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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Inactivation",doi:"10.5772/intechopen.102727",slug:"variability-and-relative-order-of-susceptibility-of-non-enveloped-viruses-to-chemical-inactivation",body:'Bacteria, fungi (yeasts and molds), mycobacteria, prions, protozoa, and viruses are common pathogens infecting humans and animals. They typically exist within the host or in the environment. It has been observed that these microorganisms exhibit a notable difference in the natural survivability in the environment, as well as susceptibility to chemical and physical inactivation. For example, under ambient and dried conditions, human coronaviruses seem to lose their infectivity in a matter of several hours to several days [1], whereas endospores and prions may remain infectious for years to decades or even indefinitely [2, 3].
As more and more data have become available regarding the survivability and susceptibility of pathogens to microbicides, it has been observed that the pathogens seem to demonstrate an order of susceptibility to chemical and physical inactivation. E. H. Spaulding first proposed a classification system for the sterilization and disinfection of medical instruments based on the infection risk in 1939 [4]. On the basis of this classification, the concept of a hierarchy of pathogen susceptibility was proposed, in which microorganisms are placed into several groups and ranked from least susceptible to most susceptible. In this hierarchy concept, bacterial spores were ranked the least susceptible, followed by mycobacteria, non-enveloped viruses, fungi, vegetative bacteria, and enveloped viruses. The susceptibility hierarchy was also believed to be related to the biochemical and biophysical characteristics of a pathogen [5, 6].
This hierarchy concept has been slightly modified and expanded over the years. For example, prions were added and considered less susceptible to inactivation by microbicides than bacterial spores; small non-enveloped viruses were considered less susceptible than large non-enveloped viruses; and the order between mycobacteria and small non-enveloped viruses was sometimes reversed (Figure 1) [7, 8, 9, 10]. Additionally, it has been suggested that the hierarchy concept may be applied either “vertically” (i.e., ranking of susceptibility
Proposed hierarchy of susceptibility of pathogens to microbicides. Note: slightly different versions of the hierarchy concept have been proposed in the literature. Mycobacteria have been placed above small non-enveloped viruses, and molds have been placed above large non-enveloped viruses in certain versions. In some versions, the small and large non-enveloped viruses are combined; and yeasts and molds may be combined.
The hierarchy concept has been quite useful for enabling scientists to better understand the innate difference among various types of pathogens. In the case of newly emerged pathogens, especially, the hierarchy concept has helped stakeholders design and implement a disinfection strategy swiftly with a reasonable level of confidence. The concept also helps the contaminant control for food, pharmaceutical, and biopharmaceutical products, as it is impractical to test every possible contaminating pathogen, and a robust infectivity assay system may be lacking for certain pathogens (e.g., hepatitis E virus).
Despite its usefulness, the hierarchy concept should be interpreted with caution, as it may oversimply the differences and trending of pathogen susceptibilities. Further examination and refinement of the concept may be necessary; and several important questions should be answered. For example, how often do exceptions to the hierarchy occur and what are the underlying reasons? Could a trending be specific to a given type of chemistry? Is the hierarchy the same between susceptibility to both chemical and physical inactivation? Why do pathogens in the same group, or even the same family or genus, sometimes exhibit striking differences in susceptibility? Is there a way to identify and separate reliable/consistent trending versus blurred/variable trending? A deeper look at the efficacy data for various types of microbicidal actives, especially for non-enveloped viruses, may help stakeholders understand the scope, reliability, and limitation of the hierarchy concept so that it can be best utilized.
This chapter reviews the inactivation efficacy data from the literature against non-enveloped viruses for several commonly used types of chemistries, either in formulated or unformulated form, in an effort to generate a separate relative order of susceptibility among these non-enveloped viruses for each type of chemistry and to differentiate consistent versus variable trending. Physical inactivation approaches are not covered in this chapter, although a significant degree of variation also exists for physical treatments. It is not clear that the physical inactivation approaches, in general, are governed by the same hierarchy to susceptibility as is observed for chemical inactivation approaches [12].
Currently, there are a total of 21 families of viruses (including enveloped and non-enveloped) identified for humans [13], which represent only a small part of the entire paradigm of viruses in nature, whose host ranges extend from vertebrates to plants to bacteria. The most common families of non-enveloped viruses for humans and animals include
Family | Example virus | Abbreviation | Genus | Genome | Size (nm) |
---|---|---|---|---|---|
Adenovirus type 2 | AdV-2 | ds DNA | 70–90 | ||
Adenovirus type 5 | AdV-5 | ds DNA | 70–90 | ||
Adenovirus type 8 | AdV-8 | ds DNA | 70–90 | ||
Human astrovirus | HAstV | ss RNA | 28–35 | ||
Feline calicivirus | FCV | ss RNA | 28–40 | ||
Human norovirus | HuNoV | ss RNA | 28–40 | ||
Murine norovirus | MNV | ss RNA | 28–40 | ||
Tulane virus | TuV | ss RNA | 28–40 | ||
Porcine circovirus | PCV | ss DNA | ∼17 | ||
Hepatitis E virus | HEV | ss DNA | 32–34 | ||
Human papillomavirus | HPV | ds DNA | 50–60 | ||
Bovine parvovirus | BPV | ss DNA | 20–28 | ||
Canine parvovirus | CPV | ss DNA | 20–25 | ||
Human parvovirus B19 | B19V | ss DNA | 23–26 | ||
Minute virus of mice | MVM (MMV) | ss DNA | 20–25 | ||
Porcine parvovirus | PPV | ss DNA | 20–25 | ||
Bovine enterovirus | BEV | ss RNA | 30–32 | ||
Coxsackievirus | Cox | ss RNA | 30–32 | ||
Echovirus 11 | Echo11 | ss RNA | 30–32 | ||
Encephalomyocarditis virus | EMCV | ss RNA | 30–32 | ||
Enterovirus 71 | EV-71 | ss RNA | 30–32 | ||
Enterovirus D68 | EV-D68 | ss RNA | 30–32 | ||
Foot and mouth disease virus | FMDV | ss RNA | 30–32 | ||
Hepatitis A virus | HAV | ss RNA | 30–32 | ||
Poliovirus type 1 | PV1 | ss RNA | 30–32 | ||
Rhinovirus | RV | ss RNA | 30–32 | ||
Seneca Valley virus | SVV | ss RNA | 30–32 | ||
Bovine polyomavirus | BPyV | ds DNA | 40–50 | ||
Simian virus 40 | SV40 | ds DNA | 40–50 | ||
Bluetongue virus | BTV | ds RNA | 60–80 | ||
Reovirus type 3 | REO-3 | ds RNA | 60–80 | ||
Rotavirus | Rota | ds RNA | 60–80 |
Common families of human and animal non-enveloped viruses.
