#17,607
Although avian H5 influenza sits currently atop our pandemic worry list, swine-variant influenza viruses remain very much in play. Just last week we looked at two mild swine-variant infections in Michigan (see CDC FluView On 2 Swine Variant Infections (H3 & H1N2v)), and it is expected that a lot of these swine spillover events are never identified.
For the most part, swine variant viruses (typically, H1 and H3) produce mild flu-like symptoms in humans, and aren't generally well transmitted. They spread from direct contact with infected pigs, often at agricultural exhibits (see EID Journal: Shortening Duration of Swine Exhibitions to Reduce Risk for Zoonotic Transmission of Influenza A Virus).
But occasionally we see a severe infection; sometimes even fatal (see WHO Risk Assessment: Fatal H1N1v Infection In Brazil). As sometimes happens, in that case, the patient had no direct contact with pigs.
The WHO wrote:
Ongoing investigations reported that the patient did not have any direct contact with pigs, however, two of her close contacts worked at the swine farm. The two contacts did not develop respiratory disease and tested negative for influenza. To date, no human-to-human transmission associated with this case has been identified.
Similarly, last fall in EID Journal: Severe Human Case of Zoonotic Infection with Swine-Origin Influenza A Virus A/H1pdm09N1av-like, Denmark, 2021, we looked at another case in a woman who lived near - but had no direct contact - with a swine farm.
While the source of these infections remains unknown - we've seen evidence of limited human-to-human transmission of these viruses - and in 2009 we saw an emerging swine-variant virus spark a mild-to-moderate influenza pandemic.
All of which brings us to a CDC EID Journal research article which compares the interspecies transmissibility and (vaccine susceptibility) of two flu viruses; H1N1 1A.3.3.2 (the 2009 pandemic virus) and a H1N1 1C (Eurasian, avian-like) A/Pavia/65/2016 collected in Italy in 2016.
Why, out of scores of swine variant viruses, did they choose H1N1 1C EA A/Pavia/65/2016?
A quick search of AFD returns a blog from February of 2017 (Eurosurveillance: Swine Origin H1N1 Infection Leading To Severe Illness - Italy, 2016), which documented an unusually severe 2016 swine H1N1 infection requiring the use of ECMO to save the patient infected in Pavia, Italy.:
"We describe a case of severe swine influenza A(H1N1) virus infection in an immunocompetent middle-aged man in October 2016 in Italy who had only indirect exposure to pigs. The patient developed a severe acute distress respiratory syndrome which was successfully supported by extracorporeal membrane oxygenation and treated with antiviral therapy. The sole risk factor for influenza was a body mass index > 30 kg/m2. After a month of hospitalisation, the patient was discharged in good health."The virus was designated H1N1 1C EA A/Pavia/65/2016. Given the severity of illness, and the apparent lack of direct exposure to pigs, that makes it very much worth exploring further.
Volume 29, Number 9—September 2023
Research
Interspecies Transmission of Swine Influenza A Viruses and Human Seasonal Vaccine-Mediated Protection Investigated in Ferret Model
Pauline M. van Diemen, Alexander M.P. Byrne, Andrew M. Ramsay, Samantha Watson, Alejandro Nunez, Ana v Moreno, Chiara Chiapponi, Emanuela Foni, Ian H. Brown, Sharon M. Brookes, and Helen E. Everett
Abstract
We investigated the infection dynamics of 2 influenza A(H1N1) virus isolates from the swine 1A.3.3.2 (pandemic 2009) and 1C (Eurasian, avian-like) lineages. The 1C-lineage virus, A/Pavia/65/2016, although phylogenetically related to swine-origin viruses, was isolated from a human clinical case. This strain infected ferrets, a human influenza model species, and could be transmitted by direct contact and, less efficiently, by airborne exposure. Infecting ferrets and pigs (the natural host) resulted in mild or inapparent clinical signs comparable to those observed with 1A.3.3.2-lineage swine-origin viruses.
Both H1N1 viruses could infect pigs and were transmitted to cohoused ferrets. Ferrets vaccinated with a human 2016–17 seasonal influenza vaccine were protected against infection with the antigenically matched 1A pandemic 2009 virus but not against the swine-lineage 1C virus. Our results reaffirm the need for continuous influenza A virus surveillance in pigs and identification of candidate human vaccine viruses.
(SNIP)
Discussion
The virologic profile of the A/Pavia/65/2016 isolate, when compared in the same interspecies transmission model to A/swine/England/1353/2009, a swine-origin H1N1 virus from the 1A.3.3.2 lineage, demonstrated that all experimentally infected animals exhibited mild or no clinical signs of influenza, mounted an effective humoral and cellular immune response, and resolved the infection.
