein and HTLV-1 proviral load. Results: Nf-L was detected in all CSF samples (Median (range) = 575pg/ml (791.8-2,349)) and positively correlated with markers of inflammation (CXCL10 (r= 0.733), neopterin (r= 0.499), cell count (r= 0.403) and protein levels (r= 0.693) in CSF; p<0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p<0.0001). Wheelchair dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10 and protein in CSF. Conclusions: Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuro-inflammation.
Orletti MPS, Assone T, Sarnaglia GD, et al., 2021, Prevalence of infection by human T Cell lymphotropic viruses (HTLV-1/2) in adult population in Vitoria-ES, BRAZILIAN JOURNAL OF INFECTIOUS DISEASES, Vol: 25, ISSN: 1413-8670
Rosadas C, Menezes MLB, Galvão-Castro B, et al., 2021, Blocking HTLV-1/2 silent transmission in Brazil: Current public health policies and proposal for additional strategies., PLoS Neglected Tropical Diseases, Vol: 15, Pages: 1-14, ISSN: 1935-2727
Human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2) are relatively common in Brazil but remain silent and neglected infections. HTLV-1 is associated with a range of diseases with high morbidity and mortality. There is no curative treatment for this lifelong infection, so measures to prevent transmission are essential. This narrative review discusses HTLV-1/2 transmission routes and measures to prevent its continuous dissemination. The public health policies that are currently implemented in Brazil to avoid HTLV-1/2 transmission are addressed, and further strategies are proposed.
A 53-year-old woman developed subacute onset of upper limb weakness, sensory loss and cerebellar dysfunction. She was known to have human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy. MR scan of the brain showed extensive T2 hyperintensity within the deep and subcortical white matter, with punctate contrast enhancement. Cerebrospinal fluid (CSF) was lymphocytic with very high levels of HTLV-1 provirus in both CSF and peripheral blood lymphocytes. We diagnosed HTLV-1 encephalomyelitis and started high-dose methylprednisolone followed by a slow corticosteroid taper. She recovered well and regained functional independence in the upper limbs. Neurological manifestations of HTLV-1 infection extend beyond classical 'tropical spastic paraparesis' and are under-recognised. We review the literature on HTLV-1 encephalitis and discuss its diagnosis and management.
Rowan AG, May P, Badhan A, et al., 2021, Optimized protocol for a quantitative SARS-CoV-2 duplex RT-qPCR assay with internal human sample sufficiency control., Journal of Virological Methods, Vol: 294, Pages: 1-7, ISSN: 0166-0934
There is growing evidence that measurement of SARS-CoV-2 viral copy number can inform clinical and public health management of SARS-CoV-2 carriers and COVID-19 patients. Here we show that quantification of SARS-CoV-2 is feasible in a clinical setting, using a duplex RT-qPCR assay which targets both the E gene (Charité assay) and a human RNA transcript, RNase P (CDC assay) as an internal sample sufficiency control. Samples in which RNase P is not amplified indicate that sample degradation has occurred, PCR inhibitors are present, RNA extraction has failed or swabbing technique was insufficient. This important internal control reveals that 2.4% of nasopharyngeal swabs (15/618 samples) are inadequate for SARS-CoV-2 testing which, if not identified, could result in false negative results. We show that our assay is linear across at least 7 logs and is highly reproducible, enabling the conversion of Cq values to viral copy numbers using a standard curve. Furthermore, the SARS-CoV-2 copy number was independent of the RNase P copy number indicating that the per-swab viral copy number is not dependent on sampling- further allowing comparisons between samples. The ability to quantify SARS-CoV-2 viral copy number will provide an important opportunity for viral burden-guided public health and clinical decision making.
Eke AC, Olagunju A, Momper J, et al., 2021, Optimizing pharmacology studies in pregnant and lactating women using lessons from HIV: a consensus statement., Clinical Pharmacology and Therapeutics, Vol: 110, Pages: 36-48, ISSN: 0009-9236
Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The IMPAACT network and the WHO-convened Paediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to: define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low- and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy PK/PD studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end-points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical.
Rosadas de Oliveira C, Woo T, Haddow J, et al., 2021, Anti-HTLV-1/2 IgG antibodies in the breastmilk of seropositive mothers, Microorganisms, Vol: 9, Pages: 1-8, ISSN: 2076-2607
Background: HTLV-1/2 mother-to-child transmission (MTCT) is an important route for the maintenance of HTLV-1/2 within populations and disproportionally contributes to the burden of HTLV-1-associated diseases. Avoidance of breastfeeding is the safest recommendation to prevent MTCT. Due to the benefits of breastfeeding, alternative methods that would allow seropositive mothers to breastfeed their babies are needed. There is limited knowledge about HTLV-1/2 infection and breastmilk. Methods: Paired blood and milk samples collected from HTLV-1/2 seropositive mothers were tested for HTLV-1 proviral load (PVL) quantification and for the detection of anti-HTLV-1/2 IgG. Results: All breastmilk samples had detectable anti-HTLV-1/2 IgG. HTLV-1/2 proviral DNA was detected in all samples except for one. HTLV-1 PVL and IgG binding ratio (BR) was similar in milk and plasma. However, antibody titer was significantly higher in blood (Median (95%CI): Milk:128 (32–512); Plasma:131,584 (16,000–131,584), p < 0.05). There was a strong correlation between HTLV-1 PVL, anti-HTLV-1/2 IgG BR, and titer when comparing milk and blood. PVL did not correlate with antibody BR nor titer in blood or milk. Conclusions: Anti-HTLV-1/2 IgG are present in milk in the same proportion as blood but in lower quantity. PVL in milk correlates with blood.
Meng B, Kemp SA, Papa G, et al., 2021, Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7, Cell Reports, Vol: 35
We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.