Among these, the
It is worth noting that viruses are typically classified taxonomically on the basis of virion properties (size, shape, envelope, physical, and chemical properties, etc.), genome organization, replication mechanism, antigenic properties, and biological properties [13, 14, 15]. The final classification is a combined consideration of these properties. However, the stability and susceptibility to inactivation of a virus may not relate to all of these properties and, as such, may not always align with the taxonomic classification system. For example, the susceptibility of a virus to surfactants may primarily be related to the envelope of the virion and not related to the genome structure or mode of replication.
The susceptibilities of non-enveloped viruses to chemicals have been found to be highly variable and somewhat hard to predict, since they do not always agree with the hierarchy concept. For example, according to the hierarchy concept as modified by Sattar [8], small non-enveloped viruses should be less susceptible than large non-enveloped viruses. Additionally, if there is a fixed hierarchy, all small non-enveloped viruses should either display similar levels of susceptibility or should demonstrate a definitive trend of relative susceptibility, regardless of the type of microbicide. Based on the literature, neither of these predictions appear to hold in every case. The relative order of susceptibility seems chemistry-dependent; and sometimes viruses within the same family or even genus have been found to exhibit unequivocal differences in their susceptibilities (reviewed in [16]). Any trending or hierarchy, therefore, must be reviewed in the context of the type of chemistry, and it should not be assumed that non-enveloped viruses within the same family or genus will always display similar susceptibilities to a given microbicide.
Viral inactivation may be achieved by chemical and/or physical methods. The subset of chemicals commonly used for inactivation of non-enveloped viruses includes alcohols, oxidizers, halogen compounds, quaternary ammonium compounds, phenolics, aldehydes, acids, and alkalines [17, 18, 19]. These differ with respect to efficacy, stability, toxicity, material or surface compatibility, cost, and sensitivity to organic soil load. Soil load is a term used to signify an organic matrix used to challenge the inactivating efficacy of a microbicide. It is intended to mimic secretions or excretions in which the virus would be released from an infected person or animal. Some chemistries (e.g., sodium hypochlorite, phenolics, and aldehydes) are mostly used for environmental or medical device disinfection. Other chemistries (e.g., ethanol) are more commonly used for hand hygiene, while some others (e.g., quaternary ammonium compounds) may be used for both environmental disinfection and skin antisepsis (Table 2).
Class | Chemical | Typical conc. | Usage | Mechanism of viral inactivation | Sensitivity to soil load |
---|---|---|---|---|---|
Alcohols | Ethanol | 50–95% | Disinfection; Antisepsis | Protein denaturation | + |
Isopropanol | 70–90% | Disinfection | Protein denaturation | + | |
Oxidizers | Sodium hypochlorite | 0.01–0.5% | Disinfection | Protein/genome damage | ++ |
Chlorine dioxide | 0.1–1 mg/L | Disinfection; Water treatment | Protein/genome damage | — | |
Hydrogen peroxide | 0.1–10% | Disinfection; Antisepsis | Lipid/protein/genome damage | + | |
Hypochlorous acid | 0.002–0.1% | Disinfection; Water treatment | Protein/genome damage | ++ | |
Peracetic acid | 0.01–1% | Disinfection; Sterilization | Protein denaturation | — | |
Povidone-iodine | 0.02–8% | Disinfection; Antisepsis | Protein/genome damage | ++ | |
Chlorohexidine | 0.02–0.2% | Antisepsis | Protein denaturation | + | |
QAC | BKC, DDAC, etc. | 0.01–0.2% | Disinfection | Lipid/protein damage | + |
Low pH | Acids | ≤ pH 4 | Sanitization; Biomanufacturing | Capsid/protein damage | — |
High pH | NaOH, etc. | ≥ pH 10 | Disinfection; Tissue processing | Capsid/genome damage | — |
Aldehydes | Glutaraldehyde | 0.02–2% | HLD; Sterilization | Crosslinking/protein & genome damage | — |
Formaldehyde | 0.1–5% | Disinfection/Preservation | Alkylating/protein & genome damage | — | |
OPA | 0.02–2% | HLD; Sterilization | Crosslinking/protein damage | — | |
Phenolics | Phenylphenol, etc. | 0.05–5% | Disinfection | Protein damage | — |
Common types of chemistries used for non-enveloped viral inactivation.
