Intranasal antisepsis to reduce influenza virus transmission in an animal model

Nassima Gaaloul ben Hnia; Mathew Kipkemboi Komen; Katie F. Wlaschin; Ranjani V. Parthasarathy; Kevin D. Landgrebe; Nicole M. Bouvier

doi:10.1111/irv.13035

Intranasal antisepsis to reduce influenza virus transmission in an animal model

Nassima Gaaloul ben Hnia, Mathew Kipkemboi Komen, Katie F. Wlaschin, Ranjani V. Parthasarathy, Kevin D. Landgrebe, Nicole M. Bouvier

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Seasonal influenza annually causes significant morbidity and mortality, and unpredictable respiratory virus zoonoses, such as the current COVID-19 pandemic, can threaten the health and lives of millions more. Molecular iodine (I₂) is a broad-spectrum, pathogen-nonspecific antiseptic agent that has demonstrated antimicrobial activity against a wide range of bacteria, virus, and fungi. Methods: We investigated a commercially available antiseptic, a non-irritating formulation of iodine (5% povidone-iodine) with a film-forming agent that extends the duration of the iodine's antimicrobial activity, for its ability to prevent influenza virus transmission between infected and susceptible animals in the guinea pig model of influenza virus transmission. Results: We observed that a once-daily topical application of this long-lasting antiseptic to the nares of either the infected virus-donor guinea pig or the susceptible virus-recipient guinea pig, or to the nares of both animals, prior to virus inoculation effectively reduced transmission of a highly transmissible influenza A virus, even when the donor and recipient guinea pigs shared the same cage. Daily treatment of the recipient guinea pig starting 1 day after initial exposure to an infected donor guinea pig in the same cage was similarly effective in preventing detectable influenza virus infection in the recipient animal. Conclusions: We conclude that a daily application of this antiseptic formulation is efficacious in reducing the transmission of influenza A virus in the guinea pig model, and further study in this and other preclinical models is warranted.

Original language	English
Article number	e13035
Journal	Influenza and other Respiratory Viruses
Volume	17
Issue number	1
DOIs	https://doi.org/10.1111/irv.13035
State	Published - Jan 2023

Keywords

guinea pig
influenza
iodine
transmission

Access to Document

10.1111/irv.13035

Cite this

@article{75892ecb67c64c699670a3356c1b4505,

title = "Intranasal antisepsis to reduce influenza virus transmission in an animal model",

abstract = "Background: Seasonal influenza annually causes significant morbidity and mortality, and unpredictable respiratory virus zoonoses, such as the current COVID-19 pandemic, can threaten the health and lives of millions more. Molecular iodine (I2) is a broad-spectrum, pathogen-nonspecific antiseptic agent that has demonstrated antimicrobial activity against a wide range of bacteria, virus, and fungi. Methods: We investigated a commercially available antiseptic, a non-irritating formulation of iodine (5% povidone-iodine) with a film-forming agent that extends the duration of the iodine's antimicrobial activity, for its ability to prevent influenza virus transmission between infected and susceptible animals in the guinea pig model of influenza virus transmission. Results: We observed that a once-daily topical application of this long-lasting antiseptic to the nares of either the infected virus-donor guinea pig or the susceptible virus-recipient guinea pig, or to the nares of both animals, prior to virus inoculation effectively reduced transmission of a highly transmissible influenza A virus, even when the donor and recipient guinea pigs shared the same cage. Daily treatment of the recipient guinea pig starting 1 day after initial exposure to an infected donor guinea pig in the same cage was similarly effective in preventing detectable influenza virus infection in the recipient animal. Conclusions: We conclude that a daily application of this antiseptic formulation is efficacious in reducing the transmission of influenza A virus in the guinea pig model, and further study in this and other preclinical models is warranted.",

keywords = "guinea pig, influenza, iodine, transmission",

author = "{Gaaloul ben Hnia}, Nassima and Komen, {Mathew Kipkemboi} and Wlaschin, {Katie F.} and Parthasarathy, {Ranjani V.} and Landgrebe, {Kevin D.} and Bouvier, {Nicole M.}",

