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Background. To investigate the potential immunostimulatory effect of interleukin (IL) 2 as a human immunodeficiency virus type 1 (HIV-1) vaccine adjuvant, we conducted a study of a plasmid coding for a fusion protein of IL-2 and immunoglobulin (IL-2/Ig). Methods. This phase I trial evaluated an HIV-1 DNA vaccine with the plasmid cytokine adjuvant (IL-2/Ig) in 70 HIV-negative adults. Subjects received placebo (group C), adjuvant alone (group A), vaccine alone (group D), increasing doses of adjuvant concurrent with vaccine (groups T1-T4), or adjuvant given 2 days after vaccine (group T5). Results. No significant differences in adverse events were observed between treatment groups. Cellular immune responses to envelope protein EnvA peptides were detected by interferon (IFN) &ggr; and IL-2 enzymelinked immunospot (ELISPOT) assays in 50% and 40% of subjects, respectively, in T4, and in 100% and 80% in T5. The median responses for groups T4 and T5, respectively, were 90 and 193 spot-forming cells (SFCs)/106 peripheral blood mononuclear cells (P = .004; T4 vs T5) for the IL-2 ELISPOT assay and 103 and 380 SFCs/106 PBMCs (P = .003; T4 vs T5) for the IFN-&ggr; ELISPOT assay. A trend to more durable cellular immune responses in T5 was observed at 1 year (T5 vs T4/D; P = .07). Higher anti-Env antibody responses were detected with T5 than with T4. Conclusions. Plasmid IL-2/Ig significantly increased immune responses when administered 2 days after the DNA vaccine, compared with simultaneous administration. These observations have important implications for the development of cytokine augmentation strategies. [ABSTRACT FROM AUTHOR]

Abstract: The pharmacokinetics of ganciclovir after oral valganciclovir versus intravenous ganciclovir were compared in allogeneic stem cell transplant recipients with stable graft-versus-host disease of the gastrointestinal tract. Twenty-two evaluable adult patients were randomized to receive a single dose of open-label study drug (900 mg of oral valganciclovir or 5 mg/kg of intravenous ganciclovir). After a washout period of 2 to 7 days, patients were crossed over to receive the alternate study drug. Ganciclovir and valganciclovir concentrations in plasma were measured over 24 hours after dosing. Noninferiority of 900 mg of valganciclovir relative to intravenous ganciclovir was concluded if the lower limit of the 1-sided 95% confidence interval of the ratio of least-square means of the ganciclovir area under the curve (AUC) for the 2 study drugs was >80%. Valganciclovir was found to be rapidly absorbed and converted into ganciclovir. The ganciclovir exposure after 900 mg of valganciclovir noninferior to that of intravenous ganciclovir (AUC0-∞, 52.1 and 53.8 μg·h/mL, respectively; 95% confidence interval of the ratio of least square means of AUC0-∞, 82.48%-118.02%). Oral valganciclovir could be a useful alternative to intravenous ganciclovir in certain stable stem cell transplant patients who require prophylaxis or preemptive therapy for cytomegalovirus infection. [Copyright &y& Elsevier]

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. Methods and findings: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). Conclusions: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. Trial registration: ClinicalTrials.gov/NCT03387150 (posted on 21 December 2017). In a Phase 1 randomised clinical trial, Stephen Walsh and colleagues assess the safety and pharmacokinetics of VRC07-523LS which has been engineered for improved breadth, potency, and a longer half-life. Author summary: Why was this study done?: Broadly neutralizing antibodies (bnAbs), which can block HIV-1 infection in laboratory settings, have considerable promise for HIV-1 prevention in people. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site (CD4bs) targeting bnAb, VRC01, was found to have 75% prevention efficacy against highly neutralization-sensitive viruses. Most circulating isolates of HIV-1 are less sensitive, and VRC01 was ineffective against those viruses. Our clinical trial was done to assess the safety and drug levels of another CD4bs bnAb called VRC07-523LS, which has been engineered for improved breadth, potency, and a longer half-life. What did the researchers do and find?: We administered VRC07-523LS to healthy volunteers without HIV using multiple routes (intravenous [IV], subcutaneous [SC], and intramuscular [IM]) and at doses ranging from 2.5 mg/kg to 20 mg/kg. VRC07-523LS was safe and well tolerated over more than 30 months of follow-up. At any given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. VRC07-523LS has a half-life of about 42 days, which is over twice as long as VRC01 (15 days). What do these findings mean?: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. The main limitations of our study are the small sizes of the individual groups and missing blood draws at the later time points due to COVID-19 restrictions, both of which lead to uncertainty in our estimates of drug levels and pharmacokinetic parameters. Presented in part at: HIV R4P 2021 Virtual (Abstract OA03.01), Cape Town, South Africa, January 2021; and IAS 2022 (Abstract PESUA14), Montréal, Canada, July 2022. [ABSTRACT FROM AUTHOR]

