The CEIRR Network conducts influenza surveillance efforts in a variety of hosts, including wild birds, poultry, swine, and an often-underappreciated group – marine mammals. Researchers from the Center for Research on Influenza Pathogenesis and Transmission (<a href="https://www.ceirr-network.org/centers/cript" target="_blank" rel="noopener noreferrer">CRIPT</a>), <a href="https://vet.tufts.edu/people/faculty/jonathan-runstadler" target="_blank" rel="noopener noreferrer">Jonathan Runstadler, D.V.M., Ph.D.</a> and <a href="https://sites.tufts.edu/runstadlerlab/people/" target="_blank" rel="noopener noreferrer">Wendy Puryear, Ph.D.</a>, lead influenza surveillance in seals, whales, sea otters, and other marine mammals from the Runstadler lab at Tufts University. The main goals of these efforts aim to 1. better understand influenza virus dynamics, 2. characterize viral traits linked with disease in mammals, and 3. inform actions that reduce risks to humans.From 2014 to today, the CEIRR Network (and previous iteration called <a href="https://www.ceirr-network.org/about/the-legacy-of-ceirs" target="_blank" rel="noopener noreferrer">CEIRS</a>) sampled over 18,000 marine mammals, of which 98% were seals. These routine samplings mostly took place across the western and northeastern US coastlines (98%) and found 235 were positive for influenza. Through Drs. Runstadler’s, Puryear’s, and the broader field’s work, a general working model developed describing avian influenza dynamics in marine systems. Shorebirds that are infected with avian influenza may shed the virus on rocks and coasts that marine mammals share. Due to habitat overlap and predation, marine mammals can be the first mammals to contract avian influenza, especially during outbreaks. As the virus continues spreading among marine mammals and shorebirds, it accumulates mutations, which can increase the risk of influenza spreading or “spilling over” into other land mammals, like humans. To dive deeper into these dynamics, the iDPCC sat down with Drs. Runstadler and Puryear to discuss the importance of marine mammal influenza surveillance from their perspectives, its implementation with partners, and insights on influenza transmission in the wild.How Did They Start Studying Influenza in Marine Mammals?Dr. Jon Runstadler started his lab in 2004 at the University of Alaska to study influenza in wild reservoir hosts, its disease ecology, and virus spillover between animal hosts. In 2012, Dr. Puryear joined Runstadler’s lab and was inspired to investigate influenza in marine mammals after an unusual mortality event in seals in the Gulf of Maine in 2011. Dr. Puryear recounted that the question circulating their lab was “whether or not seals might serve as a reservoir rather than just the spillover host.”She went on to describe the media’s short-term coverage on spillover hosts during an outbreak – often ignoring the relevance of the host or underlying transmission dynamics until the next spillover event. Scientists were no different. Most literature on influenza in marine mammals was associated with outbreaks, but no one was sampling or investigating this relationship outside those bounds. Dr. Runstadler kept coming back to the question, “Is there virus in these animals during those times when the populations are otherwise seemingly ‘healthy’ or normal?” In 2013, the lab started actively sampling marine mammals for influenza infections, mostly in seals. In their first year of sampling and every year since, they detected influenza viruses and antibodies to those viruses, confirming that influenza is indeed found in otherwise healthy populations. By 2017, the lab moved to Tufts University, where Dr. Runstadler currently serves as Chair of the Department of Infectious Disease and Global Health at the Cummings School of Veterinary Medicine.Importance of Marine Mammal SurveillanceDrs. Runstadler and Puryear often faced skepticism on the importance of their research. However, they argue that marine mammals are an ideal population to monitor since, as mammals themselves, they’re more closely related to humans than birds are. The natural interface between shorebirds and marine mammals grants them a unique opportunity to study influenza’s dynamics with little human interference. Since shorebirds are a huge reservoir for influenza, there are many opportunities for the virus to “explore” mammalian hosts that the birds interact with. Runstadler and Puryear highlight this as a model system for a broader and deeper understanding of adaptations that influenza needs to successfully infect a mammalian host.Outside of the scientific perspective, humans interact with marine mammals more often than initially thought, with each interaction posing a risk if that marine mammal has a disease. Humans work with these animals in rehabilitation settings and in veterinary clinics, find them on beaches, or their pets may even encounter them. From the conservation side, a variety of factors contribute to disease severity, including climate change, prey availability, toxicity, and other external stressors. All in all, seals and other marine mammals have a history of influenza infections and outbreaks that represent a large, susceptible mammalian reservoir with cross-species interactions within their ecosystems and with humans.Tracking the H5N1 Influenza Outbreak in Marine MammalsThe 2022 influenza outbreaks devastated marine mammal populations in Maine, receiving coverage from the <a href="https://www.washingtonpost.com/climate-environment/2024/01/15/bird-avian-flu-seal/" target="_blank" rel="noopener noreferrer">Washington Post</a> and <a href="https://e360.yale.edu/features/avian-flu-mammals-birds-seals" target="_blank" rel="noopener noreferrer">Yale Environment 360</a>, among others. The Runstadler lab worked on the front lines of this outbreak and were able to respond so quickly because of the infrastructure and connections they built over the past 10 years. Many of the groups responding in the area knew to contact the Runstadler lab, already had protocols for seal sampling, and recognized the signs of influenza infection. Academics, non-profits, volunteers, and state government employees in the