The García-Sastre laboratory focuses on viral host-pathogen interactions, vaccines, anti-viral drug development and cancer viroimmunotherapy to address global health threats.
In 1918 when WW1 was coming to an end, a mysterious disease began to affect the worldwide population. The so-called ‘Spanish Flu Pandemic‘, the deadliest pandemic in history, infected 500 million people around the world, and killed an estimated 20- to 50 million victims. Over 100 years have passed since the Spanish flu first besieged the world, and no other pandemic has approached its magnitude of fatality. It might be possible to anticipate future epidemics by accumulating knowledge through appropriate research and by monitoring their emergence using indicators from different sources.
Nowadays, infectious diseases kill 17 million people per year. No entity can stand alone in the fight against infectious diseases. With the recent emergence of virulent pathogens (including influenza virus, HIV, dengue virus, Ebola virus, and hepatitis C virus), there is a pressing need to understand the pathogenesis of viruses and develop vaccines and therapies. However, viruses can also save people’s lives by destroying cancer cells. Oncolytic cancer immunotherapy development is another novel field that highlights the importance of viruses as serial killers.
Influenza virus
Influenza (flu) is a highly contagious respiratory illness caused by influenza viruses. Most people consider influenza as a respiratory disease accompanied by mild fever and malaise that is best dealt with by resting at home for a few days. Although this perception describes the majority of influenza cases very well, most people are unaware that influenza also kills. Annually seasonal epidemics of influenza result in approximately 500,000 deaths worldwide. Some groups, such as pregnant women, the elderly, young children, and people with certain health conditions, are at high risk of serious flu complications. Secondary bacterial infections can result in pneumonia and increased mortality. Even mild cases of seasonal flu have a great economic impact in lost hours of labour and cost of medical treatment.
There are two main types of influenza virus: types A and B. Two subtypes of influenza A (H1N1 and H3N2) and two antigenically distinct lineages of influenza B co-circulate and are responsible for seasonal flu epidemics each year. While there is a vaccine to prevent influenza infections, very low efficiencies and even complete vaccine failure have been reported for the current influenza vaccine. Since there are four different influenza viruses co-circulating (and they are constantly changing), the composition of the vaccine needs to be re-formulated every year. When there is not a good antigenic match between the viruses present in the vaccine and one or more of the four circulating viruses, the protective efficacy of the vaccine drops.
In addition to seasonal human influenza viruses, people can occasionally be infected by animal influenza viruses (such as swine flu and bird flu), or by novel viruses that combine genetic elements from both human and animal influenza (reassortant viruses). Current vaccines and pre-existing immunity offer no protection against antigenically new viruses and if these viruses are efficiently transmitted among humans, the result could be an influenza pandemic.
Universal flu vaccine: myth or reality?
The best way to prevent flu is by getting vaccinated each year. However, the current flu vaccines are far from perfect.1 The seasonal influenza viruses are constantly changing, and as a result, the composition of the vaccine has to be re-evaluated twice a year, and changed to match the antigenic changes in the circulating strains. In fact, because it takes approximately six months to prepare enough doses of the vaccine, scientists need to predict the antigenicity of the viruses that will circulate six months in the future. Moreover, for an effective vaccine the prediction needs to be accurate for each one of the four seasonal viruses that co-circulate.
An additional worry is that the antigenicity of future outbreaks of zoonotic influenza, and future influenza pandemics cannot be predicted until the outbreak or the pandemic is already happening. For all these reasons, a major goal in influenza research is the development of a universal flu vaccine that has the potential to induce long-lasting protective immunity against all flu strains, including novel strains that may arise in the future.
Current vaccines induce protection by eliciting antibodies mostly against the viral protein hemagglutinin (HA). The influenza HA is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity. HA has two structural components: one called a ‘head’, that is highly immunogenic but also highly variable, and one called a ‘stalk’, which is more conserved among viral strains but is less immunogenic. The García-Sastre laboratory in collaboration with colleagues from the Icahn School of Medicine at Mount Sinai (ISMMS) in New York, has come up with a new approach to direct the immune responses to the conserved stalk, instead of the variable head.
