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The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has led to an unprecedented public health crisis. The collective global response has led to production of multiple safe and effective vaccines utilizing novel platforms to combat the virus that have propelled the field of vaccinology forward. Significant challenges to universal vaccine effectiveness remain, including immune evasion by SARS-CoV-2 variants, waning of immune response, inadequate knowledge of correlates of protection, and dosing in special populations. This review serves as a detailed evaluation of the development of the current SARS-CoV-2 vaccines, their effectiveness, and challenges to their deployment as a preventive tool.

Background Coinfection with HIV and hepatitis B (HBV) has been associated with higher risk of morbidity and mortality, especially acceleration of liver disease. HBV-active antiretroviral (ARV) regimens have significantly improved the outcome of people with HIV-HBV coinfection. B/F/TAF has been shown to be highly effective in the treatment of HIV infection based on treatment naïve and switch trials. Although it is an HBV-active regimen, there is scant data on the use of B/F/TAF for people with HIV-HBV coinfection. We hypothesize that B/F/TAF is both safe and efficacious in the treatment of coinfected adults. Methods This open label, single-arm, switch study enrolled HIV/HBV-coinfected adults from two clinical centers (Baltimore, MD and Philadelphia, PA). Patients were switched from their current ARV regimen (regardless of viral suppression) to fixed dose combination B/F/TAF taken once daily for 48 weeks. Primary efficacy endpoints were proportion of patients with HIV RNA < 50 copies/mL by FDA Snapshot Algorithm and HBV DNA < 29 IU/mL at Week 24 by missing = failure method. Results A total of 28 eligible participants were enrolled between May 2019 to December 2021. Median age was 51 years (range 34-71), majority were Black (89%), male gender (86%), and non-Hispanic (96%), 65% HIV and HBV virally suppressed. Two participants, one lost to follow-up and the other removed due to non-adherence prior to week 24, were excluded in the efficacy analysis. At baseline, 73% were HIV suppressed and 81% were HBV suppressed. Of the 21 patients with week 24 data, 20 (95%) had HIV RNA < 50 copies/mL and 19 (90%) had HBV DNA < 29 IU/mL. Eighteen (86%) were HIV and HBV suppressed, which was higher than prior to B/F/TAF use. There were ten treatment-related adverse events (AE), all of which were mild (grade 1) and transient. Most common treatment related AE was nausea (2 of 28). Four patients had elevated alanine aminotransferase at baseline, all of which normalized at week 24. There were no serious adverse events or hepatitis flare. No participants discontinued study treatment due to an AE. Conclusion B/F/TAF is efficacious and safe for patients coinfected with HIV and HBV after 6 months of treatment. Disclosures Helena Kwakwa, M.D., Viiv Healthcare: Grant/Research Support Sunny Choe, PhD, Gilead Sciences: Employee.

The severe surge of coronavirus disease 2019 (COVID-19) cases on the Indian subcontinent in early 2021 was marked by an unusually high number of COVID-19–associated mucormycosis (CAM) cases reported during this same period. This is significantly higher than predicted based on available data about prevalence and risk factors for this condition. This may be due to an unusual alignment of multiple risk factors for this condition. There is high background prevalence of mucormycosis in India likely from a high prevalence of risk factors, including undiagnosed or poorly controlled diabetes. COVID-19–induced immune dysregulation and immune suppression from steroid therapy increase the risk. The role of environmental exposure is unclear. System factors such as lack of access to healthcare during a pandemic may result in delayed diagnosis or suboptimal management with potentially poor outcomes. Here, we review currently identified risk factors and pathogenesis of CAM in a pandemic surge.