Abbreviations used: BKC, benzalkonium chloride; Conc, concentration; DDAC, didecyldimethylammonium chloride; HLD, high-level disinfection; NaOH, sodium hydroxide; OPA, ortho-phthaldehyde; QAC, quaternary ammonium compounds.
The virucidal efficacy of a product is not only determined by the type and concentration of the chemical, but is also heavily influenced by the formulation, pH, exposure (contact or dwell) time, organic soil load, temperature, and surface characteristics (as applicable), etc. [10, 20, 21, 22]. Given the differences between various testing methods, as well as the intrinsic variability of viral infectivity (titration) assays, a general conclusion on the efficacy of a particular type of active ingredient will be enhanced if the efficacy is derived from multiple sets of data and under various application conditions (such as the concentration of the microbicidal active(s), contact time, formulation matrix (as applicable), and organic soil load, etc.) Additionally, in order best to explore the relative ranking of susceptibility between viruses, or the lack thereof, efficacy data from side-by-side studies wherein the same test methodologies and conditions were used would be preferable. Care should be taken when comparing data from different studies, especially if the formulations, test methods, and test conditions were different.
Alcohols, primarily ethanol and isopropanol, are widely used for hand hygiene and environmental disinfection, and their efficacies against bacteria and viruses have been extensively studied [23, 24, 25]. Ethanol at a concentration of 70–90% and isopropanol at 70% have been broadly shown to be effective against enveloped viruses; however, their efficacies against non-enveloped viruses are much more variable.
The trending of the degree of susceptibility of non-enveloped viruses to ethanol and isopropanol is generally clearer and more consistent than it is for many other types of chemistries, thanks to the large amount of data in the literature. The relative ranking of susceptibility of non-enveloped viruses seems to differ between ethanol and isopropanol; and the ranking does not appear to align well with the classical virological taxonomy.
For ethanol, parvoviruses and the polyomavirus simian virus 40 have low susceptibility, while rotavirus (a reovirus) is susceptible (Table 3). Viruses in the
Virusa | Method | Soil/Matrixb | Log10 Reduction after | References | |||
---|---|---|---|---|---|---|---|
30 s | 1 min | 5 min | 10 min | ||||
PPV | Stainless steel | Erythrocytes + BSA | 0.3 | 0.6 | [26] | ||
MVM | Stainless steel | Erythrocytes + BSA | 0.3 | 0.7 | [26] | ||
HEV71 | Suspension test | Medium | < 1 | [27] | |||
HAV | Suspension test | Medium | 0.4 | [28] | |||
HAV | Suspension test | 20% fecal | 0.4 | [28] | |||
HuNoV | Suspension test | 20% stool | <0.5 | [29] | |||
TuV | Suspension test | Medium | <0.5 | [30] | |||
PV1 | Suspension test | 20% fecal | 0.3 | [28] | |||
PV1 | Suspension test | Medium | 0.4 | [31] | |||
PV1 | Glass | Medium | 2.3 | 1.0 | 5.0 | [31] | |
PV1 | Stainless steel | Erythrocytes + BSA | 2.1 | 1.8 | [26] | ||
PV1 | Suspension test | Medium | 4 | [28] | |||
FCV | Suspension test | Medium | 1.7 | 2.2 | [30] | ||
AdV-8 | Suspension test | Medium | 1.9 | [33] | |||
AdV-5 | Stainless steel | Erythrocytes + BSA | 2.4 | >4.1 | [26] | ||
AdV-5 | Stainless steel | Medium | ∼5 | [34] | |||
MNV | Suspension test | Medium | 5 | [30] | |||
Rotavirus | Suspension test | Medium | > 3.1 | [28] | |||
CPV | Stainless steel | Medium | 0.1 | [36] | |||
SV40 | Suspension test | Medium | <1 | [37] | |||
PV1 | Glass | Medium | 2.9 | 2.9 | 5.4 | [31] | |
TuV | Suspension test | Medium | <0.5 | [30] | |||
FCV | Suspension test | Medium | <0.5 | [30] | |||
HEV71 | Suspension test | Medium | <1 | [27] | |||
PV1 | Suspension test | medium | <1 | [37] | |||
PV1 | Glass | Medium | 1.2 | 1.3 | 1.0 | [31] | |
AdV-5 | Stainless steel | Medium | ∼1 | [34] | |||
AdV-8 | Suspension test | Medium | 2.0 | [33] | |||
MNV | Suspension test | Medium | 1.8 | 3.1 | [30] | ||
SV40 | Suspension test | Medium | >4 | [37] | |||
Rotavirus | Suspension test | Medium | > 4 | [42] |
Efficacy of alcohols against non-enveloped viruses.
See Table 1 for abbreviations used for viruses.
BSA, bovine serum albumin; medium, culture medium; RT, room temperature.
Entries in purple font indicate results from undiluted or diluted formulations with the indicated microbicidal active ingredients.