note = "Funding Information: This research was funded under a contract between the Defense Advanced Research Projects Agency (DARPA) and 3M Company (Agreement HR0011‐19‐3‐0006). Work performed at the Icahn School of Medicine at Mount Sinai was done under a subcontract with 3M. Funding Information: Dr. Bouvier reports that she is an employee of the Icahn School of Medicine at Mount Sinai, which received funding from 3M Company during the conduct of the study. Dr. Landgrebe, Dr. Parthasarathy, and Dr. Wlashin report that they are employees of 3M, which received funding from DARPA during the conduct of the study. 3M employees conceived of the study and contributed to experimental design but had no direct participation in the conduct of the experiments or the collection or analysis of the data. Dr. Landgrebe, Dr. Parthasarathy, and Dr. Wlashin also report three patents pending that are relevant to this work, entitled “Treatment and Prophylaxis of Viral Infections,” “Transmission Prevention of Viruses with Application of Antiseptic Composition,” and “Virus Transmission with Application of a Composition.” Dr. Gaaloul and Mr. Komen report having nothing to disclose. Nasal Prep (3M{\texttrademark} Skin and Nasal Antiseptic), a commercially available 5% (w/w) PVP-I solution, was used in these studies. The vehicle comparator (Nasal Prep devoid of PVP-I and sodium iodide) was produced by 3M specifically for these experiments, and the phosphate-buffered saline (PBS) comparator was purchased (Gibco). All three treatments were applied to guinea pig nares in the same way: While guinea pigs were awake and in an upright position, we used a positive-displacement pipette to deliver 50 μl to each naris (100 μl per animal). Awake administration of treatments was used instead of anesthetized administration after a comprehensive literature review38–42 and risk–benefit analysis. The viscosity of the Nasal Prep and vehicle solutions, coupled with guinea pigs' inability to protect their airways due to the loss of gag reflex while under ketamine/xylazine anesthesia, increased the risk of death by respiratory failure due to the aspiration of the solutions into the respiratory tract under anesthesia. Influenza A/Panama/2007/1999 (H3N2) virus (Pan/99) was originally derived from a 12-plasmid reverse genetics system.36 For these experiments, stock virus was subsequently propagated in Madin–Darby canine kidney (MDCK) cells stably transfected with cDNA of the human 2,6-sialyltransferase (MDCK-SIAT1)37 (Millipore Sigma/European Collection of Authenticated Cell Cultures) in Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% fetal calf serum and 1 mg/ml of G418 selective antibiotic (Geneticin 100×, Gibco) at 37°C and 5% CO2. Female Hartley strain guinea pigs weighing 300–350 g were obtained from Charles River Laboratories. Animals were allowed free access to food and water and kept on a 12-h light/dark cycle. Guinea pigs were anesthetized prior to intranasal inoculation and to nasal washing, using a mixture of ketamine (30 mg/kg) and xylazine (5 mg/kg), administered intramuscularly. All procedures were performed in accordance with the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee guidelines (protocol #IACUC-2019-0019) and were additionally approved by the US Army Medical Research and Development Command (USAMRDC) Animal Care and Use Review Office (ACURO) (protocol #DARPA-6336). During guinea pig transmission experiments, strict measures were followed to prevent any cross-contamination between animals, including handling recipient animals before donors and changing gloves between guinea pigs. Nasal Prep (3M{\texttrademark} Skin and Nasal Antiseptic), a commercially available 5% (w/w) PVP-I solution, was used in these studies. The vehicle comparator (Nasal Prep devoid of PVP-I and sodium iodide) was produced by 3M specifically for these experiments, and the phosphate-buffered saline (PBS) comparator was purchased (Gibco). All three treatments were applied to guinea pig nares in the same way: While guinea pigs were awake and in an upright position, we used a positive-displacement pipette to deliver 50 μl to each naris (100 μl per animal). Awake administration of treatments was used instead of anesthetized administration after a comprehensive literature review38–42 and risk–benefit analysis. The viscosity of the Nasal Prep and vehicle solutions, coupled with guinea pigs' inability to protect their airways due to the loss of gag reflex while under ketamine/xylazine anesthesia, increased the risk of death by respiratory failure due to the aspiration of the solutions into the respiratory tract under anesthesia. On Day 0, Pan/99 stock virus was diluted in PBS supplemented with antibiotics (Penicillin–Streptomycin 10,000 U/ml, Gibco) (PBS + P/S). An inoculum of 104 plaque-forming units (pfu) in 150 μl was instilled intranasally by applying 75 μl to each nostril. The inoculum dose was chosen to maximize the transmission rate of Pan/99 in