Retrospective data showed that when we administered ledipasvir/sofosbuvir (LDV/SOF) to patients with hepatitis B and C coinfection, there was a modest reduction in hepatitis B surface antigen (HBsAg). Therefore, we hypothesize that similar HBsAg reduction can be seen in hepatitis B virus (HBV) monoinfected subjects. Primary and secondary efficacy endpoints are the decline in HBsAg and HBV DNA at Week 12 from baseline, respectively. We conducted an open-label Phase 2 pilot study to evaluate the safety, tolerability, and antiviral activity of LDV and/or SOF for HBV. Eligible subjects were either suppressed on antivirals (Group B) or inactive chronic HBV (Group A, C, D). Group A and B received LDV/SOF. Group C and D received SOF 400 mg and LDV 90 mg, respectively. All subjects completed the study, and all related adverse events (AEs) were mild. No discontinuations due to AEs or hepatitis flare occurred. At Week 12, HBsAg decline (log

A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions.

Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support.We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040.Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed.CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19.MerckCo, National Cancer Institute, OncoImmune.

Combination regimens of direct‐acting antiviral agents (DAAs) for chronic genotype 1 hepatitis C virus (HCV) infection given for 8 or 12 weeks have high cure rates. Shortened treatment durations that maintain high cure rates may lessen treatment barriers related to affordability and drug adherence. We enrolled 12 treatment‐naïve adults with chronic genotype 1 HCV infection without cirrhosis in a single‐center, open‐label trial to receive 2 weeks of the highly potent and selective non‐nucleoside inhibitor (NNI) CDI‐31244 concurrent with 6 weeks of sofosbuvir/velpatasvir. The main efficacy endpoints were sustained virologic response at 12 (SVR12) and 24 (SVR24) weeks after treatment completion. In all patients, plasma HCV RNA levels rapidly decreased during the first 2 days of treatment and were below the lower limit of quantification by the end of the 6‐week treatment period. Eight of 12 (67%) patients achieved both SVR12 and SVR24. Four patients had virological relapse at Week 10, 4 weeks after end of treatment. The most common adverse event was headache, occurring in five (42%) patients. Pharmacokinetic analysis showed no relevant drug interactions between CDI‐31244, sofosbuvir, and velpatasvir. In this pilot study of short‐duration combination therapy involving a novel NNI with a fixed‐combination DAA, 8 of 12 treatment‐naïve patients with chronic genotype 1 HCV infection without cirrhosis achieved virologic cure. Future trials might evaluate whether extending the NNI duration beyond 2 weeks with combination DAAs results in higher cure rates comparable with currently approved longer duration therapy.

Dengue is one of the most prevalent infectious diseases around the world, present in all continents and mainly affecting developing countries. With few tools to fight and study this disease, it is imperative to have reliable animal models that not only recapitulate human disease but also contain human components to understand the pathogenic mechanism and immune responses, allowing the development of new treatments and vaccines against dengue. Humanized mice are a significant advance in the development of in vivo models to understanding the relation of the human immune system and target organs such as the liver during the infection by dengue virus, allowing basic and preclinical research. In this chapter, we describe the use of humanized NSG mice (huNSG) for the study of dengue disease. The first model describes reconstitution of the human immune system by transplanting human CD34+ stem cells in newborn or adult NSG mice. The second model combines the reconstitution with CD34+ stem cells with the transplant of human primary hepatocytes. This dual reconstituted animal will have two of the major players involved in the development of dengue infection. However, there are still more biological components missing in this model for dengue, but researchers continue working to improve the huNSG model to reconstitute other human components.

Dengue is one of the most prevalent infectious diseases around the world, present in all continents and mainly affecting developing countries. With few tools to fight and study this disease, it is imperative to have reliable animal models that not only recapitulate human disease but also contain human components to understand the pathogenic mechanism and immune responses, allowing the development of new treatments and vaccines against dengue. Humanized mice are a significant advance in the development of in vivo models to understanding the relation of the human immune system and target organs such as the liver during the infection by dengue virus, allowing basic and preclinical research. In this chapter, we describe the use of humanized NSG mice (huNSG) for the study of dengue disease. The first model describes reconstitution of the human immune system by transplanting human CD34

