Issues Magazine

Emerging Diseases – What’s New in Influenza?

Issues 75: Emerging Diseases

Issues 75: Emerging Diseases

By Greg Tannock

"Influenza is an unvarying disease caused by a varying virus." (E.D. Kilbourne, The Influenza Virus and Influenza, Academic Press, N.Y., 1975). We now know that this statement, made at a time when memories of the great pandemic of 1918–19 were beginning to fade, is true of most seasonal influenza epidemics. However, caution is needed when making sweeping generalisations about influenzal disease and influenza viruses.

In the March 2006 issue of Issues I conjectured that there was an enormous and rapidly increasing reservoir of H5N1 avian influenza viruses with a potential to infect humans. As with other influenza A viruses, mutation was an ongoing phenomenon and clear genetic divergence had been noted between strains isolated from different parts of South-East Asia since 2003. The presence of these divergent strains, or clades, complicated the task of vaccine development. I further conjectured that if critical changes to the avian virus genome took place, the virus could develop a capacity to spread rapidly in the absence of a bird host (i.e. to become humanised).

Fortunately, over the past six years such changes have not occurred and the total number of reported cases is 600–700, with a mortality of 50–60%. Mortality appears almost exclusively confined to individuals in close contact with poultry or aquatic birds.

Influenza: A Recap

Influenza (the flu) is an infectious disease caused by RNA viruses that can infect birds and mammals. Influenza A and B viruses are common causes of acute respiratory illness, with influenza A viruses being considered the greater risk for humans because of their great capacity to change and to be transmitted from animals, notably aquatic birds. Major outbreaks of illness usually follow changes to the influenza A virus. When these changes occur, entire populations are at risk (see box, p.43). Only three of the 17 influenza A subtypes – H1N1, H2N2 and H3N2 – have been responsible for pandemics over the past century.

Evading Immune Recognition

Influenza viruses are remarkably complex, both in the way they multiply within individual cells and in their capacity to cause disease. Whereas most viruses possess one gene that carries out all their functions, influenza viruses are made up of eight discrete genes that act independently of each other, a property that was long considered to be the principal reason for the random appearance of new pandemic viruses by a mechanism known as gene reassortment.

For influenza viruses, carbon copies of individual genes (rather than the genes themselves) serve as the templates for synthesis of the proteins required for infection to take place. Because this copying process is imperfect, the consequent errors produce virus mutants that may not be recognised by previous infections or by vaccination. Both the high mutation rate and the random unpredictable nature of genetic reassortment with influenza A viruses enable them to evade immune recognition, and poses significant problems in the development of strategies to prevent infection.

To further complicate matters, recent molecular archaeological evidence from the lungs of individuals who died as a consequence of the 1919 pandemic suggests that the initial triggering event was direct transmission from an avian to a human host, followed by mutational changes and/or gene reassortment.

Seasonal Influenza and Vaccination

In most years, influenza A and, to a lesser extent, influenza B viruses undergo relatively minor seasonal changes to their surface antigen genes. Largely because of these changes (known as antigenic drift), vaccine manufacturers in most non-pandemic years are required to update their product. In most years, congruity is achieved between the antigens present in the vaccine and the prevailing seasonal viruses, which is a tribute to the efficiency of surveillance networks established over 60 years by the World Health Organization. Seasonal influenza outbreaks are a significant public health problem and are responsible for severe illness and death in high-risk populations (the elderly and young children, diabetics and those with underlying respiratory disease).

Unlike other common respiratory viruses, seasonal influenza viruses are capable of producing infections of the entire respiratory tract. The outcome of an infection depends on a number of host factors that include the immune status of the individual and the presence of particular types of receptor that are present throughout the respiratory tract. Most infections by literally hundreds of other respiratory viruses are confined to specific parts of the respiratory tract, the best examples being rhinoviruses and non-SARS coronaviruses, which are responsible for most common colds. These viruses have vastly different modes of replication but do not have the capacity to undergo variation of the kind possible for influenza viruses. Also, influenza viruses are capable of producing infections of the upper respiratory tract that are clinically indistinguishable from other common cold viruses.

Vaccination is the most effective way to prevent illness by seasonal influenza viruses. Effective and safe vaccines have been available for many years but their uptake in Australia, especially in high-risk individuals, has been less than optimal.

For new pandemic viruses, where the entire population is susceptible, issues of technical feasibility and logistics figure far more prominently. In the 2009 swine flu pandemic, millions of doses were unused. The problem then and in the 1957 and 1968 pandemics was that although a need for appropriate vaccines was widely recognised, the inevitable delay in vaccine manufacture (these days a minimum of 3–6 months) meant that only a fraction of the population of developed countries and virtually no one in the developing world could be afforded protection in advance of the expected peak time for infection. Unfortunately, despite our increased knowledge, we are still unable to predict when the next pandemic will occur.

Bird Flu and Swine Flu

What have we learnt about highly pathogenic avian influenza (HPAI) viruses (the H5N1 bird flu virus) and the variant H1N1 2009 swine flu pandemic virus? We now know much about the molecular basis for virulence in HPAI viruses and why transmission between birds and humans is relatively inefficient. Unfortunately, early concerns about likely difficulties in producing effective vaccines by standard methods, using viruses grown in eggs, have proven to be largely correct. The protective H5 antigen in vaccines is a poor immunogen and must be delivered in more than one dose, preferably in the presence of an adjuvant (a booster substance frequently used to enhance vaccine performance).

In April 2009 a new pandemic virus appeared in Mexico and rapidly spread throughout the world. The virus was a triple reassortant with a genome consisting of swine, avian and human influenza genes. Like most other pandemic viruses, the origin of critical events leading to reassortment is unknown. In comparison with recent seasonal viruses, the H1N1 pandemic virus was comparable in virulence but highly transmissible. It rapidly displaced viruses of an earlier H1N1 series that had been around since 1977 (as part of the H1N1 so-called Russian viruses) and appeared to cause severe symptoms in children with neurological disease, women in their third trimester of pregnancy and others with underlying respiratory disease. Infection appeared to be confined to individuals younger than 45 years, suggesting that some earlier, and as-yet unknown, priming infections by similar viruses conferred long-term immunity.

Where to from Here?

It should be clear that the only possible take-home message from studies of human influenza A infections is to “expect the unexpected!” It is also clear that our conventional approach to vaccination, involving the accreditation of a seed pandemic virus for propagation in eggs, is unlikely to result in pandemic vaccines being widely available before the second wave of infections by the pandemic virus. Several proposals to develop so-called universal vaccines have been proposed that would allow the stockpiling of vaccines for at least temporary protection against all influenza A viruses, the object being to provide vaccine manufacturers a much wider window to prepare conventional subtype specific vaccines. Three major approaches are being pursued, using as the active component(s) of vaccines:

  • synthetic preparations of the small M2 surface protein, which is structurally similar in all influenza A viruses
  • the non-variable stalk region of the protective haemagglutinin molecule
  • intranasal administration of influenza viruses that possess defective haemagglutinin genes. These viruses are unable to multiply but produce good protective responses that are mediated by certain internal genes.

A recent paper by Professor Alain Townsend and colleagues at the University of Oxford suggests that the third of these options has considerable promise. Their approach is in a sense complementary to the use of intranasally administered live attenuated vaccines against influenza, widely used in the US and Russia, and has is both safe and protective. The vaccines are especially protective in children and will be introduced for all children in the UK by 2014 under their National Health Scheme. Live vaccines have been under development over many years and appear to produce broader and more relevant protective responses than vaccines delivered by injection.

The next few years are likely to be very exciting for influenza vaccine development.