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The influenza enigma Recent advances in microbiology and molecular sequencing have vastly improved our understanding of how human influenza viruses evolve and spread. But several unanswered questions continue to vex researchers. Patrick Adams reports.

To disease detectives at the world’s lead- the virus to cross the species barrier “Such broad questions as what specific ing public health agencies, influenza is between birds and humans, confirming forces direct the appearance and disappear- an all-too familiar foe. First isolated fears that the avian H5N1 strain that has ance of epidemics still challenge virolo- in 1932, the virus – a single-stranded been circulating in Asia could one day gists and epidemiologists,” wrote the late, member of the orthomyxovirus family do the same. long-serving CDC epidemiologist Michael – occurs every year in every country, Now, at two leading influenza Gregg in 1980. This is still the case today. seasonally and sporadically, killing be- laboratories at the University of Wis- tween 250 000 and 500 000 people and consin-Madison, in the United States causing severe illness in several million of America (USA) and Erasmus MC in more, according to the World Health Rotterdam, the Netherlands, researchers We should be Organization (WHO). have broken new ground by creating doing“ much more work Over the past three centuries, there mutant H5N1 strains. The controversial on influenza in pigs. have been at least 10 global influenza studies, which have been paused for a We know the numbers pandemics and three in the last century debate over the risks they may pose to are huge and we don’t alone, among them the so-called ‘Span- public health, demonstrate that viruses know what exactly is ish flu’ of 1918–1919. The single most equipped with a haemagglutinin protein devastating disease outbreak in human from highly pathogenic H5N1 viruses happening there. history, that pandemic is believed to can become transmissible in ferrets. Albert Osterhaus. have caused between 20 million and Ferrets are believed to be the ideal ” 50 million deaths worldwide. It is the small animal model for influenza be- prospect of another such catastrophe, cause they are susceptible to human flu Take, for example, the enduring and the staggering toll of seasonal flu, viruses and some of the symptoms seen enigma of influenza seasonality. The that has made influenza the world’s in humans. It is not yet known whether clock-like consistency of the virus’s win- second-most studied virus, behind HIV. this mutant H5N1 is transmissible in ter incidence, which peaks in temperate In recent years, those investments humans and a study to find that out zones, provides perhaps the most strik- in influenza research have yielded im- would probably not be possible. But we ing illustration of seasonality in infec- portant new insights about the virus’s can infer that there is a high likelihood tious diseases. However, clouding the genetic makeup and capacity for muta- of transmissibility based on the findings picture is the highly variable pattern of tion. Indeed, with the reconstruction in ferrets. seasonal flu outbreaks in the tropics, says of the 1918 virus at the US Centers for Yet for all of the advances afforded US National Institutes of Health (NIH) Disease Control and Prevention (CDC) by new genomic technologies, our under- epidemiologist Martha Nelson. “They in Atlanta in 2005, scientists were able to standing of the fundamental epidemiology can be associated with rainy seasons or identify the genetic changes that allowed of influenza remains far from complete. dry seasons, and you could have one epidemic or two epidemics,” she says. “It’s really not well understood.” This despite several untested and inconclusive theories being put forward as to why this is the case. Similarly puzzling is the question of where those seasonal strains come from. Although it has long been held that south-east and eastern Asia are the global source of seasonal flu epidemics, a recent study by researchers at the Duke-National University of Singapore (NUS) Graduate Medical School casts considerable doubt on that assumption. Published last November in the journal Proceedings of the National Academy of Sciences, the study compared viral migration between urban centres in seven different temperate and tropical re- gions between 2003 and 2006. And in none

WHO/Harold Ruiz WHO/Harold of the years studied could all of the new flu strains be traced back to a single region. “We found that it’s a dynamic sys- Despite many advances, influenza is still a challenge for scientists tem,” says Gavin Smith, a molecular

