BBE Scientific Publications

Frequent development of broadly neutralizing antibodies in early life in a large cohort of children living with HIV

J Infect Dis

2021 Youyi Fong

BACKGROUND: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after HIV infection compared to adults. METHODS: We evaluated plasma from 212 ART-nave, children living with HIV (1-3 years-old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity and IgG subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay. RESULTS: 1-year-old children demonstrated neutralization breadth comparable to chronically-infected adults, while 2 and 3-year olds exhibited significantly greater neutralization breadth (p=0.014). Similarly, binding antibody responses increased with age, with levels in 2 and 3 year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. Interestingly, the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, suggesting most children may develop a polyclonal neutralization response. CONCLUSIONS: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.

Early Detection Initiative: A randomized controlled trial of algorithm-based screening in patients with new onset hyperglycemia and diabetes for early detection of pancreatic ductal adenocarcinoma

Contemp Clin Trials

2022 Ying Huang; Ziding Feng; Yingqi Zhao

Pancreatic ductal adenocarcinoma (PDAC) is the only leading cause of cancer death without an early detection strategy. In retrospective studies, 0.5-1% of subjects >50 years of age who newly develop biochemically-defined diabetes have been diagnosed with PDAC within 3 years of meeting new onset hyperglycemia and diabetes (NOD) criteria. The Enriching New-onset Diabetes for Pancreatic Cancer (ENDPAC) algorithm further risk stratifies NOD subjects based on age and changes in weight and diabetes parameters. We present the methodology for the Early Detection Initiative (EDI), a randomized controlled trial of algorithm-based screening in patients with NOD for early detection of PDAC. We hypothesize that study interventions (risk stratification with ENDPAC and imaging with Computerized Tomography (CT) scan) in NOD will identify earlier stage PDAC. EDI uses a modified Zelen's design with post-randomization consent. Eligible subjects will be identified through passive surveillance of electronic medical records and eligible study participants randomized 1:1 to the Intervention or Observation arm. The sample size is 12,500 subjects. The ENDPAC score will be calculated only in those randomized to the Intervention arm, with 50% (n = 3125) expected to have a high ENDPAC score. Consenting subjects in the high ENDPAC group will undergo CT imaging for PDAC detection and an estimate of potential harm. The effectiveness and efficacy evaluation will compare proportions of late stage PDAC between Intervention and Observation arm per randomization assignment or per protocol, respectively, with a planned interim analysis. The study is designed to improve the detection of sporadic PDAC when surgical intervention is possible.

Single-cell immunology of SARS-CoV-2 infection

Nat Biotechnol

2021 Michael Zager; Yuan Tian; Raphael Gottardo; Lindsay Carpp; Helen Rodgers Miller; Evan Newell

Gaining a better understanding of the immune cell subsets and molecular factors associated with protective or pathological immunity against severe acute respiratory syndrome coronavirus (SARS-CoV)-2 could aid the development of vaccines and therapeutics for coronavirus disease 2019 (COVID-19). Single-cell technologies, such as flow cytometry, mass cytometry, single-cell transcriptomics and single-cell multi-omic profiling, offer considerable promise in dissecting the heterogeneity of immune responses among individual cells and uncovering the molecular mechanisms of COVID-19 pathogenesis. Single-cell immune-profiling studies reported to date have identified innate and adaptive immune cell subsets that correlate with COVID-19 disease severity, as well as immunological factors and pathways of potential relevance to the development of vaccines and treatments for COVID-19. For facilitation of integrative studies and meta-analyses into the immunology of SARS-CoV-2 infection, we provide standardized, download-ready versions of 21 published single-cell sequencing datasets (over 3.2 million cells in total) as well as an interactive visualization portal for data exploration.

Association between rectal gonorrhoea and HIV incidence in men who have sex with men: a meta-analysis