Vaccination reduces morbidity and mortality due to infections, but efficacy may be limited due to distinct immunogenicity at the extremes of age. This raises the possibility of employing adjuvants to enhance immunogenicity and protection. Early IFNγ production is a hallmark of effective vaccine immunogenicity in adults serving as a biomarker that may predict effective adjuvanticity. We utilized mass cytometry (CyTOF) to dissect the source of adjuvant-induced cytokine production in human blood mononuclear cells (BMCs) from newborns (~39-week-gestation), adults (~18-63 years old) and elders (>65 years of age) after stimulation with pattern recognition receptors agonist (PRRa) adjuvants. Dimensionality reduction analysis of CyTOF data mapped the BMC compartment, elucidated age-specific immune responses and profiled PRR-mediated activation of monocytes and DCs upon adjuvant stimulation. Furthermore, we demonstrated PRRa adjuvants mediated innate IFNγ induction and mapped NK cells as the key source of TLR7/8 agonist (TLR7/8a) specific innate IFNγ responses. Hierarchical clustering analysis revealed age and TLR7/8a-specific accumulation of innate IFNγ producing γδ T cells. Our study demonstrates the application of mass cytometry and cutting-edge computational approaches to characterize immune responses across immunologically distinct age groups and may inform identification of the bespoke adjuvantation systems tailored to enhance immunity in distinct vulnerable populations. An in vitro mass cytometry study focusing on age and adjuvant-specific activation of human blood mononuclear cells reveals NK cells as the key source of TLR7/8 agonist induced innate IFNγ responses. [ABSTRACT FROM AUTHOR]

Expresses opinion on the Darwinian competition and the pathogenesis of opportunistic infection in the transplant recipient. Prescription for the organ transplant recipient; Infection in organ-transplant recipients; Risk factors for the development of invasive fungal infections in allogeneic blood and marrow transplant recipients.

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies. [ABSTRACT FROM AUTHOR]

The immunology of human babesiosis is poorly investigated. We present a comprehensive investigation of a 75-year-old man with B-cell deficiency who experienced 3 episodes of babesiosis over a 6-year period. Slowly evolving clinical immunity was observed, as evidenced by milder clinical symptoms and lower peak parasite burden after each subsequent babesiosis episode. The patient exhibited several striking immunologic findings. First, the patient had exceptionally high Babesia microti –specific antibodies despite very few circulating B cells, which predominantly coexpressed CD27 (memory marker) and CD95 (death receptor). Second, we demonstrated the presence of long-lasting NK cells and expansion of T memory stem cells. Third, levels of the IP-10 cytokine directly correlated with parasite burden. These results raise fundamental questions on the priming, maintenance, and location of a B-cell population that produces high antibody levels in the face of severe B-cell deficiency. Our results should invoke interest among researchers to study the immunology and pathogenesis of human babesiosis. [ABSTRACT FROM AUTHOR]