area all communicated through the outbreaks to aid in the swift response. Dr. Runstadler added that he could not emphasize enough how they wouldn’t have been able to do this work or respond so quickly during an outbreak without these relationships.Runstadler and Puryear brought up the word “trust” when describing their relationships with collaborators. We asked them to elaborate on how they built trust with so many groups. Dr. Puryear said the key was “literally working in the trenches together.” A common issue that they wanted to avoid was a tendency for front line workers to do all the work on shoestring budgets while an outsider would swoop in, utilize their knowledge and resources, then take all the credit. Runstadler and Puryear noted they were very proactive about joining the front lines to teach what they could about viruses while learning from other frontliners about the seals. The trust was built on mutual respect, which was reinforced by checking back in to share preliminary results and recognize everyone’s efforts by providing them authorship on publications (Dr. Puryear joked that their author lists are often “more than 600!”).Elaborating on the mutual respect, Runstadler and Puryear acknowledged the complexity of their work beyond just seeing if there’s virus in these seals and figuring out what it is. These outbreaks are happening in communities. While studying the interface of influenza and marine mammals, they also needed to become proficient in interfacing with the fishing industry, recreational users of coastlines, individual towns and municipalities, public relations and media, and people who love or even hate seals. They were careful to not steamroll in with an agenda. Because of this complexity, these relationships took a lot of time to build. They started with a few groups, such as the National Oceanic and Atmospheric Administration (NOAA), and expanded from there. In each interaction, they were clear and open about their scientific goals and highlighted the mutual benefits the groups could offer each other.Further Insights on Influenza Dynamics From Marine Mammal SurveillanceThe iDPCC asked how often avian influenza viruses spilled over into marine mammals and how that contributes to the spillover risk for humans and other terrestrial mammals. Unfortunately, Runstadler and Puryear note that there’s no clear answer. From their surveillance, they know that many subtypes of influenza have been responsible for mass mortality events in marine mammals, suggesting that the spillover can happen reasonably frequently. Even beyond the outbreaks, they’ve detected many individual cases of influenza in seals. They’re now trying to tease apart whether the viruses are a. established in marine mammals and circulating among each other, or b. predominantly infecting marine mammals from multiple, independent shorebird transmissions.Digging deeper, the iDPCC wanted to know how often influenza from a marine mammal would infect shorebirds. Dr. Puryear noted that there are limited data in this area. Some mutations found in influenza isolated from seals were also detected in terns and some other birds in Argentina, but this is a developing story. Dr. Runstadler mentioned that progress on influenza infecting seals outside of an outbreak went from “maybe this happens” to “probably happens more often than we think.” But there are open questions that his lab is trying to understand:<ol><li>How frequently are these infections occurring?</li><li>Does influenza transmit in one direction more than another?</li><li>Are certain subtypes or genetic backgrounds more conducive to spillover?</li></ol>On a positive note, Runstadler and Puryear imply that the risk of marine mammals passing an influenza infection to humans is low. They recalled at least one case of a handler infected with influenza by a seal in captivity. Dr. Runstadler smiled as he noted that he stills gets excited to go to the beach, even in January and February when they sample seals the most in the northeast.To round out our discussion, Runstadler and Puryear highlight that influenza transmission in marine mammals is an incredibly dynamic system. Influenza’s rapid evolution results in multiple variants – layered on top of a rapidly changing world like animals shifting where they move, habitat overlap and use, movement/migratory patterns, among other dynamics. Dr. Runstadler ended on an inquisitive note: “We don’t know enough about how influenza viruses move and change in these wild reservoir hosts to be able to predict what’s happening … with the ‘high path’ outbreaks going on.” His lab will continue investigating the potential for zoonotic spillover from ecological interactions that drive transmission, evolution, and perpetuation of virus in these natural reservoir populations. Runstadler and Puryear hope to learn more about marine mammals’ role in influenza ecology and maybe apply what they’ve learned to other wild reservoirs.<hr>To view a PDF version of the Influenza in Marine Mammals infobyte, <a href="https://ceirr-public-website-static-prod.s3.amazonaws.com/CEIRR_marine_mammal_infobyte_v10_reduced_ebe5809bc3.pdf?updated_at=2024-04-17T21:22:34.531Z" target="_blank" rel="noopener noreferrer" download="download">click here</a>. To read more about this topic, check out:<ul><li><a href="https://www.ceirr-network.org/resources/publications?keyword=36958010" target="_blank" rel="noopener noreferrer">Puryear W. et al. (2023) Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States. Emerging Infectious Diseases. 29(4): 786–791.</a></li><li>Additional CEIRR publications on <a href="https://www.ceirr-network.org/resources/publications?keyword=marine%20mammal" target="_blank" rel="noopener noreferrer">influenza in marine mammals</a>.</li><li>The Washington Post’s coverage on <a href="https://www.washingtonpost.com/climate-environment/2024/01/15/bird-avian-flu-seal/" target="_blank" rel="noopener noreferrer">avian influenza infecting elephant seals</a>.</li><li>A Yale Environment 360 article on <a href="https://e360.yale.edu/features/avian-flu-mammals-birds-seals" target="_blank" rel="noopener noreferrer">avian influenza outbreaks in marine mammals</a>.</li></ul>

