NIH Clinical Trial of Universal Flu Vaccine Candidate Begins

Enrollment in a Phase 1 trial of a new investigational universal influenza vaccine candidate has begun at the National Institutes of Health’s Clinical Center in Bethesda, Maryland. The trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, and will evaluate the investigational vaccine for safety and its ability to elicit an immune response.

Contact

Submit a Media Request

Contact the NIAID News & Science Writing Branch.

301-402-1663
niaidnews@niaid.nih.gov
All Media Contacts

Luca Tudor Giurgea, M.D.

Section or Unit Name
Clinical Research Section
Exclude from directory
Off
Section/Unit: Location
This Researcher/Clinician’s Person Page
Parent Lab/Program
Program Description

Dr. Giurgea’s research has focused on improving our understanding of the multifaceted immune response against respiratory viruses, including refining our comprehension of correlates of protection to improve predictive modeling of clinical outcomes. This knowledge is then applied to guide development of more durable and broadly protective next-generation vaccination strategies, with the ultimate goal of achieving universal vaccines. Dr. Giurgea has a particular interest in mucosal immunity and using multi-targeted approaches to counteract the immune escape that inevitably arises in rapidly mutating RNA viruses.

Selected Publications

Visit PubMed for a complete publication listing

Major Areas of Research
  • Influenza
  • COVID-19
  • Vaccine development

Luca Tudor Giurgea, M.D.

Specialty(s): Infectious Disease, Internal Medicine
Provides direct clinical care to patients at NIH Clinical Center

Education:

M.D., 2014, SUNY Upstate Medical University, Syracuse, NY

Luca Tudor Giurgea, M.D.

Dr. Giurgea earned his medical degree from the State University of New York (SUNY) Upstate Medical University in 2014 before going on to train in internal medicine at Dartmouth-Hitchcock Medical Center. He came to NIH in 2017 for a clinical fellowship in infectious diseases, where he performed bench research and ran clinical trials, including Phase 1 vaccine trials and influenza challenge trials. He joined the Laboratory of Immunoregulation in 2022 as a staff clinician, where he continues his research on respiratory viruses.

HPAI Influenza Devastating Birds, Marine Mammals in Peru--Study Identifies Concerning Viral Mutations

NIAID Now |

NIAID-funded researchers working in Peru have signaled concern about the deaths of birds and marine mammals from highly pathogenic avian influenza (HPAI) that has been spreading globally. Historically, South America’s coastal ecosystems and poultry industry have been spared from HPAI outbreaks.

“These viruses are rapidly accruing mutations, including mutations of concern, that warrant further examination and highlight an urgent need for active local surveillance to manage outbreaks and limit spillover into other species, including humans,” the researchers say.

Their study documenting the outbreak was published Sept. 7 in Nature Communications. It was led by Mariana Leguia of Pontificia Universidad Católica del Perú in Peru and EpiCenter for Emerging Infectious Disease Intelligence (Centers for Research in Emerging Infectious Diseases [CREID] Network). Other project collaborators included the National Forest and Wildlife Service of Peru; Wildlife Conservation Society; One Health Institute; and National Center for Biotechnology Information (NCBI) at the U.S. National Institutes of Health (NIH). 

The study identifies flu type A/H5N1 lineage 2.3.4.4b, which in late 2021 spread from Europe to North America and then, in 2022, to South America. Along the way it has devastated wild birds and poultry farms. The scientists say their analyses supports a single introduction of 2.3.4.4b into Peru from North America during October 2022, presumably through the movements of migratory wild birds. The virus then infected local seabirds that share habitats with marine mammals.

Another recently published NIAID-funded study documents the evolution of the H5 virus over two decades from Europe to North America, prior to its spread to South America. The study—also in Nature Communications—involves St. Jude Children’s Research Hospital, part of NIAID’s Centers of Excellence for Influenza Research and Response (CEIRR) network.

In November 2022, scientists began documenting animal deaths along the Peruvian coast, including dolphins, sea lions, sanderlings, pelicans, and cormorants. The study—made possible by researchers quickly establishing new partnerships—identified HPAI A/H5N1 virus in the animals and analyzed how it had mutated since moving into South America. 

They singled out one mutation to monitor: “… we are particularly concerned by the presence of PB2 D701N in 2 sea lion samples, and in a human case reported in Chile, as this mutation has been specifically linked to mammalian host adaptation and enhanced transmission.”

The project involved scientists obtaining 69 samples from 28 animals; they identified influenza A in 12 animals: a dolphin, four individual sea lions, one sample pooled from five sea lions, and six sea birds. The researchers then confirmed HPAI A/H5N1 in 11 of the 12 samples (one sample was too deteriorated to determine the specific type of influenza A). The researchers say there is concern of HPAI spreading to endangered species, such as the Andean condor, Humboldt penguin, and marine otter. 

“An even larger concern,” they say, “is the possibility of spillover into human populations.” They say public awareness campaigns are needed to inform people about the presence of HPAI influenza and to avoid contact with animals that appear ill. The study notes that the outbreak in Peru occurred along the Pacific coast and during the summer, when many people go to the beach.