Dengue is the most prevalent arthropod-borne viral disease worldwide and affects approximately 2.5 billion people living in over 100 countries. Increasing geographic expansion of Aedes aegypti mosquitoes (which transmit the virus) has made dengue a global health concern. There are currently no approved antivirals available to treat dengue, and the only approved vaccine used in some countries is limited to seropositive patients. Treatment of dengue, therefore, remains largely supportive to date; hence, research efforts are being intensified for the development of antivirals. The nonstructural proteins, 3 and 5 (NS3 and NS5), have been the major targets for dengue antiviral development due to their indispensable enzymatic and biological functions in the viral replication process. NS5 is the largest and most conserved nonstructural protein encoded by flaviviruses. Its multifunctionality makes it an attractive target for antiviral development, but research efforts have, this far, not resulted in the successful development of an antiviral targeting NS5. Increase in structural insights into the dengue NS5 protein will accelerate drug discovery efforts focused on NS5 as an antiviral target. In this review, we will give an overview of the current state of therapeutic development, with a focus on NS5 as a therapeutic target against dengue.

BackgroundRespiratory infections have long been associated with higher maternal and perinatal morbidity. Early data did not report an increased risk of SARS-CoV-2 infection or disease severity in pregnancy. However, surveillance data from the Center for Disease Control and Prevention (CDC) indicates a higher risk of severe disease and death in pregnant women with symptomatic SARS-CoV-2 infection, although this data is subject to ascertainment bias.ObjectiveTo explore the association between COVID-19 disease severity and pregnancy in our university-based hospital system using measures such as COVID-19 ordinal scale severity score, hospitalization, intensive care unit admission, oxygen supplementation, invasive mechanical ventilation, and death.Study designWe conducted a retrospective, multicenter case-control study to understand the association between COVID-19 disease severity and pregnancy. We reviewed consecutive charts of adult females, ages 18-45, with laboratory-confirmed SARS-CoV-2 infection in six months between March 1, 2020, and August 31, 2020. Cases were patients diagnosed with COVID-19 during pregnancy, whereas controls were not pregnant at the time of COVID-19 diagnosis. Primary endpoints were the COVID-19 severity score at presentation (within four hours) and the nadir of the clinical course. The secondary endpoints were the proportion of patients requiring hospitalization, intensive care unit admission, oxygen supplementation, invasive mechanical ventilation, and death.ResultsA higher proportion of pregnant women had moderate to severe COVID-19 disease at the nadir of the clinical course than nonpregnant women (25% vs. 16.1%, p=0.04, respectively). While there was a higher rate of hospitalization (25.6% vs. 17.2%), ICU admission (8.9% vs. 4.4%), need for vasoactive substances (5.0% vs. 2.8%), and invasive mechanical ventilation (5.6% vs. 2.8%) in the pregnant group, this difference was not significant after the propensity score matching was applied.We found a high rate of pregnancy complications in our population (40.7%). The most worrisome is the rate of hypertensive disorders of pregnancy (20.1%).ConclusionsIn our propensity score-matched study, COVID-19 in pregnancy is associated with an increased risk of disease severity and an increased risk of pregnancy complications.

More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients.

Nipah virus (NiV) is a zoonotic paramyxovirus of the Henipavirus genus first identified in Malaysia in 1998. Henipaviruses have bat reservoir hosts and have been isolated from fruit bats found across Oceania, Asia, and Africa. Bat-to-human transmission is thought to be the primary mode of human NiV infection, although multiple intermediate hosts are described. Human infections with NiV were originally described as a syndrome of fever and rapid neurological decline following contact with swine. More recent outbreaks describe a syndrome with prominent respiratory symptoms and human-to-human transmission. Nearly annual outbreaks have been described since 1998 with case fatality rates reaching greater than 90%. The ubiquitous nature of the reservoir host, increasing deforestation, multiple mode of transmission, high case fatality rate, and lack of effective therapy or vaccines make NiV’s pandemic potential increasingly significant. Here we review the epidemiology and microbiology of NiV as well as the therapeutic agents and vaccines in development.