Sex Transm Infect

2021 Deborah Donnell

BACKGROUND: Incidence of rectal gonorrhoea (GC) has been hypothesised as a correlate of HIV exposure in prevention trials of men who have sex with men (MSM). High rectal GC incidence in MSM trials of new biomedical prevention drugs may provide supportive evidence for ongoing HIV risk. Empirical evidence of correlation between rectal GC and HIV incidence is needed to assess whether high rectal GC rates reliably correlate with high risk of HIV. METHODS: Rectal GC and HIV are routinely tested in sexual health clinics (SHCs) throughout England. Through routine surveillance data collected at visits to SHCs, we assessed HIV incidence and new rectal GC diagnoses in repeat visits by HIV-negative MSM between 2011 and 2018, predating widespread roll-out of pre-exposure prophylaxis. Meta-analysis regression assessed population-level association between HIV and rectal GC incidence over time. FINDINGS: Between 2011 and 2018, HIV and rectal GC incidence was assessed in 541 056 HIV-negative MSM attending SHCs in England. HIV incidence among MSM attending SHCs fell from 1.26/100 person-years (PYs) in 2011 to 0.28/100 PYs in 2018. Rectal GC rates increased from 3.5/100 PYs to 11.1/100 PYs over the same period. The rate of HIV incidence decreased by 22.3% for each percent increase in rectal GC (95%CI -30.8 to -14.7, p<0.001). INTERPRETATION: Among the population of MSM attending SHCs in England, rectal GC rates increased substantially while HIV incidence rates decreased between 2011 and 2018. HIV incidence likely decreased through expanded HIV testing, prompt antiretroviral treatment (ART) initiation and increased viral suppression in persons living with HIV, interventions that did not decrease rectal GC. Rectal GC may not be an ideal proxy for HIV incidence in trials, as HIV exposure risk is complex and context dependent, given effective HIV prevention interventions in MSM. INTRODUCTION:

Incidence of herpes simplex virus type 2 infection among African women using depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a nested randomized trial

Clin Infect Dis

2021 Deborah Donnell; Nelly Mugo

BACKGROUND: Globally, women have higher herpes simplex type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of intramuscular depot medroxyprogesterone acetate (DMPA-IM). METHODS: Within a randomized trial of the effect of three contraceptive methods - DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant - on HIV acquisition, we assessed HSV-2 acquisition. HSV-2 and HIV seronegative women, aged 16-35 years, and seeking effective contraception were followed for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015-2018. HSV-2 serologic testing was done at enrollment and final study visits. Intention-to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method. FINDINGS: At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval [CI] 0.65-0.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI 0.71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI 0.89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55, 95% CI 2.78-4.48). INTERPRETATION: In a randomized trial, we found no association between HSV-2 acquisition and use of three contraceptive methods.

Biomarker-based Methods and Study Designs to Calibrate Dietary Intake for Assessing Diet-Disease Associations

J Nutr

2021 Ross Prentice; Lesley Tinker; Ying Huang; Marian Neuhouser

BACKGROUND: Dietary biomarkers measured in biospecimens can play an important role in correcting for random and systematic measurement error in self-reported nutrient intake when assessing diet-disease associations. To date, high quality biomarkers for calibrating self-reported dietary intake have only been developed for a few nutrients. OBJECTIVE: To investigate new study designs and regression calibration approaches for calibrating self-reported nutrient intake for use in disease association analyses. METHODS: We studied three regression calibration approaches: (I) an existing approach built on a calibration cohort assuming the existence of an objective biomarker, i.e., biomarker with random independent measurement error, (II) a proposed approach utilizing a biomarker development cohort, and (III) a proposed two-stage approach utilizing both cohorts. We conducted simulation studies to compare performance of different study designs/methods for estimating diet-disease associations, and applied suitable methods to examine the association of sodium and potassium intake with cardiovascular disease (CVD) risk in Women's Health Initiative cohorts. RESULTS: Simulation studies showed that approach (I) can lead to biased association estimation when the objective biomarker assumption is violated; the proposed approaches (II) and (III) obviate the need for such an objective biomarker. Precision for estimating the association depends critically on sample size of the biomarker development cohort and the strength of the self-reported nutrient intake. Analyses based on approaches (II) and (III) support previously reported significant findings using approach (I) about associations of the ratio of sodium to potassium intake with CVD risk, while providing efficiency gain for some outcomes. CONCLUSIONS: Self-reported dietary intake needs to be calibrated for measurement error correction in diet-disease association analyses. When there are no existing objective biomarkers that can be used for calibration purpose, controlled feeding studies can be used to develop new biomarkers for use in calibration, or can be used to calibrate self-reported dietary intake directly.

New interpretable machine-learning method for single-cell data reveals correlates of clinical response to cancer immunotherapy

Patterns (N Y)

2021 Evan Greene; Paul Nghiem; Raphael Gottardo; Leonard D'Amico; Chihiro Moroshima; Nirasha Ramchurren; Martin Cheever; Greg Finak; Steven Fling

We introduce a new method for single-cell cytometry studies, FAUST, which performs unbiased cell population discovery and annotation. FAUST processes experimental data on a per-sample basis and returns biologically interpretable cell phenotypes, making it well suited for the analysis of complex datasets. We provide simulation studies that compare FAUST with existing methodology, exemplifying its strength. We apply FAUST to data from a Merkel cell carcinoma anti-PD-1 trial and discover pre-treatment effector memory T cell correlates of outcome co-expressing PD-1, HLA-DR, and CD28. Using FAUST, we then validate these correlates in cryopreserved peripheral blood mononuclear cell samples from the same study, as well as an independent CyTOF dataset from a published metastatic melanoma trial. Finally, we show how FAUST's phenotypes can be used to perform cross-study data integration in the presence of diverse staining panels. Together, these results establish FAUST as a powerful new approach for unbiased discovery in single-cell cytometry.

