Building global vaccine manufacturing capacity: Spotlight on Africa.

Africa is set to experience a three-fold increase in vaccine demand by 2040, yet the continent possesses few domestic capabilities for vaccine production. This lack of production capacity, heavy reliance on foreign aid, disruptions of hard-won immunization progress due to the effects of the COVID-19 pandemic, and fluctuating vaccine market dynamics threaten to hinder ongoing efforts to increase vaccination rates on the continent. In order meet the vaccine demands of a rapidly growing population, and to be able to provide novel vaccines to its population in the future, the African continent must develop a sustainable vaccine manufacturing infrastructure. The African Union, in partnership with the Africa Centres for Disease Control and Prevention, recently set forth its Program for African Vaccine Manufacturing Framework for Action, which sets the goal of Africa producing 60 % of its vaccine needs by 2040. To meet these goals, African governments and their multinational, philanthropic, and private sector partners must work to secure low-cost financing and provide a favourable regulatory environment for nascent African vaccine manufacturers. Doing so will save lives, safeguard the health of the continent's current and future citizens, and contribute to economic growth through the development of local bioeconomies.

Scalable mRNA Machine for Regulatory Approval of Variable Scale between 1000 Clinical Doses to 10 Million Manufacturing Scale Doses

The production of messenger ribonucleic acid (mRNA) and other biologics is performed primarily in batch mode. This results in larger equipment, cleaning/sterilization volumes, and dead times compared to any continuous approach. Consequently, production throughput is lower and capital costs are relatively high. Switching to continuous production thus reduces the production footprint and also lowers the cost of goods (COG). During process development, from the provision of clinical trial samples to the production plant, different plant sizes are usually required, operating at different operating parameters. To speed up this step, it would be optimal if only one plant with the same equipment and piping could be used for all sizes. In this study, an efficient solution to this old challenge in biologics manufacturing is demonstrated, namely the qualification and validation of a plant setup for clinical trial doses of about 1000 doses and a production scale-up of about 10 million doses. Using the current example of the Comirnaty BNT162b2 mRNA vaccine, the cost-intensive in vitro transcription was first optimized in batch so that a yield of 12 g/L mRNA was achieved, and then successfully transferred to continuous production in the segmented plug flow reactor with subsequent purification using ultra- and diafiltration, which enables the recycling of costly reactants. To realize automated process control as well as real-time product release, the use of appropriate process analytical technology is essential. This will also be used to efficiently capture the product slug so that no product loss occurs and contamination from the fill-up phase is <1%. Further work will focus on real-time release testing during a continuous operating campaign under autonomous operational control. Such efforts will enable direct industrialization in collaboration with appropriate industry partners, their regulatory affairs, and quality assurance. A production scale-operation could be directly supported and managed by data-driven decisions. © 2023 by the authors.

Accelerating the development of vaccine microarray patches for epidemic response and equitable immunization coverage requires investment in microarray patch manufacturing facilities.

INTRODUCTION: There is a need for investment in manufacturing for vaccine microarray patches (vMAPs) to accelerate vMAP development and access. vMAPs could transform vaccines deployment and reach to everyone, everywhere. AREAS COVERED: We outline vMAPs' potential benefits for epidemic preparedness and for outreach in low- and lower-middle-income countries (LMICs), share lessons learned from pandemic response, and highlight that investment in manufacturing-at-risk could accelerate vMAP development. EXPERT OPINION: Pilot manufacturing capabilities are needed to produce clinical trial material and enable emergency response. Funding vMAP manufacturing scale-up in parallel to clinical proof-of-concept studies could accelerate vMAP approval and availability. Incentives could mitigate the risks of establishing multi-vMAP manufacturing facilities early.

Molecular engineering of a cryptic epitope in Spike RBD improves manufacturability and neutralizing breadth against SARS-CoV-2 variants.

