Influenza

Influenza virus infection has probably shaped human populations for centuries, if not millennia. Novel influenza viruses formed by genetic reassortment of avian and mammalian viruses emerge sporadically and, if they have the necessary infectivity and transmissibility in humans, spread rapidly around the globe causing a pandemic. While mortality and morbidity varied widely between the pandemics of the last century, the loss of an estimated 50 million lives in the most devastating pandemic of 1918–1919 has had a lasting global impact. Here we briefly review the history and effects of influenza pandemics on the global human population and events of the time. Then we discuss some of the ways in which the experience of the 1918–1919 and later pandemics has influenced development of international influenza surveillance and global public health policy, the full impact of which will become apparent in future pandemics.

Influenza viruses evolved in aquatic birds. They remain there in a number of antigenically diverse forms as an enzootic reservoir¹ from which they occasionally cross into and become established in other species, including humans. Swine and horses are known to have been infected with avian influenza viruses and suggested as intermediate hosts for introduction to humans^1,2. Their domestication together with that of ducks, thousands of years ago, could have provided opportunities for repeated introductions into humans.

Outbreaks of human influenza have been chronicled from the late Middle Ages in Europe and Britain, and although outbreaks as early as the 5th century in Greece have been described by some historians, most believe that descriptions predating 1520, and possibly later, should be treated with caution^3,4. Many of these outbreaks were accompanied by high morbidity and sometimes mortality. However, it is unclear whether any of those recorded in the pre-Elizabethan period shaped world history although influenza reputedly contributed to the demise of Oliver Cromwell². A possible exception to this was the suggestion that influenza was introduced to the Americas by Columbus’s second voyage in 1492, and was the first of the Old World diseases to depopulate indigenous peoples in Hispaniola and beyond with many hundred thousand deaths⁵. Although this has been questioned, it seems probable that influenza contributed to the depopulation of the New World and other remote, immunologically naive communities including French Polynesia⁶. Similarly, the first recorded influenza outbreak in Australia in 1820 severely affected the indigenous population⁷. A disproportionate impact on indigenous populations in Australia⁸, New Zealand⁹ and elsewhere¹⁰ persists to this day.

We now know that recent, and presumably previous, influenza pandemics involved viruses bearing surface antigens, haemagglutinin (H) and neuraminidase (N), to which most or all of the population lacked immunity. These surface antigen genes originate from the avian influenza gene pool, by adaptation or genetic reassortment with circulating human or animal influenzas, thus acquiring the ability to infect and be serially transmitted in humans. Spread is global and rapid, with high morbidity and often high mortality. The new pandemic virus then persists for decades as a seasonal infection by virtue of exceptional mutability.

Although numerous epidemics with significant morbidity and mortality occurred from the 16^th century it is generally agreed that the first recorded outbreak meeting pandemic criteria is that of 1580 followed by those commencing in 1729, 1781, 1830 and 1889^3,4. The pandemic of 1918–1919 was the most deadly influenza pandemic recorded with a recent estimate of 50 million or more deaths¹¹. The pandemic was inextricably intertwined with World War I. It influenced the capacity to conduct hostilities¹² while its evolution may have been influenced by crowded conditions and soldiers’ exposure to toxic gases¹³. Remarkably the genetic blueprint of the H1N1 pandemic virus has been determined and the virus reconstructed¹⁴. Nevertheless, unanswered questions remain: how and where the virus evolved and reasons for the unusual age distribution of deaths and usually three distinct waves of differing pathogenicity.

Mortality varied across countries with sparing attributed to affluence¹⁵ and delayed introduction achieved by maritime quarantine¹⁶. Australia, where introduction was delayed until March 1919, had one of the lowest mortality rates, particularly in Tasmania¹⁶. Undoubtedly the pandemic had enormous social and economic impact in most societies but most attention was given to elucidating its cause, mode of transmission and toll, rather than to its social and cultural dimensions or consequences. It may never be possible to disentangle these from the consequences of the war. In Australia, where it stressed relations between the states, it was a catalyst for formation of the Commonwealth Department of Health¹⁷. There is, however, the intriguing possibility of one huge historical consequence. US president Woodrow Wilson suffered severe influenza absenting him from much of the WW1 armistice negotiations. This resulted in Britain and France imposing severe punitive conditions on Germany in the Treaty of Versailles which may have facilitated the rise to power of Adolf Hitler¹⁸.