Our findings therefore indicate that the A/Pavia/65/2016 strain does not have an increased pathogenicity profile compared to the 1A.3.3.2 strain when assessed in 2 animal models, as predicted from phylogenetic data, despite having originated from a human clinical case. In addition, our study reaffirms the value of the interspecies transmission model for assessing zoonotic potential (20,38,42–45).
We assessed immunity provided by the 2016–17 human seasonal influenza vaccine against the 2 swIAV isolates by cohousing naive and vaccinated ferret groups with pigs shedding the respective virus strains. All ferret groups, except the vaccinated ferrets exposed to the H1pdmN1 virus–infected pigs, had a viral nasal shedding profile consistent with productive infection and mounted a detectable humoral and cellular immune response.
Conversely, nasal shedding in the vaccinated, 1A.3.3.2 H1N1–exposed ferret group was significantly reduced, suggesting that the human seasonal vaccine provided immune protection from infection by the antigenically matched swine-origin challenge strain. However, the immune response after infection was low in that ferret group, so the correlates of protection remain unknown. In both studies, individual ferrets in single groups displayed outlier responses to infection or vaccination, possibly reflecting the differences observed in outbred populations.
Despite such limitations and the constraints of low group numbers, this study enabled effective modeling of interspecies transmission of influenza. The experimental design benefited from using pigs as a biological host for the virus strains studied. In addition, the study design provided a controlled and biologically relevant system to study interspecies airborne transmission to ferrets, a well-established animal model for human influenza; including naive and vaccinated ferret groups enabled modeling of human populations with varied prior immunity to influenza (31).
As part of the World Health Organization influenza pandemic preparedness initiative, CVVs for human seasonal vaccines are identified twice a year. Considering the increase in reports of zoonotic infections, OFFLU has contributed data for selecting swIAV-origin CVVs should a zoonotic spillover event necessitate a rapid update of human seasonal vaccine antigens.
Within-clade diversity of 1C-lineage swIAVs hampers the selection of candidate antigens, as has also been observed for 1B viruses (24,43,46) and, despite the A/Pavia/65/2016 strain being in the same 1C2.1 genetic lineage as the CVV A/Netherlands/3315/2016, antigenic cross-reactivity is low (1).
Those findings reinforce the need for continued CVV assessment for swIAVs to ensure pandemic preparedness. Furthermore, recent studies in the ferret model have demonstrated the potential for IAV and SARS-CoV-2 co-infection. Clinical severity was ameliorated by influenza vaccination, thereby demonstrating the potential importance of ensuring vaccine immunity to circulating influenza strains in the human population (47).Up until the 2009 H1N1 pandemic upset the apple cart, it was generally believed it would require an entirely new (or not recently circulating subtype) of influenza A to spark a pandemic. Prior to 2009, the sequence of pandemics going back 130 years appears to have been H2, H3, H1, H2, H3, H1 . . .
Our study confirms that vaccine and challenge strains must be antigenically matched to elicit vaccine-mediated protective immunity and that the immune status of the human population might not provide complete immunity to all currently circulating swine influenza A virus H1N1 strains. Continual evaluation and monitoring of IAVs circulating in human and swine populations is required to identify potential pandemic threats; broadly effective vaccines for both human and veterinary use are needed to mitigate these threats.
Dr. van Diemen is senior scientist in the Mammalian Influenza Research team at the Animal and Plant Health Agency, an agency of the UK Department for Environment, Food and Rural Affaires (Defra). Her research focusses on mammalian influenza, particularly viral pathogenesis, interactions between host and virus, and generation of vaccine-mediated protection.
Conventional wisdom held that humans would have some (likely substantial) immunity against any emerging H1N1 (or H3N2) virus. Many expected to see the return of H2N2 - absent in humans since the late 1960s (see Nature: A Preemptive H2N2 Vaccine Strike?).
But H1N1, which reigned from 1918 to 1957 - and then mysteriously reappeared in 1977 only to co-circulate with H3N2 - managed to break that pattern. That experience, and studies like the one above, remind us that we can't assume that H1N1 or H3N2 viruses are off the pandemic table.
Although swine influenza surveillance is quite limited around the world, tThe CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having at least some pandemic potential (2 added in 2019).
H1N2 variant [A/California/62/2018] Jul 2019 5.8 5.7 Moderate
H3N2 variant [A/Ohio/13/2017] Jul 2019 6.6 5.8 Moderate
H3N2 variant [A/Indiana/08/2011] Dec 2012 6.0 4.5 Moderate
The CDC currently ranks a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list.
While it's true the 2009 H1N1 pandemic was the mildest in a century, there are no guarantees that a different novel H1N1 (or H3N2) virus would be as accommodating.