Evaluating severity of influenza an infection in ferrets with COVID-19 historical past

In a current examine posted to the bioRxiv* pre-print server, researchers investigated the impact of extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) publicity on the severity of influenza in ferrets.

Study: Influenza infection in ferrets with SARS-CoV-2 infection history. Image Credit: Harald Schmidt/Shutterstock
Research: Influenza an infection in ferrets with SARS-CoV-2 an infection historical past. Picture Credit score: Harald Schmidt/Shutterstock


Prior to now two years because the onset of coronavirus illness 2019 (COVID-19), non-pharmaceutical interventions (NPIs) such because the necessary use of face masks, social distancing, and journey restrictions decreased shut social interactions globally. Thus, the circulation of all respiratory pathogens, together with influenza virus ‘H1N1’ was decreased significantly.

Earlier, the variety of hospitalizations attributable to H1N1 circumstances was roughly three to 5 million per 12 months globally. From March 2020, the weekly case numbers dramatically decreased from over 40,000 to zero within the following months. With decreased NPI measures in place now, there’s a rising concern for elevated influenza circumstances, notably in people with a historical past of COVID-19, particularly these experiencing long-term results of SARS-CoV-2 an infection.

Firstly of the pandemic, when the influenza virus was co-circulating with SARS-CoV-2, research demonstrated a better threat for extreme outcomes in COVID-19 circumstances with influenza co-infection; nevertheless, it’s unknown whether or not a current SARS-CoV-2 an infection may negatively affect a sequential influenza an infection.

Nonetheless, the interrupted seasonal publicity attributable to strict implementation of NPI measures has weakened immunity, elevating the chance that the residual results of COVID-19 may worsen the medical manifestations of a sequential respiratory an infection, resembling influenza.

To this point, the ferret mannequin has gave the impression to be essentially the most appropriate for finding out the results of influenza A virus (IAV) an infection following a resolved SARS-CoV-2 an infection or throughout post-acute COVID-19. Initially, ferrets develop delicate or non-clinical COVID-19, and 21 days after experimental an infection with SARS-CoV-2 has cleared, they present follicular hyperplasia within the higher airways of the lung and irritation within the nasal cavity. These observations replicate long-term or post-acute COVID-19, characterised by persistent respiratory points and fatigue.

Concerning the examine

Within the current examine, researchers investigated the affect of earlier SARS-CoV-2 publicity on the severity of sequential influenza (H1N1) an infection, together with the impact on respiratory organs.

The take a look at animals with a mean weight of 1.3 kg ± 0.1 kg had been semi-randomly allotted in three matched teams. The analysis group intranasally (i.n.) inoculated 12 male ferrets with 107 median tissue tradition infectious dose (TCID50) of SARS-CoV-2 variant of concern (VOC) Beta (B.1.351) on day 0. They had been adopted as much as 4 weeks post-infection (p.i.) for post-acute COVID-19 signs to look. Six out of twelve ferrets had been euthanized on day 28 p.i. through the post-acute part of SARS-CoV-2 Beta VOC an infection.

The remaining six SARS-CoV-2-infected ferrets had been contaminated i.n. with 106 TCID50 of H1N1. The management and mock teams comprised of 5 ferrets contaminated solely with H1N1, and three ferrets receiving 1 mL of phosphate buffer saline (PBS) i.n., respectively.

The group collected the nostril and throat swabs for virology assays on days 0, 3, 5, and 9 p.i. from SARS-CoV-2-infected animals and H1N1-infected animals on days 0, 2, 4, and 5 p.i. Moreover, they collected blood samples from the cranial vena cava on days 0, 14, 21, and 29 through the examine and by way of coronary heart puncture on days 28 and 35 after euthanasia.

They monitored all of the medical manifestations, together with behavioral exercise, respiration, nasal discharge, and sneezing, day by day for 9 days after onset of SARS-CoV-2 an infection and 5 days submit H1N1-infection. Likewise, they monitored their physique temperature by way of the implanted temperature transponder each half-hour from 5 days earlier than an infection. They decided variations within the physique temperature and physique weight relative to the baseline values famous on day 0 of every an infection.

Additional, the researchers used quantitative reverse transcription-polymerase chain response (RT-qPCR) to quantify the viral load in swabs and tissue samples from ferrets. As well as, they recorded cycle threshold (Ct) values for genomic and subgenomic ribonucleic acid (RNA) to find out the viral load and infectious viral particles, respectively. Moreover, the group harvested tissues from the trachea, bronchus, and left lung for histopathological examinations beneath mild microscopy.

They measured antibody concentrations by optical density (O.D.) at 450 nm absorbance and offered these at a 1:100 or 1:200 sera dilution for spike (S) protein and receptor-binding area (RBD), respectively.

Research findings

Though the histological proof was insignificant, after 4 weeks of SARS-CoV-2 an infection, ferrets with an H1N1 an infection confirmed elevated medical signs of influenza. This discovering demonstrated {that a} delicate COVID-19 had a slight antagonistic affect on the medical influenza signs; nevertheless, the impact of a strong SARS-CoV-2 an infection remains to be unknown.

The Beta VOC replicated solely to low ranges in male ferrets regardless of receiving a excessive infectious dose of 107 TCID50/mL, albeit it induced mobile and humoral responses. Notably, these immune responses had been related to protecting immunity in opposition to COVID-19 in people.

Sequential an infection by the H1N1 influenza virus in ferrets recovering from delicate COVID-19, induced average irritation within the nasal turbinates solely. Moreover, these ferrets confirmed insignificant histopathological alterations within the decrease respiratory tract. This indicated an inefficient replication of the Beta VOC within the ferret mannequin; nevertheless, earlier research have proven an prolonged impact of the SARS-CoV-2 an infection in ferrets contaminated with the unique SARS-CoV-2 pressure.

The authors additionally famous an inclination for extra extreme bronchitis and kind II pneumocyte hyperplasia in ferrets sequentially contaminated with SARS-CoV-2 and H1N1 influenza virus in comparison with these contaminated with H1N1 virus solely, though the distinction was statistically insignificant.


The ferret mannequin could possibly be useful to check sequential infections from SARS-CoV-2 and influenza H1N1 beneath managed settings and its findings could possibly be translated to people. The noticed acute lung damage attributable to influenza gave the impression to be worsened in ferrets with earlier SARS-CoV-2 an infection.

Due to this fact, additional research are warranted to verify the affect of extra virulent SARS-CoV-2 VOCs and the resultant growth of long-COVID. Moreover, the authors really useful together with long-COVID sufferers within the high-risk group for influenza vaccination.

*Necessary discover

bioRxiv publishes preliminary scientific studies that aren’t peer-reviewed and, due to this fact, shouldn’t be thought to be conclusive, information medical observe/health-related habits, or handled as established info.


  • Caroline Vilas Boas de Melo, Florence Peters, Harry van Dijken, Stefanie Lenz, Koen van de Ven, Lisa Wijsman, Angéla Gommersbach, Tanja Schouten, Puck B van Kasteren, Judith M.A. van den Model, Jorgen de Jonge. (2022). Influenza an infection in ferrets with SARS-CoV-2 an infection historical past. bioRxiv. doi: https://doi.org/10.1101/2022.03.22.485425 https://www.biorxiv.org/content material/10.1101/2022.03.22.485425v1

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