Interestingly, the above order of susceptibility does not appear to hold the same for isopropanol (Table 3). For example, the polyomavirus simian virus 40 is much more susceptible to isopropanol than many other non-enveloped viruses; and poliovirus appears to display a lower susceptibility, similar to that of hepatitis A virus and human enterovirus 71. Murine norovirus is still more susceptible than feline calicivirus to isopropanol, but not as susceptible as simian virus 40 or rotavirus. The apparent difference between adenovirus 5 and adenovirus 8 that has been observed for ethanol has not been observed for isopropanol.
An oxidizer or oxidizing agent is a chemical that has the ability to oxidize other molecules, i.e., to accept their electrons. Common oxidizing agents used for disinfection, sterilization, or antisepsis include hydrogen peroxide, peracetic acid, ozone, and halogen-containing compounds such as sodium hypochlorite (bleach), hypochlorous acid, povidone-iodine, chlorohexidine, and chlorine dioxide, etc. These compounds can react with and alter the proteins and nucleic acids of non-enveloped viruses and render them noninfectious. Oxidizers comprise a large group of chemicals, and the relative order of susceptibility of non-enveloped viruses to oxidizers seems to vary by specific type of active ingredient (Table 4).
Virusa | Method | Soil/Matrixb | Log10 Reduction after | References | |||
---|---|---|---|---|---|---|---|
≤ 1 min | 2 min | 5 min | 10 min | ||||
FCV | Suspension test | Medium | 3 | [29] | |||
FCV | Suspension test | 20% stool | 0.5 | [29] | |||
MNV | Suspension test | Medium | 3 | [29] | |||
MNV | Suspension test | 20% stool | 0.0 | [29] | |||
CPV | Stainless steel | 90% plasma | < 1 | [43] | |||
CPV | Stainless steel | 5% serum | 5 | [43] | |||
HAV | Stainless steel | 5% serum | 5 | [43] | |||
HAV | Stainless steel | 90% plasma | <1 | 5 | [43] | ||
HAV | Suspension test | PBS/20% fecal | 4 | [28] | |||
PV1 | Suspension test | PBS/20% fecal | 4 | [28] | |||
PPV | Stainless steel | Erythrocytes + BSA | 0.6 | 1.0 | [26] | ||
MVM | Stainless steel | Erythrocytes + BSA | 3.0 | 4.4 | [26] | ||
PV1 | Stainless steel | Erythrocytes + BSA | 2.8 | 4.5 | [26] | ||
AdV-5 | Stainless steel | Erythrocytes + BSA | 4 | [26] | |||
PV1 | Glass | Medium | 0.4 | 0.9 | [16] | ||
RV14 | Glass | Medium | >4.9 | [16] | |||
PPV | Stainless steel | Erythrocytes + BSA | 0.5 | [26] | |||
MVM | Stainless steel | Erythrocytes + BSA | 1.5 | [26] | |||
PV1 | Stainless steel | Erythrocytes + BSA | 3.9 | [26] | |||
AdV-5 | Stainless steel | Erythrocytes + BSA | 2.3 | [26] | |||
MNV | Suspension test | Medium | ∼3 | [52] | |||
HAV | Suspension test | Medium | ∼3 | [53] | |||
PV | Suspension test | Medium | >3 | [53] | |||
CPV | Stainless steel | BSA | 1.6 | [34] | |||
MVM | Stainless steel | BSA | 2.3-2.9 | [34] | |||
PPV | Stainless steel | BSA | 3.8-5.5 | [34] | |||
AdV-5 | Stainless steel | BSA | 4.9-5.8 | [34] |
Efficacy of oxidizers against non-enveloped viruses.
See Table 1 for abbreviations used for viruses.
BSA, bovine serum albumin; PBS, phosphate buffered saline; medium, culture medium; RT, room temperature.
Viral-inoculated lettuce was washed with PAA solution for a defined period of time.
Entries in purple font indicate results from undiluted original or diluted formulations with microbicidal active ingredients.
Parvoviruses are generally among the least susceptible viruses to various types of oxidizers, including sodium hypochlorite, hydrogen peroxide, and peracetic acid. However, for sodium hypochlorite, minute virus of mice appears to be more susceptible than porcine parvovirus and canine parvovirus. All picornaviruses appear to exhibit a similar degree of susceptibility to sodium hypochlorite; but within the family of
The trending for hydrogen peroxide seems more complex than that for sodium hypochlorite. For example, there seems a higher level of variability within the
For peracetic acid, hepatitis A virus also seems less susceptible than poliovirus. Both feline calicivirus and murine norovirus are susceptible to peracetic acid and so is adenovirus.
Quaternary ammonium compounds (QAC) are widely used as active ingredients for disinfectants. Among the advantages of QAC are good stability, dual function of disinfection and cleaning, surface activity, low toxicity, and lack of odor, etc. The potential limitation in the microbicidal efficacy and possible effect in promoting antimicrobial resistance of QAC have also been discussed in the literature [54, 55].