“It is not uncommon,” the study states, “for beachgoers (and their pets) to interact with sick and disoriented animals without any knowledge of the risks, or for free-roaming dogs in rural and semi-rural coastal areas to encounter sick or dead animals as they scavenge for food.”

In particular, they note, workers responsible for cleaning animal carcasses need additional training in the proper use of personal protective equipment and on waste management and disposal. “People in contact with sick and dead animals infected with HPAI A/H5N1 are at risk of infection,” the researchers say, “and human cases could be missed in the absence of active and obvious human-to-human transmission.”

These studies were funded in part by NIAID awards U01AI151814, 75N93021C00014, 75N93021C00016, HHSN272201400006C, and R01AI150745; and by the NIH's National Library of Medicine's Intramural Research Program.

References:

M Leguia, et al. Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru. Nature Communications DOI: 10.1038/s41467-023-41182-0 (2023). 

A Kandeil, et al. Rapid evolution of A(H5N1) influenza viruses after intercontinental spread to North America. Nature Communications DOI: 10.1038/s41467-023-38415-7 (2023).

Contact Information

Contact the NIAID Media Team.

301-402-1663
niaidnews@niaid.nih.gov

Search NIAID Blog

Experimental Influenza Vaccine (FluMos-v2) Study

This is a study of an experimental influenza (flu) vaccine called the FluMos-v2 vaccine. This vaccine study will provide more information about flu vaccines that may one day lead to a universal flu vaccine. A universal flu vaccine would be effective against all influenza strains.

Contact Information

Office: Vaccine Evaluation Clinic

Phone: 866-833-LIFE (5433)

Email: vaccines@nih.gov
 

Flu Antibodies Developed at UChicago Advance with Fast-Track Grant

University of Kentucky Researcher Sheds Light on Influenza D

Study Explores How Often Children Diagnosed with Flu Experience Serious Neuropsychiatric Side Effects

Publish or Event Date
Research Institution
Vanderbilt University
Short Title
Study Explores How Often Children Diagnosed with Flu Experience Serious Neuropsychiatric Side Effects
Content Coordinator

TFF Pharmaceuticals Awarded $2.97 Million to Develop Universal Influenza Vaccine

Tijana Ivanovic, Ph.D.

Section or Unit Name
Single Virion Biology and Biophysics Unit (SVBBU)

Highlight

Exclude from directory
Off
Section/Unit: Year Established
Section/Unit: Location
This Researcher/Clinician’s Person Page
Parent Lab/Program
Program Description

Viral outbreaks and pandemics arise when animal viruses adapt so that they can recognize and use human cells as their host. Viral persistence in human circulation is subsequently driven by rapid acquisition of mutations in viral proteins that allow evasion of the adaptive human immune response.

Recent research in the lab has shown that viral ability to recognize and invade host cells in the presence of immune system antibodies is determined by the viral particle structure. For example, the same antibodies binding to the same target viral protein may or may not neutralize viral infection depending on the overall structural organization of the virus particle displaying these targets.

We are further working to define how the structural organization of virus particles might enable entry into cells not displaying fitting receptors. Viral ability to establish new infections under suboptimal conditions is probed as a possible mechanism of adaptation to new hosts with the potential to lead to new pandemics. Complementing our research on virus cell entry is our effort to define the mechanisms of virus particle assembly and regulation of the assembly outcomes (i.e., structural features of virus particles such as shape, size, or viral protein incorporation). We have developed novel quantitative and high-throughput approaches for studying virus particle assembly, and detailed functional characterizations are underway.

Trainees learn how to think deeply as virologists and acquire a unique combination of interdisciplinary skills that together permit them to seek answers to sophisticated questions. We combine molecular virology, in vitro reconstitution, biophysics, and quantitative cell biology to answer difficult-to-tackle mechanistic questions in virology and build upon those discoveries to ultimately enable prediction and prevention of undesirable viral adaptation (e.g., drug resistance, immune escape, or pandemic adaptation). Our work spans diverse viral pathogens and/or their model systems, including but not limited to influenza virus and reovirus.

Viral cell-entry mechanisms

Viruses initiate infection by delivering the genomes from within the viral capsid or a membrane envelope to the target cell. Enveloped viruses accomplish this by fusing/merging their membrane with a cellular membrane. Membrane fusion is mediated by the viral surface glycoproteins, which undergo a series of large-scale conformational changes that allow them first to insert in the target membrane, then to bring the viral and cellular membranes together. By measuring the fusion kinetics of individual virus particles and their mutants in the presence or absence of antibodies or inhibitors, we have uncovered the detailed mechanism of membrane fusion by influenza virus.

Influenza cell-entry glycoprotein hemagglutinin (HA) is present at a high density on virus particles. Three to five HAs that insert next to each other cooperate to bring about membrane fusion. However, the steps leading to HA insertion are stochastic (noncooperative, random), so substoichiometric (nonsaturating) antibody or inhibitor amounts prevent fusion by the majority of particles.

