The Covid-19 pandemic continues to take a huge toll - an estimated 6.3m people have died including 178,000 in the UK. Globally 1.6bn students have missed school, 250m people will be pushed into extreme poverty and economic losses are estimated at £12tr. History shows that epidemic and pandemic threats constantly emerge, whilst SARS-CoV-2 continues to mutate as it becomes endemic. It is clear that major losses could be prevented by sustained domestic investment in public health. Work undertaken within Vax-Hub1 on responsive technologies and accelerated quality control methods enabled rapid development and manufacture of the ChAdOx1 vectored vaccine against SARS-CoV-2 (licensed for emergency use in December 2020 via a non-profit partnership with AstraZeneca). Over 2.9bn doses have now been released in 180 countries. The UK had a leading role during the pandemic and the proposed Hub builds on this success to advance novel research on a broader range of technologies. Working closely with stakeholders, Vax-Hub will enable the UK to be better prepared for the next pandemic. This investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. The Vaccine Manufacturing Hub brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry, not-for-profit organizations and policy makers together to propose radical change in vaccine development and manufacturing technologies, building on a technological innovation culture. The Hub will enhance future vaccine manufacturing through (i) de-risked manufacture of new vaccines by strategically innovating for a selected range of the most promising platform technologies (established and novel/disruptive); (ii) developing manufacturing options that improve the product quality and so immunogenicity; (iii) streamlined manufacturing process development with novel responsive solutions and advanced digitalisation strategies; (iii) a focus on enhancing stability and needle-free administration routes so they become a reality within the lifetime of the Hub. The proposed Hub would be the natural location for early-stage research before projects are transferred to a GMP manufacturing facility. The work focuses on development of improved vaccine platforms which can be flexible enough to be used for multiple product manufacture. These improved vaccine technologies are used as case studies to test rapid and responsive development tools to create a whole process mimicking vaccine manufacture, which could be easily and quickly deployed in case of epidemic/pandemic scenario. Finally the research focuses on standard and novel adjuvants to make mucosal delivery a reality, thus allowing alternative route to injection for mass administration. The Hub will establish the UK as the global centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as it is evident that diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the global community and the most vulnerable, especially children.

Vaccine manufacturing systems have undergone evolutionary optimisation over the last 60 years, with occasional disruptions due to new technology (e.g. mammalian cell cultures replacing egg-based systems for seasonal influenza vaccine manufacture). Global vaccination programmes have been a great success but the production and distribution systems from vaccines still suffer from costs associated with producing and purifying vaccines and the need to store them between 2 and 8 degrees C. This can be a challenge in the rural parts of low and middle income countries where 24 million children do not have access to appropriate vaccinations every year. An additional challenge is the need to rapidly respond to new threats, such as the Ebola and Zika viruses, that continue to emerge. The development of a "first responder" strategy for the latter means that there are two different types of challenges that future vaccine manufacturing systems will have to overcome: 1. How to design a flexible modular production system, that once a new threat is identified and sequenced, can switch into manufacturing mode and produce of the order of 10,000 doses in a matter of weeks as part of localised containment strategy? 2. How to improve and optimise existing manufacturing processes and change the way vaccines are manufactured, stabilised and stored so that costs are reduced, efficiencies increased and existing and new diseases prevented effectively? Our proposed programme has been developed with LMIC partners as an integrated approach that will bring quick wins to challenge 2 while building on new developments in life sciences, immunology and process systems to bring concepts addressing challenge 1 to fruition. Examples of strategies for challenge 1 are RNA vaccines. The significant advantage of synthetic RNA vaccines is the ability to rapidly manufacture many thousands of doses within a matter of weeks. This provides a viable business model not applicable to other technologies with much longer lag phases for production (viral vectors, mammalian cell culture), whereby procurement of the vaccine can be made on a needs basis avoiding the associated costs of stockpiling vaccines for rapid deployment, monitoring their on going stability and implementing a cycle of replacement of expired stock. In addition, low infrastructure and equipment costs make it feasible to establish manufacture in low-income settings, where all required equipment has potential to be run from a generator driven electrical supply in the event of power shortage. This fits the concept of a distributed, flexible platform technology, in that once a threat is identified, the specific genetic code can be provided to the manufacturing process and the doses of the specific vaccine can be produced without delay. Additional concepts that we will explore in this category include the rapid production of yeast and bacterially expressed particles that mimic membrane expressed components of pathogenic viruses and bacteria. Examples of strategies for challenge 2 build on our work on protein stabilisation which has been shown to preserve the function of delicate protein enzymes at temperatures over 100 degrees C. We shall exploit this knowledge to develop new vaccine stabilisation and formulation platforms. These can be used in two ways: (a) to support the last few miles of delivery from centralised cold chains to patients through reformulation and (b) for direct production of thermally stable forms, i.e. vaccines that retain their activity for months despite being not being refrigerated. We believe that the best way to deliver these step changes in capability and performance is through a team-based approach that applies deep integration in two dimensions: between UK and LMIC partners to ensure that all the LMIC considerations are "baked in" from the start and between different disciplines accounting for the different expertise that will be required to meet the challenges.