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EID Journal Perspective: Viral Interference Between Respiratory Viruses

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  • EID Journal Perspective: Viral Interference Between Respiratory Viruses

    EID Journal Perspective: Viral Interference Between Respiratory Viruses

    When Epidemic Viruses Collide


    Between the internet and mainstream media there is no lack of scholarly articles telling us how the COVID pandemic will likely end (spoiler alert: with SARS-CoV-2 becoming an endemic respiratory virus), but far less attention has been paid on how this virus will play with others.

    This omission is based, I'm guessing, partly on a desire to provide an optimistic timetable for a return to `normal' following the pandemic, and partly on a lack of applicable scientific data.

    Sixteen months ago, in When Epidemic Viruses Collide, we looked at some of these concerns, including the potential for coinfection with COVID and Flu (or other respiratory viruses), and the potential impact of `viral interference'.

    Viral interference refers to the impact infection by one virus might have on a concurrent or sequential infection by another.

    Among the questions asked (but not answered) in that blog:
    • Will we see a `twindemic', or will influenza remain subdued this winter?
    • Could contracting rhinovirus, influenza, or some other respiratory infection provide any short term immunity against COVID-19? If so, for how long?
    • Is is possible that due to prolonged social distancing and wearing of face covers, our immune `shields are down', making us more susceptible to infection if we are exposed to flu or COVID-19?
    • And if seasonal influenza remains subdued globally, will that make room for another novel flu (avian, swine, etc.) to emerge from the wild over the next year or so?

    As it turned out, between social distancing, the wearing of face covers, and other pandemic mitigation efforts the flu was a no-show for the 2020-2021 flu season. With the relaxation of these measures, the flu, RSV, and other respiratory viruses have made a bit of a comeback in the 2nd half of 2021.

    At the time of that initial blog, the COVID vaccine was still months away, and we were dealing with the original (aka `wild type') COVID virus (albeit with the European D614G mutation). Since then we've seen the evolution and global spread of the Alpha, Delta, and (now) Omicron variant.

    Coinfections between COVID and flu have been increasingly documented, but not yet at the level of calling it a `twindemic'. Early research (see Clinical and virological impact of single and dual infections with influenza A (H1N1) and SARS-CoV-2 in adult inpatients) suggests coinfection may produce more severe illness, but most of that data was based on earlier variants of the COVID virus.

    We are at a disadvantage in that we can't know what COVID variant will be dominant following Omicron, or in the years to come, and how it may react with other viruses. What we do know is that these interactions can be complicated, and may change over time.

    All of which brings us to a new perspective, published in the EID Journal, that looks at what past studies have taught us about viral interference - and more importantly - discusses we don't know yet about how COVID will be assimilated into, and interact with, the existing panoply of seasonal respiratory viruses.

    Some excerpts from the report follow, but you'll want to read it in its entirety. I'll have a brief postscript following the break.

    Volume 28, Number 2—February 2022

    Viral Interference between Respiratory Viruses
    Jocelyne Piret and Guy Boivin
    Author affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec‒Université Laval, Quebec City, Quebec, Canada


    Multiple respiratory viruses can concurrently or sequentially infect the respiratory tract and lead to virus‒virus interactions. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive (additive or synergistic) or negative (antagonistic) interaction. The concept of viral interference has been demonstrated at the cellular, host, and population levels. The mechanisms involved in viral interference have been evaluated in differentiated airway epithelial cells and in animal models susceptible to the respiratory viruses of interest.

    A likely mechanism is the interferon response that could confer a temporary nonspecific immunity to the host. During the coronavirus disease pandemic, nonpharmacologic interventions have prevented the circulation of most respiratory viruses. Once the sanitary restrictions are lifted, circulation of seasonal respiratory viruses is expected to resume and will offer the opportunity to study their interactions, notably with severe acute respiratory syndrome coronavirus 2.

    Several respiratory viruses can circulate during the same period and can concurrently or sequentially infect the respiratory tract, leading to virus‒virus interactions. At the host level, the course of infection of 1 virus might be influenced by prior or concurrent infection by another virus. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive (additive or synergistic) or negative (antagonistic) interaction.

    Positive virus‒virus interaction corresponds to a co-infection that might result in an increased disease severity and pathogenesis (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] and influenza A[H1N1]pdm09 virus) (1). Negative virus‒virus interaction can be homologous or heterologous depending on whether the 2 viruses belong to the same family or to different serotypes or families. Homologous virus‒virus interaction implies that cross-reactive immunity against a first virus prevents infection with a second virus (e.g., among different influenza subtypes or lineages) (2). Heterologous viral interference relies on induction of a nonspecific innate immune response by a first virus that reduces or prevents infection and replication of a second virus (e.g., influenza A virus [IAV] and respiratory syncytial virus [RSV]) (3). The type of virus‒virus interaction (negative or positive) is probably dependent on the respiratory viruses involved, the timing of each infection, and the interplay between the response of the host to each virus. In this perspective, we focus more specifically on viral interference.