• Stochastic interventional vaccine efficacy (SVE) analysis for clinical audience. • SVE analysis estimates how vaccine efficacy (VE) would change under hypothetical immune marker shifts. • First application of SVE to immune correlates based on phase 3 VE trial dataset. • SVE analysis of the COVE messenger RNA-1273 trial supports post dose 2 D614G titer as a CoP. • Predicting variant-specific VE proved difficult due to various reasons. Stochastic interventional vaccine efficacy (SVE) analysis is a new approach to correlate of protection (CoP) analysis of a phase III trial that estimates how vaccine efficacy (VE) would change under hypothetical shifts of an immune marker. We applied nonparametric SVE methodology to the COVE trial of messenger RNA-1273 vs placebo to evaluate post-dose 2 pseudovirus neutralizing antibody (nAb) titer against the D614G strain as a CoP against COVID-19. Secondly, we evaluated the ability of these results to predict VE against variants based on shifts of geometric mean titers to variants vs D614G. Prediction accuracy was evaluated by 13 validation studies, including 12 test-negative designs. SVE analysis of COVE supported post-dose 2 D614G titer as a CoP: estimated VE ranged from 66.9% (95% confidence interval: 36.2, 82.8%) to 99.3% (99.1, 99.4%) at 10-fold decreased or increased titer shifts, respectively. The SVE estimates only weakly predicted variant-specific VE estimates (concordance correlation coefficient 0.062 for post 2-dose VE). SVE analysis of COVE supports nAb titer as a CoP for messenger RNA vaccines. Predicting variant-specific VE proved difficult due to many limitations. Greater anti-Omicron titers may be needed for high-level protection against Omicron vs anti-D614G titers needed for high-level protection against pre-Omicron COVID-19. [ABSTRACT FROM AUTHOR]

Background Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination reduces the risk and severity of coronavirus disease 2019 (COVID-19), several variables may impact the humoral response among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods A retrospective chart review was conducted among SARS-CoV-2-vaccinated HSCT recipients between 2020 and 2022 at a single center in Boston, Massachusetts. Patients age ≥18 years who received doses of Pfizer, Moderna, or J&J vaccines were included. Anti-spike (S) immunoglobulin G (IgG) titer levels were measured using the Roche assay. Responders (≥0.8 U/mL) and nonresponders (<0.8 U/mL) were categorized and analyzed. Multivariable linear and logistic regression were used to estimate the correlation coefficient and odds ratio of response magnitude and status. Results Of 152 HSCT recipients, 141 (92.8%) were responders, with a median (interquartile range [IQR]) anti-S IgG titer of 2500 (107.9–2500) U/mL at a median (IQR) of 80.5 (36–153.5) days from last dose, regardless of the number of doses received. Higher quantitative titers were associated with receipt of more vaccine doses (coeff, 205.79; 95% CI, 30.10 to 381.47; P =.022), being female (coeff, 343.5; 95% CI, −682.6 to −4.4; P =.047), being younger (<65 years; coeff, 365.2; 95% CI, −711.3 to 19.1; P =.039), and not being on anti-CD20 therapy (coeff, −1163.7; 95% CI, −1717.7 to −609.7; P =.001). Being male (odds ratio [OR], 0.11; 95% CI, 0.01 to 0.93; P =.04) and being on anti-CD20 therapy (OR, 0.16; 95% CI, 0.03 to 0.70; P =.016) were associated with nonresponse. Conclusions Overall, most HSCT recipients had high SARS-CoV-2 antibody responses. More vaccine doses improved the magnitude of immune responses. Anti-S IgG monitoring may be useful for identifying attenuated vaccine-induced responses. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence‐based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). Methods: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. Results: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. Conclusion: Application of these recommendations should consider patients' individual risk for vaccine‐preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision‐making with patients is encouraged in clinical settings. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the use of COVID‐19 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious diseases specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results: Despite a paucity of direct evidence, statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines, including supplemental/booster dosing, in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion: These guidance statements are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients. [ABSTRACT FROM AUTHOR]

As of June 2022, the GISAID database contains more than 11 million SARS-CoV-2 genomes, including several thousand nucleotide sequences for the most common variants such as delta or omicron. These SARS-CoV-2 strains have been collected from patients around the world since the beginning of the pandemic. We start by assessing the similarity of all pairs of nucleotide sequences using the Jaccard index and principal component analysis. As shown previously in the literature, an unsupervised cluster analysis applied to the SARS-CoV-2 genomes results in clusters of sequences according to certain characteristics such as their strain or their clade. Importantly, we observe that nucleotide sequences of common variants are often outliers in clusters of sequences stemming from variants identified earlier on during the pandemic. Motivated by this finding, we are interested in applying outlier detection to nucleotide sequences. We demonstrate that nucleotide sequences of common variants (such as alpha, delta, or omicron) can be identified solely based on a statistical outlier criterion. We argue that outlier detection might be a useful surveillance tool to identify emerging variants in real time as the pandemic progresses. [ABSTRACT FROM AUTHOR]