Volz E, Mishra S, Chand M, et al., 2021, Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England, Nature, Vol: 593, Pages: 266-269, ISSN: 0028-0836
The SARS-CoV-2 lineage B.1.1.7, designated a Variant of Concern 202012/01 (VOC) by Public Health England1, originated in the UK in late Summer to early Autumn 20202. Whole genome SARS-CoV-2 sequence data collected from community-based diagnostic testing shows an unprecedentedly rapid expansion of the B.1.1.7 lineage during Autumn 2020, suggesting a selective advantage. We find that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that the VOC has higher transmissibility than non-VOC lineages, even if the VOC has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with a larger share of under 20 year olds among reported VOC than non-VOC cases. Time-varying reproduction numbers for the VOC and cocirculating lineages were estimated using SGTF and genomic data. The best supported models did not indicate a substantial difference in VOC transmissibility among different age groups. There is a consensus among all analyses that the VOC has a substantial transmission advantage with a 50% to 100% higher reproduction number.
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, SCIENCE ADVANCES, Vol: 7, ISSN: 2375-2548
Graham MS, Sudre CH, May A, et al., 2021, Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study, The Lancet Public Health, Vol: 6, Pages: e335-e345, ISSN: 2468-2667
BACKGROUND: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. METHODS: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. FINDINGS: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in repo
Pereira C, Harris B, Di Giovannantonio M, et al., 2021, Antibody response to SARS-CoV-2 infection is not associated with Post-COVID-19 Syndrome in healthcare workers, Journal of Infectious Diseases, Vol: 223, Pages: 1671-1676, ISSN: 0022-1899
It is currently unknown how Post-COVID-19 Syndrome (PCS) may affect those infected with SARS-CoV-2. This longitudinal study reports on healthcare staff who tested positive for SARS-CoV-2 between March-April 2020 and follows their antibody titres and symptomatology. Over half (n=21/38) had PCS at 7-8 months. There was no statistically significant difference between initial RT-PCR viral titres or serial antibody levels between those who did and did not develop PCS. This study highlights the relative commonality of PCS in healthcare workers and this should be considered in vaccination scheduling and workforce planning to allow adequate frontline staffing numbers.
Katsuya H, Cook LBM, Rowan AG, et al., 2021, Clonality of HIV-1 and HTLV-1 infected cells in naturally coinfected individuals., Journal of Infectious Diseases, ISSN: 0022-1899
BACKGROUND: Coinfection with HIV-1 and HTLV-1 diminishes the value of the CD4 + T-cell count in diagnosing AIDS, and increases the rate of HTLV-1-associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such clinical characteristics. Here, we investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and the clonal expansion. METHODS: We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected individuals, and from 12 HIV-1 and 13 HTLV-1 mono-infected individuals. The proviral loads (PVL) were quantified using real-time PCR. Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing. RESULTS: The PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in mono-infected individuals. The degree of oligoclonality of both HIV-1- and HTLV-1-infected cells in co-infected individuals was also greater than that in mono-infected subjects. The ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 mono-infected individuals. CONCLUSION: HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and the clonality of virus-infected cells and thus may alter the risks of both HTLV-1- and HIV-1-associated disease.
Edhom KA, Lidman C, Granberg T, et al., 2021, Expanding the etiologic spectrum of spastic ataxia syndrome: chronic infection with human T lymphotropic virus type 1, Journal of NeuroVirology, Vol: 27, Pages: 345-347, ISSN: 1355-0284
Infection with human T cell lymphotropic virus type 1 (HTLV-1) is in most cases indolent; however, some patients develop adult T cell leukemia, associated with poor prognosis, or the highly disabling and incurable HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Verdonck et al. 2007; Cooper et al. 2009). HTLV-1 is an endemic infection in Southern Japan, Iran, South America, the Caribbean basin, West Africa, and among aborigines in Australia (Verdonck et al. 2007). There are no established biomarkers to predict complications in HTLV-1; however, the percentage of peripheral blood mononuclear cells (PBMCs) harboring the provirus, called proviral load (PVL), and beta-2 microglobulin (β2M) in serum are surrogate biomarkers. Associations with neurological syndromes other than HAM/TSP have been claimed, including neuropathy, motor neuron disease (Araujo et al. 2019), as well as cerebellar ataxia (Iwasaki 4,5,6,; Kira et al. 1993; Gracia et al. 1995; e-1 to e-6). In the majority of reported cases, ataxia occurred in Japanese patients with HAM/TSP (Iwasaki 1990; Iwanaga 1993; Kira et al. 1993; e1, e-2, e-4, e-6). Here, we present an Iranian HTLV-1 positive patient with a cerebellar syndrome, elevated β2M in serum, and elevated neopterin and CXCL10 in cerebrospinal fluid (CSF).
Kemp SA, Collier DA, Datir RP, et al., 2021, SARS-CoV-2 evolution during treatment of chronic infection., Nature, Vol: 592, Pages: 277-282
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing an
Wolf S, Haddow J, Greiller C, et al., 2021, Quantification of T cell clonality in Human T cell leukaemia virus type-1 carriers can detect the development of Adult T cell Leukaemia early, Blood Cancer Journal, Vol: 11, Pages: 1-11, ISSN: 2044-5385
Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells which are infected with Human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL could be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+CCR4+CD26-T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n=38) and patients with ATL (n=30). In a third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n=106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n=14) had higher lymphocyte counts and PVLs, and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p=0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.
Collier DA, De Marco A, Ferreira IATM, et al., 2021, Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies, NATURE, Vol: 593, Pages: 136-+, ISSN: 0028-0836
Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, et al., 2021, Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19, Science Immunology, Vol: 6, Pages: 1-17, ISSN: 2470-9468
While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.
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