There is a continued need for sarbecovirus vaccines that can be manufactured and distributed in low- and middle-income countries (LMICs). Subunit protein vaccines are manufactured at large scales at low costs, have less stringent temperature requirements for distribution in LMICs, and several candidates have shown protection against SARS-CoV-2. We previously reported an engineered variant of the SARS-CoV-2 Spike protein receptor binding domain antigen (RBD-L452K-F490W; RBD-J) with enhanced manufacturability and immunogenicity compared to the ancestral RBD. Here, we report a second-generation engineered RBD antigen (RBD-J6) with two additional mutations to a hydrophobic cryptic epitope in the RBD core, S383D and L518D, that further improved expression titers and biophysical stability. RBD-J6 retained binding affinity to human convalescent sera and to all tested neutralizing antibodies except antibodies that target the class IV epitope on the RBD core. K18-hACE2 transgenic mice immunized with three doses of a Beta variant of RBD-J6 displayed on a virus-like particle (VLP) generated neutralizing antibodies (nAb) to nine SARS-CoV-2 variants of concern at similar levels as two doses of Comirnaty. The vaccinated mice were also protected from challenge with Alpha or Beta SARS-CoV-2. This engineered antigen could be useful for modular RBD-based subunit vaccines to enhance manufacturability and global access, or for further development of variant-specific or broadly acting booster vaccines.

Towards Smart Vaccine Manufacturing: A Preliminary Study during Covid-19

Biopharmaceutical community is devising modern techniques to boost the development, production, and distribution of COVID-19 vaccines in large scale with tremendous speed. This has shifted the focus towards smart manufacturing of vaccines through vaccine platforms. Vaccine platforms have great potential to rapidly generate new vaccines and can overcome the challenges of the traditional vaccine manufacturing approach without compromising on safety and efficacy. This preliminary study compares the traditional and modern vaccine manufacturing techniques, reviews COVID-19 vaccine manufacturing scenarios, and presents a framework to critique on the smartness of the novel platform-based COVID-19 vaccine development and manufacturing.

The Addis Declaration on Immunization: A binding reminder of the political support needed to achieve universal immunization in Africa.

While African countries have improved access to immunization since the start of the millennium, progress has stagnated in the last few years. One in five African children is not vaccinated with life-saving vaccines, and recent outbreaks of vaccine-preventable diseases (VPDs) including yellow fever, measles, and meningitis, among others point to gaps in immunization coverage as well as disease surveillance. In 2017, African Heads of State endorsed the Addis Declaration on Immunization (ADI) at the 28th African Union Summit and committed to ensuring universal access to immunization across the continent. Since then, countries have taken several steps to translate the ADI commitments into tangible progress. However, the continent continues to face challenges in delivering immunization services, including limited vaccine-related funding, inequitable access to immunization services and weak surveillance systems. In the absence of concerted political will, COVID-19 threatens to reverse progress made so far. This paper reflects on the effects of political will in shaping the immunization agenda on the continent and the continued need for political commitment to deliver on the ADI commitments in a post-COVID world. Data were gathered from the regular national immunization reports, WHO/UNICEF estimates of immunization coverage as well as case studies of country implementation on ADI.

Smart Vaccine Manufacturing Using Novel Biotechnology Platforms: A Study During COVID-19

Healthcare experts have come to a consensus that effective and safe vaccines are necessary to control the rapid spread of the ongoing COVID-19 pandemic across the globe. Since the traditional vaccine development and manufacturing approaches were unable to meet the rapidly growing COVID-19 vaccine demand, biopharmaceutical firms had to devise novel and smart techniques to boost the development, production, and distribution of COVID-19 vaccines in a large scale with lightning speed. This triggered their transition to smart vaccine manufacturing approaches using novel viral vector and nucleic acid biotechnology platforms. This paper tries to explore this rationality of the biopharmaceutical industry by comparing the traditional and the novel biotechnology platform-based vaccine manufacturing techniques and reviewing the COVID-19 vaccine manufacturing scenarios. To highlight the "smart" characteristics of the novel platform-based COVID-19 vaccine products and to make an effective comparison with the traditional products, a well-established product classification framework is used as a reference. Finally, the study concludes by presenting the future possibility of incorporating smart manufacturing paradigms with the novel platform-based manufacturing process. It is hoped that this study would serve as an asset for the biopharmaceutical firms to appropriately streamline their strategies, resources, and goals to meet the global vaccine requirements.