As of June 2022, the GISAID database contains more than 11 million SARS-CoV-2 genomes, including several thousand nucleotide sequences for the most common variants such as delta or omicron. These SARS-CoV-2 strains have been collected from patients around the world since the beginning of the pandemic. We start by assessing the similarity of all pairs of nucleotide sequences using the Jaccard index and principal component analysis. As shown previously in the literature, an unsupervised cluster analysis applied to the SARS-CoV-2 genomes results in clusters of sequences according to certain characteristics such as their strain or their clade. Importantly, we observe that nucleotide sequences of common variants are often outliers in clusters of sequences stemming from variants identified earlier on during the pandemic. Motivated by this finding, we are interested in applying outlier detection to nucleotide sequences. We demonstrate that nucleotide sequences of common variants (such as alpha, delta, or omicron) can be identified solely based on a statistical outlier criterion. We argue that outlier detection might be a useful surveillance tool to identify emerging variants in real time as the pandemic progresses. [ABSTRACT FROM AUTHOR]

There are limited data for the clinical efficacy of bebtelovimab in preventing severe coronavirus disease 2019. Among outpatients unable to take nirmatrelvir-ritonavir at a large health system, 10 of 377 (2.7%) patients who received bebtelovimab and 17 of 377 (4.5%) matched untreated patients were hospitalized or died. The 43% observed risk reduction with bebtelovimab was not statistically significant (P = 0.14). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial," by T. J. Walsh and colleagues in the 2007 issue.

Given widespread use of spike antibody in generating coronavirus disease vaccines, SARS-CoV-2 nucleocapsid antibodies are increasingly used to indicate previous infection in serologic surveys. However, longitudinal kinetics and seroreversion are poorly defined. We found substantial seroreversion of nucleocapsid total immunoglobulin, underscoring the need to account for seroreversion in seroepidemiologic studies. [ABSTRACT FROM AUTHOR]

Background Patients with lymphoid malignancies are at risk for poor coronavirus disease 2019 (COVID-19)-related outcomes and have reduced vaccine-induced immune responses. Currently, a 3-dose primary regimen of mRNA vaccines is recommended in the United States for immunocompromised hosts. Methods A prospective cohort study of healthy adults (n  = 27) and patients with lymphoid malignancies (n  = 94) was conducted, with longitudinal follow-up through completion of a 2- or 3-dose primary mRNA COVID vaccine series, respectively. Humoral responses were assessed in all participants, and cellular immunity was assessed in a subset of participants. Results The rate of seroconversion (68.1% vs 100%) and the magnitude of peak anti-S immunoglobulin G (IgG) titer (median anti-S IgG = 32.4, IQR = 0.48–75.0 vs median anti-S IgG = 72.6, IQR 51.1–100.1; P  = .0202) were both significantly lower in patients with lymphoid malignancies compared to the healthy cohort. However, peak titers of patients with lymphoid malignancies who responded to vaccination were similar to healthy cohort titers (median anti-S IgG = 64.3; IQR, 23.7–161.5; P  = .7424). The third dose seroconverted 7 of 41 (17.1%) patients who were seronegative after the first 2 doses. Although most patients with lymphoid malignancies produced vaccine-induced T-cell responses in the subset studied, B-cell frequencies were low with minimal memory cell formation. Conclusions A 3-dose primary mRNA series enhanced anti-S IgG responses to titers equivalent to healthy adults in patients with lymphoid malignancies who were seropositive after the first 2 doses and seroconverted 17.1% who were seronegative after the first 2 doses. T-cell responses were present, raising the possibility that the vaccines may confer some cell-based protection even if not measurable by anti-S IgG. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the use of COVID‐19 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results: Despite a paucity of direct evidence, statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines, including supplemental/booster dosing, in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion: These guidance statements are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients. [ABSTRACT FROM AUTHOR]

Background Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)–positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. Results Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody–negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. Conclusions We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. ClinicalTrials.gov registration NCT04358549. [ABSTRACT FROM AUTHOR]

