Influenza Vaccine Development – Broad protection through vaccination

Project Overview

The Project:

Recent outbreaks of Ebola, Zika and Influenza viruses have highlighted the lack of preparedness against known emerging pathogens. Vaccines are arguably the most efficacious and cost-effective preventative healthcare measure and are a global mainstay in protecting millions from infectious disease.

However, currently licensed influenza vaccines have a number of real-life limitations, including the need for annual re-formulation and an inability to induce long-lived or heterosubtypic immunity against new-variant viruses – critical in the face of a pandemic.

The risk of a virulent and lethal influenza pandemic, as evidenced by the circulation of recent strains, has generated widespread and warranted concern. This research programme will focus on developing vaccines that induce long-lived immunity against antigens that confer heterosubtypic immunity against both seasonal and pandemic influenza and thereby protect the most vulnerable population cohorts - the young and the elderly.

Training Opportunities

Training Opportunities

The Jenner Institute's activities extend from basic pre-clinical immunological research into first-in-human clinical trials. The Institute’s close integration of preclinical and clinical activities offers a near-unique opportunity for students to be involved throughout the process. This project will provide a broad range of transferable skills, with a unique insight into translational research, in areas such as molecular biology, virology, and immunology.

Care is taken to generate a stimulating, productive and collaborative learning environment, with regular informal lab meetings in addition to more formal Institute-wide seminars. All students are expected to analyse, interpret and present their data internally, at appropriate conferences and to work towards publication.

Both specialised subject training and broad transferable skill-sets will be developed to support a career in an academic or non-academic setting.

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 991

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Teresa Lambe Jenner Institute Oxford University, Old Road Campus Research Building GBR teresa.lambe@ndm.ox.ac.uk
Professor Sarah C Gilbert Jenner Institute Oxford University, Old Road Campus Research Building GBR sarah.gilbert@ndm.ox.ac.uk

Sebastian S, Lambe T. 2018. Clinical Advances in Viral-Vectored Influenza Vaccines. Vaccines (Basel), 6 (2), Read abstract | Read more

Influenza-virus-mediated disease can be associated with high levels of morbidity and mortality, particularly in younger children and older adults. Vaccination is the primary intervention used to curb influenza virus infection, and the WHO recommends immunization for at-risk individuals to mitigate disease. Unfortunately, influenza vaccine composition needs to be updated annually due to antigenic shift and drift in the viral immunogen hemagglutinin (HA). There are a number of alternate vaccination strategies in current development which may circumvent the need for annual re-vaccination, including new platform technologies such as viral-vectored vaccines. We discuss the different vectored vaccines that have been or are currently in clinical trials, with a forward-looking focus on immunogens that may be protective against seasonal and pandemic influenza infection, in the context of viral-vectored vaccines. We also discuss future perspectives and limitations in the field that will need to be addressed before new vaccines can significantly impact disease levels. Hide abstract

Tully CM, Chinnakannan S, Mullarkey CE, Ulaszewska M, Ferrara F, Temperton N, Gilbert SC, Lambe T. 2017. Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge. J. Immunol., Read abstract | Read more

Seasonal influenza viruses are a common cause of acute respiratory illness worldwide and generate a significant socioeconomic burden. Influenza viruses mutate rapidly, necessitating annual vaccine reformulation because traditional vaccines do not typically induce broad-spectrum immunity. In addition to seasonal infections, emerging pandemic influenza viruses present a continued threat to global public health. Pandemic influenza viruses have consistently higher attack rates and are typically associated with greater mortality compared with seasonal strains. Ongoing strategies to improve vaccine efficacy typically focus on providing broad-spectrum immunity; although B and T cells can mediate heterosubtypic responses, typical vaccine development will augment either humoral or cellular immunity. However, multipronged approaches that target several Ags may limit the generation of viral escape mutants. There are few vaccine platforms that can deliver multiple Ags and generate robust cellular and humoral immunity. In this article, we describe a novel vaccination strategy, tested preclinically in mice, for the delivery of novel bivalent viral-vectored vaccines. We show this strategy elicits potent T cell responses toward highly conserved internal Ags while simultaneously inducing high levels of Abs toward hemagglutinin. Importantly, these humoral responses generate long-lived plasma cells and generate Abs capable of neutralizing variant hemagglutinin-expressing pseudotyped lentiviruses. Significantly, these novel viral-vectored vaccines induce strong immune responses capable of conferring protection in a stringent influenza A virus challenge. Thus, this vaccination regimen induces lasting efficacy toward influenza. Importantly, the simultaneous delivery of dual Ags may alleviate the selective pressure that is thought to potentiate antigenic diversity in avian influenza viruses. Hide abstract

Coughlan L, Sridhar S, Payne R, Edmans M, Milicic A, Venkatraman N, Lugonja B, Clifton L, Qi C, Folegatti PM, Lawrie AM, Roberts R, de Graaf H, Sukhtankar P, Faust SN, Lewis DJM, Lambe T, Hill A, Gilbert SC. 2018. Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults. EBioMedicine, 29 pp. 146-154. Read abstract | Read more

BACKGROUND: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. METHODS: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18-46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months. FINDINGS: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T-cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1. INTERPRETATION: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. FUNDING SOURCE: Medical Research Council UK, NIHR BMRC Oxford. Hide abstract

Krammer F, Smith GJD, Fouchier RAM, Peiris M, Kedzierska K, Doherty PC, Palese P, Shaw ML, Treanor J, Webster RG, García-Sastre A. 2018. Influenza. Nat Rev Dis Primers, 4 (1), pp. 3. | Read more

Chen YQ, Wohlbold TJ, Zheng NY, Huang M, Huang Y, Neu KE, Lee J, Wan H, Rojas KT, Kirkpatrick E, Henry C, Palm AE, Stamper CT, Lan LY, Topham DJ, Treanor J, Wrammert J, Ahmed R, Eichelberger MC, Georgiou G, Krammer F, Wilson PC. 2018. Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell, 173 (2), pp. 417-429.e10. Read abstract | Read more

Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains. Hide abstract