Quaternary ammonium compounds are generally efficacious on most vegetative bacteria and enveloped viruses. Their efficacies against non-enveloped viruses, however, are generally much weaker. Nevertheless, several non-enveloped viruses, such as rotavirus, rhinovirus, and coxsackievirus A11, have been shown to be susceptible to QAC. The susceptibility levels among the
Virusa | Method | Soil/matrixb | Log10 reduction after | References | |||
---|---|---|---|---|---|---|---|
30 s | 1 min | 10 min | 60 min | ||||
PPV | Stainless steel | Erythrocytes + BSA | 0.4 | [26] | |||
MVM | Stainless steel | Erythrocytes + BSA | 0.5 | [26] | |||
PV1 | Stainless steel | Erythrocytes + BSA | 0.5 | [26] | |||
AdV-5 | Stainless steel | Erythrocytes + BSA | 1.8 | [26] | |||
AdV-8 | Suspension test | Medium | 1.0-1.8 | [57] | |||
AdV-5 | Suspension test | Medium | 3.7-5.3 | [57] | |||
TuV | Suspension test | Medium | <0.5 | [30] | |||
PV1 | Suspension test | BSA/yeast extract | 0.0 | [58] | |||
AdV-25 | Suspension test | BSA/yeast extract | 0.3 | [58] | |||
Cox A11 | Suspension test | BSA/yeast extract | >5.1 | [58] | |||
FCV | Suspension test | Medium | <0.5 | [29] | |||
MNV | Suspension test | Medium | <0.5 | [29] | |||
Rhinovirus | Glass | Medium | >3.0 | >3.3 | [16] |
Efficacy of QAC against non-enveloped viruses.
See Table 1 for abbreviations used for viruses.
BSA, bovine serum albumin; medium, culture medium; QAC, quaternary ammonium compound.
Entries in purple font indicate results from original or diluted formulations with microbicidal active ingredients.
Acids and alkalines, either used alone or in combination with other active ingredients in formulated products, can be an effective means for viral inactivation. Acids may be used for disinfection, sanitization, textile or face mask pretreatment, or viral clearance during biopharmaceutical manufacturing. Alkalines may also be used for disinfection, sanitization, and viral clearance during biopharmaceutical manufacturing and can be effective against even the least susceptible of pathogens, the prions [58].
It has been widely reported that a low-pH treatment (typically at pH 4 and below) can effectively inactivate most enveloped viruses, although some enveloped viruses, such as bovine viral diarrhea virus, still exhibit a relatively low susceptibility to this treatment pH [22]. The range of susceptibilities of non-enveloped viruses to low pH seems quite scattered and often goes against the “conventional wisdom” that non-enveloped viruses are not susceptible to acidic pH (Table 6). For instance, in the family of
Virusa | Method | Soil/Matrixb | Log10 Reduction after | References | |||
---|---|---|---|---|---|---|---|
20 min | 30 min | 45 min | 1–2 hr | ||||
REO-3 | Suspension test | Medium | 1–3 | [59] | |||
PCV | Suspension test | Medium | >3 | [60] | |||
MVM | Suspension test | Medium | <1 | [61] | |||
MNV | Suspension test | Medium | <0.5 | [30] | |||
TuV | Suspension test | Medium | <0.5 | [30] | |||
PARV4 | Suspension test | Medium | 2–3 | [61] | |||
B19V | Suspension test | Medium | > 4 | [61] | |||
FCV | Suspension test | Medium | 6.3 | [30] | |||
FCV | Suspension test | Medium | >5 | [62] | |||
PV | Suspension test | Medium | <1 | [63] | |||
PV | Suspension test | Medium | <1 | [64] | |||
HAV | Suspension test | Medium | <1 | [64] | |||
MNV | Suspension test | Medium | <0.5 | [30] | |||
TuV | Suspension test | Medium | <0.5 | [30] | |||
Cox A9 | Suspension test | Medium | <1 | [65] | |||
FCV | Suspension test | Medium | ∼3 | [30] | |||
FCV | Suspension test | Medium | ∼4.7 | [62] | |||
RV | Suspension test | Medium | >3 | [65] | |||
FMDV | Suspension test | Medium | >3 | [65] | |||
MVM | Suspension test | Medium | <1 | [66] | |||
EV71 | Suspension test | Medium | <1 | [67] | |||
EV-D68 | Suspension test | Medium | ∼4–5 | <5 | [67] | ||
B19V | Suspension test | Medium | [66] |
Efficacy of low pH against non-enveloped viruses.
The
Feline calicivirus and murine norovirus in the family
Viruses, both enveloped and non-enveloped, are generally susceptible to high pH. At an environment of pH 12 or above, most if not all non-enveloped viruses would be inactivated, with extent depending both on temperature and contact time. Reovirus, simian virus 40, hepatitis A virus, canine parvovirus, poliovirus, murine norovirus, and Tulane virus seem to be less susceptible than minute virus of mice, feline calicivirus, adenovirus, rotavirus, and foot-and-mouth disease virus. It may be worth noting that the order of susceptibility to high pH seems to be in discord with the hierarchy concept by the greatest degree: in this case, an enveloped virus, bovine viral diarrhea virus, seems to be less susceptible than most, if not all, non-enveloped viruses [22]; parvoviruses are not necessarily less susceptible than many other non-enveloped viruses; and the size of the viral particle does not seem to matter much with regard to the degree of susceptibility (Table 7).
