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Background Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding US National Institutes of Health.

Background Diethylcarbamazine citrate (DEC) treatment of loiasis is complicated by adverse reactions that are correlated with the number of circulating microfilariae (mf). The cause of these reactions is unknown, but they are accompanied by a dramatic interleukin-5 (IL-5)-dependent increase in eosinophilia and evidence of eosinophil activation. Methods To explore the role of IL-5 driven eosinophilia in post-DEC reactions, 8 adults with confirmed loiasis and Results Baseline characteristics were comparable between the two groups. Single dose reslizumab lowered the AEC by 77% prior to initiation of DEC therapy (vs. 12% in the placebo group, P Conclusions In summary, although reslizumab was able to blunt peripheral eosinophilia post-DEC treatment in subjects with loiasis and had no effect on microfilarial clearance, the reduction in AEC appeared to have been insufficient to prevent post-treatment AEs.

Chikungunya virus (CHIKV) disease is an ongoing public health threat. We aimed to evaluate the safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted formulation of a CHIKV virus-like particle (VLP) vaccine.This randomised, double-blind, parallel-group, phase 2 trial was conducted at three clinical trial centres in the USA. Eligible participants were healthy CHIKV-naïve adults aged 18-45 years. Participants were stratified by site and randomly assigned (1:1:1:1:1:1:1:1) to one of the eight vaccination groups using a block size of 16. Group 1 received two doses of unadjuvanted PXVX0317 28 days apart (2 × 20 μg; standard); all other groups received adjuvanted PXVX0317: groups 2-4 received two doses 28 days apart (2 × 6 μg [group 2], 2 × 10 μg [group 3], or 2 × 20 μg [group 4]; standard); group 4 also received a booster dose 18 months after the first active injection (40 μg; standard plus booster); groups 5-7 received two doses 14 days apart (2 × 6 μg [group 5], 2 × 10 μg [group 6], or 2 × 20 μg [group 7]; accelerated); and group 8 received one dose (1 × 40 μg; single). The primary endpoint was the geometric mean titre of anti-CHIKV neutralising antibody on day 57 (28 days after the last vaccination), assessed in the immunogenicity-evaluable population. Additionally, we assessed safety. This trial is registered at ClinicalTrials.gov, NCT03483961.This trial was conducted from April 18, 2018, to Sept 21, 2020; 468 participants were assessed for eligibility. Of these, 415 participants were randomly assigned to eight groups (n=53 in groups 1, 5, and 6; n=52 in groups 2 and 8; n=51 in groups 3 and 7; and n=50 in group 4) and 373 were evaluable for immunogenicity. On day 57, serum neutralising antibody geometric mean titres were 2057·0 (95% CI 1584·8-2670·0) in group 1, 1116·2 (852·5-1461·4; p=0·0015 vs group 1 used as a reference) in group 2, 1465·3 (1119·1-1918·4; p=0·076) in group 3, 2023·8 (1550·5-2641·7; p=0·93) in group 4, 920·1 (710·9-1190·9; p0·0001) in group 5, 1206·9 (932·4-1562·2; p=0·0045) in group 6, 1562·8 (1204·1-2028·3; p=0·14) in group 7, and 1712·5 (1330·0-2205·0; p=0·32) in group 8. In group 4, a booster dose increased serum neutralising antibody geometric mean titres from 215·7 (95% CI 160·9-289·1) on day 547 to 10 941·1 (7378·0-16 225·1) on day 575. Durability of the immune response (evaluated in groups 1, 4, and 8) was shown up to 2 years. The most common solicited adverse event was pain at the injection site, reported in 12 (23%) of 53 participants who received the unadjuvanted vaccine (group 1) and 111 (31%) of 356 who received the adjuvanted vaccine. No vaccine-related serious adverse events were reported.PXVX0317 was well tolerated and induced a robust and durable serum neutralising antibody immune response against CHIKV up to 2 years. A single 40 μg injection of adjuvanted PXVX0317 is being further investigated in phase 3 clinical trials (NCT05072080 and NCT05349617).Emergent BioSolutions.

In 2016, the United States (U.S.) Food and Drug Administration (FDA) licensed Vaxchora® for active immunization against disease caused by Vibrio cholerae serogroup 01 in adults. Vaxchora was the first US-licensed vaccine for which the primary evidence supporting effectiveness was derived from human challenge studies. Following this precedent, FDA has received numerous inquiries from manufacturers, academic researchers, funders and other stakeholders regarding how controlled human infection models (CHIMs) can be used to support the development of safe and effective vaccines to address public health needs. The aims of this article are to discuss: (1) Chemistry, Manufacturing and Controls (CMC) for challenge inocula, (2) conduct of controlled human infection studies under US IND and (3) use of CHIMs to support vaccine development. General concepts and regulatory considerations for the safe conduct of CHIMs and use of CHIMs to evaluate vaccine effectiveness are discussed.