our model. In our hands, peak nasal wash titers in donor guinea pigs reliably occur by Day 3 post inoculation at this dose (unpublished observations), and the time to peak nasal wash titer in donor guinea pigs has been shown by others to correlate inversely with transmission rate to recipients.43 Inoculated guinea pigs were placed supine, in a nose-up position. Guinea pigs were then placed in the appropriate cages based on the experiment type (airborne or contact transmission). Transmission experiments were performed at constant temperature (20°C) and relative humidity (RH) (20% RH) in environmentally controlled chambers (model 6030, Caron Products & Services, Inc.). For every transmission experiment, a virus-inoculated guinea pig donor was paired with a virus-na{\"i}ve recipient in specific cages depending on the experimental model (airborne or contact). In the contact model, each pair of animals (donor and recipient) was housed in the same cage (Figure 2A). In the airborne model, each pair of animals was housed individually in two identical transmission cages (Figure 2B), which have an open wire top and a wire-mesh grid side panel. The transmission cages were then placed into the environmental chamber with two cages per shelf, such that the wire grids opposed each other at a separation distance of 5 cm; such an arrangement allows air to flow between cages but prevents contact between guinea pigs. Guinea pigs were kept together for a total of 7 days. Nasal washing was performed on Days 1, 3, 5, and 7 post inoculations by instilling a total of 1 ml of PBS + P/S into both nares and allowing it to drain onto a sterile Petri dish. Nasal treatments were reapplied every 24 h. Nasal wash samples were collected in 1.5-ml tubes on ice, centrifuged to pellet debris, and stored at −80°C until titration by plaque assay, as previously described.44 These exploratory experiments were performed in the absence of existing data to inform an estimate for effect size; thus, power calculations were not carried out a priori. Transmission experiments were performed in groups of four or eight transmission pairs (eight or 16 guinea pigs) in one or two transmission chambers at a time. Experiments were designed sequentially, with prior results informing the next experimental scheme to be tested, and the results are presented in the order in which experiments were conducted. Given the exploratory nature of these experiments, not every possible combination of intranasal treatment (Nasal Prep, vehicle, or PBS), treated animal (inoculated virus donor, susceptible virus recipient, or both), or transmission model (contact or airborne) was tested. Where possible, we minimized animal use by omitting groups that were unlikely to be substantively additionally informative, given prior results; the rationales for these omissions are noted in the text describing each experiment. Because power calculations were not performed and group sizes not established a priori, Bayesian methods45 were used to evaluate the strength of the evidence in favor of the null hypothesis (the virus transmission rates are not different in different treatment groups) or its alternative (the transmission rates are different between different treatment groups). Transmission experiment results were tabulated in 2 × 2 matrices, with treatment group in rows and transmission (yes or no) as columns. Bayes factors and posterior probabilities were calculated in R46,47 with the package BayesFactor (v.0.9.12–4.2)45,48,49 (Text S1). Because the result of interest is the proportion of successful transmission events in each treatment group, the Bayes factor for independent multinomial sampling was calculated as a test for equality of proportions, with the row (treatment) margins fixed.45 The magnitude of the Bayes factor quantifies the strength of evidence in support of the alternative hypothesis over the null hypothesis. For example, a Bayes factor of 5 means that, given the data observed, the alternative hypothesis is five times more likely to be correct than the null hypothesis, while a Bayes factor of 0.2 (the reciprocal of 5) indicates that the alternative hypothesis is five times less likely than the null hypothesis.45 Bayes factors, being essentially odds ratios, can alternatively be expressed as the percent likelihood, from 0% to 100%, that a given hypothesis is likely to be the correct one, given the observed data (i.e., the posterior probability).48 Seasonal influenza typically causes significant global morbidity and mortality. In the United States alone, 31.4 million outpatient visits,1 140,000 to 710,000 hospitalizations,2 and between 12,000 and 52,000 deaths2 result from influenza each year, with a total annual economic burden estimated in the billions of US dollars.1,3 Influenza virus is associated with a range of symptoms, from mild upper respiratory disease characterized by fever, chills, lethargy, headache, cough, sore throat, and runny nose to severe pneumonia that