Future Vaccine Manufacturing Hub: Advancing the manufacture and deployment of cost effective vaccines

Lead Research Organisation: Imperial College London
Department Name: Infectious Disease

Abstract

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.

Planned Impact

The production and delivery of vaccines over the last decades has been one of the global public health success stories, with smallpox eradicated and polio only prevalent in very specific locations. However, population growth, global travel, intensified farming and underlying mutations mean that new threats continue to emerge leading to the need for rapid response platforms and there are still many challenges to ensuring cost-effective and widespread vaccinations, such as the cost and need for a cold chain through to the patient.

The medicinal and life sciences have been discovering and developing a number of exciting new technologies with the potential to make a step change in the production, formulation and delivery of vaccines. These are generally characterised by a move away from mammalian cell-based production of subunit proteins and viral vectors towards technologies capable of rapid scale up and low cost production including Synthetic vaccines (DNA, RNA), virus like particle (VLP) vaccines generated in yeast and baculovirus/insect cell culture platforms, and GMMA particles produced in bacteria. These are complemented by developments in formulation and protein stabilisation science which hold promise for thermally stable vaccines.

At Imperial College's Department of Medicine, together with collaborators in the UK and LMIC countries a number of such developments have been underway. Sitting algonside, Imperial's Departments of Life Science and Chemical Engineering have a strong reputation for their industrially-relevant research in bioprocessing, biochemicals manufacturing, process development and design, synthetic biology and the translation of this to industrial application. Our proposed programme exploits and extends existing collaborations between these departments with a view to enabling rapid translation from concept discovery to manufacturing platform. We will ensure this by combining leading research and development, engineering and scale up with demonstration and translation in LMIC countries enabled through deep end user engagement by our LMIC partners (who operate manufacturing facilities) coupled with capacity building and training in the UK and overseas.

Our proposed programme will benefit a wide range of stakeholders including: immunologists and public health specialists, life scientists, chemical and process engineers, chemists and formulation scientists, vaccine producers and most importantly populations in LMIC countries who will ultimately benefit from (a) reduced cost and increased availability of large scale vaccines and (b) rapid public health response to emerging threats.

To ensure this impact, we have engaged several relevant partners in the preparation of this proposal (in particular Hilleman Labs (India), MRC Ugandan Virus Research Institute, Dalian Hissen Bio-pharm, China, Incepta, Bangladesh, and VABIOTECH, Vietnam) as initial stakeholders in our research programme, together with the Developing Countries Vaccine Manufacturing Network which represents 50 manufacturers in 17 countries. We have also engaged GSK Vaccines Institute for Global Health (GVGH, Italy) who have a track record for development of vaccines for LMIC countries. Representatives from each of these collaborating organisations will not only be closely involved in shaping and refining the programme but working with us as an integrated team with a view to maximising impact and ensuring large scale outcomes.
There is great training potential in our proposed programme. We shall catalyse UK and LMIC researchers in a truly multidisciplinary programme which will provide many opportunities for cross-fertilisation of ideas and training. The researchers will therefore become advocates and practitioners of advanced vaccine manufacturing systems and will be at the forefront of innovations in this sector.

A global and UK/RoI research network will complement the Hub and Spoke research programme and support community building.

Publications

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Blakney AK (2019) Effects of cationic adjuvant formulation particle type, fluidity and immunomodulators on delivery and immunogenicity of saRNA. in Journal of controlled release : official journal of the Controlled Release Society

 
Description The Future Vaccines Manufacturing Research Hub has successfully identified the most cost-effective emerging technologies that can be applied within LMIC settings. Outer membrane vesicle vaccines were found to be most feasible to be implemented within LMIC manufacturing sites, followed by RNA platforms, insect cell-baculovirus platform for recombinant vaccines and yeast platforms. These manufacturing protocols were judged based on technology readiness, complexity, ease of scale-up, flexibility, thermo-stability and speed of response.

The FVMR Hub has progressed well in transferring technologies to Vietnam (baculovirus) and Bangladesh (yeast). A supply chain modelling workshop was successfully delivered to over 50 vaccine manufacturers from over 9 LMIC countries, in Hanoi, Vietnam in November 2019. RNA vaccine research is progressing well, with proof of concept work based at Imperial and training sessions being planned in a pilot lab at the UVRI in Entebbe, Uganda, in 2020. The FVMR Hub is also supporting Quality Control (QC) assays for DCVMN members in 2020, for vaccines against pathogens such as influenza, polio, Hep B, diphtheria, tetanus, pertussis, meningitis, measles and rubella.