We examined the prevalence of Strongyloides stercoralis (Ss) infection in a cohort of AIDS patients from a US urban centre. We monitored our cohort for possible cases of dissemination or immune reconstitution inflammatory syndrome after antiretroviral therapy (ART) initiation.One hundred and three HIV-infected participants were prospectively sampled from a cohort observational study of ART-naive HIV-1-infected patients with CD4 ≤100 T cells/μl. Clinical symptoms, corticosteroid therapy, eosinophilia, CD4 count, and plasma HIV-RNA were reviewed. Sera were tested by an enzyme-linked immunosorbent assay (CrAg-ELISA) to crude Ss extract or to an Ss-specific recombinant protein (NIE) and by luciferase immunoprecipitation system assay (LIPS) for Ss-specific antibodies.Twenty-five per cent of study participants were Strongyloides seropositive by CrAg-ELISA and 62% had emigrated from Strongyloides-endemic areas. The remaining 38% of the seropositives were US born and tested negative by NIE and LIPS. CrAg-ELISA-positive participants had a median CD4 count of 22 T cells/μl and a median HIV-RNA of 4·87 log(10) copies/ml. They presented with diarrhea (27%), abdominal pain (23%), and skin manifestations (35%) that did not differ from seronegative patients. Peripheral blood eosinophilia was common among seropositive patients (prevalence of 62% compared to 29% in seronegatives, P = 0·004). Seropositive patients were treated with ivermectin. There were no cases of hyperinfection syndrome.Strongyloidiasis may be prevalent in AIDS patients in the USA who emigrated from Ss-endemic countries, but serology can be inconclusive, suggesting that empiric ivermectin therapy is a reasonable approach in AIDS patients originating from Strongyloides endemic areas.

We used a species-specific approach to treat 10 patients with cutaneous leishmaniasis diagnosed using polymerase chain reaction. Non-antimony treatments (oral miltefosine, ketoconazole, and liposomal amphotericin B) were chosen as an alternative to pentavalent antimony drugs based on likely or proven drug efficacy against the infecting species. Leishmania Viannia panamensis was diagnosed in three patients and treated successfully with oral ketoconazole. Miltefosine treatment cured two patients with L. infantum chagasi. A wide variety of Leishmania responded to liposomal amphotericin B administered for 5-7 days. Three patients with L. V. braziliensis, one patient with L. tropica, and two patients with L. infantum chagasi were treated successfully. One person with L. V. braziliensis healed slowly because of a resistant bacterial superinfection, and a second patient with L. infantum chagasi relapsed and was retreated with miltefosine. These drugs were reasonably well-tolerated. In this limited case series, alternative non-antimony-based regimens were convenient, safe, and effective.

A 55-year-old woman with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL) and a history of previously treated Strongyloides stercoralis infection received anti-CD52 monoclonal antibody therapy with alemtuzumab on a clinical trial. After an initial response, she developed ocular involvement by ATL. Alemtuzumab was stopped and high-dose corticosteroid therapy was started to palliate her ocular symptoms. Ten days later, the patient developed diarrhea, vomiting, fever, cough, skin rash, and a deteriorating mental status. She was diagnosed with disseminated S. stercoralis. Corticosteroids were discontinued and the patient received anthelmintic therapy with ivermectin and albendazole with complete clinical recovery.

Centers for Disease Control guidelines for schistosomiasis and strongyloidiasis in Sudanese and Somali refugees are not widely implemented. Given limited prevalence data, we conducted a seroprevalence study of schistosomiasis, strongyloidiasis, and loiasis in Sudanese refugees across diverse ages. Sudanese refugees, ages 4-78, were recruited via community organizations. Half of the patients (86/172), were seropositive for schistosomiasis (46/171; 26.9%), strongyloidiasis (56/172; 33%), or both (16/171; 9.4%). No Loa loa infections were detected. Infection rates were similar in adults and children except that no schistosomiasis was detected in children < 4 years of age at the time of immigration to the United States. The high prevalence of schistosomiasis and strongyloidiasis in a community-based sample of Sudanese confirms the urgency for compliance with CDC refugee health guidelines. We detected no co-infection with Loa loa using the most sensitive serologic techniques, allowing use of ivermectin, the most effective treatment of strongyloidiasis.

We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.