CEIRR Infobyte: Influenza in Marine Mammals

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In The News

Influenza

CRIPT

iDPCC

Outbreaks

Surveillance

Infobyte

CEIRR researchers study the when, how, and why of avian influenza virus spillover from wild birds into marine mammals for pandemic preparedness and research response.

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Influenza in Marine Mammals: An Important Interface

<figure class="image image-style-align-right"><img src="https://ceirr-public-website-static-prod.s3.amazonaws.com/Florian_Krammer_Headshot_350x263_fc2fc3c6c2.jpg?updated_at=2024-03-22T20:51:38.946Z"><figcaption>Florian Krammer, Ph.D.</figcaption></figure><a href="https://www.ceirr-network.org/search?keyword=Florian%20Krammer#searchBar" target="_blank" rel="noopener noreferrer">Florian Krammer, Ph.D.</a>, an internationally renowned expert in influenza immunity and vaccine development, has <a href="https://www.meduniwien.ac.at/web/en/ueber-uns/news/2024/news-im-februar-2024/florian-krammer-takes-over-professorship-of-infection-medicine-at-meduni-vienna-1/" target="_blank" rel="noopener noreferrer">taken up a professorship</a> of Infection Medicine at the University of Vienna on March 1, 2024. At the Icahn School of Medicine at Mount Sinai, he serves as an investigator in the CEIRR Center for Research on Influenza Pathogenesis and Transmission (<a href="https://www.ceirr-network.org/centers/cript" target="_blank" rel="noopener noreferrer">CRIPT</a>) and as Principal Investigator of the Sinai-Emory Multi-Institutional Collaborative Influenza Vaccine Innovation Center (<a href="https://www.niaidcivics.org/sinai-emory-multi-institutional-civic/" target="_blank" rel="noopener noreferrer">SEM CIVIC</a>). Dr. Krammer will alternate his work between the two institutions.&nbsp;Dr. Krammer’s laboratory investigates broadly protective immune responses to RNA viruses, with a focus on influenza. By understanding the mechanisms behind immunity, his group works toward developing therapeutics and vaccines against viruses. In Vienna, he will leverage this knowledge to extend his research program in characterizing viral pathogens and developing vaccines against them. His Vienna group’s focus will emphasize viruses with pandemic potential and will include human influenza and SARS-CoV-2.&nbsp;&nbsp;Rector Markus Müller, President of the Medical University (MedUni) of Vienna, stated that he is “delighted to welcome Florian Krammer to MedUni Vienna” and continued to explain that Dr. Krammer “will make a significant contribution to research in this important area.”&nbsp;Congratulations, Dr. Krammer!&nbsp;You can learn more about Dr. Florian Krammer’s work in this <a href="https://www.youtube.com/watch?embeds_referring_euri=https%3A%2F%2Fwww.meduniwien.ac.at%2F&amp;source_ve_path=MTY0NTA2LDE2NDUwMw&amp;feature=emb_share&amp;v=0o9-hKkoWKw" target="_blank" rel="noopener noreferrer">video</a> where he introduces himself to the Medical University of Vienna.&nbsp; &nbsp;