A further consequence of the mechanism of membrane fusion we uncovered is that very large particles are virtually impossible to inhibit. Tens of micrometers-long viral filaments require more than 90% of HAs to be inactivated for any reduction in the fusion yield. This insight led to a model where the pre-existing diversity in virus particle size in pleomorphic (mixed-shape) viruses enables viral adaptation to cell-entry pressure in a way that does not require an initiating genetic change.

We are asking:

  1. How does virus particle shape influence viral adaptation to cell-entry pressure?
  2. What is the mechanism of membrane fusion by other pleomorphic viruses (e.g., Ebola virus)?
  3. What role do other viral structural features (e.g., glycoprotein density) play in the mechanism of membrane fusion?
  4. What role do the interactions between viral glycoproteins and cellular receptors play in membrane fusion?
Composite of three images regarding SVBBU entry mechanisms

Left: Electron micrograph revealing pleomorphic influenza A virions. A filamentous and a spherical virion are indicated. Pleomorphic virus structure is employed by other circulating (e.g., measles and RSV) or emerging (e.g., highly pathogenic avian influenza, Ebola, Nipah, and Hendra viruses) devastating viral pathogens. Middle: Home-built TIRF microscope for single-virion and single-molecule imaging. As our research evolves, we update the design of our microscopes to meet the changing experimental needs. Right: Longest filamentous virions are effectively resistant to inhibition by HA-targeting antibodies.

Credit: NIAID

Viral assembly mechanisms

We have established a total internal reflection fluorescence (TIRF)-based single-particle platform for quantitative real-time imaging of reovirus assembly, disassembly, and transcription.

Reovirus virion consists of two concentric icosahedral protein shells. The inner, core particle encloses the genome and serves as the transcriptional unit in the infected cell cytoplasm. The outer capsid delivers the core across the cellular membrane to initiate infection. Disassembly of the outer capsid activates cores for transcription, and its assembly around cores represses transcription.

In our experiment, fluorescently labeled cores are immobilized on microscope coverslips. Fluorescently tagged oligonucleotides detect nascent viral transcripts. Fluorescently tagged outer-capsid components assemble around immobilized cores and repress transcription. We are working toward a quantitative model of reovirus outer-capsid assembly and transcriptional regulation.

In addition to studying the assembly of regularly shaped, icosahedral virions, we are interested in mechanisms of assembly of irregularly shaped pleomorphic viruses. For this, we have developed a novel, high-throughput assay enabling quantification of virus particle size distributions directly in the medium around infected cells.

We are asking:

  1. What is the mechanism of pleomorphic virion assembly?
  2. How is the shape of pleomorphic virions regulated?
  3. What are the viral and cellular determinants of viral assembly outcomes?
  4. How do viruses with segmented genomes ensure efficient packaging of the full genome complement?
Black and white photos next to a model image of SVBBU assembly mechanisms

Left: Electron micrograph of Reovirus virions, cores, and recoated cores in vitro. Reovirus virions display a regular, icosahedral particle structure. Recoated cores are indistinguishable from virions in structure and function. Right: Single particle platform for study of reovirus assembly, disassembly, and transcription. Schematic of the experiment design and illustration of what transcription/assembly might look like under the microscope. Red square: dots correspond to viral cores (all particles). Blue and green squares: cores that have incorporated the outer-capsid proteins sigma1 (blue) and mu1/sigma3 (green). Orange square: actively transcribing cores.

Credit: NIAID
Selected Publications

Partlow EA, Jaeggi-Wong A, Planitzer SD, Berg N, Li Z, Ivanovic T. Influenza A Virus Infections Sense Host Membrane Tension to Dynamically Tune Assembly. bioRxiv [Preprint], 2023 Aug 28:2023.08.28.555166.

Li Z, Li T, Liu M, Ivanovic T. Hemagglutinin Stability Determines Influenza A Virus Susceptibility to a Broad-Spectrum Fusion Inhibitor Arbidol. ACS Infec Dis. 2022 Aug 12;8(8):1543-1552. 

Li T, Li Z, Deans EE, Mittler E, Liu M, Chandran K, Ivanovic T. The shape of pleomorphic virions determines resistance to cell-entry pressure. Nat Microbiol. 2021 May;6(5):617-629. 

Ivanovic T, Harrison SC. Distinct functional determinants of influenza hemagglutinin-mediated membrane fusion. Elife. 2015 Nov 27;4:e11009. 

Ivanovic T, Choi JL, Whelan SP, van Oijen AM, Harrison SC. Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates. Elife. 2013 Feb 19;2:e00333. 

Major Areas of Research
  • Viral cell-entry and assembly mechanisms
  • Virus particle shape regulation in pleomorphic viruses
  • Structure/function relationship for uniformly shaped, icosahedral virus particles
  • Viral adaptation – crosstalk between phenotypic and genetic diversity
  • Novel antivirals
Research Group Page