Transmission electron micrograph of an influenza virus particle, or “virion” (Photo Credit: Cynthia Goldsmith, Content Providers(s): CDC/ Dr. Erskine. L. Palmer; Dr. M. L. Martin)
Influenza - constant threat of a pandemic
Despite nearly 3.3 million deaths globally caused by the COVID-19 pandemic, influenza virus is still one of the greatest threats of a pandemic. Development of effective antiviral therapeutics and vaccines, particularly to emerging viral threats and those with a natural history capable of causing a pandemic is essential.
Influenza is a highly contagious respiratory disease caused by influenza viruses that are responsible for seasonal epidemics and sporadic pandemics in humans. Seasonal epidemic influenza is among the top 10 leading causes of death in the United States (~50,000/year), and in a typical year, causes 250,000-500,000 deaths worldwide. The natural history of influenza virus make it a constant pandemic threat. Of the four types of influenza viruses A, B, C and D; Influenza A and B both co-circulate in the human population and cause seasonal epidemics almost every winter.
Influenza A virus can be divided into subtypes based on antigenicity of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), with 18 known subtypes of HA (H1-H18) and 11 subtypes of NA (N1-N11). Influenza B virus diverged into two lineages, Victoria and Yamagata since 1980.
Pandemic influenza virus has occurred several times over the past 100 years, specifically in 1918 (H1N1, Spanish Flu), 1957 (H2N2, Asian Flu), 1968 (H3N2, Hong-Kong Flu), 2009 (H1N1, Swine Flu or A(H1N1)pdm09 Flu). Occasionally, other influenza A subtypes such as those from avian strains H5N1, H5N6, H6N1, H7N7, H7N9, H9N7 and H10N8 infect humans, presenting the threat for a new pandemic, but to date there has been no human-to -human transmission of these subtypes that would lead to a pandemic.
Pathogenesis
There are two recognized mechanisms by which influenza virus antigenicity, tropism, pathogenicity, and virulence can be altered. The first, termed antigenic drift, is a combination of the high error rate of the viral RNA-dependent RNA polymerase and selective pressure of the immune system. This combination leads to adaptive mutations in the globular variable domain of viral HA that change the antigenicity of HA. Adaptive mutations also occur in NA, but at a slower rate, and discordant with that of HA. The variations in antigenicity of HA and NA through antigenic drift are the root cause of seasonal influenza epidemics. The second mechanism by which influenza viruses adapt, termed antigenic shift, is a reassortment of genetic materials between two or more influenza virus A subtypes. This occurs when two or more subtypes infect a single host. Influenza A viruses have an eight segment single strand RNA genome. When two or more virus subtypes infect a single cell, the eight segments can mix and match to create a new subtype with altered antigenicity and virulence. Influenza pandemics are the result of antigenic shift creating novel subtypes of influenza A virus by reassortment of viral genomic segments.
Medical countermeasures are central to the public health response to mitigate the impact of influenza pandemics that include safe and effective vaccines and antiviral drugs. Currently, the most effective prophylaxis against influenza is immunization with trivalent or quadrivalent influenza vaccines.
Vaccines
Influenza vaccines have been used since 1940s. Current licensed vaccines are multivalent to cover a range of circulating strains identified through the surveillance programs and are composed of either inactivated or live attenuated influenza viruses. They are safe but induce narrow, strain specific immune responses and have variable effectiveness depending on how well they match the circulating strains. The vaccines are focused on immunity to the globular head domain of the major viral glycoprotein HA; however, the head domain of HA exhibits high genetic plasticity and is subject to alteration by antigenic drift; as such, they do not provide robust protection against antigenically drifted variants, different influenza viral subtypes, or durable protection extending beyond the next influenza season.
The World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) employ influenza surveillance programs to monitor influenza activity, and characterize which strains and subtypes of influenza are circulating in humans and the natural environment. These data are used to forecast the strains and subtypes likely to cause seasonal epidemics and inform the production of effective seasonal vaccines. Current seasonal influenza vaccine production is thus a system of proactive surveillance followed by a reactionary response as manufacturers must produce and distribute the vaccine 6 months after the WHO announces strains for the following season.
The holy grail for influenza vaccine would be a single formulation that durable, cross-protective activity against all current and future strains. The development of Universal vaccine remains a challenging goal. Recent discoveries of cross-reactive monoclonal antibodies specific to HA and NA, and the success of “non-traditional” vaccine platforms in the development of SARS-CoV-2 vaccines have given hope that a universal influenza vaccine may be possible.
Antiviral Drugs
In addition to immunization, treatment with influenza antivirals is an option to protect human health against influenza virus infection. The mounting threat of emerging pandemic viruses, such as pathogenic avian H5N1 and H7N9 viruses, and the catastrophic impact on human health caused by the COVID-19 pandemic has increased interests and efforts toward to the development novel antivirals.
There are four antiviral drugs FDA-approved for the treatment of influenza. There three are neuraminidase inhibitors (NAI): oral oseltamivir phosphate (Tamiflu®), inhaled Zanamivir® (Relenza), intravenous peramivir (Rapivab®), and the other (Xofluza) inhibits the viral RNA polymerase complex. Anti-influenza drugs have been approved by US FDA for use within 48 hours of symptom onset. The primary benefit of treatment is a decrease in symptom duration by 24 hours when treatment is initiated within 2 days and a reduction in diseases severity. Antivirals can be recommended for all asymptomatic patients and can be considered for certain staff especially unvaccinated or recently vaccinated people.
However, the durability of therapeutic and prophylactic efficacy of NAIs against seasonal influenza infections is compromised by the emergence of NAI-resistant viruses. Currently, no antivirals have been shown to definitively reduce serious complications, hospitalizations, or mortality in clinical trials. Thus there is a need for the development of antivirals which could inhibit transmission/replication of virus, rapidly decrease viral burden, reduce the morbidity associated with viral infections, and have a high barrier to resistance. Ideally, these therapeutics would be and active against multiple subtypes and strains of influenza including novel strains.
Preclinical Development
Pre-clinical evaluation of antivirals and influenza vaccines is an essential step towards the development of effective anti-influenza strategies. The FDA has released Guidance for Developing drugs for treatment and/or prophylaxis of influenza viruses. Specifically, this guidance addresses the Food and Drug Administration’s current thinking regarding the overall development program and designs of clinical and non-clinical studies to support the development of influenza drug products. Within the context of the non-(or pre-) clinical studies are two categories of evaluations, in vitro and in vivo. These include pre-clinical virological assessments to evaluate the range of action, mechanism of action, barrier of resistance, immunogenicity, dosing regimens and routes of administration of prospective therapeutic or prophylactic treatments of influenza virus infection. Together, data from both in vitro and in vivo virological studies along with pre-clinical toxicology and PK/PD inform protocols for clinical trials to develop influenza drug products.
At Noble Life Sciences, we have an array of model systems to aid in preclinical evaluation of drugs for treatment and/or prophylaxis of influenza viruses https://noblelifesci.com/resources/cotton-rat-influenza-model-technical-note/