Virusa | Method | Soil/Matrixb | Log10 Reduction after | References | |||
---|---|---|---|---|---|---|---|
≤ 1 min | 10 min | 30 min | 1 hr | ||||
MNV | Suspension test | Medium | ∼2 | [30] | |||
TuV | Suspension test | Medium | ∼2.2 | [30] | |||
FCV | Suspension test | Medium | >5.5 | [30] | |||
REO-3 | Suspension test | Medium | 3 | [68] | |||
Cox B | Suspension test | Medium | 5 | [69] | |||
Echo 11 | Suspension test | Medium | 6 | [68] | |||
BVDV | Suspension test | Medium | 2.5 | [70] | |||
HAV | Suspension test | Medium | 2.7 | [59] | |||
SV40 | Suspension test | Medium | 3.9 | [70] | |||
HAV | Stainless steel | 5% serum | 3.0 | [43] | |||
HAV | Stainless steel | 90% plasma | 3.6 | [43] | |||
CPV | Stainless steel | 5% serum | 3.5 | [43] | |||
CPV | Stainless steel | 90% plasma | 5.2 | [43] | |||
MVM | Suspension test | Medium | >4.7 | [71] | |||
MVM | Suspension test | Medium | >4 | [66] | |||
CPV | Suspension test | Medium | 5.6 | [70] | |||
PV | Suspension test | Medium | 5.9 | [70] | |||
AdV-2 | Suspension test | Medium | >6.9 | [70] | |||
AdV-5 | Suspension test | Medium | >6 | [72] | |||
HAV | suspension test | Medium | 2.4 | [59] | |||
PV | suspension test | Medium | 4.1 | [63] | |||
Avian Reo | Suspension test | Medium | 4 | [73] | |||
PV | Suspension test | Medium | 5.1 | [73] | |||
Bovine Rota | Suspension test | Medium | >6 | [73] |
Efficacy of high pH against non-enveloped viruses.
Entries in purple font indicate results from undiluted or diluted formulations with microbicidal active ingredients.
Aldehydes, such as glutaraldehyde, formaldehyde, and
Virusa | Method | Soil/Matrixb | Log10 Reduction after | References | |||
---|---|---|---|---|---|---|---|
5 min | 10 min | 30 min | 60 min | ||||
HAV | Suspension test | Medium | 3.0 | [75] | |||
PPV | Stainless steel | BSA | 1.7–2.8 | [34] | |||
MVM | Stainless steel | BSA | 2.5–3.3 | [34] | |||
PV1 | Suspension test | Medium | >3 | [76] | |||
AdV-5 | Stainless steel | BSA | 4.9–6.3 | [34] | |||
PPV | Stainless steel | Erythrocytes + BSA | 3.6 | [26] | |||
MVM | Stainless steel | Erythrocytes + BSA | >4.4 | [26] | |||
AdV-5 | Suspension test | Medium | >5.0 | [77] | |||
Ortho-phthaldehyde, 0.55% | |||||||
PPV | Stainless steel | Erythrocytes + BSA | 3.6 | [26] | |||
MVM | Stainless steel | Erythrocytes + BSA | >4. | [26] |
Efficacy of aldehydes against non-enveloped viruses.
See Table 1 for abbreviations used for viruses.
BSA, bovine serum albumin; medium, culture medium; RT, room temperature.
Entries in purple font indicate results from original or diluted formulations with microbicidal active ingredients.
In the simplified hierarchy of susceptibility of pathogens to microbicides concept, small non-enveloped viruses are considered less susceptible than large non-enveloped viruses, and both groups of non-enveloped viruses are believed to be less susceptible than enveloped viruses. The hierarchy concept also assumes that the ranking applies to all types of microbicidal actives. Additionally, the hierarchy concept can generally lead to common notions that viruses that share similar virological properties (e.g., same family or genus of virus) may be expected to display similar degrees of susceptibility and that the smaller a virus is, the less susceptible it will be to microbicides in general.
These generalizations are correct, to a degree. For example, most enveloped viruses are indeed more susceptible than non-enveloped viruses to chemical inactivation. It should be noted though that exceptions to the hierarchy concept do exist, e.g., especially in the case of viral susceptibility to acids and alkalines [22], and exceptions are not uncommon for certain other chemistries. The hierarchy concept was never applied specifically to physical inactivation approaches, nor should it be. The evidence for heat inactivation, UV inactivation, and gamma irradiation indicates differing rankings of susceptibility to these modalities. Envelope status and particle size do not, in each case, relate to susceptibility for inactivation by these physical approaches [22, 78, 79, 80].
The validity of the hierarchy concept
The accuracy and usefulness of a hierarchy concept can be improved if the model is broken into separate chemistries for non-enveloped viruses, since many viruses do exhibit a reliable and consistent trend of susceptibility for a specific type of chemical. Table 9 and Figure 2 provide a summary of the relative order of susceptibility for selected non-enveloped viruses under specific types of chemistry.
