The risk of a swine influenza pandemic: still a concern?

KEYWORDS:

• Swine influenza
• human
• pig
• pandemic influenza

1. Introduction

Swine influenza is a respiratory disease of pigs caused by type A influenza viruses (IAVs) that regularly cause outbreaks in pigs. Like human influenza viruses, there are different subtypes and strains of swine influenza viruses. The main swine influenza viruses circulating in pigs in recent years have been swine triple reassortant (tr) H1N1 influenza virus, trH3N2 virus, and trH1N2 virus.

Pigs are a ‘mixing vessel’ for IAVs because of their ability to be infected by avian and human IAVs at the same time and their propensity to facilitate viral genomic reassortment events. Furthermore, as IAVs may evolve differently in swine and humans, pigs can become a reservoir for old human strains against which the human population has become immunologically naive.

Swine flu viruses do not normally infect humans. However, sporadic human infections with influenza viruses that normally circulate in swine have occurred. When this happens, these viruses are called ‘variant viruses’ (e.g. H1N1v, H3N2v, and H1N2v). If this new virus causes illness in people and can be transmitted easily from person-to-person, an influenza pandemic can occur. This is what happened in April 2009, when a novel A(H1N1) virus, named A(H1N1)pdm09) or H1N1pdm, emerged in humans in North America and quickly spread in the human population worldwide leading to the first pandemic of twenty-first century [1]. This virus, suspected to have resulted from a reassortment event between influenza A viruses (IAVs) of swine-origin, was rapidly transmitted to pigs worldwide.

Ten years after this episode, what is the risk that other pandemics occur?

2. Mechanisms of swine influenza pandemic

The ecology of IAV is complex and involves a broad range of avian and mammalian host species. Influenza viruses have high mutation rates and are constantly changing, which enables the virus to quickly adapt to changes in the host environment, as is the case during interspecies transmission. The rapid evolution results from two mechanisms: reassortment and point mutations. Reassortment occurs when two different strains infect the same cell of a given host, allowing for the exchange of intact gene segments. When reassortment involves either the HA or NA segments, it is termed antigenic shift. Point mutations occur due to an error-prone polymerase devoid of a proof-reading and correction mechanism. When point mutations are fixed in the HA or NA segments it is called antigenic drift. Both of these mechanisms play pivotal roles in the emergence of novel influenza viruses that could jump the host barrier. Once the virus jumps into a new host, it must adapt and change to be able to spread and become established in the new population [2].

A large diversity of IAVs within the H1N1/N2 and H3N2 subtypes circulates in pigs globally, with different lineages predominating in specific regions of the globe. A common characteristic of the ecology of IAVs in swine in different regions is the periodic spillover of human seasonal viruses that have a major role on the epidemiology of swine IAVs.

Such human viruses resulted in sustained transmission in swine, leading to the establishment of novel IAVs lineages in the swine host and contributing to the genetic and antigenic diversity of influenza observed in pigs. For example, a triple-reassortant H3N2 virus derived from human seasonal H3N2 viruses and the internal genes from H1N1pdm has recently spread among swine in Denmark and Mexico [3,4]. Human-origin IAVs have also been reported circulating in pigs across the continents [5,6] including countries with large swine populations like Brazil [7], Vietnam [8] or Chile [9].

As highlighted by the 2009 pandemic, once generated in swine, that serve as intermediate hosts, these reassortant viruses may lead to sporadic human infections that may evolve in human pandemics.

3. Swine influenza in humans

Human infections with swine influenza viruses have been sporadically detected since the late 1950s. Most commonly, human infections with variant viruses occur in people with direct or indirect exposure to infected pigs (e.g. workers in the swine industry). Since 2009/2010, there have been documented cases of multiple people becoming sick after exposure to one or more infected pigs and also cases of limited spread of variant influenza viruses from person-to-person. In the USA, between 2010 and 2018, 9 A(H1N1)v, 25 A(H1N2)v, 430 A(H3N2)v and 1 A(H7N2) influenza human cases were reported. Most infections with variant viruses have occurred in children and most cases have reported direct or indirect exposure to swine prior the onset of illness. Limited transmission from close contact with an infected person has been observed in some investigations of these infections, but sustained human-to-human transmission has not been documented [10].

