First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens.

BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. METHODS: Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). RESULTS: All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. CONCLUSIONS: SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated. CLINICAL TRIALS REGISTRATION: NCT01705990.

Influenza Among Young Children in Bangladesh: Clinical Characteristics and Outcomes From a Randomized Clinical Trial.

BACKGROUND: Influenza causes substantial morbidity in children worldwide, although influenza vaccine is seldom used in low-resource settings. More information on the clinical presentation of influenza and the efficacy of vaccine is needed to inform policy. METHODS: In 2013 we conducted a randomized, placebo-controlled clinical trial of live attenuated influenza vaccine (LAIV) in children aged 24-59 months in Bangladesh (N = 1761). If participants met prespecified specimen collection criteria, we collected nasopharyngeal washes for testing by singleplex reverse-transcription polymerase chain reaction (RT-PCR) for laboratory-confirmed influenza virus infection (LCI). A panel of RT-PCR assays was used to detect noninfluenza respiratory viruses. Primary efficacy results have been reported. In this analysis of prespecified and post hoc objectives from the trial, we compared signs and symptoms between LCI and non-LCI cases and estimated the efficacy of LAIV against moderate-to-severe LCI and other prespecified non-LCI clinical outcomes including all-cause pneumonia and acute otitis media. RESULTS: The most common signs and symptoms of LCI were fever, cough, and runny nose. The combination of subjective fever and cough had a 63% sensitivity for LCI. The combination of measured fever, cough, and runny nose was most specific (90%) but had low sensitivity (32%) for LCI. The efficacy of LAIV against vaccine-strain moderate-to-severe LCI was 56.7% (95% confidence interval, 9.5%-79.2%). No statistically significant vaccine efficacy was found against the non-laboratory-confirmed clinical outcomes. CONCLUSIONS: It was not possible to distinguish LCI from noninfluenza viral infections on clinical evaluations alone in this population of Bangladeshi children. LAIV was efficacious against moderate-to-severe LCI. CLINICAL TRIALS REGISTRATION: NCT01797029.

Hemophilia Liver Transplantation Observational Study.

Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation. Whether transplant outcomes are worse in hemophilic (H) rather than nonhemophilic (NH) candidates is unknown. In order to determine rates and predictors of pretransplant and posttransplant survival, we conducted a retrospective observational study using United Network for Organ Sharing national transplant registry data, comparing HCV+ H and NH candidates. We identified 2502 HCV+ liver transplant candidates from 8 US university-based transplant centers, between January 1, 2004 to December 31, 2010, including 144 HIV+ (6%) and 2358 HIV-; 36 H (1%) and 2466 NH; 1213 (48%) transplanted and 1289 not transplanted. Other than male predominance and younger age, each were P < 0.001. Baseline data were comparable between H and NH. In univariate analysis, 90-day pretransplant mortality was associated with higher baseline Model for End-Stage Liver Disease (MELD; hazard ratio [HR] = 1.15; P < 0.001), lower baseline platelet count (HR = 0.9 per 25,000/µL; P = 0.04), and having HIV/HCV+ hemophilia (P = 0.003). In multivariate analysis, pretransplant mortality was associated with higher MELD (P < 0.001) and was significantly greater in HIV+ than HIV- groups (P = 0.001). However, it did not differ between HIV+ H and NH (HR = 1.7; P = 0.36). Among HIV/HCV+, posttransplant mortality was similar between H and NH, despite lower CD4 in H (P = 0.04). In conclusion, this observational study confirms that hemophilia per se does not have a specific influence on transplant outcomes and that HIV infection increases the risk of mortality in both H and NH patients. Liver Transplantation 23 762-768 2017 AASLD.

Impact of Genetic Defects on Coronary Atherosclerosis among Turkish Cypriots.

BACKGROUND: The distribution of gene variants in the Turkish Cypriot population with coronary artery disease has not been investigated. In this study, we sought to research different genetic variants in the susceptibility to coronary artery disease and to identify possible associations between various clinical parameters and the genes involved in blood coagulation as well as glucose and lipid metabolism among the Turkish Cypriots and compared the results with the respective Turkish patients from Turkey. Methods: A total of 187 individuals with coronary artery disease, namely 87 Turkish Cypriot individuals from Northern Cyprus, and 100 Turkish patients from Turkey, were investigated. The presence of CAD was documented with coronary angiography. The genetic susceptibility to coronary artery disease in the cohorts was studied using the variants FV Leiden (G1691A), Factor V R2 mutation (FVR2)(H1299R), PTH (G20210A), FXIII (V34L), ß-Fibrinogen (-455 G>A), PAI-1 (4G/5G), HPA1 (a/b), MTHFR [C677T] and [A1298C], ACE (I/D), Apo B (R3500Q), and Apo E, in addition to the well-known risk factors associated with coronary artery disease. RESULTS: Age, male sex, diabetes mellitus, hyperlipidemia, triglycerides, HDL, and triglyceride/HDL ratio were significantly associated with (P < .05); LDL (P = .05) and total cholesterol (P = .08) was marginally associated with coronary artery disease in the Turkish Cypriot population. The mutations in the MTHFR [C677T] gene variant were marginally higher in the Turkish Cypriot cohort when compared with the Turkish patients from Turkey (P = .06). No significant direct association of any of the gene variants with coronary artery disease in the Turkish Cypriot cohort could be defined. Several of the genetic variants were associated indirectly with the risk factors for coronary artery disease in Turkish Cypriots. MTHFR [A1298C] was found to be marginally associated with low HDL cholesterol (P = .08). MTHFR [C677] wild-type allele was significantly associated with a decreased rate of high LDL cholesterol (P < .05). The HPA-1 a/b variant was significantly associated with an increased rate of high total cholesterol levels (P < .05). Conclusion: Turkish Cypriot patients with coronary artery disease may be more affected by secondary factors, such as diabetes, hypertension, obesity, and sedentary life style when compared with genetic factors, which may be responsible for coronary artery disease.

Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in Kenya.

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a "relaxed" definition (accounting for off-prescription dosing) and 40 % per a "strict" definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.

Vitamin D status of human immunodeficiency virus-positive patients with advanced liver disease enrolled in the solid organ transplantation in HIV: multi-site study.

An optimal vitamin D status may benefit liver transplantation (LT) patients. Higher levels of 25-hydroxyvitamin D [25(OH)D] mitigate steroid-induced bone loss after LT, correlate with better hepatitis C virus treatment responses, and increase graft survival. This study investigated 25(OH)D levels and assessed strategies for vitamin D deficiency prevention in human immunodeficiency virus (HIV)-positive patients with advanced liver disease who were enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study. 25(OH)D was measured in banked specimens from 154 LT candidates/recipients with the DiaSorin assay; deficiency was defined as a 25(OH)D level < 20 ng/mL. Information about vitamin D supplement use after LT was obtained from medication logs and via surveys. Logistic regression, Cox regression, and linear repeated measures analyses were performed with SAS software. We found that none of the 17 academic medical centers in the United States routinely recommended vitamin D supplements before LT, and only a minority (4/17) recommended vitamin D supplements to all patients after LT. Seventy-one percent of the 139 patients with pre-LT values had vitamin D deficiency, which was significantly associated with cirrhosis (P = 0.01) but no other variable. The vitamin D status improved modestly after LT; however, the status was deficient for 40% of the patients 1 year after LT. In a multivariate linear repeated measures model, a higher pre-LT 25(OH)D level (P < 0.001), specimen collection in the summer (P < 0.001), a routine vitamin D supplementation strategy after LT (P < 0.001), and the time elapsing since LT (P = 0.01) were significantly associated with increases in the post-LT 25(OH)D level; black race was associated with a decreased level (P = 0.02). In conclusion, the majority of patients awaiting LT were vitamin D deficient, and approximately half were vitamin D deficient after LT. More extensive use of vitamin D supplements, more sun exposure, or both are needed to prevent this deficiency in HIV-positive LT candidates and recipients.

Outcomes of kidney transplantation in HIV-infected recipients.

