Vaccine Vector Design and Construction
Science is moving at an ever-increasing speed, which provides the 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’. Earlier this year a spinout company based on technology developed in The Jarvis Laboratory was incorporated to provide an additional vehicle for vaccine development.
Zoonoses Barrier Vaccines (ZBV)
Infected animals and their products are the most common route by which deadly microbes enter the human population. The list of these so called zoonotic (transmitted from animals to humans) microbes is extensive, but includes many known and perhaps not so well known agents, including: Crimean Congo hemorrhagic fever (CCHF), Ebola, Marburg and Lassa viruses, SARS and MERS coronaviruses, and Rift Valley Fever virus (RVFV). If it wasn’t for pasteurization of milk, which kills the causative bacterium, bovine tuberculosis (bTB) would similarly fall within this zoonotic category. ZBVs target Emerging Infectious Disease (EID) pathogens within the animal species involved in zoonotic transmission rather than within humans themselves. ZBVs therefore provide protection to humans indirectly by vaccination of the animals involved in transmission. The ZBV-based strategy greatly reduces time to licensing due to the lower stringency of approval requirements for animal vaccines. Consistent with this strategy, the recently published R&D blueprint for control of the EID MERS published by the World Health Organization (WHO) identified that: “It will be important to shore up funds for a camel vaccination option, as this may be the fastest developmental and regulatory route toward licensing a product that can prevent human MERS-CoV infections and deaths”. We currently have a number of projects funded by a diverse group of funders focused on the application of ZBV technology targeting many different pathogens and their diseases, including: Ebola, RVFV and Q fever (Innovate UK), and bTB. The Vaccine Group Ltd is a recent spinout company directed towards the socially responsible, ethical commercialization of this technology.
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. 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 (see below) 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, and 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. These studies are funded by NIH, Innovate UK and the UK Department of Overseas Development.
CMV-based vaccines against pandemic flu
This project is focused on the use of CMV as a means to induce cross-reactive immunity against the 18 possible multiple influenza A (IA) viruses that can cause flu. Flu is one of the most common causes of respiratory tract infection in humans and causes significant morbidity and mortality annually. IA pandemics with potentially catastrophic levels of mortality result from introduction of a ‘new’ IA virus into an immunologically naïve human population. Seasonal flu vaccines provide protection by inducing immunity against the circulating IA virus, but are unable to provide cross protection against the remaining IA types that could emerge as the next pandemic strain. Currently there are no commercially available vaccines able to induce immunity against multiple IA strains and thereby protect against pandemic flu. Taking advantage of the ability of CMV to induce and maintain high levels of immunity, we are developing CMV as a vaccine platform for use against pandemic flu by increasing the breadth of protection from targeting of regions of IA that are conserved between all types of IA viruses. This project is funded by a Marie Curie Sklodowska Career Integration Grant.
Vaccination against bTB
We are developing a number of novel herpesvirus-based vaccines to control bTB both in cattle as well as in the European badger reservoir. The bTB problem is complex and will require multiple overlapping complementing strategies for its control. There is currently no vaccine suitable for control of the causative agent of bTB, mycobacterium bovis, in either cattle or badgers. We are currently exploiting the unique qualities of the herpesvirus vector platform to develop durable, single-shot vaccines that enable discrimination of infected from vaccinated animal (DIVA) for use in cattle and wildlife. These vaccines will also be suitable for use in low and middle income countries (LMICs), where bTB remains a serious problem to human health as well as to the economy. These studies are funded by a number of funding agencies including The Seale Hayne Educational Trust.
Vaccination against Hepatitis C
Hepatitis C (HCV) is a major cause of severe liver disease in the estimated 160 million people infected with the virus. While there is treatment available, such treatments are not expected to be able to stem the spread of HCV and the large numbers of new infections every year. These treatments are also prohibitively expensive for use in all but the most wealthy of countries. Development of an effective preventative or prophylactic vaccine for HCV is therefore a pressing clinical need, both in the UK and worldwide. The current project, which is led by researchers at the University of Oxford, will investigate the effectiveness of novel vaccines based on the cytomegalovirus (CMV) or adenovirus (AdV) vectors. Based on our experience with these vaccines, we believe they have the potential to provide effective immunity against HCV, which could translate very rapidly into human clinical trials, both for prevention and cure. The current project is funded by the MRC.
For modern 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 LMIC ‘hot-spots’ 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 on a variety of projects with multiple collaborators using this approach for Ebola virus in apes and bats, Lassa virus in rats and bTB in European badgers.
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.