The serodiagnosis of Strongyloides stercoralis infection by enzyme-linked immunosorbent assays based on crude antigen (CrAg-ELISA), while useful, has been limited by the reliance on crude parasite extracts. Newer techniques such as the luciferase immunoprecipitation system assay (LIPS), based on a 31-kDa recombinant antigen (termed NIE) from S. stercoralis and/or the recombinant antigen S. stercoralis immunoreactive antigen (SsIR), or the NIE-ELISA have shown promise in controlled settings. We compared each of these serologic assays in individuals from both regions of the world in which S. stercoralis is endemic and those in which it is not. A comprehensive stool evaluation (sedimentation concentration, Baermann concentration with charcoal cultures, agar plate, and Harada-Mori) and four different serologic techniques using CrAg-ELISA or recombinant NIE-ELISA as well as LIPS using NIE alone or in combination with a second recombinant antigen (NIE/SsIR-LIPS) were compared among individuals with parasitologically proven infection ( n = 251) and healthy controls from regions of the world in which the infection is nonendemic ( n = 11). Accuracy was calculated for each assay. The prevalence of S. stercoralis infection was 29.4% among Argentinean stool samples ( n = 228). Sedimentation concentration and Baermann were the most sensitive stool-based methods. NIE-LIPS showed the highest sensitivity (97.8%) and specificity (100%) of the serologic assays. The calculated negative predictive value was highest for both the NIE-LIPS and CrAg-ELISA (>97%) irrespective of disease prevalence. No cross-reactivity with soil-transmitted helminths was noted. NIE-LIPS compares favorably against the current CrAg-ELISA and stool evaluation, providing additional accuracy and ease of performance in the serodiagnosis of S. stercoralis infections irrespective of disease prevalence.

Centers for Disease Control guidelines for schistosomiasis and strongyloidiasis in Sudanese and Somali refugees are not widely implemented. Given limited prevalence data, we conducted a seroprevalence study of schistosomiasis, strongyloidiasis, and loiasis in Sudanese refugees across diverse ages. Sudanese refugees, ages 4-78, were recruited via community organizations. Half of the patients (86/172), were seropositive for schistosomiasis (46/171; 26.9%), strongyloidiasis (56/172; 33%), or both (16/171; 9.4%). No Loa loa infections were detected. Infection rates were similar in adults and children except that no schistosomiasis was detected in children4 years of age at the time of immigration to the United States. The high prevalence of schistosomiasis and strongyloidiasis in a community-based sample of Sudanese confirms the urgency for compliance with CDC refugee health guidelines. We detected no co-infection with Loa loa using the most sensitive serologic techniques, allowing use of ivermectin, the most effective treatment of strongyloidiasis.

Although Strongyloides stercoralis often causes chronic and clinically asymptomatic infection, the number of Strongyloides parasites can increase substantially in immunocompromised hosts, leading to hyperinfection, dissemination, and death if unrecognized [1]. Early recognition of S. stercoralis infection is challenging because of scanty and intermittent excretion of larvae in chronically infected immunocompetent hosts [2]. Despite this, the mainstay of diagnostic testing for S. stercoralis infection has been stool examination, although more recently ELISAs have been used to measure antibodies to crude larval antigen. Serologic approaches to the diagnosis of S. stercoralis infection, however, have been hampered by poor specificity, reliance on crude parasite extracts, and the time needed to perform the assays [3–5]. A major drawback to ELISA-based diagnosis of S. stercoralis infection has been a reliance on crude antigen that must be prepared by isolating worms from the feces of heavily infected patients or experimental animals. Thus, investigators have turned to recombinant antigens, which can be purified easily and produced in large amounts [6]. Indeed, a 31-kDa recombinant antigen (termed NIE) derived from an S. stercoralis L3 cDNA library provided the basis for an ELISA that approaches the sensitivity and specificity of the crude antigen–based ELISA [5]. An attractive alternative to ELISA-based methods, luciferase immunoprecipitation systems (LIPS), has been successfully applied to the characterization of antibody responses to Pneumocystis jirovecii, HIV, and hepatitis viruses [7]. LIPS is a relatively straightforward technology for identifying serum containing antigen-specific antibodies and for generating quantitative antibody response profiles. Briefly, this approach involves fusion of a protein antigen to the enzyme reporter Renilla luciferase (Ruc), expression of the Ruc-antigen fusion in mammalian COS cells, immobilization of the Ruc-antigen fusion on protein A/G beads, and quantitation of antigen-specific antibody by the addition of a coelenterazine substrate and the measurement of light production [8]. This assay represents a major improvement over ELISA technology in that it produces a low background often with a 7-log dynamic range, thereby generating values with substantial separation between negative and positive antibody responses. The low background and high signal seen in the LIPS method can be credited, in part, to the use of a solution-phase immunoprecipitation assay that allows detection of a large number of conformational epitopes. The use of mammalian cells produces antigens free of contaminating bacterial proteins. An additional advantage of LIPS is that, once the Ruc-antigen constructs are made, relatively little time is needed to perform the assay. Recently, we reported the use of Ruc-antigen fusion proteins, produced in COS1 monkey kidney cells, in an immunoprecipitation assay to measure human antibody responses to tumor-associated proteins [8] and to a variety of infectious agents [7]. In this study, we have broadened the application of LIPS to the diagnosis and monitoring of S. stercoralis infection. To develop a more rapid, specific, and standardized assay, we first developed a LIPS assay based on IgG (or IgG4) antibody to NIE and compared it with a standard NIE ELISA. Our data, generated using serum samples from S. stercoralis–infected patients, filaria-infected patients, and uninfected control subjects, demonstrated the clear benefit of the LIPS method. Moreover, when a second antigen, S. stercoralis immunoreactive antigen (SsIR), was used in combination with NIE in the LIPS format, we found an even greater degree of sensitivity and specificity. Finally, we assessed the ability of LIPS to evaluate the success of treatment in the follow-up of S. stercoralis–infected patients.

