Warning Signals from the Volatile World of Influenza Viruses

Image courtesy of WHO Collaborating Center for Studies on the Ecology of Influenza in Animals, Memphis, Tenn.

The current global influenza situation is characterized by a number of trends that must be closely monitored. These include: an increase in the variety of animal influenza viruses co-circulating and exchanging genetic material, giving rise to novel strains; continuing cases of human H7N9 infections in China; and a recent spurt of human H5N1 cases in Egypt. Changes in the H3N2 seasonal influenza viruses, which have affected the protection conferred by the current vaccine, are also of particular concern.

The diversity and geographical distribution of influenza viruses currently circulating in wild and domestic birds are unprecedented since the advent of modern tools for virus detection and characterization. The world needs to be concerned.

Viruses of the H5 and H7 subtypes are of greatest concern, as they can rapidly mutate from a form that causes mild symptoms in birds to one that causes severe illness and death in poultry populations, resulting in devastating outbreaks and enormous losses to the poultry industry and to the livelihoods of farmers.

Since the start of 2014, the Organization for Animal Health, or OIE, has been notified of 41 H5 and H7 outbreaks in birds involving seven different viruses in 20 countries in Africa, the Americas, Asia, Australia, Europe and the Middle East. Several are novel viruses that have emerged and spread in wild birds or poultry only in the past few years.

Some of the outbreaks notified to OIE have involved wild birds only. Such notifications are indicative of the heightened surveillance and improved laboratory detection that have followed the massive outbreaks of highly pathogenic H5N1 avian influenza that began in Asia in late 2003.

Detection of highly pathogenic avian influenza viruses in wild birds signals the need for a close watch over poultry farms. Migratory waterfowl, immune to the disease, are known to spread avian viruses to new areas by quickly crossing continents along the routes of several flyways. These migratory waterfowl subsequently mix with local wild birds and poultry that then become infected.

The world’s first three human cases of infection with the H7N9 avian influenza viruses were reported by China on March 31, 2013. Investigations by Chinese authorities determined that the earliest likely cases had symptom onset in mid-February. That event also marked the first time that this H7N9 subtype had been detected in humans, poultry or any other animals.

To date, 602 human H7N9 cases and 227 deaths have been reported, the vast majority in mainland China. This total includes four cases reported by the Taipei Centers for Disease Control and 13 cases reported by the Centre for Health Protection, Hong Kong SAR, China. Malaysia reported one case in a Chinese traveller in 2014, and Canada reported two mild cases in travelers returning from China in January 2015.

The epidemiological pattern seen during 2013 showed a sharp spike in cases in March and April followed by only two cases reported during the summer. The official closing of live poultry markets in several provinces in April may have contributed to this decline. A second wave of infections began more slowly in October.

A similar pattern of seasonality was seen during 2014, but with a higher and earlier spike in January and more cases reported during the spring compared with 2013. Again, cases virtually ceased over the summer, then gradually increased in November. Cases increased in January 2015, but not as sharply as seen during the same month in 2014.

Like H5N1, the H7N9 virus causes serious illness in humans. But unlike H5N1, H7N9 does not cause illness or deaths in birds. The absence of signs of disease in infected birds omits the warning signal calling for heightened surveillance for human cases. Consequently, the detection of human cases has triggered a search for the virus in birds.

As observed, a substantial proportion of human cases have reported direct exposure to live poultry or contaminated environments, including live poultry markets. In addition, careful studies have shown that exposure to live poultry and poultry markets are risk factors for H7N9 infection.

All evidence indicates that the H7N9 virus does not spread easily from one person to another, though it may transmit from poultry to humans more readily than H5N1.

In a few small clusters of human cases, the possibility of limited human-to-human transmission cannot be excluded. However, all possible transmission chains have been short, with no evidence of spread into the wider community.

Approximately 36 percent of reported human cases have been fatal. It is not yet known whether significant numbers of asymptomatic or mild cases also are occurring without being detected. The existence of asymptomatic and mild cases would lower the percentage of people who died from this infection.

The highly pathogenic H5N1 avian influenza virus, which has been causing poultry outbreaks in Asia almost continuously since 2003 and is now endemic in several countries, remains the animal influenza virus of greatest concern for human health. From end-2003 through January 2015, 777 laboratory-confirmed human cases of H5N1 virus infection have been reported to WHO from 16 countries. Of these cases, 428 (55.1 percent) have been fatal.

Over the past two years, H5N1 has been joined by newly detected H5N2, H5N3, H5N6, and H5N8 strains, all of which are currently circulating in different parts of the world. In China, H5N1, H5N2, H5N6, and H5N8 are currently co-circulating in birds together with H7N9 and H9N2.