Background Measles, mumps, and rubella (MMR) vaccine is a live-attenuated vaccine usually contraindicated within the first 2 years of hematopoietic cell transplant (HCT). The objective of this study was to assess the safety of MMR vaccine when administered within 2 years of HCT. Methods We conducted a retrospective review of patients who received MMR vaccination within 2 years of an autologous or allogeneic HCT, mostly in the context of the 2019 measles outbreak. Adverse reactions were collected for 42 days postvaccination, and all hospitalizations and deaths following vaccination were reviewed. Results A total of 129 patients (75 autologous and 54 allogeneic HCT) were vaccinated 300–729 days after HCT (median, 718 days), and 39 (30%) of these were vaccinated earlier than 23 months post-transplant. Ten adverse reactions in 7 patients (5%) were identified within 42 days of vaccination: 6 respiratory tract infections (3 with fever) and 1 rash. The rash was seen in a 37-year-old female who had an allogeneic HCT 542 days before vaccination. She presented with a centrifugal maculopapular rash, confirmed to be caused by the vaccine strain rubella virus. She fully recovered. No other vaccine-associated illness was identified in the cohort after a median follow-up of 676 days. Conclusions MMR vaccine appears to be well tolerated in select HCT recipients when given between 300 and 729 days after transplant. An uncomplicated case of vaccine-associated rubella illness was seen after vaccination. Assessment of potential risks and benefits of MMR vaccination given within 2 years of HCT remains important. [ABSTRACT FROM AUTHOR]

Naive and memory CD4+ T cells reactive with human immunodeficiency virus type 1 (HIV-1) are detectable in unexposed, unimmunized individuals. The contribution of preexisting CD4+ T cells to a primary immune response was investigated in 20 HIV-1–seronegative volunteers vaccinated with an HIV-1 envelope (Env) plasmid DNA prime and recombinant modified vaccinia virus Ankara (MVA) boost in the HVTN 106 vaccine trial (clinicaltrials.gov NCT02296541). Prevaccination naive or memory CD4+ T cell responses directed against peptide epitopes in Env were identified in 14 individuals. After priming with DNA, 40% (8/20) of the elicited responses matched epitopes detected in the corresponding preimmunization memory repertoires, and clonotypes were shared before and after vaccination in 2 representative volunteers. In contrast, there were no shared epitope specificities between the preimmunization memory compartment and responses detected after boosting with recombinant MVA expressing a heterologous Env. Preexisting memory CD4+ T cells therefore shape the early immune response to vaccination with a previously unencountered HIV-1 antigen. [ABSTRACT FROM AUTHOR]

Background. We conducted a clinical trial of the safety and immunogenicity of modified vaccinia Ankara (MVA) to examine the effects of dose and route of administration. Methods. Seventy-two healthy, vaccinia virus-naive subjects received 1 of 6 regimens of MVA (ACAM3000) or placebo consisting of 2 administrations given 1 month apart. Results. MVA was generally well tolerated at all dose levels and by all routes. More pronounced local reactogenicity was seen with the intradermal and subcutaneous routes than with intramuscular administration. Binding antibodies to whole virus and neutralizing antibodies to the intracellular mature virion and extracellular enveloped virion forms of vaccinia virus were elicited by all routes of MVA administration and were greater for the higher dose by each route. Similar levels of neutralizing antibodies were seen at a 10-fold-lower dose given intradermally ( median 1 × 107 tissue culture infective doses [TCID50]), compared with responses after 1 × 108 TCID50 given intramuscularly or subcutaneously. T cell immune responses to vaccinia virus were detected by an interferon g enzyme-linked immunospot assay but had no clear relationship to dose or route. Conclusions. These data suggest that intradermal immunization with MVA provides a dose-sparing effect by eliciting antibody responses similar in magnitude and kinetics to those elicited by the intramuscular or subcutaneous routes but at a 10-fold-lower dose. [ABSTRACT FROM AUTHOR]