On the large-scale production of a new vaccine

Large-scale production of a new vaccine, such as the COVID-19 vaccine, is characterized by evolving demand and production yield uncertainties. Further, following its FDA approval for efficacy and safety, a vaccine may not even be manufacturable due to its low production yield and the resulting lack of profitability. To deal with those challenges in practice, a vaccine manufacturer can (stochastically) increase the uncertain yield of a vaccine prior to launching large-scale production by learning through small-scale, experimental production runs about manufacturing conditions that are conducive to raising that yield. After starting large-scale production and receiving revenues from the sale of the vaccine, the manufacturer can continue to stochastically improve vaccine yield by acquiring knowledge from real-time production data. The two key decisions faced by a vaccine manufacturer concern the optimal timing and capacity of the vaccine's large-scale production. To determine the structure of vaccine manufacturer's optimal decisions, we formulate and solve a stochastic, multiperiod, sequential-decision model, while incorporating the dynamic evolution of vaccine yield uncertainty under those two yield improvement strategies. We establish the optimality of a threshold stopping policy for the timing of the large-scale vaccine production. This policy depends in a fundamental way on the relative stochastic rates of the two yield improvement strategies. We characterize the manufacturer's optimal capacity decision and identify conditions under which optimal capacity and production yield become substitutes. We analyze the implications of our results for rendering a new vaccine large-scale manufacturable, and bringing it to the market sooner during a pandemic period. © 2022 Production and Operations Management Society.

Global Pandemic Preparedness: Optimizing Our Capabilities and the Influenza Experience.

The coronavirus disease 2019 (COVID-19) pandemic has prompted rapid investigation and deployment of vaccine platforms never before used to combat human disease. The severe impact on the health system and the high economic cost of non-pharmaceutical interventions, such as lockdowns and international border closures employed to mitigate the spread of COVID-19 prior to the arrival of effective vaccines, have led to calls for development and deployment of novel vaccine technologies as part of a "100-day response ambition" for the next pandemic. Prior to COVID-19, all of the pandemics (excluding HIV) in the past century have been due to influenza viruses, and influenza remains one of the most likely future pandemic threats along with new coronaviruses. New and emerging vaccine platforms are likely to play an important role in combatting the next pandemic. However, the existing well-established, proven platforms for seasonal and pandemic influenza manufacturing will also continue to be utilized to rapidly address the next influenza threat. The field of influenza vaccine manufacturing has a long history of successes, including approval of vaccines within approximately 100 days after WHO declaration of the A(H1N1) 2009 influenza pandemic. Moreover, many advances in vaccine science and manufacturing capabilities have been made in the past decade to optimize a rapid and timely response should a new influenza pandemic threat emerge.

Towards smart vaccine manufacturing: A preliminary study during covid-19

Biopharmaceutical community is devising modern techniques to boost the development, production, and distribution of COVID-19 vaccines in large scale with tremendous speed. This has shifted the focus towards smart manufacturing of vaccines through vaccine platforms. Vaccine platforms have great potential to rapidly generate new vaccines and can overcome the challenges of the traditional vaccine manufacturing approach without compromising on safety and efficacy. This preliminary study compares the traditional and modern vaccine manufacturing techniques, reviews COVID-19 vaccine manufacturing scenarios, and presents a framework to critique on the smartness of the novel platform-based COVID-19 vaccine development and manufacturing. Copyright © 2021 by ASME and The United States Government.

CoVAC: A P2P smart contract-based intelligent smart city architecture for vaccine manufacturing.