Influenza viruses were first isolated in the early 1930s, and shortly afterwards the first inactivated virus vaccines were produced and used by the allied forces in the Second World War. In 1947, a major antigenic change in the circulating Type A viruses resulted in vaccine failures. This kindled fears of another influenza pandemic like 1918–1919 and was a driver for an informal meeting of influenza experts during the 4th International Congress of Microbiology in Copenhagen in July 1947. They recommended to the Interim Commission of the World Health Organization (WHO) that an international surveillance program for influenza be initiated. Following adoption by WHO in September 1947, a World Influenza Centre was established at the National Institute for Medical Research, London, to work with regional laboratories and, later, national centres to study epidemiology and isolate new influenza strains¹⁹. In Australia, the Commonwealth Serum Laboratories were designated as a Regional Influenza Centre in 1951, upgraded to Collaborating Centre in 1992, until 2006 when the responsibility for the Centre was transferred to the Victorian Infectious Diseases Reference Laboratory. Today, there are 141 national centres in 101 countries and six WHO Collaborating Centres for Influenza in London, Atlanta, Melbourne, Beijing, Tokyo and Memphis, the latter concerned with the Ecology of Influenza in Animals. The efficacy of the network in surveillance was demonstrated during the 1957 and 1968 pandemics and the re-emergence of H1N1 in 1977²⁰.

The pandemics of 1957 (Asian) and 1968-69 (Hong Kong) were far milder than that of 1918–1919. The first was moderately severe globally and spread quickly, reaching Australia within 3 months of its origin in China²¹, while the second was a ‘smouldering’ pandemic and had a delayed peak in many countries including Australia in 1970²². In addition to demonstrating the difficulty in producing vaccine in the necessary timeframe²³, these pandemics provided the viruses which allowed elucidation of the origins of pandemic viruses.

In 1976 a small influenza outbreak occurred among military recruits at Fort Dix, New Jersey, with severe respiratory disease in 13 soldiers and one death. The outbreak involved a combination of H3N2 virus and a virus related to early swine-like H1N1 strains derived from the 1918–1919 pandemic²⁴. Concerned that it might signal a re-introduction of a 1918 pandemic-like virus, and in a divisive decision, the US Government planned to immunise the whole country; scientific and medical evidence did not support the decision. The program was stopped after an epidemiologic association between vaccination and increased incidence of Guillain-Barré Syndrome was reported, something which has not been significant in subsequent surveillance²⁵. The incident prompted the beginnings, in 1978, of formal pandemic preparedness planning by the USA and a handful of other countries, although WHO did not release its first pandemic planning document until 1999.

The 1950s discovery that fowl plague was due to an influenza A virus, followed by the isolation of many additional avian influenza viruses, revealed the role of birds as a virus reservoir and the multiplicity of virus subtypes. H7 (responsible for fowl plague) and H5 can be highly pathogenic in domestic poultry, with exceptionally high mortality, and outbreaks of both subtypes have been recorded around the world, including Australia, since the 1950s²⁶. Before 1997, recorded transmission of avian influenza to humans was rare, restricted to H7 viruses and almost always mild²⁷.