The Hub, which started in December 2017, has met its objectives targeted in 2018 and 2019.
Exploitation Route We are advising LMIC partners on their manufacturing protocols and gathering information to better implement more rapid and efficient manufacturing of vaccines against emerging epidemics, in LMIC locations, and is of great value to industrial manufacturers benefiting or within LMICs. The FVMR Hub has been exemplary in our interactions with international vaccine manufacturers in terms of engagement, training, and technology transfer, whilst our Director, Professor Robin Shattock, has appeared in news outlets such as BBC, CNN and Sky News, regarding the recent outbreak of Sars-CoV-2 / Covid-19, which highlights the urgent need for more rapid and flexible vaccine manufacturing platforms.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The Future Vaccines Manufacturing Hub comprises partners across 8 European institutions (7 in UK) and 6 LMIC entities. Our Hub is active across 8 workstreams to enable more efficient manufacturing protocols tailored for implementation and deployment within LMICs. We are grateful to the funders for their support. The Hub has proceeded very well in 2018 and 2019 and all progress is on track. Regarding non-academic impacts, the Hub held a half day symposium in 2018 at the Annual Developing Countries Vaccine Manufacturing Network meeting in Kunming (China) to present the project and engage additional collaborations, which was followed by our opening session at the 2019 DCVMN Annual Meeting in Rio de Janeiro (Brazil). The FVMR Hub has continued our call for proposals to engage the hub in additional vaccine manufacturing development projects. In early 2019, two successful applicants (1 from a vaccine manufacturer in India and 1 in China) were awarded to improve their manufacturing capacity and range of vaccines produced. Applications are currently being assessed from the continued 2nd consultancy call. The FVMR Hub has learned that DCVMN members are in need of close collaborations and training from UK institutes. In 2019, the FVMR Hub announced training offered by NIBSC to DCVMN members, to be carried out in 2020. This training will embody the largest scale LMIC vaccine manufacturing engagement to date, supported by a Future Medicines Hub. In addition, we are actively engaging with our partners Dalian Hissen (China), Vabiotech (Vietnam), Incepta (Bangladesh), Hilleman labs (India), and the UVRI (Uganda), which has been supported by close collaborations (all), secondments (China staff members at Imperial; Vietnam staff members at Bristol; Bangladesh staff members at Imperial; Uganda staff members at Imperial), pilot lab implementation (Uganda) and technology transfer (Vietnam; Bangladesh; Uganda). Furthermore, we are engaging with UK manufacturers external to the Hub to support new partnerships, supported by Innovate UK's Knowledge Transfer Network. In 2019, we welcomed new partners Excivion, ImmBio, Enesi as well as the University of Leeds to research a number of innovative vaccine candidates against pathogens such as zika virus and polio.
First Year Of Impact 2017
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description EML-VAC: Multivalent replicon vaccine against Ebola, Marburg and Lassa viruses
Amount £1,999,712 (GBP)
Funding ID 971617 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2020
 
Description Enesi-Imperial (Shattock) 
Organisation Enesi Pharma
Country United Kingdom 
Sector Private 
PI Contribution With Enesi, the Shattock team from the FVMR Hub is engaging in collaborating together on solid RNA vaccine designs. The Shattock team has designed the RNA vaccine and will test in vitro.
Collaborator Contribution The Enesi team is formulating a solid dose that encapsulates the RNA active ingredient, to be tested at Imperial.
Impact The study is ongoing (Feb-Mar 2020), and we expect preliminary results by April 2020.
Start Year 2019
 
Description Excivion-CPIIS 
Organisation Excivion
Country United Kingdom 
Sector Private 
PI Contribution CPIIS will perform research on characterising oligomers of zika virus assemblies, to better understand a zika virus vaccine candidate, developed by Excivion.
Collaborator Contribution Excivion have a zika virus vaccine candidate in the pipeline, which is an innovative technology.
Impact This collaboration is ongoing, preliminary results are expected by the summer 2020.
Start Year 2019
 
Description ImmBio-CPIIS 
Organisation Imbio, LLC
Country United States 
Sector Private 
PI Contribution ImmBio is research a protein-based vaccine candidate against pneumococcal disease. CPIIS is supporting their characterisation needs.
Collaborator Contribution ImmBio is closely collaborating with CPIIS to progress the characterisation study, which is ongoing.
Impact The collaboration involves vaccine manufacturing and characterisation, and it is still active.
Start Year 2019
 
