Vaccine Vector Design and Construction
Science is moving at break-neck speed, which provides our laboratory with a continuous source of new ideas and inspiration for vaccine vector design. This is an area of our laboratory that is therefore always ‘Under Construction’.
Cytomegalovirus (CMV)-based Vaccine against Ebola Virus
Ebola virus is deadly hemorrhagic disease that enters the human population from wildlife (apes and bats), but then spreads through human to human contact. Such a scenario is believed to have resulted in the 2014/2015 Ebola virus epidemic in West Africa, an epidemic that is still ‘not over yet’ with 20-30 new infections every week. We are developing a vaccine based on a CMV vaccine platform that could either be used as a conventional vaccine for direct inoculation of people or as a disseminating vaccine to target wildlife involved in the initial transmission of Ebola virus to humans. A recent study has identified an 'at risk' area for Ebola virus representing 22 African countries with a population of 22 million. Vaccination can be an important component of a public health response to Ebola virus, especially for protection of healthcare workers and other individuals at high risk of infection during an ongoing Ebola virus outbreak in areas with poor healthcare infrastructure. Currently there are no licensed vaccines or therapeutic countermeasures against Ebola virus.
CMV-based vaccines against pandemic flu
This project is focused on the use of a novel highly immunogenic persistent vaccine vector called cytomegalovirus (CMV) that is biased towards induction of cytotoxic T lymphocyte (CTL) immunity, as a means to induce cross-reactive (heterosubtypic) immunity against the 18 possible multiple influenza A virus (IA) serotypes (based on hemagglutinin (HA) type). IA is one of the most common causes of respiratory tract infection in humans and causes significant morbidity and mortality annually. IA pandemics with high mortality result from ‘antigenic shift’ following introduction of a virus with a new HA into an immunologically naïve population. In contrast IA epidemics are a consequence of ‘antigenic drift’ as a result of mutation of the HA serotype already circulating within the human population. Seasonal flu vaccines provide protection by inducing antibodies primarily directed against the HA envelope glycoprotein of the circulating flu strain (homosubtypic immunity), and are unable to provide cross protection against the remaining flu serotypes. Currently there are no commercially available vaccines able to induce immunity against multiple IA subtypes and thereby provide heterosubtypic immunity for pandemic flu. Taking advantage of the ability of CMV to induce and maintain high levels of T cell responses, we propose that CMV may make a promising vaccine platform for use against pandemic flu by increasing the breadth of protection from targeting of conserved internal IA proteins: nucleoprotein (NP), polymerase acidic protein (PA) and the non-structural protein 2 (NS2) of the IA virus genome. This project is funded by a Marie Curie Sklodowska Career Integration Grant.
Disseminating vaccines to control emerging infectious disease
For modern emerging infectious disease (EIDs), it is estimated that over 70% of zoonotic pathogens originate in wildlife. The global community is beginning to direct resources towards the identification of these EID threats in the ‘hot-spot’ regions of South America, Asia and Africa where these pathogens most commonly emerge. However, there is currently no consistently effective means to control pathogens identified as posing an imminent threat at their animal source before transmission to humans. Self-disseminating vaccines are one innovative vaccine strategy that may be better suited than conventional vaccines for use in these challenging conditions. Disseminating vaccines are designed to exploit the ability of replicating virus-based vectors to spread through their animal host populations without the need for direct inoculation of every animal. In this strategy, vaccination of a limited number of ‘founder’ animals is used for initial introduction of the vaccine into the target population. As the vaccine is engineered to express target antigens from the EID pathogen of interest, its spread from vaccinated to non-vaccinated animals is designed to coordinately spread EID specific immunity throughout the targeted animal population. We are currently engaged with multiple collaborators using this approach for Ebola virus in apes and bats, Lassa virus in multimammate rats and bovine tuberculosis in European badgers.
Disseminating vaccine to prevent Mycobacterium bovis (Mb) transmission from European badgers to cattle
We are developing a novel herpesvirus-based ‘disseminating’ Mb vaccine that has potential to confer life-long widespread immunity within European badger populations following spread from a few initially inoculated animals. Mb is a zoonosis that infects cattle resulting in bovine TB (bTB) with severe socio-economic consequences and impact on animal health. The control of Mb is difficult in the UK and Ireland because of a persistent source of infection to cattle from European badgers (Meles meles) that serve as a reservoir of infection. In the absence of improved control the projected economic burden to the UK over the next decade is predicted to be £1 billion. Disease control based on badger culling is extremely controversial and limited in scope and practicality, and is recognized not to be a long-term solution. Vaccination of badgers using conventional vaccines is a viable alternative but is currently limited to the use of a licensed injectable attenuated Mb vaccine, bacillus Calmette-Guerin (BCG), which is expensive, labour-intensive and may not provide life-long immunity. A disseminating Mb vaccine therefore has the potential to offer a complete ‘sea change’ in the management bTB.
Vaccination combined with host immune modulation to target cancer
Although effective drug protocols exist for some cancers, many cancers remain untreatable. We are developing a novel cancer vaccine that targets ‘universal’ tumor-associated antigens (TAAs) as a therapeutic vaccine against cancer for both humans and canine companion animals. Universal TAAs are a unique group of tumor proteins in that they are required for the tumor growth and persistence. This means that in addition to being found in most different types of cancer, universal TAAs are also required by the tumor for its own survival. This requirement forces the tumor to continuously make the universal TAAs, which maintains it as a target for the immune system. Enhancement of the patient’s immune system to target the tumor has recently been achieving remarkable results, even in advanced cancers, primarily melanoma. Combined with targeting of universal tumor antigens, our vaccine also uses a pharmacological strategy to recruit tumor-specific immune responses induced by vaccination into the tumor to increase the therapeutic efficacy of cancer vaccination.