With the Corona Virus Disease 2019 (COVID-19) outbreak, vaccination is an urgent need worldwide. Internet of Things (IoT) has a vital role in the smart city for vaccine manufacturing with wearable sensors. According to the advanced services in intelligent manufacturing, the fourth resolution is also changing in Industry 5.0 and utilizes high-definition connectivity sensors. Traditional manufacturing companies rely on trusted third parties, which may act as a single point of failure. Access control, big data, and scalability are also challenging issues in existing systems because of the demand response data (DRD) in advanced manufacturing. To mitigate these challenges, CoVAC: A P2P Smart Contract-based Intelligent Smart City Architecture for Vaccine Manufacturing is proposed with three layers, including connection, conversion, and intelligent cloud layer. Smart contract-based blockchain is utilized at the conversion layer for resolving access control, security, and privacy issues. Deep learning is adopted in the intelligent cloud layer for big data analysis and increasing production for vaccine manufacturing in smart city environments. A case study is carried out wherein access data are collected from the various smart plants for vaccines using smart manufacturing to validate the effectiveness of the proposed architecture. Simulation of the proposed architecture is performed on the collected advanced sensor IoT plants data to address the challenges above, offering scalable production in the vaccine manufacturing for the smart city.

Addressing Different Needs: The Challenges Faced by India as the Largest Vaccine Manufacturer While Conducting the World's Biggest COVID-19 Vaccination Campaign.

The COVID-19 pandemic has highlighted some of the challenges that countries face when balancing domestic and global necessities, for example with regard to vaccine needs, production and distribution. As India hosts one of the world's largest vaccine manufacturing industries and has one of the most extensive vaccination strategies, the country is particularly exposed to these challenges. This has become all the more obvious as the country experienced a second pandemic wave in the first half of 2021, which has led to a total ban on exports of COVID-19 vaccines. An analysis of the national vaccination strategy and the domestic vaccine industry through review of peer-reviewed literature, grey literature, and news reports showed the fragile balance between domestic and international needs. A numerical comparison of India's domestic COVID-19 vaccine needs, export agreements, and production capacities was conducted. It was found that at current production rates as of April 2021, meeting all of the needs and complying with all of the agreements would be impossible. Scale-ups in production, as promised by the industry, however, will enable the achievement of all targets in the long term.

Pharma 4.0 Continuous mRNA Drug Products Manufacturing.

Continuous mRNA drugs manufacturing is perceived to nurture flow processes featuring quality by design, controlled automation, real time validation, robustness, and reproducibility, pertaining to regulatory harmonization. However, the actual adaptation of the latter remains elusive, hence batch-to-continuous transition would a priori necessitate holistic process understanding. In addition, the cost related to experimental, pilot manufacturing lines development and operations thereof renders such venture prohibitive. Systems-based Pharmaceutics 4.0 digital design enabling tools, i.e., converging mass and energy balance simulations, Monte-Carlo machine learning iterations, and spatial arrangement analysis were recruited herein to overcome the aforementioned barriers. The primary objective of this work is to hierarchically design the related bioprocesses, embedded in scalable devices, compatible with continuous operation. Our secondary objective is to harvest the obtained technological data and conduct resource commitment analysis. We herein demonstrate for first time the feasibility of the continuous, end-to-end production of sterile mRNA formulated into lipid nanocarriers, defining the equipment specifications and the desired operational space. Moreover, we find that the cell lysis modules and the linearization enzymes ascend as the principal resource-intensive model factors, accounting for 40% and 42% of the equipment and raw material, respectively. We calculate MSPD 1.30-1.45 €, demonstrating low margin lifecycle fluctuation.

Vaccine Production Process: How Much Does the General Population Know about This Topic? A Web-Based Survey.