may be fatal, particularly in elderly persons and in those with immunosuppressive conditions.4,5 The main strategy for prevention and control of seasonal influenza has been vaccination. However, influenza vaccines are not optimally protective against influenza virus infection,6 and vaccine uptake is incomplete. In the United States, vaccination rates have not significantly changed since 2013, ranging from 41.7% in 2015–2016 to an estimated 37.1% in 2017–2018 among adults.7 Additionally, current influenza vaccine technologies cannot be preemptively deployed in anticipation of pandemic influenza; instead, they can be implemented only in response to a pandemic that is already underway. Nonpharmaceutical interventions (NPIs), such as mask wearing, hand hygiene, indoor ventilation, quarantine of symptomatic individuals, and social distancing for asymptomatic persons are variably effective at preventing the spread of influenza and other respiratory viruses,8–10 including pandemic SARS-CoV-2,11–14 although the simultaneous implementation of multiple NPIs may be more effective than any one NPI alone.9,12 Additional pathogen-nonspecific interventions that are effective at hindering or preventing person-to-person disease transmission and that can be implemented in concert with other NPIs may help to mitigate the impact of future zoonoses like COVID-19 or pandemic influenza. The use of iodine as a topical antiseptic dates back nearly as far as its discovery in 181115 and predates the widespread understanding of germ theory.16 Iodine-based antiseptics are broadly antimicrobial; they are active against bacteria, fungi, mycobacteria, protozoa, and viruses, including influenza virus.17,18 The inhalation of iodine vapors to treat various respiratory diseases was proposed as early as 1829,19 and topical, inhalational, and oral iodine preparations were used empirically to prevent influenza during the 1918 “Spanish flu”20–23 and the 1957 “Asian flu”24 pandemics. In experiments conducted in the 1940s, the application of an ethanol-based tincture of iodine to the snouts of mice prevented disease upon exposure to a dose of aerosolized influenza virus lethal to control mice.25 Subsequently, povidone-iodine (PVP-I) was introduced in the 1950s as a novel iodine-based antiseptic. PVP-I is a complex of the polymer povidone (polyvinylpyrrolidone) and triiodide (I3−) that does not require additional iodine solubilizers and is less irritating to the skin than tincture of iodine while retaining its broad-spectrum antimicrobial activity.17,18 Because aqueous solutions of PVP-I maintain a low but constant concentration of free iodine (the active antimicrobial agent) in dynamic equilibrium with the PVP–triiodide complex, they are less irritating to the skin and have a shorter duration of antimicrobial activity than molecular iodine formulations like tincture of iodine or Lugol's solution.26–28 Thus, the use of iodine as a pathogen-nonspecific intervention to prevent viral or bacterial infection typically entails a trade-off between the duration of its antimicrobial activity after application and the degree to which it irritates the skin to which it is applied. 3M{\texttrademark} Skin and Nasal Antiseptic (PVP-I solution 5% w/w [0.5% available iodine] USP) Patient Preoperative Skin Preparation Non-Sterile Solution (herein after abbreviated as “Nasal Prep”) is a safe and effective formulation of 5% PVP-I with a proprietary film-forming composition that extends the duration of the iodine's antimicrobial activity. It has broad-spectrum microbiocidal activity against respiratory pathogens such as Streptococcus pneumoniae,29 Haemophilus influenzae,29 methicillin-susceptible and -resistant Staphylococcus aureus,29 influenza A virus,30 and coronaviruses,30 including SARS-CoV-2.31,32 Clinical studies33,34 have shown that same-day application of Nasal Prep to the nares of preoperative patients is equivalent to or better than a 5-day course of intranasal mupirocin at preventing postoperative surgical site infections due to S. aureus. In addition, polymer and excipients in the Nasal Prep formulation protect PVP-I from inactivation by nasal mucins and other organic compounds and increase its adhesion to mucosal surfaces,35 potentially imparting a longer-lasting antimicrobial effect in the nose than other PVP-I preparations lacking these properties. We hypothesized that the PVP-I in Nasal Prep, applied intranasally, would prevent influenza virus infection in a guinea pig model of influenza virus transmission, as had been previously shown in mice that had tincture of iodine applied to their snouts.25 We hypothesized further that the film-forming property of Nasal Prep would maintain its antiviral activity over a longer duration than with standard aqueous PVP-I solutions (typically 30–60 min),27 thus enabling a practicable, once-daily reapplication interval. Publisher Copyright: {\textcopyright} 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.",