Description ImmBio-NIBSC 
Organisation ImmBio
Country United Kingdom 
Sector Private 
PI Contribution ImmBio is collaborating with NIBSC, a core members of the FVMR Hub, to research new assays for their protein-based pneumococcal vaccine candidate. NIBSC has world-leading expertise in assaying vaccine candidates.
Collaborator Contribution ImmBio has an exciting, innovative protein-based pneumococcal vaccine candidate and are closely collaborating with NIBSC towards a better understanding of this material.
Impact The collaboration is based on interactions between vaccine manufacturers and immunobiologists.
Start Year 2019
 
Description Leeds-CPIIS 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution CPIIS has researched conditions to express stable virus like particles against polio, based on research plans provided by Leeds.
Collaborator Contribution CPIIS has compiled a matrix of results to support the next steps for Leeds to proceed researching polio VLPs.
Impact This collaboration is still ongoing. Fields of expertise include vaccinologists and characterisation.
Start Year 2019
 
Title Microfluidic Filtration Apparatus 
Description Microfluidic Filtration Apparatus 
IP Reference 1906421.1 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Impact remains to be seen; the application has been filed.
 
Title Microfluidic Processing Apparatus and Method 
Description Microfluidic Processing Apparatus and Method 
IP Reference 1906413.8 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Impact remains to be seen; the application has been filed.
 
Title Microfluidic Sensing and Control System 
Description Microfluidic Sensing and Control System 
IP Reference Application number 1906422.9 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Impact remains to be seen; the application has been filed.
 
Title PABOLs for saRNA delivery 
Description Process for the synthesis of linear SS-PAAs of greater than 5kDa and their tailored use for delivery of saRNA (>5000Kb). 
IP Reference 1914659.6 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact This patent has been recently filed - we expect impacts shortly.
 
Title Stabilisation of therapeutic proteins 
Description Stabilisation of therapeutic proteins. 
IP Reference 1908914.3 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Impact remains to be seen; the application has been filed.
 
Title Stealthicons: RNA replicons with cis-encoded viral protein interferon inhibitors 
Description Stealthicons: RNA replicons with cis-encoded viral protein interferon inhibitors. 
IP Reference 1908729.5 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Impact remains to be seen; the application has been filed.
 
Description "RNA vaccines for outbreak infections", Prof Robin Shattock's lecture at World Economic Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Prof Robin Shattock promoted work of the FVMR hub, at the World Economic Forum
Year(s) Of Engagement Activity 2019
 
Description Annual meeting of the Developing Countries Vaccine Manufacturing Network 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact This event was representative of over 45 manufacturers from across the globe. Outcome was dissemination of knowledge, active engagement of additional companies with the Hub.
Year(s) Of Engagement Activity 2018
 
Description BBC Radio 4 Today Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed by BBC Radio 4 hosts to provide information to the general public on Vaccine Manufacture
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b09jqtb1
 
Description DCVMN Annual Meeting 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Operations Manager Ben Pierce presented for and represented the FVMR Hub at the 20th Annual Meeting for the DCVMN, in Rio de Janeiro, Brazil, in Oct 2019. Nearly 500 manufacturers from developing countries were in attendance.
Year(s) Of Engagement Activity 2019
URL https://www.dcvmn.org/DCVMN-20th-Annual-General-Meeting
 
Description DCVMN Regional Training Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation on the work of Future vaccine manufacturing technologies under development within the Hub. Representation from 15 Asian manufacturing companies. Outcome was dissemination of technical know how to LMIC partners, promotion of collaboration.
Year(s) Of Engagement Activity 2018
 
Description European Research & Innovation days 'Science is Wonderful!' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact FVMR Hub members Anna Blakney and Karnyart Samnuan presented at the recent European Research & Innovation days 'Science is Wonderful!' event in Brussels, which consisted of educating 1500 children over two days about vaccines.
Year(s) Of Engagement Activity 2019
 
Description Financial Times Article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Article describing Professor Shattock's research efforts to tackle viral epidemics worldwide
Year(s) Of Engagement Activity 2017
URL https://www.ft.com/content/afdc493e-e716-11e7-97e2-916d4fbac0da
 
Description Global Science Policy Forum: Developing a Vaccine Revolution 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact FVMR Hub Director Professor Robin Shattock and Hub member Professor Jason Hallett presented at the Imperial Global Science Policy Forum on 23 May 2019 in London, UK
Year(s) Of Engagement Activity 2019
URL http://www.imperial.ac.uk/news/191321/developing-vaccine-revolution-imperial-experts-take/
 