Chemical | Lower susceptibility | Medium susceptibility | Higher susceptibility |
---|---|---|---|
Ethanol | Animal parvovirus | Poliovirus | Murine norovirus |
Simian virus 40 | Foot and mouth disease virus | Rhinovirus | |
Hepatitis A virus | Human norovirus | Adenovirus 5 | |
Enterovirus 71 | Feline calicivirus | Rotavirus | |
Adenovirus 2, 8 | |||
Isopropanol | Animal parvovirus | Adenovirus 5, 8 | Simian virus 40 |
Hepatitis A virus | Murine norovirus | Rotavirus | |
Enterovirus 71 | |||
Poliovirus | |||
Feline calicivirus | |||
NaOCl | Porcine parvovirus | Minute virus of mice | Feline calicivirus |
Hepatitis A virus | Hepatitis A virus | Adenovirus | |
Poliovirus | Rotavirus | ||
Enterovirus 71 | |||
Murine norovirus | |||
H2O2 | Animal parvovirus | Poliovirus | Rhinovirus |
Hepatitis A virus | Murine norovirus | Feline calicivirus | |
Adenovirus | Rotavirus | ||
PAA | Animal parvovirus | Poliovirus | Feline calicivirus |
Hepatitis A virus | Murine norovirus | ||
Adenovirus | |||
QAC | Animal parvovirus | Feline calicivirus | Rotavirus |
Poliovirus | Murine norovirus | Rhinovirus | |
Adenovirus 8, 25 | Adenovirus 5 | Coxsackievirus A11 | |
Low pH | Minute virus of mice | Human parvovirus 4 | Feline calicivirus |
Hepatitis A virus | Rhinovirus | ||
Poliovirus | Foot and mouth disease virus | ||
Enterovirus 71 | Enterovirus EV-D68 | ||
Coxsackievirus A9 | Human parvovirus B19 | ||
Murine norovirus | |||
Rotavirus | |||
Reovirus | |||
High pH | Bovine viral diarrhea virus | Reovirus | Murine minute virus |
Simian virus 40 | Feline calicivirus | ||
Hepatitis A virus | Adenovirus | ||
Canine parvovirus | Rotavirus | ||
Poliovirus | Foot and mouth disease virus | ||
Murine norovirus | |||
Tulane virus | |||
Aldehydes | Porcine parvovirus | Minute virus of mice | Poliovirus |
Hepatitis A virus | |||
Feline calicivirus | |||
Adenovirus | |||
Reovirus | |||
Rotavirus |
Relative order of susceptibility of non-enveloped viruses to chemical inactivation.
Abbreviations used: H2O2, hydrogen peroxide; NaOCl, sodium hypochlorite; PAA, peracetic acid; QAC, quaternary ammonium compound.
Relative order of susceptibility of non-enveloped viruses per microbicidal chemistry. Note: various types of adenoviruses exhibit different degrees of susceptibility to ethanol and quaternary ammonium compounds.
The Spaulding concept of the hierarchy of susceptibility of pathogens to microbicidal inactivation, along with its modifications, has been widely influential. Multiple industries as well as regulatory agencies have adopted or referenced this concept to various degrees [9, 10, 81, 82]. The concept does provide a good tool for understanding the innate differences and trending of susceptibility among various types of pathogens. For the most part, the hierarchy is insightful and valuable. It is particularly helpful when a pathogen is newly emerged, and limited or no knowledge is yet available regarding its level of susceptibility to microbicides [83, 84]. In fact, the United States Environmental Protection Agency (U.S. EPA) and Centers for Disease Control and Prevention (U.S. CDC) use the hierarchy concept as the basis of the Emerging Viral Pathogen Guidance for Antimicrobial Pesticides and public hygiene [10, 82, 85, 86] specifically to deal with just such a possibility.
It should be cautioned, however, that the hierarchy concept is largely oversimplified and by no means perfect [87]. For viruses, although enveloped viruses are usually more susceptible than non-enveloped viruses, certain enveloped viruses such as bovine viral diarrhea virus can be less susceptible than some non-enveloped viruses (e.g., feline calicivirus) under certain chemistries (e.g., low pH and high pH).
The accuracy and applicability of the hierarchy concept are more complex and limited among non-enveloped viruses. The trending is highly dependent on the type of chemistry; and the size of the virion is not always a primary determinant of viral susceptibility among non-enveloped viruses. If a clearer and more consistent trending can be identified among non-enveloped viruses, albeit only specific to a given type of chemistry, the knowledge should be useful.
To generalize an order of susceptibility, for a specific chemistry, data from side-by-side studies wherein viruses are evaluated concurrently by the same test method and under the same conditions should, ideally, be used. When results from different studies are used, caution should be taken to exclude conditional or case-specific differences that result from the test methodology and/or condition. For instance, a surface (carrier) test may give different log10 reduction results than a suspension test of the same microbicide or formulation under certain situations [88]. For example, the data of Kindermann et al. [47] and Tyler et al. [31] indicate that sodium hypochlorite causes a higher log10 reduction value (LRV) when tested in a suspension test than in a surface test. On the other hand, glutaraldehyde has been found to cause similar log reduction in either methodology, while hydrogen peroxide causes higher LRV in the surface test, which is thought to be likely related to the consumption of hydrogen peroxide by the protein in the virus-suspending solution [31].
The organic soil load in which the challenge virus is suspended prior to inoculation can also impact the viral inactivation outcome, especially for oxidizers, alcohols, and QAC. It would be inaccurate or even misleading if a result from a light organic load (e.g., 5% animal serum or phosphate-buffered saline) were to be directly compared with a test that used a heavier organic load (e.g., 90% blood or 20% fecal suspension). Tung
Other testing conditions may also affect the reduction results. For instance, a higher contact temperature may work in the favor of the virucide under investigation, which may result in a higher log reduction. Nemoto et al. [56] reported that a 0.125% glutaraldehyde solution completely inactivated rotavirus after 10 min under ambient temperature, but not when evaluated on ice. The pH and other components in the product formulation could also affect the viral reduction outcome, presumably by activating the chemical and/or by a synergistic or additive effect between the pH and the active chemical [22, 39, 89]. The efficacy of formulated versus non-formulated microbicides may differ even within the same type and concentration of active(s). For example, formulated QAC and ethanol products have been reported to exhibit strong activities against certain non-enveloped viruses albeit the efficacy may be weaker for non-formulated solutions [45, 54, 90, 91]. Therefore, the formulation of the microbicidal active must be considered. The viral stock (i.e., inoculum) preparation method and the challenge viral titer may also affect the reported viral reduction efficacy. For example, purified virus may be more susceptible than crude virus preparations [49]; viral clumps can make the virus less susceptible [92]; and a higher viral challenge titer could make the chemical harder to achieve an expected log10 reduction. Sometimes, viruses propagated in different host cell types may behave differently. It would therefore be ideal if all studies could use a standardized viral preparation and infectivity assay protocol. This is, of course, practically challenging. Last, but not least, the method for preparing the microbicide and the verification of the active concentration might also differ from lab to lab, thus potentially influencing the efficacy results obtained.