BACKGROUND: The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS: We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS: Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS: In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

Chronic kidney disease after liver transplantation in human immunodeficiency virus/hepatitis C virus-coinfected recipients versus human immunodeficiency virus-infected recipients without hepatitis C virus: results from the National Institutes of Health multi-site study.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are both associated with chronic kidney disease (CKD), a major complication after orthotopic liver transplantation (OLT). The aim of this study was to assess predictors of post-OLT CKD in HIV/HCV-coinfected recipients versus HIV-infected recipients without HCV (HIV/non-HCV recipients). Data from a National Institutes of Health study of 116 OLT recipients (35 HIV/non-HCV recipients and 81 HIV/HCV-coinfected recipients) from 2003 to 2010 (Solid Organ Transplantation in HIV: Multi-Site Study) were analyzed for the pretransplant CKD prevalence [estimated glomerular filtration rate (eGFR) < 60 mL/minute for ≥3 months] and the incidence of CKD up to 3 years posttransplant. Proportional hazards models were performed to assess predictors of posttransplant CKD. A contemporaneous cohort of HCV-monoinfected transplant recipients from the Scientific Registry of Transplant Recipients database was also analyzed. The median age at transplant was 48 years, the median serum creatinine level was 1.1 mg/dL, and the median eGFR was 77 mL/minute. Thirty-four patients were suspected to have pretransplant CKD; 20 of these patients (59%) had posttransplant CKD. Among the 82 patients without pretransplant CKD (26 HIV/non-HCV patients and 56 HIV/HCV-coinfected patients), the incidence of stage 3 CKD 3 years after OLT was 62% (55% of HIV/non-HCV patients and 65% of HIV/HCV-coinfected patients), and the incidence of stage 4/5 CKD was 8% (0% of HIV/non-HCV patients and 12% of HIV/HCV-coinfected patients). In a multivariate analysis, older age [[hazard ratio (HR) = 1.05 per year, P = 0.03] and the CD4 count (HR = 0.90 per 50 cells/µL, P = 0.01) were significant predictors of CKD. HCV coinfection was significantly associated with stage 4/5 CKD (HR = 10.8, P = 0.03) after adjustments for age. The cumulative incidence of stage 4/5 CKD was significantly higher for HIV/HCV-coinfected patients versus HIV/non-HCV transplant recipients and HCV-monoinfected transplant recipients (P = 0.001). In conclusion, CKD occurs frequently in HIV-infected transplant recipients. Predictors of posttransplant CKD include older age and a lower posttransplant CD4 count. HCV coinfection is associated with a higher incidence of stage 4/5 CKD.

Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV-1 infected liver and kidney transplant recipients.

Solid organ transplantation in human immunodeficiency virus 1 (HIV)-infected individuals requiring the concomitant use of immunosuppressants (IS) [e.g. cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g. protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. This paper describes the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs or combined NNRTIs + PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. Cyclosporine and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV-IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS pharmacokinetics (PK) by comparing the ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to the increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in the apparent oral bioavailability over time as well as a decreased apparent oral clearance, while subjects on TAC and EFV showed time-dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in patients on these complex medication regimens. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Malignancy in the HIV-infected patients undergoing liver and kidney transplantation.

PURPOSE OF REVIEW: The transplant community has seen the gradual acceptance of liver and kidney transplantation in carefully selected HIV-positive patients. The addition of transplant immunosuppressants to an already immunocompromised state, however, may increase the risk of malignancy. RECENT FINDINGS: Kidney transplantation and liver transplantation have been successful in large series of carefully selected HIV-infected patients, with graft and patient survival approaching those of non-HIV-infected patients. The incidence of acute cellular rejection (kidney transplantation) and of recurrent hepatitis C (liver transplantation) remains challenging. Hepatocellular carcinoma (HCC), which is a common indication for liver transplantation, seems to occur at a younger age and to have a generally worse outcome in the HIV-positive patients. Liver transplantation outcomes for HCC in these patients, however, do not seem to be compromised. Rates of Kaposi's sarcoma and other de-novo malignancies such as skin cancer are relatively low after transplant. Kaposi's sarcoma may regress with the use of the mammalian target of rapamycin inhibitor sirolimus. In HIV-positive patients followed closely for human papilloma virus (HPV)-related anal neoplasia after transplantation, there may be an increased risk of progression to high-grade squamous intraepithelial lesions. SUMMARY: The risk of recurrent or de-novo malignancy after solid-organ transplantation in HIV patients is low. HPV-related neoplasia, however, requires further study.

Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection.

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV-positive donor (HR = 2.5), and a body mass index < 21 kg/m(2) (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes.