Semiparametric additive time-varying coefficients model for longitudinal data with censored time origin


2021 Peter Gilbert

Statistical analysis of longitudinal data often involves modeling treatment effects on clinically relevant longitudinal biomarkers since an initial event (the time origin). In some studies including preventive HIV vaccine efficacy trials, some participants have biomarkers measured starting at the time origin whereas others have biomarkers measured starting later with the time origin unknown. The semiparametric additive time-varying coefficient model is investigated where the effects of some covariates vary nonparametrically with time while the effects of others remain constant. Weighted profile least squares estimators coupled with kernel smoothing are developed. The method uses the expectation maximization approach to deal with the censored time origin. The Kaplan-Meier estimator and other failure time regression models such as the Cox model can be utilized to estimate the distribution and the conditional distribution of left censored event time related to the censored time origin. Asymptotic properties of the parametric and nonparametric estimators and consistent asymptotic variance estimators are derived. A two-stage estimation procedure for choosing weight is proposed to improve estimation efficiency. Numerical simulations are conducted to examine finite sample properties of the proposed estimators. The simulation results show that the theory and methods work well. The efficiency gain of the two-stage estimation procedure depends on the distribution of the longitudinal error processes. The method is applied to analyze data from the Merck 023/HVTN 502 Step HIV vaccine study. This article is protected by copyright. All rights reserved.

Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study

PLoS Med

2021 James Kublin; Mary Trahey; Larry Corey; Leigh Fisher; Ollivier Hyrien; April Randhawa; Shuying Li; Maurine Miner; Shannon Grant; Michelle Karuna

BACKGROUND: People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity. METHODS AND FINDINGS: This analysis comprises an observational cohort of 329 HIV-seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) illness (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed. CONCLUSIONS: In summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally. TRIAL REGISTRATION: NCT04403880.

Integration of pre-exposure prophylaxis services into public HIV care clinics in Kenya: a pragmatic stepped-wedge randomised trial

Lancet Glob Health

2021 Nelly Mugo; Deborah Donnell

BACKGROUND: Successful and sustainable models for HIV pre-exposure prophylaxis (PrEP) delivery in public health systems in Africa are needed. We aimed to evaluate the implementation of PrEP delivery integrated in public HIV care clinics in Kenya. METHODS: As part of Kenya's national PrEP roll-out, we conducted a stepped-wedge cluster-randomised pragmatic trial to catalyse scale-up of PrEP delivery integrated in 25 public HIV care clinics. We selected high-volume clinics in these regions (ie, those with a high number of people living with HIV enrolled in HIV care and treatment). Clinics (each representing a cluster) were stratified by region and randomly assigned to the order in which clinic staff would receive PrEP training and ongoing technical support using numbered opaque balls picked from a bag. There was no masking. PrEP provision was done by clinic staff without additional financial support. Data were abstracted from records of individuals initiating PrEP. The primary outcome was the number of people initiating PrEP per clinic per month comparing intervention to control periods. Other outcomes included PrEP continuation, adherence, and incident HIV infections. This trial is registered with, NCT03052010. FINDINGS: After the baseline period, which started in January, 2017, every month two to six HIV care clinics crossed over from control to intervention, until August, 2017, when all clinics were implementing the intervention. Of 4898 individuals initiating PrEP (27 during the control period and 4871 during the intervention period), 2640 (54%) were women, the median age was 31 years (IQR 25-39), and 4092 (84%) reported having a partner living with HIV. The mean monthly number of PrEP initiations per clinic was 01 (SD 05) before the intervention and 75 (27) after intervention introduction (rate ratio 237, 95% CI 142-395, p<00001). PrEP continuation was 57% at 1 month, 44% at 3 months, and 34% at 6 months, and 12% of those who missed a refill returned later for PrEP re-initiation. Tenofovir diphosphate was detected in 68 (96%) of 71 blood samples collected from a randomly selected subset of participants. Six HIV infections were observed over 2531 person-years of observation (incidence 024 cases per 100 person-years), three of which occurred at the first visit after PrEP initiation. INTERPRETATION: We observed high uptake, reasonable continuation with high adherence, frequent PrEP restarts, and low HIV incidence. Integration of PrEP services within public HIV care clinics in Africa is feasible. FUNDING: National Institute of Mental Health and Bill & Melinda Gates Foundation.