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COUNTERMEASURES FOR RESPIRATORY TRACT INFECTIONS

A basic strategy for controlling the spread of an infectious disease is to interrupt the transmission cycle. This strategy relies on having a fundamental understanding of the virus, host(s), and environmental factors contributing to virus spread. Countermeasures for controlling a pathogen typically rely on inhibiting infection or replication, but a variety of chemicals (soaps, sanitizers, disinfectants, and/or detergents) can also be used to minimize or eliminate potential environmental exposure. Effective prevention can also be achieved through interventions such as preventing contact through isolation or wearing PPE. Unfortunately, transmission often occurs before infection control measures are put in place due to vague (or no) symptoms initially present with many respiratory diseases and as such, transmission may still occur despite adequate infection control strategies once a putative diagnosis is made. This delay between initial onset of pathogen shedding and diagnosis then necessitates further prophylactic countermeasures directed to those exposed, but not yet showing disease, or as therapeutics to those with symptoms of the disease (either pre- or postlaboratory confirmation, if confirmation is possible depending on the agent involved).

There are a number of therapeutic countermeasures available where antimicrobial agents target susceptible stages in the replicative cycle of the pathogen. Unfortunately, there are very few antiviral drugs that are broadly effective for respiratory viruses. However, many new candidate drugs that target host genes and pathways used by the virus for replication are being identified on a regular basis [83-86]. Many of these drugs can be rapidly repurposed with their safety having been previously established [84,85]. These host-targeted drugs may provide means to target multiple viruses with a single drug, but the efficacy of this type of broad-spectrum approach has yet to be established. With many respiratory infections, and specifically viral ones, lack of effective therapeutic interventions often leads to increased disease severity due to the host immune response, secondary or opportunistic pathogen involvement, etc. For example, bronchiolitis is a common sequela of uncontrolled viral replication in the lower reaches of the respiratory tract, especially in newborns, and often causes considerable morbidity and occasional mortality. RSV is one of the several agents capable of inducing bronchiolitis (often referred to as croup) in newborn children, as well as being the primary cause for hospitalization due to respiratory diseases in early childhood [87,88]. The treatment of infants with bronchiolitis is largely supportive as there are no truly efficacious therapies for bronchiolitis relative to reducing clinical endpoints such as duration of ICU or hospital stay.

Beyond antiviral drugs, vaccines have been used to help mitigate the transmission of respiratory viruses where possible. Key to aerosol vaccination efficacy is that the vaccine must generate humoral and/or mucosal immune correlates of protection that are biologically capable of preventing the initial infection, preventing reinfection, and/or reducing clinical disease in the vaccinee. The vaccine should provide robust, long-term protection and result in few or no side effects or adverse reactions, induction of clinical disease, enhanced virulence of endemic strains, etc. Ideally, administration should require a simple regimen in a form acceptable to the target population [89].

There are several categories of vaccines including live-attenuated, killed/ inactivated, subunit, vectored, and DNA, and these have all been tested for pulmonary delivery in the respiratory tract. Vaccine design, application, and actual field use vary among target pathogens. Influenza virus vaccines are a good example as seasonal vaccines include virus strains projected to circulate in the target region during the next flu season [90]. Historically, influenza vaccines were formulated as a trivalent mixture to provide protection against influenza A H3N2, H1N1, and an influenza B strain. However, continued circulation of two distinct clusters of influenza B led to the development and implementation of quadrivalent vaccines that include both the circulating influenza B lineages [90].

Vaccine delivery to the airways became feasible with the advent of commercially available pressurized metered-dose inhalers (MDIs) that were initially developed to treat asthma and chronic obstructive pulmonary disease (COPD) patients. However, MDIs suffered from difficulties due to the propellant used in the device to deliver vaccines and drugs [91]. Depending on the formulation of the preparation to be administered, that is, solution or suspension, issues arose regarding solubility and/or stability. Additionally, the devices had a low efficiency of drug targeting to the small airways and reformulation of the compound(s) to be aerosolized was required.

Approaches to overcome these limitations led to the development of dry powder inhalers (DPIs) [91]. The DPIs were designed to reproducibly deliver the vaccine to the lower respiratory tract and alveoli, typically via a mass median aerodynamic diameter of 1-5 pm. However, the extent and depth deposition within the airways was largely due to the patient’s inspiratory flow rate and volume, either of which can drastically affect the actual dosage received at a given region in the lower airways [92].

As a major issue with aqueous vaccines is loss of efficacy due to degradation many are instead prepared as a dry powder to enhance stability [93]. This method has the added benefit of limiting hydrolysis, which can further compromise the efficacy of the final product, and dry powder formulations are typically more cost effective and can reduce or eliminate cold chain requirements compared with aqueous products [93]. Several dry powder formulations are available for use with protein subunit vaccines, whole virus vaccines, and DNA vaccines, while several techniques can be utilized for the actual generation of the powder including spray-drying, freeze-drying (lyophilization), and spray-freeze-drying [93,94]. There are additional factors that affect vaccine stability and efficacy that become critically important for the stability of powdered formulations. The particle size distribution is just one of these critical factors that impact dry powder vaccine efficacy [93]. Dry powder vaccines targeting mucosal surfaces have shown promising stability and antigenicity in several preclinical and clinical studies, suggesting an expanded role for this route of administration in the future [93,95-97].

There is increasing interest in the pulmonary route for delivering both drugs and vaccines. DPIs are a promising option for the delivery of vaccines to certain patient populations, and the recent introduction of disposable devices will expand the range of DPI vaccine applications. Currently, there is a demand for needleless, shelf- stable/cold chain-independent vaccines—two inherent features of DPI-based vaccines [93]. Dry powder vaccines against respiratory pathogens have been shown to induce protective immunity in several animal models [96-98]. Most effort has been focused on influenza, with respect to the variations in the generation of the antigenic component of the vaccine such as whole inactivated virus, split virus, subunit, and virosomal vaccines. The rationale is that there is a yearly demand for influenza vaccines produced by lyophilization, spray-drying, freeze-drying, spray-freeze-drying, and/or vacuum drying due to their enhanced shelf stability [93,98,99], and effective dry powder influenza vaccines can be accurately and efficiently delivered to a variety of target populations with minimal cold chain and equipment requirements. With respect to drug delivery via a DPI system, other technologies exist for drug isolation/purification, including supercritical fluid technology, solvent precipitation (using ultrasonic waves), double emulsion/solvent evaporation, and particle replication in nonwetting templates [100]. While DPI remains a promising technology, the agent being delivered and its ability to be purified or concentrated into a powder formulation, and that powder’s specific structural characteristics, plays a large role in the success or failure of administration using a specific DPI device and powder formulation.

 
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