Comparison of SARS-CoV-2 anti-spike receptor binding domain IgG antibody responses after CoronaVac, BNT162b2, ChAdOx1 COVID-19 vaccines, and a single booster dose: a prospective, longitudinal population-based study.

BACKGROUND: Vaccination is an efficient strategy to control the COVID-19 pandemic. In north Cyprus, vaccine distribution started with CoronaVac followed by BNT162b2, and ChAdOx1 vaccines. An option to obtain a third booster dose with BNT162b2 or CoronaVac was later offered to people fully inoculated with CoronaVac. There are few simultaneous and comparative real-world antibody data for these three vaccines as well as boosters after CoronaVac vaccination. Our study was aimed at evaluating antibody responses after these vaccination schemes. METHODS: We did a prospective, longitudinal population-based study to measure SARS-CoV-2 anti-spike receptor binding domain (RBD) IgG concentrations, assessed by assaying blood samples collected, in participants in north Cyprus who had received the BNT162b2, ChAdOx1, or CoronaVac vaccine at 1 month and 3 months after the second dose. Participants were recruited when they voluntarily came to the laboratory for testing after vaccination, solicited from health-care access points, or from the general population. We also evaluated antibody responses 1 month after a booster dose of BNT162b2 or CoronaVac after primary CoronaVac regimen. Demographics, baseline characteristics, vaccination reactions, and percentage of antibody responders were collected by phone interviews or directly from the laboratory summarised by vaccine and age group. Antibody levels were compared between groups over time by parametric and non-parametric methods. FINDINGS: Recruitment, follow-up, and data collection was done between March 1 and Sept 30, 2021. BNT162b2 induced the highest seropositivity and anti-spike RBD IgG antibody titres, followed by ChAdOx1, and then by CoronaVac. In addition, the rate of decline of antibodies was fastest with CoronaVac, followed by ChAdOx1, and then by BNT162b2. For the older age group, the rate of seropositivity at 3 months after the second dose was 100% for BNT162b2, 90% for ChAdOx1, and 60% for CoronaVac. In the multivariate repeated measures model, lower antibody titres were also significantly associated with male sex, older age, and time since vaccination. Boosting a two-dose CoronaVac regimen at 6 months with a single BNT162b2 dose led to significantly increased titres of IgG compared with boosting with CoronaVac; for the 60 years and older age group, the geometric mean fold rise in antibody titre after the booster relative to 1 month post-baseline was 7·9 (95% CI 5·8-10·8) in the BNT162b2 boost group versus 2·8 (1·6-5·0) in the CoronaVac group. INTERPRETATION: These longitudinal data can help shape vaccination strategies. Given the low antibody titres and fast decline in the CoronaVac group in individuals 60 years or older, more potent vaccine options could be considered as the primary vaccination or booster dose in these high-risk populations to sustain antibody responses for longer. FUNDING: Crowdfunded in north Cyprus.

MELD score is an important predictor of pretransplantation mortality in HIV-infected liver transplant candidates.

BACKGROUND & AIMS: Human immunodeficiency virus (HIV) infection accelerates liver disease progression in patients with hepatitis C virus (HCV) and could shorten survival of those awaiting liver transplants. The Model for End-Stage Liver Disease (MELD) score predicts mortality in HIV-negative transplant candidates, but its reliability has not been established in HIV-positive candidates. METHODS: We evaluated predictors of pretransplantation mortality in HIV-positive liver transplant candidates enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study (HIVTR) matched 1:5 by age, sex, race, and HCV infection with HIV-negative controls from the United Network for Organ Sharing. RESULTS: Of 167 HIVTR candidates, 24 died (14.4%); this mortality rate was similar to that of controls (88/792, 11.1%, P = .30) with no significant difference in causes of mortality. A significantly lower proportion of HIVTR candidates (34.7%) underwent liver transplantation, compared with controls (47.6%, P = .003). In the combined cohort, baseline MELD score predicted pretransplantation mortality (hazard ratio [HR], 1.27; P < .0001), whereas HIV infection did not (HR, 1.69; P = .20). After controlling for pretransplantation CD4(+) cell count and HIV RNA levels, the only significant predictor of mortality in the HIV-infected subjects was pretransplantation MELD score (HR, 1.2; P < .0001). CONCLUSIONS: Pretransplantation mortality characteristics are similar between HIV-positive and HIV-negative candidates. Although lower CD4(+) cell counts and detectable levels of HIV RNA might be associated with a higher rate of pretransplantation mortality, baseline MELD score was the only significant independent predictor of pretransplantation mortality in HIV-infected liver transplant candidates.