Dr. Krammer (CRIPT) will alternate his influenza research efforts between the Icahn School of Medicine at Mount Sinai and the University of Vienna.&nbsp;&nbsp;

Headshot of Florian Krammer wearing a black collared shirt with a window in the background.

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Florian Krammer Starts Professorship of Infection Medicine at the Medical University of Vienna

<figure class="image image-style-align-right"><img src="https://ceirr-public-website-static-prod.s3.amazonaws.com/Flu_Hub_Network_Hub_Red_952_1_a8e5cab65a.png"><figcaption>Flu Hub contributing networks.</figcaption></figure>The <a href="https://www.fluhub.org/?utm_source=news-article&amp;utm_medium=web-link&amp;utm_campaign=fluhub-launch" target="_blank" rel="noopener noreferrer">Flu Hub</a> website centralizes networks, programs, &amp; resources within the <a href="https://www.niaid.nih.gov/" target="_blank" rel="noopener noreferrer">National Institute of Allergy and Infectious Diseases</a> (NIAID) that support the Universal Influenza Vaccine Strategic Plan, and Flu Hub houses more information about the <a href="https://www.fluhub.org/strategic-plan?utm_source=news-article&amp;utm_medium=web-link&amp;utm_campaign=fluhub-launch" target="_blank" rel="noopener noreferrer">Universal Influenza Vaccine Strategic Plan</a> itself, including descriptions of the three featured Research Areas.&nbsp;On the site, you can browse the NIAID influenza research <a href="https://www.fluhub.org/networks?utm_source=news-article&amp;utm_medium=web-link&amp;utm_campaign=fluhub-launch" target="_blank" rel="noopener noreferrer">Networks</a> that make up Flu Hub and learn more about their individual goals. Each network is categorized by research types (basic, clinical, and translational) and the Research Areas addressed in the Strategic Plan.In addition, the Flu Hub <a href="https://www.fluhub.org/resources?utm_source=news-article&amp;utm_medium=web-link&amp;utm_campaign=fluhub-launch" target="_blank" rel="noopener noreferrer">Resources</a> page lists publicly available information and outputs from the NIAID Flu Hub networks, including pre-clinical services, clinical trial details, databases, computational research networks, GitHub applications, facilities, and influenza reagents.The Flu Hub website also offers a <a href="https://www.fluhub.org/resources/cohort?utm_source=news-article&amp;utm_medium=web-link&amp;utm_campaign=fluhub-launch" target="_blank" rel="noopener noreferrer">Cohort Studies</a> page that centralizes influenza-focused clinical studies funded by the Division of Microbiology and Infectious Diseases and others that align with the universal influenza vaccine strategic initiative. The webpage includes a grid that displays an overview of each study with PubMed Unique Identifier (PMID) or National Clinical Trials Identifier (NCTID) links available. All studies are searchable and filterable by meta-data using the left sidebar.If you have any suggestions for future content, please reach out to <a href="mailto:support@fluhub.org" target="_blank" rel="noopener noreferrer">support@fluhub.org</a>.

