Aminoglycosides induce immune activation but is insufficient for systemic viral control: a double-blind randomized-controlled clinical trial

Mucosally-applied aminoglycosides have demonstrated host-directed antiviral activity in preclinical models through induction of interferon-stimulated genes (ISGs). However, it remains unknown if systemically administered aminoglycosides elicit comparable effects in humans. We conducted a single-centre randomized, double-blind, placebo-controlled trial in Singapore in 32 healthy adults who were randomized 1:1 using sequentially sealed envelopes, to receive single-dose intravenous gentamicin 5 mg/kg or placebo. Participants were subsequently challenged with live-attenuated yellow fever 17D (YF17D) virus and followed for 30 days. The primary outcome was the proportion of participants with detectable YF17D RNAemia. Secondary outcomes included RNAemia levels, symptom rates, neutralizing antibody titers, and innate immune transcriptomic changes. We found no significant differences between the gentamicin and placebo groups in detectable RNAemia (62.5% [n = 10/16] vs. 68.8% [n = 11/16], p > 0.99), mean RNAemia levels (3.93 log10 area under the curve [AUC] vs. 3.51 log10 AUC, p = 0.81), symptom rates (56% [n = 9/16] vs. 25% [n = 4/16], p = 0.15) or antibody titers (mean log10 PRNT50 titer: 3.89 vs. 3.71, p = 0.37). However, transcriptomic profiling demonstrated upregulation of ISGs RSAD2 and OASL and the transcription factor IRF3 in gentamicin-treated individuals, with concomitantly higher protein expression of chemokines CCL2, CXCL12 and IL-27. This study represents, to our knowledge, the first in humans to evaluate the host-directed antiviral effects of systemic aminoglycosides. Our findings suggest that, whilst modest and insufficient to control systemic viral infection, the immunomodulatory effects of aminoglycosides warrant continued exploration as a potential preventive strategy against mucosal viral infections. Studies in animal models have shown that aminoglycoside antibiotics applied to mucosal surfaces can help prevent viral infections by stimulating innate immune responses. We investigated whether similar effects occur in humans when aminoglycosides are given intravenously. In this study, 32 healthy adults were randomly assigned to receive either gentamicin (an aminoglycoside antibiotic) or a placebo before being exposed to a weakened yellow fever virus. Gentamicin did not reduce the amount of virus in the blood, symptoms, or antibody responses. However, it did increase activity in some immune pathways linked to antiviral defence. These findings suggest that intravenous gentamicin does not prevent systemic viral infection, but it may still have potential to enhance immune responses at mucosal surfaces Sivanandam et al., conduct a randomised controlled trial to evaluate the systemic immunostimulatory and antiviral effects of the aminoglycoside gentamicin. Gentamicin induces modest activation of systemic innate immune responses, but it is insufficient to control systemic viral infection.