Modified HA proteins: chimeric hemagglutinins
The team takes advantage of the principle that immune responses against an antigen are faster and stronger when the same antigen has already previously been recognised by the immune system. In order to make an universal flu vaccine, we have used sequential vaccination with influenza viruses with modified HA proteins in which the stalk region is constant, while the head region is replaced by antigenically different viruses. These modified HAs were called chimeric hemagglutinins (cHA).2,3 A trial of this strategy’s safety and immune response is underway on approximately 65 healthy volunteers.4
In a phase I clinical trial, several different cHA based vaccination regimens were tested to determine which ones could stimulate the human body to produce antibodies that would be able to protect against flu in general. A single vaccination with an adjuvanted cHA-based (inactivated influenza virus vaccine) was successful in activating antibodies that fight several different types of flu virus.
Preliminary studies showed that the vaccine induces a broad antibody response, which was not only cross-reactive for currently circulating human influenza virus but also to avian and bat influenza virus subtypes. An inactivated formulation with adjuvant induced a very strong anti-stalk response already after the prime, suggesting that one vaccination might be enough to induce protection against pandemic influenza viruses yet to arise.5
FluOMICS: when influenza virus meets technology
The interactions between viruses and their hosts are very complex. A better understanding of the mechanisms underlying viral pathogenesis and how the host immune system responds to viral infection is required to guarantee future progress in the fields of virology, immunology and vaccinology.
Different OMICS approaches have come of age and are used to perform large scale studies that focus on genes (genomics), RNA transcripts (transcriptomics), proteins (proteomics) and metabolites (metabolomics) during influenza infection. A multidisciplinary approach with strong computational and statistical focus is required to generate, analyse and integrate OMICS data, linking them with infection data obtained from human cohorts of patients or preclinical data sets from infection experiments using laboratory animals and relevant primary human cells. Such an approach allows for the study of infection biology as an integrated system, with tunable input variables that result in changes in output.
Funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health in US, the aim of the FluOMICS project was originally to use systems approaches as discovery tools to generate predictive models of influenza virus pathogenesis. Influenza viruses that induce different degrees of disease severity were used to infect cell lines, a preclinical animal model, or primary human immune cells. This allowed the study of molecular networks that underlay disease severity during influenza infection or that regulate the complex mechanism of pathogen recognition by the immune system.6,7 For the continuation of this project during ‘FluOMICS: The NEXT Generation’, we have reassembled our highly diverse team of investigators. This has allowed us to expand our research to natural infection samples from a clinical human cohort.
Multiple OMICS-based systems level measurements are now integrated using modelling approaches and machine learning algorithms. This allows to further unravel host-virus networks that modulate influenza A virus disease severity, as well as the gene products that drive them in both model systems and humans. Such ‘network drivers’ can be considered as crucial elements that control the network outcome or without which, the network cannot exist.
In order to validate the importance of these networks, it is crucial that network activation states are monitored in vivo during infection. Therefore, another aim of the FluOMICS project is the discovery of biomarkers in patient blood that reflect network activation states. Once activation states and network drivers are known, novel host targets for therapeutic interventions can be suggested. Validation of host targets is then performed in preclinical animal models using transgenic mice, siRNA technology or small molecule inhibitors. The output generated by the FluOMICS project will provide a solid base for further fundamental research as well as steer rational vaccine and antiviral drug development.
Going viral against cancer: oncolytic viroimmunotherapy
The application of viruses as cancer therapeutics in humans has only recently started to gain acceptance in the oncological community, particularly noted after the FDA approval in 2015 of T-VEC (a genetically modify herpes simplex virus for the treatment of advanced melanoma). T-VEC incorporation to the clinics has propelled the interest of oncolytics research and eased the transition of different viral platforms into clinical trials. However, there is not yet a complete cure of cancer reported using viral agents and, mirroring the progression of recent cancer immunotherapies, some of the oncolytic strategies already tested in humans would need to be revisited and turned back to pre-clinical models.
In the García-Sastre laboratory, the study of viruses as cancer therapeutics started almost two decades ago. The first contribution of Dr García-Sastre to the field coincided with his research on influenza virus and the interferon antagonist protein ‘NS1’.8 The work published by the journal Cancer Research in 2001 described for the first time a genetically modified influenza virus called ‘ΔNS1’, and its potential use as a cancer therapeutic. Although in the following years the group would transition to the study of the anti-tumour capacity of non-human viruses, the work with ΔNS1 already pointed out what is nowadays centrepiece of the cancer research carried out in his laboratory: the duality of the interferon response as a driver of cancer progression and major determinant in the success of oncolytic therapy.9
The avian pathogen Newcastle disease virus (NDV) has been the main viral platform used by the García-Sastre group and its therapeutic potential has been interrogated in different preclinical murine tumour models, such as melanoma, colon carcinoma lung carcinoma or lymphoma.10 Their research on NDV has not only highlighted the benefits that NDV-based cancer therapy has to offer, but in contrast to other platforms developed in the oncology community, the NDV technology improves upon safety, versatility and broad-applicability. More importantly, their studies have served to rationally improve NDVs anti-tumour potential by genetically engineered novel recombinant viruses with enhanced therapeutic features.11,12 This novel and promising oncolytic immunotherapy comes to light as a result of the collaborative effort of the García-Sastre and Palese laboratories at ISMMS, and Zamarin laboratory at Memorial Sloan Kettering Cancer Center.
