Pharmacokinetic-based failure of a detergent virucidal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nasal infections: A preclinical study and randomized controlled trial

Abstract

Background: The nose is the portal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, suggesting the nose as a target for topical antiviral therapies. The purpose of this study was to assess both the in vivo and in vitro efficacy of a detergent-based virucidal agent, Johnson and Johnson's Baby Shampoo (J&J), in SARS-CoV-2-infected subjects.

Methods: Subjects were randomized into three treatment groups: (1) twice daily nasal irrigation with J&J in hypertonic saline, (2) hypertonic saline alone, and (3) no intervention. Complementary in vitro experiments were performed in cultured human nasal epithelia. The primary outcome measure in the clinical trial was change in SARS-CoV-2 viral load over 21 days. Secondary outcomes included symptom scores and change in daily temperature. Outcome measures for in vitro studies included change in viral titers.

Results: Seventy-two subjects completed the clinical study (n = 24 per group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces.

Conclusion: In this randomized clinical trial of subjects with SARS-CoV-2 infection, a topical detergent-based virucidal agent had no effect on viral load or symptom scores. Complementary in vitro studies confirmed a lack of efficacy, reflective of pharmacokinetic failure and rapid absorption from nasal surfaces.

Trial registration: ClinicalTrials.gov NCT04347538.

Keywords: SARS-CoV-2; epithelial cell; irrigations; saline; surfactants; topical therapy for chronic rhinosinusitis; virus.

Conflict of interest statement

The authors have no competing interests to report.

© 2022 ARS-AAOA, LLC.

Figures

FIGURE 1

Consort diagram describing the screened and enrolled subjects for the randomized study of J&J/S, HTS, and no‐intervention control groups. Diagram is based on the CONSORT transparent reporting of trials (http://www.consort‐statement.org/). Abbreviations: HTS, hypertonic saline; J&J/S, Johnson & Johnson/saline solution.

FIGURE 2

In vitro safety and efficacy data. (A) Rt relative to baseline after administration of J&J Shampoo/normal saline at three concentrations (0.1, 0.5, or 1 tsp in 240 ml of normal saline) or PBS to cultured human nasal epithelial (HNE) cells. *p <0.05 different than baseline, **p <0.01. (B) Whole‐mount immunofluorescent staining images of HBE cultures. Representative fluorescent images of HBE cells after the administration of J&J Baby Shampoo at a concentration of ½ tsp/240 ml of PBS for 1, 15, or 30 min, or 24 h shown. The HBE cells were fixed and stained with α‐tubulin (cilia; green), CCSP (club cell; red), phalloidin (f‐actin; magenta), MUC5B protein (secretory cell; white), and DAPI (nuclei; blue). Scale bar = 20 μm. (C) Virucidal activity of J&J Shampoo (½ tsp J&J/240 ml saline) at a 1:1 dilution with SARS‐CoV‐2 viral stocks assayed varying viral titers. Initial SARS‐CoV‐2 stock titers ranged from 105 to 107 PFU/ml. *p <0.05 of measured viral titers versus starting viral titer. Abbreviations: CCSP, Clara cell secretory protein; DAPI, 4′,6‐diamidino‐2‐phenylindole; HNE, human bronchial epithelial; ND, zero titer detected; PBS, phosphate‐buffered saline; PFU, plaque‐forming units; Rt, transepithelial resistance; SARS‐CoV‐2, severe acute respiratory syndrome–coronavirus‐2.

FIGURE 3

Clinical trial data. (A) Cross point (Ct) PCR‐based measure of N1 primer‐based viral load in the nasal cavity of SARS‐CoV‐2–infected subjects as a function of treatment group. n = 72; 24/group. Note, lower absolute Ct value reflects greater viral load. (B) Time‐dependent change in viral shedding for each of the three treatment groups, defined as log10 change in Ct value between day 1 and maximum (T value) day between the two values. n = 24/treatment group. (C) Nasal WURSS‐21 symptom score of SARS‐CoV‐2–infected subjects as a function of treatment group over the study interval. (D) WURSS‐21 data describing altered smell/taste in the SARS‐CoV‐2–infected subjects for each of the three treatment groups over the study interval. n = 24/group. Abbreviations: Ct, threshold cycle; PCR, polymerase chain reaction; SARS‐CoV‐2, severe acute respiratory syndrome–coronavirus‐2; WURSS‐21, Wisconsin Upper Respiratory Symptom‐21 survey.

FIGURE 4

Pharmacokinetic data. (A) D614G SARS‐CoV‐2 viral titer data at the times post inoculum designated. Statistical analyses of changes in J&J/S and PBS 72 lavage groups compared to 48 h pi values shown in (E). (B) Change in HNE cell viral titers from the 48 h pi value at 72, 76, and 96 h pi with DG14G SARS‐CoV‐2 virus at an MOI = 0.1. Note, at 72 h the lavage solution was either J&J/S (½ tsp/240 ml saline) or PBS. (C) Concentrations of various chain lengths of CAPB, as determined by mass spectrometry, in J&J/S solution and after application of J&J Shampoo (200 μl, ½ tsp/240 ml normal saline concentration) to cultured HNE and harvested 1 min and 30 min later for analysis. (D) Relative virucidal activities of three detergents contained with J&J Baby Shampoo that vary by chain length. *p <0.05 versus starting viral titer (PBS). Abbreviations: CAPB, cocamidopropyl betaine; HNE, human nasal epithelial; J&J/S, J&J Baby Shampoo/saline combination; MOI, multiplicity of infection; PBS, phosphate‐buffered saline; pi, postinoculation; SARS‐CoV‐2, severe acute respiratory syndrome–coronavirus‐2.