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swine to create variant H3N2 (H3N2v) gate threats posed by an outbreak. “The viruses that have infected 12 humans in big overarching question is when you the USA since July 2011, with limited have scarce resources globally, which human-to-human transmission and countries and which peoples benefit? posing a potential pandemic threat. Right now, we don’t have a mechanism Albert Osterhaus, head of the de- to address this.” partment of virology at Erasmus MC While opinions differ on where and a co-author on the mutant H5N1 best to focus scarce resources, experts study, agrees. “Monitoring birds is very agree on the prime importance of a important,” he says, “but we should be universal vaccine. “Having a highly doing much more work on influenza in protective agent against multiple strains pigs. We know the numbers are huge would clearly be a game-changer,” says and we don’t know what exactly is hap- Michael Osterholm, director of the pening there.” A veterinarian turned Center for Infectious Disease Research virologist, Osterhaus’s research team and Policy at the University of Minne- was the first to show, in 1997, that H5N1 sota. “It would fundamentally change is transmissible to humans from birds. the whole picture.” Moreover, given Since then, he’s sounded the alarm for the backlog of what he calls “poten- pandemic preparedness, calling for tially outstanding candidates,” it’s also WHO/Tom Pietrasik WHO/Tom closer monitoring of bird populations, a realistic goal. greater uptake of existing vaccines and “We have the science,” he says. “But Good respiratory hygiene helps prevent the the creation of a global database that no one is prepared to take a candidate spread of flu integrates information on both animal vaccine across the ‘valley of death’– from and human influenzas. Phases I and II to Phase III to licensure.” Osterholm attributes the problem to a epidemiologist at Duke-NUS and the general misconception about currently senior author of the study. “Rather than available vaccines, the benefits of which, a single source, you have a number of Having a highly he argues, have been grossly oversold. local epidemics that overlap in time and “protective agent “They’re not nearly as effective as we’ve feed into one another.” Though the data against multiple strains told the public they are,” he says, and set isn’t globally representative, he says, would clearly be a he backs that claim with the findings larger studies in the future could offer game-changer. of a meta-analysis he and colleagues a glimpse of what virus dissemination conducted last year. patterns might look like in a pandemic. Michael Osterholm. ” Using highly restrictive criteria, “If you knew how the virus enters, say, Osterholm and three other influenza South America, you could tailor inter- researchers screened more than 5700 ventions to prevent that.” Adding to concerns about animal studies of the efficacy of vaccines Another glaring gap in influenza influenza is the increasing intensifica- licensed in the USA that had been epidemiology, say experts, is the dearth tion of south-east Asia’s agriculture and published since the 1960s. From 31 of surveillance data on influenza in farming sectors, both of which have ex- eligible studies – only those whose domestic and wild animal populations, perienced enormous growth in recent endpoints were laboratory-confirmed particularly birds and pigs. decades. “We’re in a different world influenza – they found that on aver- “We need to learn more about now,” says Richard Coker, director of age the seasonal flu vaccine was about which of the viruses circulating in those the Bangkok-based Communicable 59% effective in individuals aged 18 to populations we need to be worried Diseases Policy Research Group. “A lot 65 years – far lower than the 70–90% about,” says Richard Webby, a flu virolo- more virus mixing, greater potential previously believed – with at best a gist at the St Jude Children’s Research for reassortment and greater selec- 4% reduction in mortality among the Hospital in Memphis, Tennessee, in tion pressures” – all of which, he says, elderly. In this case ‘effective’ meant the USA. seem to have raised the risk of a new able to prevent laboratory-confirmed Webby notes that, while in 2009 pandemic. influenza, regardless of severity. The surveillance efforts were focused on “We don’t know, for example, if study was published in Lancet Infec- avian viruses in Africa and Asia, it was industrial poultry production gener- tious Diseases. through pigs in the Americas that H1N1 ates new viruses or simply acts as an While Osterholm acknowledges went pandemic. With receptors for both amplifier for the viruses that enter those that public health officials face a difficult human and avian viruses, pigs can serve systems.” If we knew this, says Coker, challenge in convincing an already wary as ‘mixing vessels’ for the recombination we could focus surveillance activities public of the merits of vaccination, he of different viruses’ genomic material. more effectively and design food sys- says that at the end of the day public This phenomenon, known as reassort- tems better, making them more secure. health has one requirement: “Tell the ment, can produce novel strains with Compounding the problem, he adds, are truth. Just tell the truth. We have not pandemic potential. issues of equitable access to drugs and been forthright with our public or our Already, pandemic H1N1 viruses vaccines and the investments in health medical professionals about just how are reassorting with H3N2 viruses in systems that might be needed to miti- effective this vaccine really is.”■

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