The H9N2 virus has been an important addition to this mix, as it served as the “donor” of internal genes for the H5N1 and H7N9 viruses. Over the past four months, two human infections with H9N2 occurred in China. Both infections were mild and the patients fully recovered.

Virologists interpret the recent proliferation of emerging viruses as a sign that co-circulating influenza viruses are rapidly exchanging genetic material to form novel strains. Viruses of the H5 subtype have shown a strong ability to contribute to these so-called “reassortment” events.

The genomes of influenza viruses are neatly segmented into eight separate genes that can be shuffled like playing cards when a bird or mammal is co-infected with different viruses. With 18 HA (haemagluttinin) and 11 NA (neuraminidase) subtypes known, influenza viruses can constantly reinvent themselves in a dazzling array of possible combinations. This appears to be happening now at an accelerated pace.

For example, H5N2 viruses recently detected in poultry in Canada and in wild birds in the US are genetically different from H5N1 viruses circulating in Asia. These viruses have a mix of genes from a Eurasian H5N8 virus, likely introduced into the Pacific Flyway in late 2014, along with genes from North American influenza viruses.

Little is known about the potential of these novel viruses to infect humans, but some isolated human infections have been detected. For example, the highly pathogenic H5N6 virus, a novel reassortant, was first detected at a poultry market in China in March 2014. The Lao People’s Democratic Republic reported its first outbreak in poultry, also in March, followed by Viet Nam in April. Genetic studies showed that the H5N6 virus resulted through exchange of genes from H5N1 viruses and H6N6 viruses that had been widely circulating in ducks.

China detected the world’s first human infection with H5N6, which was fatal, in April 2014, followed by a second severe human infection in December 2014. On 9 February 2015, a third human H5N6 infection, which was fatal, was reported.

The emergence of so many novel viruses has created a diverse virus gene pool made especially volatile by the propensity of H5 and H9N2 viruses to exchange genes with other viruses. The consequences for animal and human health are unpredictable yet potentially ominous.

The sudden increase in the number of H5N1 human infections in Egypt that began in November 2014 and continued during January and February 2015 awakened concern. From the start of November to 23 February, Egypt reported 108 human cases and 35 deaths. The number of cases over this period is larger than yearly totals reported by any country since human H5N1 virus infections re-emerged in late 2003.

According to FAO, a total of 76 outbreaks of highly pathogenic H5N1 avian influenza were detected in 20 of Egypt’s 27 governorates between 18 January and 7 February 2015. Of these outbreaks, the majority – 66 – occurred in household poultry.

Although all influenza viruses evolve over time, preliminary laboratory investigation has not detected major genetic changes in the viruses isolated from patients or animals compared to previously circulating isolates that would help to explain the sudden increase in human cases.

Health and agricultural officials in Egypt have extensive experience with this disease. In their view, more widespread circulation of H5N1 in poultry during this time, combined with the large number of households that keep small flocks with poor understanding of the associated health risks, is the most likely explanation for this spurt in new cases.

This observation, in turn, signals an urgent need for agricultural investigations to identify, and reduce, the source of this heavy viral contamination. A second motivation is the very real risk that poultry trade, whether legal or illegal, will introduce the virus to new countries. The detection of cases with moderate illness suggests that surveillance on the human side is reasonably good.

On 10 February, Egyptian authorities notified WHO of a case of H9N2 infection in a three-year-old boy. The illness was mild and the boy was discharged from hospital fully recovered. However, the fact that H9N2 is co-circulating with H5N1 is cause for concern.

Experts convened by the World Health Organization (WHO) decide on the composition of seasonal influenza vaccines for the northern hemisphere in February of each year. Doing so gives manufacturers sufficient time to have doses of vaccines ready before the start of the flu season, usually in October or November.

Since February 2014, the genetic make-up and antigenic properties of the H3N2 virus, the predominant seasonal virus circulating in North America and Europe, changed significantly. This change allowed most of the viruses circulating in the flu season to elude protection provided by the vaccine which was designed for an older virus with distinctly different characteristics.

As a result, interim estimates of the effectiveness of the current seasonal vaccine in reducing the risk of medical visits associated with influenza infection – in all age groups – was only 23 percent in the U.S. This is lower protection than usual but is not unexpected for seasons when there is a significant rapid change in the properties of circulating viruses. Seasons where there is a significant reduction in seasonal vaccine protection due to the rapid and unpredictable evolution of influenza A viruses are relatively rare with only four seasons during the past 25 years.

Since the 2004–2005 influenza season, U.S. researchers have produced annual estimates of vaccine effectiveness. Estimated vaccine effectiveness in the US has ranged from 10 percent to 60 percent, with effectiveness in most years being 40 percent to 60 percent. This calls for better vaccines.

On many levels, the world is better prepared for an influenza pandemic than ever before.