Flu Hub is a centralized website dedicated to networks, programs, and resources supporting the National Institute of Allergy and Infectious Diseases (NIAID) Universal Influenza Vaccine Strategic Plan.

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Flu Hub: Your One Stop Shop for NIAID’s Influenza Vaccine Initiatives

A recently published study has taken us one step closer to creating a universal flu vaccine, a widely sought after solution to the ever-changing nature of influenza antigens. <a href="https://mcb.illinois.edu/directory/profile/rlei001" target="_blank" rel="noopener noreferrer">Dr. Ruipeng Lei</a> and <a href="https://www.ceirr-network.org/centers/cript" target="_blank" rel="noopener noreferrer">CRIPT</a> researchers, <a href="https://profiles.mountsinai.org/florian-krammer" target="_blank" rel="noopener noreferrer">Dr. Florian Krammer</a> and <a href="https://pathology.wustl.edu/people/ali-ellebedy-phd/" target="_blank" rel="noopener noreferrer">Dr. Ali H. Ellebedy</a>, contributed to <a href="https://pubmed.ncbi.nlm.nih.gov/37967533/" target="_blank" rel="noopener noreferrer">this study</a> published in Immunity. The authors characterized three protective antibodies that cross react with neuraminidases from various seasonal H3N2 strains.<figure class="image image-style-align-right"><img src="https://ceirr-public-website-static-prod.s3.amazonaws.com/Adobe_Stock_Lei_et_al_NA_vaccine_350x233_d5dab9b358.png?updated_at=2024-02-15T17:46:30.727Z"><figcaption>Influenza virion with hemagglutinin (red) and neuraminidase (blue), falsely colored.</figcaption></figure>The influenza virus has two main antigens on its surface: hemagglutinin (HA) and neuraminidase (NA). Historically, seasonal influenza vaccine development focused on targeting the hemagglutinin antigen, but the current vaccine’s suboptimal protection has led researchers to investigate the less characterized NA. Compared to HA, the molecular characterization of the antibody response to NA is still lacking even though the NA antibody response does make up a correlate of protection independent of the HA response.Using electron microscopy, the researchers characterized the structure of three NA antibodies isolated from a recently vaccinated individual. All three of these antibodies bound to overlapping conserved epitopes on the underside of the NA head domain, distant from the NA active site where antibodies typically bind. All three antibodies could bind across multiple seasonal influenza H3N2 subtypes, with one antibody, binding to an H9N2 subtype, a non-seasonal N2 strain. The authors speculate that these antibodies may have broad reactivity across influenza subtypes due to their binding at conserved regions, but further testing beyond N2 subtypes is required.Though these antibodies bound far from the NA active site, two of the three antibodies inhibited viral growth in vitro, likely via steric hindrance dependent on the positioning of the antibody. Other in vitro experiments demonstrated that all three antibodies could provide both therapeutic and prophylactic protection, indicating the importance of cell-mediated immunity. When assessed in vivo, all antibodies conferred protection, indicating that partial inhibition of viral growth is still sufficient for in vivo protection.Overall, Lei et al. indicate that targeting regions outside of the normal antigenic regions can provide a cross-strain, broadly protective immunity that might outlast the antigenic changes of seasonal influenza. These antibodies represent new candidate targets for a universal flu vaccine, a much sought after replacement for the yearly influenza vaccine.<a href="https://pubmed.ncbi.nlm.nih.gov/37967533/" target="_blank" rel="noopener noreferrer">Lei R. et al. (2023) Leveraging vaccination-induced protective antibodies to define conserved epitopes on influenza N2 neuraminidase. Immunity. 56(11): 2621–2634.</a>

Publication Commentary

Vaccine

CRIPT researchers isolated three protective antibodies that cross react with neuraminidases from various seasonal H3N2 strains.

Zoom in on influenza virion with the structures of hemagglutinin and neuraminidase shown.

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