Background. Despite the success of smallpox vaccination, the immunological correlates of protection are not fully understood. To investigate this question, we examined the effect of immunization with modified vaccinia Ankara (MVA) on subsequent challenge with replication-competent vaccinia virus (Dryvax). Methods. Dryvax challenge by scarification was conducted in 36 healthy subjects who had received MVA ( ) or placebo ( ) in a n=29 n=7 previous study of doses and routes of immunization. Subjects were followed up for clinical take, viral shedding, and immune responses. Results. MVA administration attenuated clinical takes in 21 (72%) of 29 subjects, compared with 0 of 7 placebo recipients (P=.001). Attenuation was most significant in MVA groups that received 1 × 107 median tissue culture infective doses (TCID50) intradermally ( ) and TCID50 Pp.001 1 × 107 intramuscularly (P=.001). Both duration and peak titer of viral shedding were reduced in MVA recipients. Peak neutralizing antibody responses to vaccinia virus or MVA previously induced by MVA immunization were associated with attenuated takes (P=.02) and reduced duration (P < .001) and titer (P=.005) of viral shedding. Conclusions. MVA immunization results in clinical and virologic protection against Dryvax challenge. Protection is associated with prior induction of neutralizing antibodies to MVA or vaccinia virus. MVA administered intradermally has protective and immunologic responses similar to those of a 10-fold-higher dose given subcutaneously.

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients. [ABSTRACT FROM AUTHOR]

BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 μg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). Methods: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID‐19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9‐point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. Results: Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID‐19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. Conclusion: These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID‐19 vaccines and to facilitate implementation of vaccination strategies for RMD patients. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID‐19) pandemic. Methods: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by email and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1–9‐point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7–9, 4–6, and 1–3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. Results: Draft guidance statements approved by the task force have been combined to form final guidance. Conclusion: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated. [ABSTRACT FROM AUTHOR]

Background Experimental human immunodeficiency virus (HIV)-1 vaccines frequently elicit antibodies against HIV-1 that may react with commonly used HIV diagnostic tests, a phenomenon known as vaccine-induced seropositivity/seroreactivity (VISP/VISR). We sought to determine, under clinic conditions, whether a patient-controlled HIV test, OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, detected HIV-1 vaccine-induced antibodies. Methods Plasma assessment of HIV-1 cross-reactivity was examined in end-of-study samples from 57 healthy, HIV-uninfected participants who received a candidate vaccine that has entered Phase 2B and 3 testing. We also screened 120 healthy, HIV-uninfected, unblinded HIV-1 vaccine participants with VISP/VISR for an assessment using saliva. These participants came from 21 different parent vaccine protocols representing 17 different vaccine regimens, all of which contained an HIV-1 envelope immunogen. OraQuick ADVANCE was compared with results from concurrent blood samples using a series of commercial HIV screening immunoassays. Results Fifty-seven unique participant plasma samples were assayed in vitro, and only 1 (1.8%) was reactive by OraQuick ADVANCE. None of the 120 clinic participants (0%; 95% confidence interval, 0% to 3.7%) tested positive by OraQuick ADVANCE, and all were confirmed to be uninfected by HIV-1 viral ribonucleic acid testing. One hundred eighteen of the 120 (98.3%) participants had a reactive HIV test for VISP/VISR: 77 (64%) had at least 1 reactive fourth-generation HIV-1 diagnostic test (P  < .0001 vs no reactive OraQuick ADVANCE results), and 41 (34%) only had a reactive test by the less specific third-generation Abbott Prism assay. Conclusions These data suggest that this widely available patient-controlled test has limited reactivity to HIV-1 antibodies elicited by these candidate HIV-1 vaccines. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID‐19) pandemic. Methods: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by e‐mail and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1–9‐point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7–9, 4–6, and 1–3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. Results: To date, the task force has approved 80 guidance statements: 36 with moderate and 44 with high consensus. These were combined, resulting in 27 final guidance statements. Conclusion: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian β-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections. Author summary: The environmental mold Aspergillus fumigatus commonly causes lung infections in people with impaired immunity or those suffering from a chronic lung disease. While neutrophils are a key cell type necessary for the eradication of this infection, the precise mechanism of their recruitment to the site of infection remains incompletely understood. Here we show that the secreted mammalian protein galectin-3 plays an important role in helping neutrophils reaching the fungus within the airways. We found that both mice and humans produce galectin-3 when infected with A. fumigatus, and mice lacking galectin-3 were more susceptible to infection than normal mice. Galectin-3-deficient mice had impaired neutrophil recruitment to the site of infection. In the absence of galectin-3, neutrophils exhibited reduced motility in mouse lungs and in tissue culture. Our study offers insights into the mechanisms underlying the recruitment of neutrophils to the airways during A. fumigatus infection and reveals a new role for galectin-3 in increasing neutrophil motility. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID‐19) pandemic. Methods: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included 2 rounds of asynchronous anonymous voting by e‐mail and 3 webinars with the entire panel. Task force members voted on agreement with draft statements using a 1–9‐point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7–9, 4–6, and 1–3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. Results: The task force approved 77 initial guidance statements: 36 with moderate and 41 with high consensus. These were combined, resulting in 25 final guidance statements. Conclusion: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated. [ABSTRACT FROM AUTHOR]