Today, the García-Sastre laboratory possesses a multidisciplinary oncolytic immunotherapy research program that combines different scientific disciplines including molecular virology, molecular and cell biology, genetics and immunology. The group has incorporated novel non-human viruses with high oncolytic potential to their viral platform as well as expanded their preclinical models. Keeping a strong focus on translational research, their ongoing studies aim to understand the interplay between virus, tumor and immune response in a cancer-specific manner and to rationally design better viral immunotherapeutic strategies to translate into the clinics.
The future of virus research
In recent decades, the issue of emerging and re-emerging infectious diseases, especially those related to viruses, has become an increasingly important area of concern in public health. Influenza viruses are globally important human pathogens infecting millions of people annually. It is the ultimate goal of the scientific community to prevent or reduce deaths by influenza through promoting research dedicated to unravelling the factors that predispose specific individuals to lethal influenza disease and to better prevent and treat severe influenza infection.
With the recent emergence of highly pathogenic avian influenza (HPAI) strains, there is a pressing need to understand the pathogenesis of influenza A and develop better vaccines and therapies. Same principles apply to several other human emerging viruses from different animal reservoirs, such as Ebolaviruses or the animal-origin coronaviruses, including MERS-coronavirus and the newly emergent SARS-like coronavirus.
Viruses can also affect people’s lives in positive ways. They can be used in oncolytic viroimmunotherapy. However, in this research area, we still have a lot of work to do. We still need to understand how viruses interact with cancer cells and develop cancer therapies vaccines that use a virus to boost the immune system’s own response to fight cancer cells. The García-Sastre laboratory has a proven record in performing top translational science with huge potential impact on public health. By turning viruses into tools to fight both infectious diseases and cancer, the García-Sastre laboratory is at the forefront of current and future vaccinology. Over the next years, the support of our philanthropic partners, the scientific community, public, and private organisations will make our research progress possible. It will allow us to make a tremendous impact in our fight of deadly viruses and cancer. Join us and support our efforts.
References
1 Krammer, F., and Palese, P. 2015. Nat Rev Drug Discov. 14:167
2 Liu, W.C., Nachbagauer, R., and Stadlbauer, D. et al. 2019. Front Immunol. 10:756
3 Choi, A., Bouzya, B., and Cortés Franco, K.D. et al. 2019. Immunohorizons. 3:133
4 Bernstein, D., Guptill, J., and Naficy, A. et al. 2020. Lancet Infect Dis. 20:80
5 Nachbagauer, R., Salaun, B., and Stadlbauer, D. et al. 2019. NPJ Vaccines. 4:51
6 Soonthornvacharin, S., Rodriguez-Frandsen, A., and Zhou, Y. et al 2017. Nat Microbiol. 2:17022
7 Tripathi, S., Pohl, M.O., and Zhou, Y. et al. 2015. Cell Host Microbe. 18:723
8 Bergmann, M., Romirer, I., Sachet, M. et al. 2001. Cancer Res. 61:8188
9 Muster, T., Rajtarova, J., and Sachet, M. et al. 2004. Int J Cancer. 110:15
10 Vigil, A., Park, S., and Martinez, O. et al. 2007. Cancer Res. 67:8285
11 Cuadrado-Castano, S., Ayllon, J., and Mansour, M. et al. 2015. Mol Cancer Ther. 14:1247.
12 Zamarin, D., Martínez-Sobrido, L., Kelly, K. et al. 2009. Mol Ther. 17:697
Professor Adolfo García-Sastre
Professor, Department of Microbiology
Director, Global Health and Emerging
Pathogens Institute
Icahn School of Medicine
+1 212 241 7769
adolfo.garcia-sastre@mssm.edu
http://icahn.mssm.edu/research/labs/garcia-sastre-laboratory
Co-Authors:
Marlene Espinoza-Moraga
Ignacio Mena
Sara Cuadrado-Castano
Michael Schotsaert
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