Objectives Primary Objective: To evaluate the efficacy and safety of oral administration of imatinib combined with the Best Conventional Care (BCC) versus placebo plus BCC in hospitalized patients with COVID-19. Hypothesis: Addition of imatinib to the BCC will provide a superior clinical outcome for patients with COVID-19 compared with BCC plus placebo. This hypothesis is on the basis of 1) intralysosomal entrapment of imatinib will increase endosomal pH and effectively decrease SARS-CoV-2/cell fusion, 2) kinase inhibitory activity of imatinib will interfere with budding/release or replication of SARS-CoV-2, and 3) because of the critical role of mechanical ventilation in the care of patients with ARDS, imatinib will have a significant clinical impact for patients with critical COVID-19 infection in Intensive Care Unit (ICU). Trial design This is an individual patient-level randomized, double-blind, placebo-controlled, two-parallel arm phase 3 study to evaluate the safety and efficacy of imatinib for the treatment of hospitalized adults with COVID-19. Participants will be followed for up to 60 days from the start of study drug administration. This trial will be conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. Participants Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: 1) Ability to understand and willingness to sign a written informed consent document. Informed consent must be obtained prior to participation in the study. For patients who are too unwell to provide consent such as patients on invasive ventilator or extracorporeal membrane oxygenation (ECMO), their Legally Authorized Representative (LAR) can sign the informed consent, 2) Hospitalized patients ≥18 years of age, 3) Positive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in the respiratory tract sample (oropharyngeal, nasopharyngeal or bronchoalveolar lavage (BAL)) by Center for Disease Control or local laboratory within 7 days of randomization, 4) Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study. Exclusion Criteria: Patients meeting any of the following criteria are not eligible for the study: 1) Patients receiving any other investigational agents in a clinical trial. Off-label use of agents such as hydroxychloroquine is not an exclusion criterion, 2) Pregnant or breastfeeding women, 3) Patients with significant liver or renal dysfunction at the time of screening as defined as: 3.1) Direct bilirubin >2.5 mg/dL, 3.2) AST, ALT, or alkaline phosphatase >5x upper limit of normal, 3.3) eGFR ≤30 mL/min or requiring renal replacement therapy, 4) Patients with significant hematologic disorder at screen as defined as: 4.1) Absolute neutrophil count (ANC) Both men and women of all races and ethnic groups are eligible for this trial. University of Maryland Medical Center, Baltimore, MD is the initiating site. The study may be opened in other centers on the basis of the accrual rate or the magnitude of the COVID-19 pandemic. Intervention and comparator Imatinib: All doses of imatinib should be administered with a meal and a large glass of water. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. In this study, patients with confirmed positive COVID-19 tests receive imatinib for a total of 14 days; 400 mg orally daily Days 1-14. Imatinib 400 mg tablets will be encapsulated using size 000 capsules and cellulose microcrystalline filler. For patients on ventilator or ECMO, imatinib will be given as oral suspension (40 mg/mL). To make the oral suspension, imatinib tablets will be crushed and mixed in Ora-sweet solution to yield a concentration of 40 mg/mL suspension by pharmacy. Additionally, in the absence of supportive microbiological testing results, we confirm that the in-use stability period for the prepared imatinib suspensions will be 24 hours at room temperature or 7 days at refrigerated conditions. The pharmacy staff will follow the American Society Health-System Pharmacists (ASHP) guidelines for handling hazardous drugs. Placebo: The matching placebo will be packaged by Investigational Drug Service Pharmacy at University of Maryland Medical Center. The placebos will be prepared using size 000 capsules and cellulose microcrystalline filler. Imatinib 400 mg capsules and placebo capsules will be identical form and color. For patients on ventilator or ECMO, placebo will be given as oral suspension with similar process for making imatinib suspension. Concomitant Medications/supportive care: In both arms, patients can receive concomitant available local standard of care antipyretics, antibacterials, antivirals, antifungals and anti-inflammatory including hydroxychloroquine at the discretion of the treating physician as necessary. For other drug-drug interactions particularly with CYP P450, the treating physician should consider the risk and benefit of drug administration based on available information. Co-administration of off-label immunomodulatory treatments for COVID-19 including but not limited to corticosteroids, sarilumab, clazakizumab, tocilizumab, and anakinra will be allowed but may affect interpretability of study outcomes. The timing, dosing, and duration of these treatments will be meticulously collected, including any of these treatments that may be used for participants who experience progression of COVID-19 disease after study enrollment. Two analyses will be performed, the primary analysis will compare the primary endpoint in the two trial arms irrespective of any other treatment; the second analysis will be stratified for co-administration of immunomodulatory drugs. Main outcomes The primary endpoint is the proportion of patients with a two-point improvement at Day 14 from baseline using the 8-category ordinal scale. The ordinal scale is an evaluation of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 8) Death. The secondary endpoints include: All-cause mortality at Day 28, All-cause mortality at Day 60, Time to a 2-point clinical improvement difference over baseline, Duration of