The most frequent virus, Influenza A(H3N2)v with the gene from the H1N1pdm virus, was first detected in humans in July 2011. During 2011, 12 human infections with H3N2v were detected and during 2012, there were multiple outbreaks of H3N2v resulting in 309 reported cases [11,12]. Sporadic infections with H3N2v have continued to be detected since that time. Infections with H3N2v have mostly been associated with prolonged exposure to pigs at agricultural fairs. No sustained or community spread of H3N2v has been identified at this time [10].

Illness associated with variant virus infection is mostly mild with symptoms similar to those of seasonal flu. Like seasonal flu, serious illness, resulting in hospitalization and death is possible as in 2012, where, among the 309 H3N2v cases, 16 people, at high risk of serious influenza-related complication, were hospitalized and one of these people died [12].

4. Risk of a new swine pandemic

The 2009 pandemic has led to an increased concern about the transmission of swine viruses to humans. However, the A(H1N1)pdm09 influenza virus is, so far, the only swine influenza virus that has shown the capacity to spread rapidly between humans.

Surveillance programs have shown that human viruses are frequently transmitted to pigs in a sustained basis which will inexorably lead to the emergence of new variants in the coming years. Indeed, de novo transmissions of H1N1pdm virus from Human to swine each year during seasonal epidemics were highly suspected by phylogenetic analyses [13].

Several factors such as swine density, human population, and rate of exposure of the human population to swine are associated with the risk of emergence of swine influenza pandemic [14].

Although most of the human infections with variant influenza viruses do not result in person-to-person spread, it’s possible that sporadic infections and even localized outbreaks among people with these viruses will continue to occur and that one of them will cause a new pandemic.

Furthermore, another concern is that the continued detection of human-origin influenza virus lineages in swine over several decades with little or unpredictable antigenic drift indicates that isolated swine populations can act as antigenic archives of human influenza viruses, raising the risk of reemergence in humans when sufficient susceptible populations arise.

Because of all the factors involved, some of them unpredictable, the exact risk of a new swine pandemic, which will be different depending on time, place and population, is difficult to assess.

5. Control measures

Crossing the species’ barriers may lead to the emergence of novel IAVs that could represent an increased risk for both Human and swine health [15]. Additional surveillance is necessary to understand the diversity of IAVs circulating in different regions and the participation of human-origin strains in this overall diversity. Human infections with a swine influenza virus recall the importance of implementing ad hoc biosecurity measures in pig farms to avoid interspecies transmissions as much as possible [16]. They also provide supporting evidence that pig industry workers should be offered annual seasonal influenza vaccination in a ‘One Health’ perspective, both to prevent them from infection with the H1N1pdm virus excreted by pigs and to minimize the risk of transmission of human IAVs into pigs. Surveillance is also critical for antigenic characterization of the strains that are circulating in a particular area to allow an accurate selection of representative swine vaccine strains that will provide an optimal protection.

Human cases of variant influenza viruses should be monitor worldwide and each case of human infection with a swine influenza virus should be fully investigated to be sure that such viruses are not spreading in an efficient and ongoing way in humans.

The exposure of humans to infected animals may be limited when following some recommendations such as washing hands with soap and water before and after exposure to pigs; avoiding close contact with pigs that look or act ill and taking protective measures when coming in contact with pigs that are known or suspected to be sick [16]. A few studies trying to assess the predictive modeling of the emergence of swine influenza pandemic in taking into consideration time of exposure and concentration of virus in air found that the exact level of risk may be high under certain assumptions but can be reduced by the use of appropriate respiratory masks [17].

Pigs vaccination has also been studied in other stochastic models that found that although some herd vaccination schemes (batch-to-batch vaccination) had a beneficial effect in breeding sows by reducing the persistence of swine IAVs, none of the vaccination strategies achieved swine IAVs fade-out within the entire pig herd [18].

Finally, in case of a new pandemic, the quick development and large distribution of influenza vaccine will be challenging. New technologies and methods to increase vaccine immunogenicity and availability such as the use of adjuvant or new antigen cultivation technologies to avoid the slow process of vaccine production in eggs (e.g. recombinant vaccine) will be needed to stretch a limited vaccine supply. The emerging new production platforms will here have a pivotal role.

Declaration of interest

O Launay has been Principal Investigator in clinical trials on pandemic influenza vaccines with GSK and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.