Background: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10–1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10–1074 in healthy adults. Methods: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18–65 years to receive one infusion of 3BNC117 immediately followed by 10–1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10–1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536. Findings: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10–1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10–1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics. Interpretation: Single and repeated doses of the combination of 3BNC117 and 10–1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10–1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P =.045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P =.044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Cancer chemotherapy-associated febrile neutropenia (FN) is a common condition that is deadly when bacteremia is present. Detection of bacteremia depends on culture, which takes days, and no accurate predictive tools applicable to the initial evaluation are available. We utilized metabolomics and transcriptomics to develop multivariable predictors of bacteremia among FN patients. Methods: We classified emergency department patients with FN and no apparent infection at presentation as bacteremic (cases) or not (controls), according to blood culture results. We assessed relative metabolite abundance in plasma, and relative expression of 2,560 immunology and cancer-related genes in whole blood. We used logistic regression to identify multivariable predictors of bacteremia, and report test characteristics of the derived predictors. Results: For metabolomics, 14 bacteremic cases and 25 non-bacteremic controls were available for analysis; for transcriptomics we had 7 and 22 respectively. A 5-predictor metabolomic model had an area under the receiver operating characteristic curve of 0.991 (95%CI: 0.972,1.000), 100% sensitivity, and 96% specificity for identifying bacteremia. Pregnenolone steroids were more abundant in cases and carnitine metabolites were more abundant in controls. A 3-predictor gene expression model had corresponding results of 0.961 (95%CI: 0.896,1.000), 100%, and 86%. Genes involved in innate immunity were differentially expressed. Conclusions: Classifiers derived from metabolomic and gene expression data hold promise as objective and accurate predictors of bacteremia among FN patients without apparent infection at presentation, and can provide insights into the underlying biology. Our findings should be considered illustrative, but may lay the groundwork for future biomarker development. [ABSTRACT FROM AUTHOR]

Background: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed.Methods and Findings: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits.Conclusions: VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials.Trial Registration: Clinical Trials Registration: NCT02165267. [ABSTRACT FROM AUTHOR]

Background: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. Methods: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination. Results: All regimens were well tolerated and safe. Full dose DgDgM_M and DgDgMM_M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one-year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF. Conclusion: This DNA/MVA prime-boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Summary While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral “Fc fingerprint.” Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive. [ABSTRACT FROM AUTHOR]