hospitalization, Duration of ECMO or invasive mechanical ventilation (for subjects who are on ECMO or mechanical ventilation at Day 1), Duration of ICU stay (for subjects who are in ICU at Day 1), Time to SARS-CoV-2 negative by RT-PCR, Proportion of patients with negative oropharyngeal or nasopharyngeal swab for SARS-CoV-2 by RT-PCR on days 5, 10, 14, 21, and 28 after starting treatment, Proportion of subjects with serious adverse events, Proportion of subjects who discontinue study drug due to adverse events. The exploratory endpoints include: Determine the impact of treatment arms on IL-6 levels, Obtain blood/peripheral blood mononuclear cells (PBMCs) for storage to look at transcriptomics in severe disease, Association of major histocompatibility complex (MHC) with severity of illness, Mean change in the ordinal scale from baseline, Time to an improvement of one category from admission using an ordinal scale, Duration of hospitalization, Duration of new oxygen use, Number of oxygenation free days, Duration of new mechanical ventilation, Number of ventilator free days. Randomization Eligible patients will be uniformly randomized in 1:1 ratio to receive either imatinib or placebo for 14 days. Both groups will receive the BCC. The randomized treatment allocations use stratified, permuted block randomization with a variable block size; blocks are generated using a validated random number generator. In order to balance the severity of the respiratory illness between the two arms, randomization will be stratified based on radiographic findings and oxygen requirements: 1) Severe disease: evidence of pneumonia on chest X-ray or CT scan OR chest auscultation (rales, crackles), and SpO2 ≤92% on ambient air or PaO2/FiO2 Blinding (masking) The participants, caregivers, and the statistician are blinded to group assignment. The only people who are not blinded are Site Pharmacists. Blinding will be performed via a specific randomization process. Centralized, concealed randomization will be executed by the Primary Site’s Pharmacist. Data on eligible consented cases will be submitted electronically on the appropriate on-study form to the pharmacy, where the patient is randomized to imatinib or placebo. Imatinib 400 mg capsules and placebo capsules will be identical form and color. For patients on ventilator or ECMO, placebo will be given as oral suspension with similar process for making imatinib suspension. Numbers to be randomized (sample size) The trial is designed as a double-blind, two-parallel arm, randomized controlled trial with a uniform (1:1) allocation ratio to: Arm A) Imatinib or Arm B) Placebo. Patients in both arms will receive the BCC per local institutional standards at the discretion of the treating physician. Group sample sizes of 102 in Arm A and 102 in Arm B achieve 80.6% power to detect a difference between the group proportions of 0.20. The proportion in Arm A (imatinib treatment arm) is assumed to be 0.30 under the null hypothesis and 0.50 under the alternative hypothesis. The proportion in Arm B (placebo control arm) is 0.30. The test statistic used is the two-sided Fisher's Exact Test. The significance level of the test is targeted at 0.05. The significance level actually achieved by this design is α=0.0385. The power of the test is calculated using binomial enumeration of all possible outcomes. The primary analysis will be conducted using an intention to treat principle (ITT) for participants who at least receive one dose of study drug or placebo. The sample size is not inflated for dropouts. All patients will be evaluable irrespective of the clinical course of their disease. Trial Status Current protocol version is 1.2 from May 8, 2020. The recruitment started on June 15, 2020 and is ongoing. We originally anticipated that the trial would finish recruitment by mid 2021. We are aware of the enrollment requirement of approximately 200 patients, which is required to provide scientific integrity of the results. We are also aware of the fact that enrolling this number of patients in a single-site at University of Maryland Medical Center (UMMC) may take longer than expected, particularly taken into account other competing studies. For this reason, we are actively considering opening the protocol in other sites. After identification of other sites, we will fulfill all regulatory requirements before opening the protocol in other sites. Trial registration ClinicalTrials.gov Identifier: NCT04394416. First Posted: May 19, 2020; Last Update Posted: June 4, 2020. FDA has issued the “Study May Proceed” Letter for this clinical trial under the Investigational New Drug (IND) number 149239. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Dengue is a major public health problem in hyperendemic countries like Colombia,the understanding of the epidemiological trends is important for the development of efficientpublic health policies. We conducted a systematic review of the epidemiologic data on dengue inColombia from 1971 to 2020. A total of 375 relevant citations were identified, 36 of which fulfilled theinclusion criteria. The data of dengue and severe dengue cases, infection fatality rate, and serotypedistribution were used to understand and identify gaps in the epidemiological knowledge in Colombia.The epidemiology of dengue in this country was characterized by five main outbreaks in 1998, 2002,2010, 2013, and 2019 with high fatality rates in comparison with the average values reported in theAmericas. The case fatality rate of severe dengue exceeded 2% and all four serotypes co-circulatethroughout the country with some regional variations. Overall, the behavior of dengue in Colombia isinfluenced by multiple factors including seasonal temperature variation and socioeconomic conditions.Additionally, the most important barriers in the epidemiological surveillance of dengue may be dueto the insufficient notification rate in some regions and the low active search for the circulation ofdifferent serotypes.

