By Dr Tomislav Meštrović, MD, PhD
Influenza viruses are important pathogens that can cause sporadic respiratory diseases, annual epidemics and (in case of influenza A virus) periodic pandemics. Thus innovative and continuous research is needed in order to better understand viral pathogenesis and genomics, body's immune response to the infection and the epidemiology of the virus in order to create adequate countermeasures.
Collaborating Centers of the World Health Organization (WHO) in Atlanta, London, Melbourne, Beijing and Tokyo are responsible for conducting research on influenza viruses circulating among humans in different countries around the world. This information is then used by the WHO to make recommendations on which viruses should be a part of annual seasonal influenza vaccines for the northern and southern hemispheres.
Influenza researchers at five sites in the United States received funds from the American National Institute of Allergy and Infectious Diseases (NIAID) to collaborate with scientists worldwide in a network designed to advance understanding of influenza viruses – especially how they cause disease. The centers are based in Icahn School of Medicine at Mount Sinai (New York City), Emory University (Atlanta), St. Jude Children’s Research Hospital (Memphis), University of Rochester Medical Center (Rochester) and Johns Hopkins University (Baltimore).
A key mission of such network of Centers of Excellence for Influenza Research and Surveillance is to foster innovative and cooperative basic research on influenza viruses, including how they evolve and adapt to both human and animal hosts. The network has a global reach, with collaborations in Asia, Southeast Asia, the Middle East, Europe, South America and Australia. Gained information help in understanding why influenza pandemics occur and how to avoid them in the future.
Developing therapeutics for influenza
Two classes of antiviral medications are currently used for the treatment of influenza, but each has limitations in scope and its effectiveness. Antigenic diversity of the virus and constant influx of new subtypes allow the virus to become resistant to these antiviral drugs and evade vaccines. There is therefore a continuing need for new anti-influenza therapeutics using novel targets and creative strategies.
Broad research efforts resulted in a new generation of neuraminidase (NA) inhibitors which suggests that NA may continue to be a rational target for newer inhibitors in the future, effective against viruses that developed resistance to the older inhibitors. Multiple drug cocktails that target several viral functions and monoclonal antibodies have also shown much promise.
An aggressive immune response known as the cytokine storm plays an important role in causing significant tissue injury and mortality following human pathogenic influenza virus infection. New research has shown that dampening such host’s immune response by using specific immunomodulatory sphingosine-1-phosphate receptor agonists can provide substantial protection from mortality over that observed by the neuraminidase inhibitor oseltamivir.
The antiviral approach based on the use of small synthetic interfering RNAs (siRNAs) has several advantages when compared to traditional antiviral compounds; siRNAs can act as a highly potent antiviral agents with both preventive and therapeutic value, they can be designed and synthesized in hours and applied in combination with other siRNAs in a multidrug regimen to reduce the odds of resistance, or to target multiple co-infecting viruses.
Innovative vaccine models
Despite advances in the field, most vaccine formulations for influenza are still produced by rather old-fashioned techniques that have been in use for over 60 years. Such methods involve the growth and passaging of the vaccine strains in embryonated chicken eggs, therefore production and subsequent formulation can take several months and rely upon the availability of the eggs.
Increasing demands for influenza vaccines, especially during pandemic where there is a need for a rapid production of pandemic influenza vaccines, necessitates new research approaches that will result in the development of new egg-independent manufacturing platforms. The first egg-free recombinant influenza vaccine (produced in an insect cell line) was approved by the US Food and Drug Administration in January 2013 and was available for the influenza season of 2013-2014, demonstrating the proof of principle.
In addition, a myriad of T cell-based vaccines have been developed and tested in both animals and humans, offering additional avenues for the stimulation of heterosubtypic immunity. Conserved internal proteins of the virus represent targeted antigens in this approach.
With the next generation of vaccines, researchers aim to induce more broadly reactive, long-lasting immunity against a wide range of influenza virus types and subtypes. The end-goal is a universal influenza vaccine which would provide protection from unexpected epidemics and pandemics in the future.
- Nicholson KG, Webster RG, Hay AJ. Textbook of Influenza. Blackwell Science, Oxford, 1998.
- Lamb RA, Krug RM. Orthomyxoviridae: The viruses and their Replication. In: Fields Virology fourth edition, Knipe DM, Howley PM eds, Lippincott, Philadelphia 2001, pp 1487-1531.
Last Updated: Nov 9, 2014