year = "2023",

month = jan,

doi = "10.1111/irv.13035",

language = "English",

volume = "17",

journal = "Influenza and other Respiratory Viruses",

issn = "1750-2640",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "1",

}

TY - JOUR

T1 - Intranasal antisepsis to reduce influenza virus transmission in an animal model

AU - Gaaloul ben Hnia, Nassima

AU - Komen, Mathew Kipkemboi

AU - Wlaschin, Katie F.

AU - Parthasarathy, Ranjani V.

AU - Landgrebe, Kevin D.

AU - Bouvier, Nicole M.

N1 - Funding Information: This research was funded under a contract between the Defense Advanced Research Projects Agency (DARPA) and 3M Company (Agreement HR0011‐19‐3‐0006). Work performed at the Icahn School of Medicine at Mount Sinai was done under a subcontract with 3M. Funding Information: Dr. Bouvier reports that she is an employee of the Icahn School of Medicine at Mount Sinai, which received funding from 3M Company during the conduct of the study. Dr. Landgrebe, Dr. Parthasarathy, and Dr. Wlashin report that they are employees of 3M, which received funding from DARPA during the conduct of the study. 3M employees conceived of the study and contributed to experimental design but had no direct participation in the conduct of the experiments or the collection or analysis of the data. Dr. Landgrebe, Dr. Parthasarathy, and Dr. Wlashin also report three patents pending that are relevant to this work, entitled “Treatment and Prophylaxis of Viral Infections,” “Transmission Prevention of Viruses with Application of Antiseptic Composition,” and “Virus Transmission with Application of a Composition.” Dr. Gaaloul and Mr. Komen report having nothing to disclose. Nasal Prep (3M™ Skin and Nasal Antiseptic), a commercially available 5% (w/w) PVP-I solution, was used in these studies. The vehicle comparator (Nasal Prep devoid of PVP-I and sodium iodide) was produced by 3M specifically for these experiments, and the phosphate-buffered saline (PBS) comparator was purchased (Gibco). All three treatments were applied to guinea pig nares in the same way: While guinea pigs were awake and in an upright position, we used a positive-displacement pipette to deliver 50 μl to each naris (100 μl per animal). Awake administration of treatments was used instead of anesthetized administration after a comprehensive literature review38–42 and risk–benefit analysis. The viscosity of the Nasal Prep and vehicle solutions, coupled with guinea pigs' inability to protect their airways due to the loss of gag reflex while under ketamine/xylazine anesthesia, increased the risk of death by respiratory failure due to the aspiration of the solutions into the respiratory tract under anesthesia. Influenza A/Panama/2007/1999 (H3N2) virus (Pan/99) was originally derived from a 12-plasmid reverse genetics system.36 For these experiments, stock virus was subsequently propagated in Madin–Darby canine kidney (MDCK) cells stably transfected with cDNA of the human 2,6-sialyltransferase (MDCK-SIAT1)37 (Millipore Sigma/European Collection of Authenticated Cell Cultures) in Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% fetal calf serum and 1 mg/ml of G418 selective antibiotic (Geneticin 100×, Gibco) at 37°C and 5% CO2. Female Hartley strain guinea pigs weighing 300–350 g were obtained from Charles River Laboratories. Animals were allowed free access to food and water and kept on a 12-h light/dark cycle. Guinea pigs were anesthetized prior to intranasal inoculation and to nasal washing, using a mixture of ketamine (30 mg/kg) and xylazine (5 mg/kg), administered intramuscularly. All procedures were performed in accordance with the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee guidelines (protocol #IACUC-2019-0019) and were additionally approved by the US Army Medical Research and Development Command (USAMRDC) Animal Care and Use Review Office (ACURO) (protocol #DARPA-6336). During guinea pig transmission experiments, strict measures were followed to prevent any cross-contamination between animals, including handling recipient animals before donors and changing gloves between guinea pigs. Nasal Prep (3M™ Skin and Nasal Antiseptic), a commercially available 5% (w/w) PVP-I solution, was used in these studies. The vehicle comparator (Nasal Prep devoid of PVP-I and sodium iodide) was produced by 3M specifically for these experiments, and the phosphate-buffered saline (PBS) comparator was purchased (Gibco). All three treatments were applied to guinea pig nares in the same way: While guinea pigs were awake and in an upright position, we used a positive-displacement pipette to deliver 50 μl to each naris (100 μl per animal). Awake administration of treatments was used instead of anesthetized administration after a comprehensive literature review38–42 and risk–benefit analysis. The viscosity of the Nasal Prep and vehicle solutions, coupled with guinea pigs' inability to protect their airways due to the loss of gag reflex while under ketamine/xylazine anesthesia, increased the risk of death by respiratory failure due to the aspiration of the solutions into the respiratory tract under anesthesia. On Day 