Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia

ABSTRACT There remains an unmet need to address the substantial morbidity and mortality associated with severe community-acquired pneumonia (sCAP). Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse animal models of infectious and noninfectious inflammation. This blinded dose-escalation safety study involved non-intensive care unit (ICU) patients admitted for mild CAP and randomized 3:1 to receive adjunctive rhu-pGSN or placebo intravenously. Thirty-three subjects were treated: 8 in the single-dose phase and 25 in the multidose phase. For the single-dose phase, rhu-pGSN at 6 mg/kg of body weight was administered once. For the multidose phase, a daily rhu-pGSN dose of 6, 12, or 24 mg/kg was given on 3 consecutive days. Adverse events (AEs) were generally mild in both treatment groups irrespective of dose. The only serious AE (SAE) in the single-dose phase was a non-drug-related pneumonia in a rhu-pGSN recipient who died after institution of comfort care. One single-dose placebo recipient had a drug-related AE (maculo-papular rash). In the multidose phase, there were 2 SAEs in 1 placebo recipient, including a fatal pulmonary embolism. In the 18 rhu-pGSN recipients in the multidose phase, there were no serious or drug-related AEs, and nausea and increased blood pressure were each reported in 2 patients. The median rhu-pGSN half-life exceeded 17 h with all dosing regimens, and supraphysiologic levels were maintained throughout the 24-h dosing interval in the 2 highest dosing arms. Rhu-pGSN was well tolerated overall in CAP patients admitted to non-ICU beds, justifying a larger proof-of-concept trial in an ICU population admitted with sCAP. (This study has been registered at ClinicalTrials.gov under identifier NCT03466073.)

Novel Strategy To Adapt Simian-Human Immunodeficiency Virus E1 Carryingenvfrom an RV144 Volunteer to Rhesus Macaques: Coreceptor Switch and Final Recovery of a Pathogenic Virus with Exclusive R5 Tropism

ABSTRACTThe phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses,envoriginates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carryingenvisolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-κB sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8+cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4+T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4+T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans.IMPORTANCEUnderstanding the protective principles that lead to a safe, effective vaccine against HIV in nonhuman primate (NHP) models requires test viruses that allow the evaluation of anti-HIV envelope responses. Reduced HIV acquisition risk in RV144 has been linked to nonneutralizing IgG antibodies with a range of effector activities. Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive-immunization studies in NHPs with a relevant test virus. We have generated such a virus by insertingenvfrom an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs. The final SHIV-E1p5 isolate, grown in rhesus monkey peripheral blood mononuclear cells, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed a coreceptor switch, again mimicking HIV biology in humans. Thus, our series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies.