Respiratory Viral Infections: Progress and Innovation

The ongoing COVID-19 pandemic has brought into focus the impact that respiratory viral infections have on the health and well-being of the world’s populations. While so-called “emerging” pathogens like the SARS, MERS, and SARS-2 coronaviruses, along with avian and pandemic influenza, tend to grab the headlines, less well-recognized is the fact that respiratory infections caused by more “common” viruses--seasonal influenza, respiratory syncytial virus (RSV), parainfluenza, adenovirus, and rhinovirus-- are actually among the leading causes of global morbidity and mortality on an annual basis. While funding and technological constraints have historically limited progress in combating these traditional respiratory viral diseases, recent advances in diagnostics, therapeutics, and prophylaxis, many of which have been born of innovations stimulated by the spectre of pandemic influenza and the devastation of COVID-19, are bearing fruit in the form of promising new countermeasures targeting these other pathogens.

 

Contract Research Organizations like Allucent are standing with the global community, actively supporting the fight against COVID-19 by bringing new therapies and vaccines to patients in need.

 

Innovation is everywhere

Diagnostics

Molecular amplification and other technologies that enhance speed, accuracy, and portability have transformed the diagnostic landscape for respiratory viral infections in recent years. Multiplex assays for simultaneous detection of multiple respiratory viruses, isothermal amplification of pathogen nucleic acids, lateral-flow assays, enhanced antigen detection schemes, chemiluminescence, and other platforms have dramatically improved our ability to quickly and accurately diagnose these infections…in many cases, without the need for highly trained personnel and dedicated laboratories. For genome sequencing and other high-tech assays requiring more sophisticated and specialized infrastructure, and in order to more efficiently analyze and interpret disease trends, consolidation of clinical microbiology laboratories on a regional or national level has become more frequent, enhancing both understanding and communication of data for these infections.

 

Therapeutics

Influenza, RSV, and more recently SARS-CoV-2, have been the primary (though not exclusive) focus of efforts to develop small molecule and biologic antiviral therapeutics…efforts that have begun expanding more aggressively to other virus families as well. The successes with oseltamivir (Tamiflu™) for seasonal influenza, palivizumab (Synagis™) for RSV in premature infants, and remdesivir (Veklury™) for COVID-19 patients are testament to the potential for effectively targeting these viruses and has stimulated research and development of complementary and/or “next generation” drugs and biologics for these infections. Further, discoveries underlying these drugs as well as that for other (non-respiratory) virus infections (e.g. filoviruses, hepatitis viruses) are being leveraged for the development of drugs and biologics to counter other respiratory pathogens (e.g. rhinoviruses, adenoviruses). In addition, more novel, non-traditional approaches to antiviral therapeutics are being explored. For example, manipulation of the respiratory microbiome, and “biologic” enhancement of innate immune responses (e.g. via intranasal instillation of attenuated influenza strains or Bacillus subtilis spores) are under active investigation.

Host-directed therapies represent an alternative and complementary approach to these respiratory viral infections, with strategies that have gained higher visibility in the context of COVID-19 than perhaps previously. Monoclonal antibodies targeting cytokines and other molecules in the inflammatory cascade (e.g. tocilizumab, baricitinib) have been shown to accelerate improvement and reduce mortality in patients with severe COVID-19, and small-molecule drugs that act to modulate pathogenic inflammatory responses (e.g. N-acetyl-cysteine and bucillamine antioxidants that scavenge pathologic reactive oxygen species in response to inflammation) are under evaluation in influenza and COVID-19 patients.

 

Prophylaxis

The need to rapidly respond to emerging pathogen threats has driven a revolution in vaccine development for respiratory (and other) viruses. The speed by which mRNA vaccines have been created and deployed to prevent and contain the spread of the SARS-CoV-2 virus across the globe is without historical precedent, and augers favorably for application to other respiratory viral pathogens; indeed, mRNA vaccine candidates targeting influenza and RSV are currently under active development and evaluation in preclinical and clinical studies. Viral (e.g. adenovirus, vaccinia) vector and other platforms have likewise been leveraged to create and deploy safe and effective SARS-CoV-2 vaccines in record time, and hold promise for similar success with other respiratory viruses. Similarly, nanoparticle subunit vaccines that enable presentation of critical antigenic sites to the immune system in the context of different matrices are showing great promise in the fight against COVID-19, RSV, and other respiratory viruses. Even more novel approaches such as naked DNA, bacterial outer membrane vesicles engineered to display heterologous proteins of SARS-CoV-2 and other pathogens, so-called “universal” influenza vaccine candidates based upon the highly conserved stalk region of the virus hemagglutinin, live-attenuated vaccines with re-designed and “optimized” molecular structures, chimeric antigen constructs, and others are likewise under active investigation and beginning to show promise in human trials targeting RSV and influenza. Many of these and more traditional (e.g. whole virus inactivated, live-attenuated) vaccine technologies are further enhanced by new and more effective adjuvants to more precisely target and steer host immune responses.

Complementing the field of “active” (i.e. vaccine) prophylaxis is an emerging focus on so-called “passive” immunoprophylaxis using hyperimmune plasma and monoclonal antibodies. Monoclonal antibodies engineered to increase half-life (e.g. YTE mutation) and/or to modify effector functions (e.g. LALA mutation) offer potential alternatives for preventing respiratory infections in immunocompromised individuals and others unable or unwilling to receive active vaccination. Trials to assess the effectiveness of these approaches, with and without concurrent vaccine use, are ongoing.

 

Bioinformatics and global Information Sharing to Advance Respiratory Virus Research

Perhaps on the broadest scale in modern history, the global crisis of COVID-19 has fast-tracked the disciplines of statistics and bioinformatics, as well as cross-border, intercontinental information sharing. Systems and tools for analysis of SARS-CoV-2 virus isolates have been critical to understanding the evolution and spread of this pathogen; these analytic techniques will no doubt be leveraged to better understand the epidemiology and transmission dynamics of influenza, RSV, and other pathogens in the near future. In an article published by the European Commission in Horizon in fall 2020, experts across Europe emphasized the importance of developing standards for collecting, compiling, and sharing genomic data. The standardization of mobile communication networks makes it more possible than ever to democratize and easily move vital information.

 

The Future State

It is clearly impossible to provide an exhaustive layout of the new and emerging technologies that are being brought to bear in addressing respiratory viral pathogens. Suffice it to say that even as SARS-CoV-2 continues to proliferate, mutate, adapt, and require urgent attention, the larger world of clinical and drug research continues to address respiratory virus infections as a whole. Pharmaceutical and non-pharmaceutical interventions alike have the power to limit future outbreaks of diseases, which reduces the burden of care for healthcare systems. 

With better tracking and information sharing, models are being developed that equip and inform healthcare professionals to manage public health events. While circulating strains of various viruses have the inherent unpredictability of transmissibility and evolutionary dynamics, progress is being made in many sectors to better predict, detect, and treat respiratory illnesses.

For more information on how Allucent supports innovation in research activities for respiratory infections and more, contact us.