Safety, immunogenicity, and efficacy of NDV-3A against Staphylococcus aureus colonization: A phase 2 vaccine trial among US Army Infantry trainees.

BACKGROUND: Military trainees are at increased risk for Staphylococcus aureus colonization and infection. Disease prevention strategies are needed, but a S. aureus vaccine does not currently exist. METHODS: We enrolled US Army Infantry trainees (Fort Benning, GA) in a phase 2, randomized, double-blind, placebo-controlled trial of NDV-3A, a vaccine containing a recombinant adhesin/invasion protein of Candida albicans that has structural similarity to the S. aureus protein clumping factor A. Study participants received one intramuscular dose of NDV-3A or placebo (adjuvant alone) within 72 h of arrival on base. Longitudinal nasal and oral (throat) swabs were collected throughout the 14-week Infantry training cycle. Safety, immunogenicity, and efficacy of NDV-3A against S. aureus nasal / oral acquisition were the endpoints. RESULTS: The NDV-3A candidate had minimal reactogenicity and elicited robust antigen-specific B- and T-cell responses. During the 56-day post-vaccination period, there was no difference in the incidence of S. aureus nasal acquisition between those who were randomized to receive NDV-3A vs. placebo (25.6% vs. 29.1%; vaccine efficacy [VE]: 12.1%; p = 0.31). In time-to-event analysis, there was no difference between study groups with respect to the S. aureus colonization-free interval (VE: 13%; p = 0.29). Similarly, the efficacy of NDV-3A against S. aureus oral acquisition was poor (VE: 2.4%; p = 0.52). CONCLUSIONS: A single dose of NDV-3A did not prevent nasal nor oral acquisition of S. aureus in a population of military trainees at high risk for colonization.

Joint Investigation of 2-Month Post-diagnosis IgG Antibody Levels and Psychological Measures for Assessing Longer Term Multi-Faceted Recovery Among COVID-19 Cases in Northern Cyprus.

Following the outbreak of COVID-19, multidisciplinary research focusing on the long-term effects of the COVID-19 infection and the complete recovery is still scarce. With regards to long-term consequences, biomarkers of physiological effects as well as the psychological experiences are of significant importance for comprehensively understanding the complete COVID-19 recovery. The present research surveys the IgG antibody titers and the impact of COVID-19 as a traumatic experience in the aftermath of the active infection period, around 2 months after diagnosis, in a subset of COVID-19 patients from the first wave (March-April 2020) of the outbreak in Northern Cyprus. Associations of antibody titers and psychological survey measures with baseline characteristics and disease severity were explored, and correlations among various measures were evaluated. Of the 47 serology tests conducted for presence of IgG antibodies, 39 (83%) were positive. We identified trends demonstrating individuals experiencing severe or critical COVID-19 disease and/or those with comorbidities are more heavily impacted both physiologically and mentally, with higher IgG titers and negative psychological experience compared to those with milder disease and without comorbidities. We also observed that more than half of the COVID-19 cases had negative psychological experiences, being subjected to discrimination and verbal harassment/insult, by family/friends. In summary, as the first study co-evaluating immune response together with mental status in COVID-19, our findings suggest that further multidisciplinary research in larger sample populations as well as community intervention plans are needed to holistically address the physiological and psychological effects of COVID-19 among the cases.

Host Genetics at the Intersection of Autoimmunity and COVID-19: A Potential Key for Heterogeneous COVID-19 Severity.

