A Randomized, Placebo-controlled, Double-blind Pilot Study of Single-dose Humanized Anti-IL5 Antibody (Reslizumab) for the Reduction of Eosinophilia Following Diethylcarbamazine Treatment of Loa loa Infection.

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 <5000 mf/mL blood were enrolled in a randomized, double-blind, placebo-controlled trial of the humanized anti-IL-5 antibody, reslizumab, (1.0 mg/kg IV) administered 3 to 7 days prior to initiation of DEC treatment (9 mg/kg/day for 21 days). The primary endpoint was the reduction in absolute eosinophil count (AEC) during the first week of DEC treatment. 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 < .05). More importantly, AEC remained below baseline in the first week of DEC treatment in all subjects who received reslizumab and in none of the placebo subjects. Mf clearance occurred within 2 days of initiation of DEC in all 7 mf-positive subjects. Mild to moderate adverse events were seen in all 8 subjects and were not significantly different between the groups. 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.

Safety and immunogenicity of a modified mRNA-lipid nanoparticle vaccine candidate against COVID-19: Results from a phase 1, dose-escalation study.

This phase 1, open-label, dose-escalation, multi-center study (NCT05477186) assessed the safety and immunogenicity of a booster dose of an mRNA COVID-19 vaccine (CV0501) encoding the SARS-CoV-2 Omicron BA.1 spike protein. Participants aged ≥ 18 years previously vaccinated with ≥ 2 doses of an mRNA COVID-19 vaccine received CV0501 doses ranging from 12 to 200 µg. After assessment of safety and immunogenicity of the 12 µg dose in 30 adults, 30 adults ≤ 64 years were randomized to receive either a 3 or 6 µg dose. Solicited adverse events (AEs) were collected for 7 days, unsolicited AEs for 28 days, and serious AEs (SAEs), medically attended AEs (MAAEs), and AEs of special interest (AESIs) until day (D) 181 post-vaccination. Serum neutralizing titers specific to SARS-CoV-2 BA.1, wild-type, Delta, and additional Omicron subvariants were assessed at D1, D15, D29, D91, and D181. Of 180 vaccinated participants (mean age: 49.3 years; 57.8% women), 70.6% had prior SARS-CoV-2 infection. Most solicited local (98.1%) and systemic (96.7%) AEs were of mild-to-moderate severity; the most common were injection site pain (57.5%; 33.3-73.3% across groups) and myalgia (36.9%; 13.3-56.7%). Unsolicited AEs were reported by 14.4% (6.7-26.7%) of participants (mild-to-moderate severity in 88.5% of the participants). Three participants (1.7%) reported SAEs, 16.7% (6.7-30.0%) reported MAAEs, and 8.3% (0.0-13.3%) reported AESIs (15 COVID-19 cases), none related to vaccination. Geometric means of serum neutralizing titers increased from baseline to D15 and D29 (dose-dependent), and then decreased over time. The safety and immunogenicity results supported advancement to a phase 2 trial.

What is the context? Since 2019, more than 776 million people have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, and more than 7 million people have died due to COVID-19.The virus changes over time and new variants may evade the protection provided by vaccines that are effective against previous variants.Therefore, it is necessary to develop vaccines that can be quickly updated to better protect against COVID-19 caused by new SARS-CoV-2 variants.We developed an mRNA vaccine, CV0501, that encodes a key protein on the surface of the SARS-CoV-2 Omicron BA.1 variant to instruct the immune system for future protection against COVID-19. The mRNA is encased in lipid nanoparticles that can increase the immune response to the vaccine.What is new? We administered different dose levels (that is, different amounts of mRNA) of CV0501 to adults who had previously been vaccinated at least twice with a different COVID-19 vaccine.We found that even at increased dose levels, CV0501 caused mostly mild side effects that resolved within a few days. Serious adverse events or events that required medical attention were not related to the vaccine.We also found that CV0501 generated immune responses not only against the Omicron BA.1 subvariant (vaccine antigen) but also against the original SARS-CoV-2 variant, the Delta variant, and other Omicron subvariants, at all dose levels tested.What is the impact? Our findings indicate that the CV0501 vaccine was well tolerated and induced immune responses against vaccine target variant as well as other SARS-CoV-2 variants.Other vaccines against COVID-19 based on the mRNA technology used for CV0501 will be further evaluated.

Safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted chikungunya virus-like particle vaccine: a randomised, double-blind, parallel-group, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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; p<0·0001) 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. INTERPRETATION: 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). FUNDING: Emergent BioSolutions.