In 1997, 18 H5N1 cases in humans with 6 deaths signalled poultry infections in Hong Kong. Culling appeared to stamp out the virus; however it reappeared in Thailand and Vietnam in 2003, and has since spread widely in birds and caused over 660 human cases with more than 390 deaths across 16 countries²⁸. Global concern over the pandemic potential of H5N1, so soon after SARS, reinvigorated pandemic planning nationally and internationally. An International Partnership on Avian and Pandemic Influenza was forged at a high-level Plenary Meeting of the United Nations (UN) General Assembly in 2005, and the UN Secretary-General, Kofi Annan, subsequently pledged that the UN would do all it could to ensure all countries, rich and poor, were protected and prepared for an avian influenza pandemic. A UN Systems Coordinator for Avian and Human Influenza (UNSIC) was appointed and International Ministerial Conferences on Avian and Pandemic Influenza (IMCAPI) were convened. These provided the impetus for a global response to emerging diseases and a One Health approach to manage zoonotic diseases²⁹. In Australia, the National Action Plan for Human Influenza Pandemic and the Australian Health Management Plan for Pandemic Influenza have continued to be refined^30,31.

The H5N1 zoonotic also prompted the Government of Indonesia in 2006 to raise an issue of international equity. Developing countries share potential pandemic influenza viruses, such as A(H5N1), with WHO to support the development of vaccines and other interventions but cannot afford to purchase those products for the protection of their own people. Indonesia stopped sending H5N1 viruses to international WHO laboratories in protest. Several other countries lent their support to the campaign.

In response, WHO convened a series of technical, intergovernmental and working group meetings between 2007 and 2011. Discussions were technically, legally and politically complex, spanning influenza virology, commercial vaccine development and production, intellectual property, and sovereign rights of nations over their biological materials³². Ultimately, the meetings produced a new framework, the Pandemic Influenza Preparedness Framework for sharing of influenza viruses and access to vaccines and other benefits, adopted by the World Health Assembly in 2011^33,34, a crucial feature of which is the sharing of vaccines, antiviral drugs and other benefits through donations and financial contributions to WHO by manufacturers.

Implementation of the Framework faces challenges, including the use of genetic approaches to vaccine development that bypass the need to share the viruses themselves. Regardless, the Framework has embedded the principle of equity in the activities of the WHO’s Global Influenza Surveillance and Response System. The true test will come with the next pandemic.

In March 2009 a respiratory outbreak in Mexico was caused by a reassortant swine H1N1 virus more closely related to pre-1950s viruses than to recent strains. With initial indications of high mortality in Mexico and rapid spread through North America and beyond, the WHO issued escalating alerts until 11 June when a pandemic was declared. Many countries, including Australia, had already activated their pandemic plans and placed orders for many millions of doses of vaccine. In retrospect mortality was well below the early indications from Mexico and, while virus spread and major target groups were generally similar to previous pandemics, overall impact was moderate. Vaccine availability again lagged behind the peak of the outbreak, invigorating efforts to develop “universal” influenza vaccines that will protect against diverse subtypes, as well as novel delivery systems and faster production processes³⁵. There were allegations that the WHO and national responses had been unduly influenced by commercial interests and it became clear that planning documents lacked the flexibility to tailor responses according to ongoing assessment of severity³⁶. While these issues have been largely addressed, pandemic preparedness and public support may have been damaged³⁷.

Today, H5N1 remains widespread in poultry and human infections continue. This large family of viruses has diversified genetically and antigenically, to the extent that a single vaccine would not protect against all circulating strains. In some H5N1 strains, only a few further mutations may enable respiratory droplet transmission between mammals³⁸.

In 2013, a new threat emerged with human infections (>440) and deaths (>120) due to a novel H7N9 avian influenza in China³⁹. Although this virus, unlike H5N1, causes a silent infection in poultry, human infections are strongly associated with exposure to live bird markets. These viruses have several features of adaptation to mammalian infection.

Although these and other novel influenza viruses pose a continuing pandemic risk, China’s response to H7N9 exemplifies the benefits of the international networks and frameworks developed as a result of the 1918–1919 pandemic and later events outlined here. Early announcement of the outbreak, sharing of sequences and viruses, and openness about the epidemiology enabled rapid preparation of diagnostic reagents and candidate vaccine viruses by WHO laboratories and early interventions to limit spread. While sporadic influenza pandemics are an inevitable companion to human history, such international cooperation is the key to minimising their future impact on its course.