COVID-19 presentation is very heterogeneous across cases, and host factors are at the forefront for the variables affecting the disease manifestation. The immune system has emerged as a key determinant in shaping the outcome of SARS-CoV-2 infection. It is mainly the deleterious unconstrained immune response, rather than the virus itself, which leads to severe cases of COVID-19 and the associated mortality. Genetic susceptibility to dysregulated immune response is highly likely to be among the host factors for adverse disease outcome. Given that such genetic susceptibility has also been observed in autoimmune diseases (ADs), a number of critical questions remain unanswered; whether individuals with ADs have a significantly different risk for COVID-19-related complications compared to the general population, and whether studies on the genetics of ADs can shed some light on the host factors in COVID-19. In this perspective, we discuss the host genetic factors, which have been under investigation in association with COVID-19 severity. We touch upon the intricate link between autoimmunity and COVID-19 pathophysiology. We put forth a number of autoimmune susceptibility genes, which have the potential to be additional host genetic factors for modifying the severity of COVID-19 presentation. In summary, host genetics at the intersection of ADs and COVID-19 may serve as a source for understanding the heterogeneity of COVID-19 severity, and hence, potentially holds a key in achieving effective strategies in risk group identification, as well as effective treatments.

Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls.

OBJECTIVES: To evaluate the impact of liver and kidney transplantation on survival in HIV-positive transplant candidates and compare outcomes between HIV-positive and negative recipients. DESIGN: Observational cohort of HIV-positive transplant candidates and recipients and secondary analysis comparing study recipients to HIV-negative national registry controls. METHODS: We fit proportional hazards models to assess transplantation impact on mortality among recipients and candidates. We compared time to graft failure and death with HIV-negative controls in unmatched, demographic-matched, and risk-adjusted models. RESULTS: There were 17 (11.3%) and 46 (36.8%) deaths among kidney and liver recipients during a median follow-up of 4.0 and 3.5 years, respectively. Transplantation was associated with survival benefit for HIV-infected liver recipients with model for end-stage liver disease (MELD) greater than or equal 15 [hazard ratio (HR) 0.1; 95% confidence interval (CI) 0.05, 0.01; P < 0.0001], but not for MELD less than 15 (HR 0.7; 95% CI 0.3, 1.8; P = 0.43) or for kidney recipients (HR 0.6; 95% CI 0.3, 1.4; P = 0.23). In HIV-positive kidney recipients, unmatched and risk-matched analyses indicated a marginally significant HR for graft loss [1.3 (P = 0.07) and HR 1.4 (P = 0.052)]; no significant increase in risk of death was observed. All models demonstrated a higher relative hazard of graft loss or death in HIV-positive liver recipients; the absolute difference in the proportion of deaths was 6.7% in the risk-matched analysis. CONCLUSION: Kidney transplantation should be standard of care for well managed HIV-positive patients. Liver transplant in candidates with high MELD confers survival benefit; transplant is a viable option in selected candidates. The increased mortality risk compared with HIV-negative recipients was modest. TRIAL REGISTRATION: ClinicalTrials.Gov; NCT00074386; http://clinicaltrials.gov/.

Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The rates of influenza illness and associated complications are high among children in Bangladesh. We assessed the clinical efficacy and safety of a Russian-backbone live attenuated influenza vaccine (LAIV) at two field sites in Bangladesh. METHODS: Between Feb 27 and April 9, 2013, children aged 2-4 years in urban Kamalapur and rural Matlab, Bangladesh, were randomly assigned in a 2:1 ratio, according to a computer-generated schedule, to receive one intranasal dose of LAIV or placebo. After vaccination, we monitored children in weekly home visits until Dec 31, 2013, with study clinic surveillance for influenza illness. The primary outcome was symptomatic, laboratory-confirmed influenza illness due to vaccine-matched strains. Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT01797029. FINDINGS: Of 1761 children enrolled, 1174 received LAIV and 587 received placebo. Laboratory-confirmed influenza illness due to vaccine-matched strains was seen in 93 (15·8%) children in the placebo group and 79 (6·7%) in the LAIV group. Vaccine efficacy of LAIV for vaccine-matched strains was 57·5% (95% CI 43·6-68·0). The vaccine was well tolerated, and adverse events were balanced between the groups. The most frequent adverse events were tachypnoea (n=86 in the LAIV group and n=54 in the placebo group), cough (n=73 and n=43), and runny nose (n=68 and n=39), most of which were mild. INTERPRETATION: This single-dose Russian-backbone LAIV was safe and efficacious at preventing symptomatic laboratory-confirmed influenza illness due to vaccine-matched strains. LAIV programmes might reduce the burden of influenza illness in Bangladesh. FUNDING: The Bill & Melinda Gates Foundation.

Broad HIV-1 inhibition in vitro by vaccine-elicited CD8(+) T cells in African adults.

We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8(+) T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.