The ability to diagnose Loa loa infection readily and accurately remains a demanding task. Among the available diagnostic methods, many are impractical for point-of-care field testing. To investigate whether luciferase immunoprecipitation systems (LIPS) can be used for rapid and specific diagnosis of L. loa infection, a LIPS assay was developed based on immunoglobulin G (IgG) and IgG4 subclass antibodies to a recombinant L. loa SXP-1 (designated LlSXP-1) antigen and tested with sera from healthy controls or patients with proven infection with L. loa, Mansonella perstans, Onchocerca volvulus, Strongyloides stercoralis , or Wuchereria bancrofti . A LIPS test measuring IgG antibody against LlSXP-1 readily differentiated L. loa -infected from uninfected patients and demonstrated markedly improved sensitivity and specificity compared with an LlSXP-1 IgG4-based enzyme-linked immunosorbent assay (67% sensitivity and 99% specificity). No significant immunoreactivity was observed with S. stercoralis -infected sera, but a small number of patients infected with O. volvulus, M. perstans , or W. bancrofti showed positive immunoreactivity. Measuring anti-IgG4-specific antibodies to LlSXP-1 showed a significant correlation ( r ∼ 0.85; P < 0.00001) with the anti-IgG results but showed no advantage over measuring the total IgG response alone. In contrast, a rapid LIPS format (called QLIPS) in which the tests are performed in less than 15 minutes under nonequilibrium conditions significantly improved the specificity for cross-reactive O. volvulus patient sera (100% sensitivity and 100% specificity). These results suggest that LIPS (and the even more rapid test QLIPS) represents a major advance in the ability to diagnose L. loa infection and may have future applications for point-of-care diagnostics.

Strongyloides stercoralis is an intestinal nematode acquired in the tropics or subtropics. Most often, it causes chronic, asymptomatic infection, but a change in immune status can increase parasite numbers, leading to hyperinfection syndrome, dissemination, and death if unrecognized. Corticosteroid use is most commonly associated with hyperinfection syndrome. Diagnosis of Strongyloides infection is based on serology and serial stool examinations for larvae. The treatment of choice for chronic, asymptomatic infection is oral ivermectin. Alternative pharmacologic agents include albendazole and thiabendazole. For hyperinfection syndrome, ivermectin remains the drug of choice, though therapy duration must be individualized with the end point being complete parasite eradication. Recurrent strongyloidiasis should prompt an evaluation for human T-cell lymphotropic virus type 1 coinfection. No test of cure is currently available, although immunoglobulin G antibody levels have been shown to decline within 6 months of successful treatment.

Background: Treatment of patients with early Lyme disease has trended toward longer duration despite the absence of supporting clinical trials. Objective: To evaluate different durations of oral doxycycline treatment and the combination of oral doxycycline and a single intravenous dose of ceftriaxone for treatment of patients with early Lyme disease. Design: Randomized, double-blind, placebo-controlled trial. Setting: Single-center university hospital. Patients: 180 patients with erythema migrans. Intervention: Ten days of oral doxycycline, with or without a single intravenous dose of ceftriaxone, or 20 days of oral doxycycline. Measurements: Outcome was based on clinical observations and neurocognitive testing. Efficacy was assessed at 20 days, 3 months, 12 months, and 30 months. Results: At all time points, the complete response rate was similar for the three treatment groups in both on-study and intention-to-treat analyses. In the on-study analysis, the complete response rate at 30 months was 83.9% in the 20-day doxycycline group, 90.3% in the 10-day doxycycline group, and 86.5% in the doxycycline-ceftriaxone group (P> 0.2). The only patient with treatment failure (10-day doxycycline group) developed meningitis on day 18. There were no significant differences in the results of neurocognitive testing among the three treatment groups and a separate control group without Lyme disease. Diarrhea occurred significantly more often in the doxycycline-ceftriaxone group (35%) than in either of the other two groups (P < 0.001). Conclusions: Extending treatment with doxycycline from 10 to 20 days or adding one dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.