0, Pan/99 stock virus was diluted in PBS supplemented with antibiotics (Penicillin–Streptomycin 10,000 U/ml, Gibco) (PBS + P/S). An inoculum of 104 plaque-forming units (pfu) in 150 μl was instilled intranasally by applying 75 μl to each nostril. The inoculum dose was chosen to maximize the transmission rate of Pan/99 in our model. In our hands, peak nasal wash titers in donor guinea pigs reliably occur by Day 3 post inoculation at this dose (unpublished observations), and the time to peak nasal wash titer in donor guinea pigs has been shown by others to correlate inversely with transmission rate to recipients.43 Inoculated guinea pigs were placed supine, in a nose-up position. Guinea pigs were then placed in the appropriate cages based on the experiment type (airborne or contact transmission). Transmission experiments were performed at constant temperature (20°C) and relative humidity (RH) (20% RH) in environmentally controlled chambers (model 6030, Caron Products & Services, Inc.). For every transmission experiment, a virus-inoculated guinea pig donor was paired with a virus-naïve recipient in specific cages depending on the experimental model (airborne or contact). In the contact model, each pair of animals (donor and recipient) was housed in the same cage (Figure 2A). In the airborne model, each pair of animals was housed individually in two identical transmission cages (Figure 2B), which have an open wire top and a wire-mesh grid side panel. The transmission cages were then placed into the environmental chamber with two cages per shelf, such that the wire grids opposed each other at a separation distance of 5 cm; such an arrangement allows air to flow between cages but prevents contact between guinea pigs. Guinea pigs were kept together for a total of 7 days. Nasal washing was performed on Days 1, 3, 5, and 7 post inoculations by instilling a total of 1 ml of PBS + P/S into both nares and allowing it to drain onto a sterile Petri dish. Nasal treatments were reapplied every 24 h. Nasal wash samples were collected in 1.5-ml tubes on ice, centrifuged to pellet debris, and stored at −80°C until titration by plaque assay, as previously described.44 These exploratory experiments were performed in the absence of existing data to inform an estimate for effect size; thus, power calculations were not carried out a priori. Transmission experiments were performed in groups of four or eight transmission pairs (eight or 16 guinea pigs) in one or two transmission chambers at a time. Experiments were designed sequentially, with prior results informing the next experimental scheme to be tested, and the results are presented in the order in which experiments were conducted. Given the exploratory nature of these experiments, not every possible combination of intranasal treatment (Nasal Prep, vehicle, or PBS), treated animal (inoculated virus donor, susceptible virus recipient, or both), or transmission model (contact or airborne) was tested. Where possible, we minimized animal use by omitting groups that were unlikely to be substantively additionally informative, given prior results; the rationales for these omissions are noted in the text describing each experiment. Because power calculations were not performed and group sizes not established a priori, Bayesian methods45 were used to evaluate the strength of the evidence in favor of the null hypothesis (the virus transmission rates are not different in different treatment groups) or its alternative (the transmission rates are different between different treatment groups). Transmission experiment results were tabulated in 2 × 2 matrices, with treatment group in rows and transmission (yes or no) as columns. Bayes factors and posterior probabilities were calculated in R46,47 with the package BayesFactor (v.0.9.12–4.2)45,48,49 (Text S1). Because the result of interest is the proportion of successful transmission events in each treatment group, the Bayes factor for independent multinomial sampling was calculated as a test for equality of proportions, with the row (treatment) margins fixed.45 The magnitude of the Bayes factor quantifies the strength of evidence in support of the alternative hypothesis over the null hypothesis. For example, a Bayes factor of 5 means that, given the data observed, the alternative hypothesis is five times more likely to be correct than the null hypothesis, while a Bayes factor of 0.2 (the reciprocal of 5) indicates that the alternative hypothesis is five times less likely than the null hypothesis.45 Bayes factors, being essentially odds ratios, can alternatively be expressed as the percent likelihood, from 0% to 100%, that a given hypothesis is likely to be the correct one, given the observed data (i.e., the posterior probability).48 Seasonal influenza typically causes significant global morbidity and mortality. In the United States alone, 31.4 million outpatient visits,1 140,000 to 710,000 hospitalizations,2 and between 12,000 and 52,000 deaths2 result from influenza each year, with a total annual economic burden estimated in the billions of US dollars.1,3 Influenza virus is associated