Hepatitis B surface antigen (HBsAg) level plays an important role in conjunction with other markers such as hepatitis B envelope antigen (HBeAg) and hepatitis B virus (HBV) deoxyribonucleic acid levels to predict disease activity in chronic Hepatitis B (CHB). Quantification of HBsAg is useful in differentiating carriers from active hepatitis in HBeAg negative patients, and current guidelines ecommend monitoring of pegylated interferon alpha treatment in CHB infection. However, there are only few studies about the role of quantitative HBsAg (qHBsAg) monitoring in HIV-HBV coinfected patients. Studies have shown that tenofovir based antiretroviral therapy regimen leads to a very slow decline in HBsAg levels and a predicted time of 10-42 years to lose the HBsAg, in majority of patients. Rapid drop in HBsAg levels and gain in CD4 within the 1st year of treatment and low baseline HBsAg level are associated with faster seroconversion. The reported rate of HBsAg loss in this population is less than 15%. In this review, we discuss tility of qHBsAg in monitoring disease activity and treatment in HIV-HBV coinfected population.

Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research.

Background About 10% of patients living with the human immunodeficiency virus (HIV) are coinfected with chronic hepatitis B infection (HBV). Individuals with HIV are at increased risk of having HBV progress to chronic infection. Current guidelines recommend at least two active agents against HBV in HIV/HBV coinfected patients one of which must include tenofovir. Due to the increased risk of developing fibrosis and hepatocellular cancer (HCC) in this population, current guidelines recommend yearly evaluation of the liver function with imaging, liver function tests (LFTs), and vaccination against Hepatitis A. In our study, we sought to determine the characteristics of dual-infected patients in our clinic and our management practices in accordance with guidelines. Methods A retrospective, observational, single-center cohort study in adults coinfected with HIV and chronic HBV from 2013 to 2018 at an urban HIV outpatient practice. Patients with acute hepatitis B infection and isolated hepatitis B core antibody were not included in our study. The study assessed the management practices evaluating appropriate medication for HBV, screening for hepatocellular cancer, and Hepatitis A vaccination. Results Of the 3,248 HIV patients seen at our clinic within this period, 128 patients (3.9%) were HBV coinfected. Only active patients (N = 81) were included in the quality improvement analysis. Although 90% of coinfected patients were on appropriate anti-HBV therapy, and 96% had annual LFTs done, only 39.5% had documented hepatitis A vaccination and only a quarter (25.9%) had HCC screening done at the recommended interval. Conclusion Long-term management of HIV/HBV involves preventing and monitoring for liver failure and HCC. Based on our clinic data, our management practices for ensuring that our patients receive imaging for HCC will need to be revised. Disclosures All authors: No reported disclosures.