The level of alert is high, supported by elevated virological surveillance in both human and animal populations. For example, during 2014, the 142 laboratories in 112 countries in the WHO Global Influenza Surveillance and Response System tested more than 1.9 million clinical specimens. By keeping a close watch over the volatile world of influenza viruses, these laboratories operate as a sensitive early warning system for the detection of viruses with pandemic potential.

More national laboratories are now equipped, staffed, and trained to conduct early detection, isolation, and characterization of viruses. Drawing on support from laboratories in the WHO System, WHO offers all interested laboratories – anywhere in the world – free diagnostic reagents and test kits for seasonal viruses and for viruses of the H5 and H7 subtypes.

During the 2009 H1N1 pandemic, WHO and its collaborating laboratories were able to start shipping diagnostic reagent kits in 7 days after the declaration of a public health emergency of international concern. The mechanisms worked out for accomplishing this rapid response will be another asset when the next pandemic inevitably begins.

Countries that have experienced human cases of avian influenza know the disease well and have mechanisms in place to detect cases quickly, track the likely source of infection, and monitor close contacts for symptoms and any evidence of human-to-human transmission.

WHO, through its Global Influenza Surveillance and Response System network, is closely monitoring the emergence and evolution of influenza viruses with pandemic potential, assessing associated risks, and developing candidate vaccine viruses for pandemic preparedness purposes.

Ways are being found to shorten the time between the emergence of a pandemic virus and the availability of safe and effective vaccines. Advances in synthetic vaccine technology mean that candidate vaccine viruses can be produced in about two weeks following detection of a virus with pandemic potential.

Fast-track procedures for regulatory approval have been developed. In Europe, advance studies using “mock-up” vaccines can greatly expedite regulatory approval. These studies use an influenza strain that has not circulated recently in human populations to mimic the novelty of a pandemic virus.

Strengthened surveillance, advances in vaccine production technology, and regulatory preparedness can possibly shorten the time lapse between the detection of a pandemic virus and the availability of vaccines to three to four months. With WHO support, more low- and middle-income countries now have facilities for manufacturing vaccines. According to a recent estimate, the maximum annual global manufacturing capacity has risen to 1.5 billion doses of seasonal influenza vaccines and the potential of 6.2 billion doses in the event of a pandemic.

Safety and immunogenicity data on pandemic vaccines are now substantial. These data draw on more than 130 clinical trials of H5 vaccines and vaccines combining protection against H5 with protection against seasonal influenza.

More antiviral medicines, including peramivir and laninamivir as well as oseltamivir and zanamivir, are now available to treat influenza and reduce the duration and severity of infection.

The WHO Pandemic Influenza Preparedness framework, which came into effect in May 2011, provides mechanisms for ensuring that the information and benefits that accrue from sharing influenza viruses and biological materials are fairly distributed, as expressed through increased access of developing countries to vaccines and other medical products needed during a pandemic. The framework includes provisions for manufacturers to share a fixed proportion of their pandemic vaccines with WHO as these vaccines roll off the production line.

In the final analysis, as was shown during the 2009 H1N1 pandemic, the overall response of health systems, especially in the developing world, will have a major impact on how well available vaccines and other medical interventions can be provided to protect populations during the next pandemic.

Critical capacities needed include adequate storage and delivery channels, an ability to quickly extend services to large numbers of people in all age groups, a well-developed laboratory system, and sufficient numbers of staff and hospital beds. Experience in conducting mass public education campaigns, supported by public confidence in the health system, is another key asset. However, these capacities are lacking in a large number of developing countries.

Though the world is better prepared for the next pandemic than ever before, it remains highly vulnerable, especially to a pandemic that causes severe disease. Nothing about influenza is predictable, including where the next pandemic might emerge and which virus might be responsible. The world was fortunate that the 2009 pandemic was relatively mild, but such good fortune is no precedent.

WHO and its collaborating laboratories continue to help countries strengthen their alert, surveillance, and response capacities. A quality assurance program has been conducted by WHO since 2007 to maintain global influenza virus laboratory detection capacity, with panels of testing materials being provided free-of-charge to countries once or twice a year. To further capacity building in countries, particularly developing countries, nearly $17 million was provided in 2014 through the Pandemic Influenza Preparedness framework.

Virological research, which has done so much to aid the detection and understanding of novel viruses, assess their pandemic risks, and track their international spread, needs to continue at an accelerated pace.

More R&D is needed to develop better vaccines and shorten the production time. During a severe pandemic, many lives will be lost in the 3 to 4 months needed to produce vaccines.

An influenza pandemic is the most global of infectious disease events currently known. It is in every country’s best interests to prepare for this threat with equally global solidarity.

Source: World Health Organization