Significant progress has been made in the development, investigation, and clinical application of immunosuppressive agents to treat a variety of autoimmune disorders. The expansion of clinical applications of these new agents requires the performance of large multicenter clinical trials. These large clinical trials are particularly important as one considers these agents for the treatment of type 1 diabetes, which although autoimmune in its pathogenesis, is not classically treated as an autoimmune disorder. Although these agents hold promise for amelioration or cure of this disease, they have the potential to facilitate infectious complications. There are limited data regarding the prospective assessment of infectious risks with these agents in trials of this nature. Pediatric subjects may be at greater risk due to the higher likelihood of primary infection. A subgroup of experts associated with TrialNet (a National Institutes of Health [NIH]-funded Type 1 diabetes mellitus research network) with expertise in infectious diseases, immunology, and diagnostics developed an approach for screening and monitoring of immunosuppression-associated infections for prospective use in clinical trials. The goals of these recommendations are to provide a structured approach to monitor for infections, to identify specific laboratory testing and surveillance methods, and to consider therapies for treatment of these potential complications. Prospective evaluations of these infectious risks allow for greater scientific rigor in the evaluation of risk, which must be balanced with the potential benefits of these therapies. Our experience supports an important role for investigators with expertise in infections in immunocompromised individuals in protocol development of immunosuppressive trials in type 1diabetes and potentially other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective--To evaluate clinical data for cold-stunned Kemp's ridley turtles (Lepidochelys kempii) with Enterococcus spp infections during rehabilitation. Design--Retrospective case series. Animals--50 stranded cold-stunned Kemp's ridley turtles hospitalized between 2006 and 2012. Procedures--Medical records for turtles from which Enterococcus spp were isolated were reviewed retrospectively, and clinical data, including morphometric data, body tempera-ture at admission, physical examination findings, antimicrobial medication history history of medications administered IV, environmental data, day of diagnosis, clinical signs at di-agnosis, microbiological testing results, sources of positive culture results, hematologic and plasma biochemical data, cytologic and histopathologic results, radiographic findings antimicrobial treatments, time to first negative culture result, treatment duration, results of subsequent cultures, and case outcome, were collated and analyzed. Results Enterococcus spp were isolated from bacteriologic cultures of blood, bone, joint, and respiratory tract samples and a skin lesion, with supporting evidence of infection provided by histopathologic, cytologic, and radiographic data. Positive culture results were associated with clinical problems such as lethargy, anorexia, and lameness. Most (34/43 [79%]) turtles for which an antemortem diagnosis was made survived with treatment and were released into the wild. Conclusions and Clinical Relevance--Cold-stunned Kemp's ridley turtles may be af-fected by serious Enterococcus spp infections during rehabilitation. Recognition and treat-ment of these infections are important for successful rehabilitation. [ABSTRACT FROM AUTHOR]

Abstract: The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials. [Copyright &y& Elsevier]

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease. [ABSTRACT FROM AUTHOR]

Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient''s sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation. [Copyright &y& Elsevier]

Background: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. Methodology/Principal Findings: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with doseescalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response. Conclusions/Significance: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. [ABSTRACT FROM AUTHOR]

Background: The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean Methods: 480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (1010 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost Results: The vaccine was well tolerated and safe. T-cell responses, detected by interferon-&ggr;(IFN-&ggr;) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus seronegative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted $2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients Conclusion: The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies [ABSTRACT FROM AUTHOR]

Background. Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine primingMethods. GeoVax pGA2/JS7 DNA (D) and MVA/HIV62 (M) vaccines encode noninfectious virus-like particles. Intramuscular needle injections were used to deliver placebo, 2 doses of DNA followed by 2 doses of rMVA (DDMM), one dose of DNA followed by 2 doses of rMVA (DMM), or 3 doses of rMVA (MMM) to HIV-seronegative participants.Results. Local and systemic symptoms were mild or moderate. Immune response rates for CD4 + and CD8 + T cells were highest in the DDMM group and lowest in the MMM group (77% vs 43% CD4 + and 42% vs 17% CD8 +). In contrast, response rates for Env binding and neutralizing Ab were highest in the MMM group. The DMM group had intermediate response rates. A 1/10th-dose DDMM regimen induced similar T cell but reduced Ab response rates compared with the full-dose DDMM.Conclusions. MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine. [ABSTRACT FROM PUBLISHER]

Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer ≥1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy. [Copyright &y& Elsevier]

Background. Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine primingMethods. GeoVax pGA2/JS7 DNA (D) and MVA/HIV62 (M) vaccines encode noninfectious virus-like particles. Intramuscular needle injections were used to deliver placebo, 2 doses of DNA followed by 2 doses of rMVA (DDMM), one dose of DNA followed by 2 doses of rMVA (DMM), or 3 doses of rMVA (MMM) to HIV-seronegative participants.Results. Local and systemic symptoms were mild or moderate. Immune response rates for CD4 + and CD8 + T cells were highest in the DDMM group and lowest in the MMM group (77% vs 43% CD4 + and 42% vs 17% CD8 +). In contrast, response rates for Env binding and neutralizing Ab were highest in the MMM group. The DMM group had intermediate response rates. A 1/10th-dose DDMM regimen induced similar T cell but reduced Ab response rates compared with the full-dose DDMM.Conclusions. MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine. [ABSTRACT FROM PUBLISHER]

Background. Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1r3)-b-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. Methods. We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. Results. A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level ⩾80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59- 8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level ⩾80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. Conclusions. BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD. [ABSTRACT FROM AUTHOR]