    Conclusions and Perspectives

    Recent viral infections of the respiratory tract might induce a refractory period during which the host is less likely to be infected by another respiratory virus. This viral interference requires closely spaced virus co-exposures, implying that both viruses share common ecologic conditions (e.g., cold weather). Factors that could predict an interference between respiratory viruses include the capacity of the interfering virus to induce a rapid IFN response; the degree of susceptibility of the second virus to immune mediators; the extent to which the different viruses counteract the induction and antiviral effects of IFN; and the differential innate immune response patterns triggered by each viruses in the upper and lower respiratory tracts.

    The duration of the refractory period at the host level has not been determined, but might correspond to the period of virus shedding and the associated transient innate immune response. Mathematical models that simulate the co-circulation of seasonal IAV and HRV confirmed that the temporary immunity provided by an IFN response might be sufficient to produce the asynchronous epidemic peaks recorded for these 2 viruses (12). At the population level, the concept of viral interference corresponds to an ecologic phenomenon in which the epidemic caused by one virus delays the start or advances the end of the epidemic caused by another virus.
    These episodes are difficult to demonstrate because the transmission dynamics of respiratory viruses might be influenced by social behaviors for different age groups. The contact rate between persons might also vary according to different periods of the year, such as during school opening and closing. Furthermore, a large proportion of respiratory infections are asymptomatic and do not require testing, thus, excluding this part of the population from studies. Environmental conditions such as temperature and humidity can be confounding factors for viral interference. Prospective epidemiologic studies enabling detection of multiple respiratory viruses in serial nasopharyngeal swab specimens of participants over several epidemic periods would enable demonstration of viral interference. The type of interaction between respiratory viruses producing distinct epidemic peaks should be then confirmed by evaluating their likelihood of co-detection in patients, as well as the mechanisms involved in ex vivo and in vivo models.

    The reappearance of H1N1 virus during 1977 and the 2009–2011 pH1N1 pandemic offered the opportunity to study the epidemiologic interactions between the newly circulating virus and seasonal respiratory viruses in northern and southern hemispheres and thus strengthened the concept of viral interference. During the COVID-19 pandemic, nonpharmacologic interventions have prevented the circulation of most respiratory viruses. Therefore, their potential interactions with SARS-CoV-2 could not be determined in epidemiologic studies, except in some reports at the onset of the pandemic. A systematic review and meta-analysis showed that the more common respiratory viruses co-detected with SARS-CoV-2 were influenza viruses, RSV, and HRV (50). Once the sanitary restrictions are lifted, the circulation of seasonal respiratory viruses should resume and different types of interactions are expected to occur.

    Mathematical modeling predicting the timing and magnitude of epidemics caused by SARS-CoV-2 and seasonal respiratory viruses might improve public health interventions to protect persons at risk for co-infection through introduction of nonpharmacologic measures, adjustment of vaccine schedules, or use of prophylactic agents. Finally, the interfering and immunostimulatory activities of DVGs make them attractive candidates for development of prophylactic broad-spectrum antiviral drugs or vaccine adjuvant, which would be based on the concept of viral interference (47).

    Dr. Piret is a biologist and a project leader at the Research Center in Infectious Diseases at Laval University, Quebec City, Quebec, Canada. Her primary research interests include pathogenesis of infections caused by herpesviruses and Zika virus, emergence of drug resistance, and interactions between respiratory viruses.
    Dr. Boivin is an infectious disease specialist and the head of the virology laboratory at the Research Center in Infectious Diseases at Laval University. His primary research interests include pathogenesis of infections caused by respiratory viruses, as well as development of vaccines, antiviral drugs, and immunomodulatory agents.

    In 2017's PLoS Comp. Bio.: Spring & Early Summer Most Likely Time For A Pandemic, researchers used `viral interference' and/or temporary immunity hypothesis as plausible explanations why historically pandemics almost always emerge in the spring or early summer; after the end of regular flu season.

    This hypothesis may also help explain why the Flu Vaccination May Offer Some Protection Against COVID Infection.

    But the truth is, the interactions between multiple viruses, and our own (only partially understood) immune systems, are far more complicated than we imagine. Scientists struggle, and often fail, to predict what seasonal influenza will do six months from now when they gather to design vaccines twice a year.

    Making any predictions about what life with COVID will be like 12 or 18 months from now highly speculative, at best.
    All medical discussions are for educational purposes. I am not a doctor, just a retired paramedic. Nothing I post should be construed as specific medical advice. If you have a medical problem, see your physician.

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