Background A primary challenge for HIV vaccine development is to raise antiviral antibodies capable of recognizing highly variable viral antigens. The full-length single chain (FLSC) gp120-CD4 chimeric protein was designed to present a highly conserved CD4-induced HIV-1 envelope structure that evokes cross-reactive humoral responses (Figure 1). IHV01 is an FLSC subunit vaccine formulated in alum adjuvant. The safety and immunogenicity of IHV01 was evaluated in this first-in-human phase 1a trial. Methods This randomized, double-blind placebo-controlled study involved three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Eligible participants were HIV-1 uninfected healthy volunteers aged 18 to 45 years. Participants in each cohort were block randomized in groups of four in a 3:1 ratio to receive either vaccine or placebo. Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. Crossreactive antibody binding titers against diverse HIV envelopes and antigens and specific CD4i epitopes on gp120 were assessed. Results Sixty-five volunteers were enrolled—49 vaccine and 16 placebo. Majority (81%) of vaccinations with IHV01 produced no localized or systemic reactions; no different from the control group. The overall incidence of adverse events (AEs) was not significantly different between groups. Majority (89%) of vaccine-related AEs were mild in severity. The most common vaccine-related AEs were injection site pain (31%), pruritus (10%), and headache (10%). There were no vaccine-related serious AE, discontinuation due to AE, or intercurrent HIV infection. By the final vaccination, all subjects in all cohorts had developed antibodies against IHV01; all placebo recipients were negative. The antibodies induced by IHV01 reacted with envelope antigens from diverse HIV-1 strains (Figure 2). Conclusion IHV01 vaccine was safe, well tolerated, and immunogenic in all doses tested. The vaccine raised broadly reactive humoral responses against multiple gp120 domains, transition state structures, and CD4i epitopes. Disclosures All Authors: No reported Disclosures.

Chronic hepatitis C (HCV) is estimated to infect about 80–130 million people worldwide [1,2]. A significant proportion of patients with chronic HCV will progress to develop liver cirrhosis, and sub...

As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase.We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin.Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Patients with illnesses caused by ticks may present with flulike symptoms. Physicians should learn how to recognize these illnesses by specific aspects in the patients' histories and physical examinations. Prevention of mortality and morbidity may depend on correct early diagnosis and treatment. Illness prevention may result with early removal of the tick, because infection usually requires 24 to 48 hours of attachment to the host. A bite from one tick may transmit several different pathogens leading to concurrent infections. The prevention of tick-borne illnesses can start with advice on how to prevent tick bites, especially during summer time.

Herpes zoster, also known as shingles, is a disease that results from the reactivation of a latent infection of the varicella zoster virus, which is usually encountered during early childhood. Aging is associated with an increased risk for herpes zoster and its complications. Boosting immunological memory is the key strategy for keeping the latent varicella zoster virus infection under control. A live attenuated virus vaccine is safe, effective and approved for use among healthy elderly adults aged 60 years or older. However, significant problems remain in the prevention of herpes zoster with the current vaccine. Future studies for improved vaccines and studies into the epidemiology of herpes zoster are required in order to address this significant public health burden.

Vaccination is the most effective means for the prevention of influenza, including pandemic strains. An ideal pandemic influenza vaccine should provide effective protection with the fewest number of doses in the shortest amount of time, and among the greatest proportion of the population. The current manufacturing processes required for embryonated chicken-egg-based influenza vaccines are limited in their ability to respond to pandemic situations - these limitations include problems with surge capacity, the need for egg-adapted strains, the possibility of contamination, and the presence of trace egg protein. Several vaccine strategies to circumvent the deficiencies intrinsic to an egg-based influenza vaccine are in various phases of development. These include the use of cell-culture-based growth systems, concomitant use of adjuvants, whole virus vaccines, recombinant protein vaccines, plasmid DNA vaccines, virus-like particle vaccines, and universal flu vaccines.