with a range of symptoms, from mild upper respiratory disease characterized by fever, chills, lethargy, headache, cough, sore throat, and runny nose to severe pneumonia that may be fatal, particularly in elderly persons and in those with immunosuppressive conditions.4,5 The main strategy for prevention and control of seasonal influenza has been vaccination. However, influenza vaccines are not optimally protective against influenza virus infection,6 and vaccine uptake is incomplete. In the United States, vaccination rates have not significantly changed since 2013, ranging from 41.7% in 2015–2016 to an estimated 37.1% in 2017–2018 among adults.7 Additionally, current influenza vaccine technologies cannot be preemptively deployed in anticipation of pandemic influenza; instead, they can be implemented only in response to a pandemic that is already underway. Nonpharmaceutical interventions (NPIs), such as mask wearing, hand hygiene, indoor ventilation, quarantine of symptomatic individuals, and social distancing for asymptomatic persons are variably effective at preventing the spread of influenza and other respiratory viruses,8–10 including pandemic SARS-CoV-2,11–14 although the simultaneous implementation of multiple NPIs may be more effective than any one NPI alone.9,12 Additional pathogen-nonspecific interventions that are effective at hindering or preventing person-to-person disease transmission and that can be implemented in concert with other NPIs may help to mitigate the impact of future zoonoses like COVID-19 or pandemic influenza. The use of iodine as a topical antiseptic dates back nearly as far as its discovery in 181115 and predates the widespread understanding of germ theory.16 Iodine-based antiseptics are broadly antimicrobial; they are active against bacteria, fungi, mycobacteria, protozoa, and viruses, including influenza virus.17,18 The inhalation of iodine vapors to treat various respiratory diseases was proposed as early as 1829,19 and topical, inhalational, and oral iodine preparations were used empirically to prevent influenza during the 1918 “Spanish flu”20–23 and the 1957 “Asian flu”24 pandemics. In experiments conducted in the 1940s, the application of an ethanol-based tincture of iodine to the snouts of mice prevented disease upon exposure to a dose of aerosolized influenza virus lethal to control mice.25 Subsequently, povidone-iodine (PVP-I) was introduced in the 1950s as a novel iodine-based antiseptic. PVP-I is a complex of the polymer povidone (polyvinylpyrrolidone) and triiodide (I3−) that does not require additional iodine solubilizers and is less irritating to the skin than tincture of iodine while retaining its broad-spectrum antimicrobial activity.17,18 Because aqueous solutions of PVP-I maintain a low but constant concentration of free iodine (the active antimicrobial agent) in dynamic equilibrium with the PVP–triiodide complex, they are less irritating to the skin and have a shorter duration of antimicrobial activity than molecular iodine formulations like tincture of iodine or Lugol's solution.26–28 Thus, the use of iodine as a pathogen-nonspecific intervention to prevent viral or bacterial infection typically entails a trade-off between the duration of its antimicrobial activity after application and the degree to which it irritates the skin to which it is applied. 3M™ Skin and Nasal Antiseptic (PVP-I solution 5% w/w [0.5% available iodine] USP) Patient Preoperative Skin Preparation Non-Sterile Solution (herein after abbreviated as “Nasal Prep”) is a safe and effective formulation of 5% PVP-I with a proprietary film-forming composition that extends the duration of the iodine's antimicrobial activity. It has broad-spectrum microbiocidal activity against respiratory pathogens such as Streptococcus pneumoniae,29 Haemophilus influenzae,29 methicillin-susceptible and -resistant Staphylococcus aureus,29 influenza A virus,30 and coronaviruses,30 including SARS-CoV-2.31,32 Clinical studies33,34 have shown that same-day application of Nasal Prep to the nares of preoperative patients is equivalent to or better than a 5-day course of intranasal mupirocin at preventing postoperative surgical site infections due to S. aureus. In addition, polymer and excipients in the Nasal Prep formulation protect PVP-I from inactivation by nasal mucins and other organic compounds and increase its adhesion to mucosal surfaces,35 potentially imparting a longer-lasting antimicrobial effect in the nose than other PVP-I preparations lacking these properties. We hypothesized that the PVP-I in Nasal Prep, applied intranasally, would prevent influenza virus infection in a guinea pig model of influenza virus transmission, as had been previously shown in mice that had tincture of iodine applied to their snouts.25 We hypothesized further that the film-forming property of Nasal Prep would maintain its antiviral activity over a longer duration than with standard aqueous PVP-I solutions (typically 30–60 min),27 thus enabling a practicable, once-daily reapplication interval. Publisher Copyright: © 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.