Despite these practically hard-to-avoid differences in test methodology and conditions, some generalizations on the pattern of susceptibility among non-enveloped viruses can still be made with confidence. For instance, it is quite apparent that the
The family
Different types of adenoviruses seem to exhibit varying degrees of susceptibility to ethanol and QAC. For example, adenovirus type 5 appears to be notably more susceptible to ethanol than are adenovirus types 2 and 8. In general, however, adenoviruses are more susceptible than many other non-enveloped viruses. Considering that adenovirus type 5 is listed as one of the allowable challenge viruses for a generic or “broad-spectrum” virucidal efficacy claim (i.e., a product that is effective for adenovirus type 5 may be considered effective against all viruses) [97, 98], this practice may not represent a challenge and lead to an insufficient safety margin, which is not supported by the published data.
Parvoviruses are among the smallest of non-enveloped viruses. The animal parvoviruses (e.g., minute virus of mice, porcine parvovirus, bovine parvovirus, canine parvovirus, etc.) are considered to exhibit very low susceptibility to chemical inactivation [99] and are commonly used as a worst-case model for viral inactivation studies. This literature review generally supports this notion, although it should be noted that the animal parvoviruses do not appear to represent a worst-case challenge for high-pH inactivation, and porcine parvovirus seems less susceptible than minute virus of mice at times. Additionally, human parvovirus B19 seems especially susceptible to acid treatment [100].
It has been observed that the particle size of a virus is not an exclusive or even a primary determinant of susceptibility to microbicides for non-enveloped viruses, albeit this characteristic may play a role. There are numerous reports demonstrating that larger non-enveloped viruses, such as adenoviruses and reoviruses, are less susceptible than some of the smaller non-enveloped viruses for certain chemistries. Interestingly though, rotavirus, a large non-enveloped virus, indeed seems to be the most susceptible among non-enveloped viruses, except to low pH.
The mechanisms underlying the large variation in susceptibility among non-enveloped viruses and the chemistry dependency are not always clear, but they could presumably be related to the physicochemical properties of the virus as well as the mechanisms of action of the chemical inactivants. For alcohols, for instance, it has been proposed that the hydrophobicity or hydrophilicity of the viral particles is an important determinant of susceptibility [101]. Poliovirus, which is hydrophilic, is more susceptible to ethanol than it is to isopropyl alcohol. This is attributed to the fact that ethanol is more hydrophilic than isopropanol. In comparison, the hydrophobic simian virus 40 is susceptible to isopropanol but not to ethanol [101]. Enterovirus 71 (EV71) and enterovirus EV-D68 (EV-D68) are both enteroviruses in the family
A review of the relative order of susceptibility for non-enveloped viruses under each chemistry reveals that the order for some chemicals (e.g. aldehydes) seems to fit the traditional hierarchy concept well (e.g., parvoviruses are less susceptible than larger viruses); but the order for some other chemistries (e.g., low pH) does not seem to agree with the concept as well.
The variability in viral susceptibility to physical treatments is not covered in this chapter; however, a marked degree of variation also exists for physical treatments, both within non-enveloped viruses and between enveloped and non-enveloped viruses [12, 16, 21, 49]. A comparison of the order of susceptibility of viruses to chemical versus physical treatments and an exploration of the underlying mechanisms would be interesting and revealing.
This chapter reviewed the literature on chemical inactivation of non-enveloped viruses, with an emphasis on the relative difference and trending of susceptibility among some relevant (from a public health perspective) non-enveloped viruses under each type of chemistry. The traditional concept of a hierarchy of susceptibility to microbicides provides a useful tool in understanding and predicting the susceptibility of a pathogen; however, the concept tends to be oversimplified. The order of susceptibility among non-enveloped viruses depends on the type of chemistry, and there is no universal order that holds true for all types of chemistries. Picornaviruses and caliciviruses exhibit a particularly high degree of intrafamily variation, and the order may even be reversed between viruses, depending on the chemistry. Additionally, larger non-enveloped viruses are not always more susceptible than some of the smaller non-enveloped viruses. It may be inappropriate to consider adenovirus type 5 as a worst-case non-enveloped virus; and even the animal parvoviruses, universally considered among the least susceptible to chemical inactivation, do not actually represent the least susceptible virus type for certain chemistries.
The author thanks Drs. Raymond Nims and M. Khalid Ijaz for the critical review of the manuscript and discussion.
The author declares no conflict of interest.
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\\n\\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported and Creative Commons 4.0 International License, a license which allows for the broadest possible reuse of published material.
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The CC BY 3.0 and CC BY 4.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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\\n\\nAll rights to Books and Journals and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
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\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported and Creative Commons 4.0 International License, a license which allows for the broadest possible reuse of published material.
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\n\nDISCLAIMER: Neither the CC BY 3.0 license, CC BY 4.0, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and Journals and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
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\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
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\n\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
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