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Zoonotic spillovers: H5N1 an old influenza A virus with new pandemic potential

How H5N1 influenza in domesticated birds could be a threat to human health.

In the last 150 years there have been at least 5 well documented influenza pandemics. The first was the 1889-1890 pandemic caused by H2N2 virus. (Controversy exists as some data suggests it could have been an H3 influenza or a coronavirus). The virus rapidly spread along trade routes from Europe and central Asia to the rest of the world resulting in over a million deaths.

A few decades later, as the Great War was coming to an end, H1N1 influenza virus emerged as a deadlier adversary than any of the wars’ battle fields. The virus rapidly raged through the susceptible population, evolving under host immune selection pressure, and eventually adapting into an endemic virus. In subsequent years it reappeared in the winter months as seasonal influenza. The H1N1 influenza pandemic was responsible for 50 million deaths and left a trail of death that inspired investments in scientific enquiry and the establishment of a pandemic response infrastructure. By the 1930s scientists had demonstrated that the respiratory illness was caused by a virus not a bacterium and by the 1940s both influenza A and B viruses had been identified. Countries such as the United States established their Centers for Disease Control (CDC), and the World Health Organization (WHO) took an increasing role in responding to global pathogen outbreaks and pathogen surveillance. In the 1950s the WHO created the Global Influenza Surveillance Response System GISRS, a network of laboratories across the world whose responsibilities include early detection and surveillance.

In 1957-1958 an H2N2 influenza pandemic occurred. This viral strain arose from the seasonal descendant of the 1918 H1N1 and an avian H2N2 virus and spread rapidly across the globe. There were over 1 million deaths globally and 100,000 in the United States. In response to this devastating disease burden the US started to recommend annual influenza vaccination particularly among the vulnerable elderly population. A decade later in 1968 an H3N2 influenza outbreak occurred. This strain was a combination of parts of the H2N2 virus and an H3 avian influenza. The outbreak emerged in Asia and spread globally, resulting in over 1 million deaths.

The first major influenza pandemic of the twenty-first century occurred in 2009. The outbreak was caused by an H1N1 influenza virus that has origins from human, avian and swine influenzas. It was first reported in North America and rapidly spread globally resulting in hundreds of millions of cases reported in over 74 countries, and 200,000 estimated deaths globally. In the United States there were over 60 million cases, 274,000 hospitalizations and 12,000 deaths (US CDC). The most striking feature of this outbreak is that over 80% of mortality was in individuals younger than age 65 years. This further emphasized the need to broaden influenza vaccination to younger individuals.

Influenza is an RNA virus that consists of eight single stranded RNA segments. Viral strains are identified based on two surface proteins - hemagglutinin (H) and neuraminidase (N). The H protein facilitates host cell entry while the N protein facilitates exit. There are at least 18 H types and 11 N types. In most individuals a robust immune response is generated in response to infection that leads to the development of antibody and T cell responses. However, the immune response is often quite specific to a viral strain and may not have as much effect on emerging strains. In developing new strains the virus uses several mechanisms that assist it to evade human immune pressure. These include random insertion of mutations into its genome or rearrangement of its eight gene segments in a process known as reassortment. The mutations are often responsible for the changes that make the influenza virus different from one season to the next. These genetic changes are part of the reason why we need to develop new vaccines for influenza each year. Coinfection of a single cell by two different influenza viruses e.g. a human and a bird influenza, can result in a novel virus consisting of rearranged gene segments. These reassortment events can lead to new viruses and have been responsible for many of the previous pandemics.

The highly pathogenic avian influenzas such as the H5N1 viruses are of particular concern. H5N1 virus is responsible for an ongoing outbreak in domesticated poultry and has been detected in wild birds and one reported human case in the United States. H5N1 was first isolated from farmed geese in southern China in 1996. By 2000 it had spread to domesticated ducks leading to the 2003-2004 outbreaks in domestic and wild birds. The first cases of human infection were reported in 1997 in Hong Kong. The virus has spread extensively over the years often following the seasonal migratory patterns of birds. To date over 800 cases have been reported by several countries in Asia and North Africa. Human infection is associated with a high average mortality of 50%. Most of the reported cases have been in individuals who have had close contact with poultry. The co-circulation of human and animal influenzas provides an opportunity for reassortment that can lead to novel strains with enhanced transmissibility or virulence. These kinds of changes may convert a virus with low human to human spread into one that can easily spread by respiratory droplets and lead to a significant global pandemic.

In the age of inflation and rising food prices we all love a $4.99 rotisserie chicken however it comes at a cost. The rising need for cheap animal protein in growing and urbanizing populations is fueling poultry monoculture in the developing world. Factory farming practices that are common in the West are increasing common in Africa and other parts of the developing world. As a result of monoculture, the genetic diversity of chickens that our grandmothers raised in the backyard is being replaced by fast growing genetically identical chickens. These chickens are often raised in overcrowded conditions making them more susceptible to infectious disease outbreaks. The intensification and industrialization of animal husbandry can create the right conditions for avian, swine and human influenzas to thrive, mutate and reassort.

H5N1 could be the cause of a new zoonotic influenza pandemic if the conditions are right. (A zoonosis is an infection that can be transmitted from animals to humans). As industrial agriculture advances, and humans encroach into previously uninhabited geographies we are likely to encounter more zoonotic diseases. In the twenty-first century animal and human health are significantly intertwined. A One Health approach to pandemic preparedness is critical to build and maintain an infrastructure that can support routine surveillance and early detection of emergent pathogens many of which will be zoonoses. If we are going to achieve the 7-1-7 goal (7 days to detect a suspected infectious disease outbreak, 1 day to notify public health authorities and 7 days to complete an initial response) we must capacitate weak surveillance systems throughout the world and strengthen community based reporting of disease outbreaks. Globally, pathogen surveillance will only be as strong as the capacity to detect, notify and respond in the weakest country. Animal health is human health and the health of all of species and the environment is global health.

References/Additional reading

Lai, S et. Al. Lancet Infect Dis 2016; 16(7): e108-e118

Kessler et al Viruses 2021 13(11):2250

Patrick Berche Press Med 51 (2022)104111

Siomonsen et al Plos Med 2013: 10(11): e1001558

Author: A. Tariro Makadzange, MD PhD is an infectious disease physician and viral immunologist, and founder of CRMG and Mutala. CRMG and Mutala are focused on conducting clinical trials, public health and basic science research to address medical issues pertinent to Africa. Reviewed and edited by Tashinga Chigodora intern at Mutala.

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