Throughout history, influenza epidemics appear to have affected the population causing widespread illness and death. In the last century, four novel strains of the viruses have emerged each responsible for a global pandemic. One of the notably worst pandemics recorded historically was in 1918 causing around 546,000 excess deaths in the United States alone and an estimated 50 million people worldwide. And, the first pandemic of the 21st century caused by the H1N1 influenza virus has resulted in approximately 151,700 to 575,400 deaths globally during the time it circulated in the first year. For decades, World Health Organization has also continued the surveillance of the viruses involving several generations of renowned influenza scientists’, yet, it still is a great challenge among the scientific community and continues to remain a threat to humans. In an effort to reduce the number of influenza-related illness and its associated deaths globally, WHO twice a year organizes consultations with various experts from WHO Collaborating Centers (CCs), Essential Regulatory Laboratories (ERLs) and other partners to make the recommendations on influenza vaccine composition. In order to combat influenza, various surveillance systems and centers were developed that both monitors and provides information about the influenza viruses which can be used by the health researchers for the development of a vaccine with high efficacy and also by acting a source for the development of a novel anti-influenza treatments in the future.

2009 Pandemic Swine Flu

It is believed to have emerged from Mexico in April 2009 and within weeks, the disease has spread over 30 countries and by July, it was reported in 122 countries. On 11 June 2009, WHO declared a global influenza pandemic which officially was over in August 2010. According to CDC, the virus is believed to be the result from reassortment which involves a process where two or more influenza viruses can exchange genetic information by infecting an individual or an animal host. This form of abrupt major changes in influenza viruses is known as ‘antigenic shift’ meaning most of the people have little or no protection against the new virus. As this form of genetic mixing can result in the emergence of viruses that can potentially cause pandemic among humans, the need for better surveillance of the virus among pigs and other animals are needed.

Future Pandemic Preparedness

Even with the current knowledge, predicting the future pandemic is not entirely possible including when and where it will occur or what the subtype will be. WHO has developed a guidance document on Pandemic Influenza Preparedness and Response that provides information such as situation monitoring and assessment, planning and executing a preparedness exercise, reducing the spread of the disease, rapid containment training package and recommends actions before, during and after a pandemic. Also, the Global Influenza Surveillance and Response System (GISRS) and the Pandemic Influenza Preparedness Framework will assist various countries for the access of antiviral drugs, vaccines and prepare for the management of pandemics.

In the Future: Universal Flu vaccine?

Immunization against influenza is an important public health intervention in order to prevent, control and manage both the seasonal flu and pandemic influenza.  Because of the constantly evolving nature of influenza viruses, global monitoring is essential for the reformulation of the vaccine components. The production of vaccine takes around 6 months and according to WHO/Europe, the two types of influenza vaccine available are the inactivated vaccines (IIV) and live attenuated influenza vaccines (LAIV).  However, researchers across the globe and at the University of Rochester Medical Center are developing a ‘universal’ flu shot that can offer protection against all seasonal and pandemic strains of the virus. The report suggests that the most promising strategies are creating a vaccine that targets the ‘stalk’ of a protein enveloping the virus. The ‘stalk’ of the virus appears to be relatively constant and by directing a vaccine and the immune response of the body towards the stalk could provide a broad protection against the infection.

Anti-Influenza Treatment

During the late 20th Century, antivirals were developed to treat influenza. In 1964, amantadine as an inhibitor of influenza was reported which provided the basis for the recent development of neuraminidase inhibitors. The current anti-influenza drugs are the neuraminidase (NA) inhibitors (Oseltamivir and Zanamivir) and M2 ion-channel inhibitors amantadine and rimantadine. However, the efficacies of these drugs are declining as the drug-resistant variants of virus continue to emerge and clearly, the development of a novel antiviral drug remains essential.

Emerging trends in drug development

FDA approved new drug for the treatment of influenza: After nearly 20 years, U.S Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza. It can be used for individuals 12 years or older and when treatment is initiated within 48 hours, it can reduce the symptoms and the duration of the illness. The safety and efficacy of the drug were demonstrated in two randomized controlled clinical trials of 1,832 individuals who either received a Xofluza, a placebo or another antiviral drug within 48 hours of the onset of symptoms. In both the trials, those who took Xo`fluza had a shorter time to alleviation of symptoms.

Favipiravir – It is a new antiviral drug and when taken orally, it interferes with the replication of influenza viral RNA by inhibiting the RNA polymerase activity.

siRNA as antiviral – although there are reports that siRNA could trigger innate immune reactions such as the Toll-Like Receptor (TLR), the novel second generation transfection reagents and nanoparticle technology that are developed can bypass the TLP pathway showing promising results as an anti-influenza treatment option.

Fludase – This antiviral drug has completed preclinical development and has entered the clinical development to prove its safety and efficacy when used among humans. The Emergency Investigational New Drug Application granted by US FDA allowed the treatment of a severely immunocompromised individual with Fludase after undergoing an allogeneic stem cell transplantation and the result showed improvement in the patient’s respiratory status.

Immunomodulatory Therapy – Its role remains unclear with a limited number of published data based on randomized controlled trials (RCTs). In some studies, the passive immunotherapy such as convalescent plasma and hyperimmune globulin has demonstrated benefit when given as an adjunctive therapy for severe influenza. One study has supported the use of a triple combination of oseltamivir, clarithromycin and naproxen for severe influenza although confirmatory studies could be very valuable.

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198166/
  2. https://www.ncbi.nlm.nih.gov/pubmed/29727518
  3. https://www.cdc.gov/flu/spotlights/pandemic-global-estimates.htm
  4. https://www.urmc.rochester.edu/news/story/5177/in-pursuit-of-a-universal-flu-shot.aspx
  5. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm
  6. https://www.pharmaceutical-journal.com/opinion/comment/research-and-developments-of-vaccines-and-drug-treatments-for-influenza/11050937.article?firstPass=false
  7. https://www.drugdevelopment-technology.com/projects/fludase/
  8. https://www.ncbi.nlm.nih.gov/pubmed/29325970
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185718/
  10. http://www.who.int/wer/2009/wer8421.pdf?ua=1
  11. https://www.cdc.gov/h1n1flu/information_h1n1_virus_qa.htm