Description Imperial College London launches The Forum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Imperial College London launched The Forum, hosted by the UK Government Chief Scientific Adviser Sir Patrick Vallance, which highlighted the Future Vaccine Manufacturing Research Hub.
Year(s) Of Engagement Activity 2019
URL http://www.imperial.ac.uk/news/191994/government-chief-scientific-adviser-speaks-the/
 
Description Joint one day meeting hosted by FVMR hub and the Knowledge Transfer Network (KTN, Innovate UK). 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact "Future vaccines research and development: advancing the manufacturing and deployment of cost-effective vaccines in a changing landscape". Representative of UK SMEs and Academic groups were in attendance. Outcomes were dissemination of the work of the Hub, engagement of collaborations with additional academics and SMEs working in vaccine R&D.
Year(s) Of Engagement Activity 2018
 
Description Press release from Biospectrum Asia 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Biospectrum Asia highlights Imperial College's Future Vaccine Manufacturing Hub.
Year(s) Of Engagement Activity 2018
URL https://www.biospectrumasia.com/news/38/10095/imperial-college-to-lead-a-vaccine-manufacturing-hub.h...
 
Description Press release from Imperial College on Prof Robin Shattock's presentation at WEF 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Imperial College highlighted Prof Robin Shattock's presentation at the WEF, discussing research from within the Future Vaccine Manufacturing Hub.
Year(s) Of Engagement Activity 2018
URL https://www.imperial.ac.uk/news/189957/imperial-scientists-present-vaccine-revolution-world/
 
Description Prof Robin Shattock describes SARS-CoV-2 and vaccine development (Sky News) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Prof Robin Shattock describes SARS-CoV-2 and vaccine development.
Year(s) Of Engagement Activity 2020
URL https://twitter.com/KayBurley/status/1221711134606155776
 
Description Prof Robin Shattock describes activities for vaccine development against SARS-CoV-2 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Prof Robin Shattock describes race towards a vaccine against SARS-CoV-2.
Year(s) Of Engagement Activity 2020
URL http://www.imperial.ac.uk/news/195055/imperial-researchers-race-develop-coronavirus-vaccine/
 
Description Prof Robin Shattock describes vaccine development for SARS-CoV-2 (BBC) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Robin Shattock, who is the scientist leading the UK's research into the vaccine at Imperial College London, says his team have made a significant breakthrough by reducing part of the normal development time to just 14 days. However, it may still be months before vaccines can be distributed to those at risk.
Year(s) Of Engagement Activity 2020
URL https://www.bbc.co.uk/programmes/p082gt9b
 
Description Prof Robin Shattock describes vaccine development for SARS-CoV-2 (CNN) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Prof Robin Shattock describes vaccine development for SARS-CoV-2.
Year(s) Of Engagement Activity 2020
URL https://www.youtube.com/watch?v=ATndga6ZMSs
 
Description Prof Robin Shattock describes vaccine development for SARS-CoV-2 (Telegraph) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Prof Robin Shattock describes race for new vaccine against SARS-CoV-2.
Year(s) Of Engagement Activity 2020
URL https://www.telegraph.co.uk/news/2020/02/05/uk-scientists-make-significant-breakthrough-race-coronav...
 
Description Supply Chain Modelling Workshop for DCVMN members 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Experts from the FVMR Hub delivered a workshop on vaccine supply chain improvements through modelling, to educate manufacturers on how to better deliver vaccines to ODA and LMIC populations. The workshop was in Hanoi, Vietnam, in Nov 2019, and it was attended by over 50 manufacturing staff, coming from 9 countries.
Year(s) Of Engagement Activity 2019
URL https://www.dcvmn.org/DCVMN-Training-workshop-on-Supply-Chain-Management-Quality-by-Design-and-Suppl...
 
Description Times Higher Education Article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact To describe the establishment of a new hub to help UK scientists to respond quickly to emerging infectious diseases
Year(s) Of Engagement Activity 2017
URL https://www.timeshighereducation.com/news/new-hub-puts-scientists-front-line-against-disease-outbrea...
 
Description World Economic Forum video, from Future Vaccine Manufacturing Hub's Prof Robin Shattock 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "RNA vaccines for outbreak infections" was delivered by Prof Robin Shattock, lead of Imperial College's Future Vaccine Manufacturing Hub.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=3J8eL9f-fEs