PY - 2023/1

Y1 - 2023/1

N2 - Background: Seasonal influenza annually causes significant morbidity and mortality, and unpredictable respiratory virus zoonoses, such as the current COVID-19 pandemic, can threaten the health and lives of millions more. Molecular iodine (I2) is a broad-spectrum, pathogen-nonspecific antiseptic agent that has demonstrated antimicrobial activity against a wide range of bacteria, virus, and fungi. Methods: We investigated a commercially available antiseptic, a non-irritating formulation of iodine (5% povidone-iodine) with a film-forming agent that extends the duration of the iodine's antimicrobial activity, for its ability to prevent influenza virus transmission between infected and susceptible animals in the guinea pig model of influenza virus transmission. Results: We observed that a once-daily topical application of this long-lasting antiseptic to the nares of either the infected virus-donor guinea pig or the susceptible virus-recipient guinea pig, or to the nares of both animals, prior to virus inoculation effectively reduced transmission of a highly transmissible influenza A virus, even when the donor and recipient guinea pigs shared the same cage. Daily treatment of the recipient guinea pig starting 1 day after initial exposure to an infected donor guinea pig in the same cage was similarly effective in preventing detectable influenza virus infection in the recipient animal. Conclusions: We conclude that a daily application of this antiseptic formulation is efficacious in reducing the transmission of influenza A virus in the guinea pig model, and further study in this and other preclinical models is warranted.

AB - Background: Seasonal influenza annually causes significant morbidity and mortality, and unpredictable respiratory virus zoonoses, such as the current COVID-19 pandemic, can threaten the health and lives of millions more. Molecular iodine (I2) is a broad-spectrum, pathogen-nonspecific antiseptic agent that has demonstrated antimicrobial activity against a wide range of bacteria, virus, and fungi. Methods: We investigated a commercially available antiseptic, a non-irritating formulation of iodine (5% povidone-iodine) with a film-forming agent that extends the duration of the iodine's antimicrobial activity, for its ability to prevent influenza virus transmission between infected and susceptible animals in the guinea pig model of influenza virus transmission. Results: We observed that a once-daily topical application of this long-lasting antiseptic to the nares of either the infected virus-donor guinea pig or the susceptible virus-recipient guinea pig, or to the nares of both animals, prior to virus inoculation effectively reduced transmission of a highly transmissible influenza A virus, even when the donor and recipient guinea pigs shared the same cage. Daily treatment of the recipient guinea pig starting 1 day after initial exposure to an infected donor guinea pig in the same cage was similarly effective in preventing detectable influenza virus infection in the recipient animal. Conclusions: We conclude that a daily application of this antiseptic formulation is efficacious in reducing the transmission of influenza A virus in the guinea pig model, and further study in this and other preclinical models is warranted.

KW - guinea pig

KW - influenza

KW - iodine

KW - transmission

UR - http://www.scopus.com/inward/record.url?scp=85139713211&partnerID=8YFLogxK

U2 - 10.1111/irv.13035

DO - 10.1111/irv.13035

M3 - Article

AN - SCOPUS:85139713211

SN - 1750-2640

VL - 17

JO - Influenza and other Respiratory Viruses

JF - Influenza and other Respiratory Viruses

IS - 1

M1 - e13035

ER -

Intranasal antisepsis to reduce influenza virus transmission in an animal model

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