Disseminated Strongyloides stercoralis infection in HTLV-1-associated adult T-cell leukemia/lymphoma.

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.

Use of controlled human infection models (CHIMs) to support vaccine development: US regulatory considerations.

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.

Iatrogenic Cushing syndrome after epidural triamcinolone injections in an HIV type 1-infected patient receiving therapy with ritonavir-lopinavir.

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.

Rapid, novel, specific, high-throughput assay for diagnosis of Loa loa infection.

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 approximately 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.

Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial.

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.

Prevalence of Strongyloides stercoralis in an urban US AIDS cohort.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

A species-specific approach to the use of non-antimony treatments for cutaneous leishmaniasis.

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.

Microarray-based analysis of differential gene expression between infective and noninfective larvae of Strongyloides stercoralis.

BACKGROUND: Differences between noninfective first-stage (L1) and infective third-stage (L3i) larvae of parasitic nematode Strongyloides stercoralis at the molecular level are relatively uncharacterized. DNA microarrays were developed and utilized for this purpose. METHODS AND FINDINGS: Oligonucleotide hybridization probes for the array were designed to bind 3,571 putative mRNA transcripts predicted by analysis of 11,335 expressed sequence tags (ESTs) obtained as part of the Nematode EST project. RNA obtained from S. stercoralis L3i and L1 was co-hybridized to each array after labeling the individual samples with different fluorescent tags. Bioinformatic predictions of gene function were developed using a novel cDNA Annotation System software. We identified 935 differentially expressed genes (469 L3i-biased; 466 L1-biased) having two-fold expression differences or greater and microarray signals with a p value<0.01. Based on a functional analysis, L1 larvae have a larger number of genes putatively involved in transcription (p = 0.004), and L3i larvae have biased expression of putative heat shock proteins (such as hsp-90). Genes with products known to be immunoreactive in S. stercoralis-infected humans (such as SsIR and NIE) had L3i biased expression. Abundantly expressed L3i contigs of interest included S. stercoralis orthologs of cytochrome oxidase ucr 2.1 and hsp-90, which may be potential chemotherapeutic targets. The S. stercoralis ortholog of fatty acid and retinol binding protein-1, successfully used in a vaccine against Ancylostoma ceylanicum, was identified among the 25 most highly expressed L3i genes. The sperm-containing glycoprotein domain, utilized in a vaccine against the nematode Cooperia punctata, was exclusively found in L3i biased genes and may be a valuable S. stercoralis target of interest. CONCLUSIONS: A new DNA microarray tool for the examination of S. stercoralis biology has been developed and provides new and valuable insights regarding differences between infective and noninfective S. stercoralis larvae. Potential therapeutic and vaccine targets were identified for further study.

Improved diagnosis of Strongyloides stercoralis using recombinant antigen-based serologies in a community-wide study in northern Argentina.

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.

Community based parasitic screening and treatment of Sudanese refugees: application and assessment of Centers for Disease Control guidelines.

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.

Strongyloides stercoralis infection in the immunocompromised host.

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.

A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection.

BACKGROUND: We investigated whether luciferase immunoprecipitation systems (LIPS) can be the basis for a more rapid, specific, and standardized assay for the diagnosis of Strongyloides stercoralis infection. METHODS: A LIPS assay was developed based on immunoglobulin (Ig) G or IgG4 antibody to a recombinant Strongyloides antigen (NIE) and was compared with an NIE enzyme-linked immunosorbent assay (ELISA). A second antigen, S. stercoralis immunoreactive antigen (SsIR), was tested alone and in combination with NIE. The assays were tested using serum samples from patients with parasitologically proven S. stercoralis or filarial infections and from healthy, uninfected control subjects. RESULTS: The NIE LIPS assay based on IgG antibody easily differentiated between S. stercoralis-infected and uninfected patients (P< .0001) and demonstrated improved specificity compared with the NIE ELISA (100% vs. 95%). Serum from filaria-infected patients did not cross-react when tested with the NIE LIPS assay. When SsIR was used in combination with NIE in the LIPS format, sensitivity and specificity improved to 100%, with a 7-fold difference between positive and negative values. No advantage was found in using a LIPS assay based on IgG4. At posttreatment follow-up, a significant decline in antibody titers was detected using the NIE ELISA (P< .0017) and the NIE LIPS assay (P< .0001). CONCLUSIONS: LIPS addresses several limitations of current ELISAs and represents a major advance in the diagnosis of S. stercoralis infection.