BACKGROUND: Vaccine hesitancy has been recognized as a major global health threat by the World Health Organization. Many studies have investigated vaccine safety as a determinant for vaccine hesitancy; however, not much attention has been paid to vaccine production and quality control during the vaccine production process or whether knowledge about this topic may influence vaccine confidence. The aim of this study was to characterize the common knowledge about the vaccine production process. METHODS: A freely accessible online questionnaire was developed on Google Modules and disseminated through social networks. A descriptive analysis of the collected answers was performed, and the chi-square test was used to assess significant differences for the sociodemographic characteristics of the study population (age, gender, work or education and training in the healthcare setting, minor offspring). A binary logistic regression model was performed considering these socio-demographic categories as independent variables. RESULTS: The number of collected questionnaire was 135. Most of the participants (127/135, 94.1%) were aware that quality control measures are carried out during manufacturing, although some knowledge gaps emerged in specific aspects of the vaccine production process, without statistically significant differences between age groups. Working in the healthcare setting or being educated in healthcare may be considered predictors for a better understanding that more than 50% of the production time is spent on quality control (AOR = 3.43; 95% CI: 1.84-8.14, p = 0.01) and that considering quality control performed during the vaccine production process is adequate for avoiding contamination (AOR = 7.90; 95% CI: 0.97-64.34; p = 0.05). CONCLUSIONS: This study allowed for a characterization of common knowledge about the vaccine production process. It highlighted the need to implement specific strategies to spread correct information about the vaccine production process. This study may contribute to increased confidence and trust in vaccines and vaccination among the general population.

The politics of COVID-19 vaccination in middle-income countries: Lessons from Brazil.

As the world struggles to meet the challenges of vaccination against COVID-19, more attention needs to be paid to issues faced by countries at different income levels. Middle-income countries (MICs) typically lack the resources and regulatory capacities to pursue strategies that wealthier countries do, but they also face different sets of challenges and opportunities than low-income countries (LICs). We focus on three dimensions of vaccination: procurement and production; regulation of marketing registration; and distribution and uptake. For each dimension we show the distinct challenges and opportunities faced by MICs. We illustrate these challenges and opportunities with the case of Brazil, showing how each dimension has been affected by intense political conflicts. Brazil's procurement and production strategy, which builds on a long trajectory of local production and technology transfer, has been riddled by conflicts between the national government and state governments. The regulatory approval process, based around one of Latin America's most highly-regarded regulatory authorities, has also been subject to acute inter- and intra-governmental conflicts. And with regard to distribution and uptake, in the face of high uncertainty, even with a solid health infrastructure, Brazil encounters difficulties in promoting vaccine delivery. The research also reveals the importance of coordination among these dimensions, in Brazil and beyond. Pandemic preparedness and response must include sharing knowledge of how to produce vaccines and recognition of the crucial linkages between procurement, regulation, delivery, and uptake that are necessary for ensuring access to these products.

Investigating the Interaction between Negative Strand RNA Viruses and Their Hosts for Enhanced Vaccine Development and Production.

The current pandemic has highlighted the ever-increasing risk of human to human spread of zoonotic pathogens. A number of medically-relevant zoonotic pathogens are negative-strand RNA viruses (NSVs). NSVs are derived from different virus families. Examples like Ebola are known for causing severe symptoms and high mortality rates. Some, like influenza, are known for their ease of person-to-person transmission and lack of pre-existing immunity, enabling rapid spread across many countries around the globe. Containment of outbreaks of NSVs can be difficult owing to their unpredictability and the absence of effective control measures, such as vaccines and antiviral therapeutics. In addition, there remains a lack of essential knowledge of the host-pathogen response that are induced by NSVs, particularly of the immune responses that provide protection. Vaccines are the most effective method for preventing infectious diseases. In fact, in the event of a pandemic, appropriate vaccine design and speed of vaccine supply is the most critical factor in protecting the population, as vaccination is the only sustainable defense. Vaccines need to be safe, efficient, and cost-effective, which is influenced by our understanding of the host-pathogen interface. Additionally, some of the major challenges of vaccines are the establishment of a long-lasting immunity offering cross protection to emerging strains. Although many NSVs are controlled through immunisations, for some, vaccine design has failed or efficacy has proven unreliable. The key behind designing a successful vaccine is understanding the host-pathogen interaction and the host immune response towards NSVs. In this paper, we review the recent research in vaccine design against NSVs and explore the immune responses induced by these viruses. The generation of a robust and integrated approach to development capability and vaccine manufacture can collaboratively support the management of outbreaking NSV disease health risks.

Improving pandemic preparedness through better, faster influenza vaccines.

Introduction. Timely availability of effective influenza vaccine will be critical to mitigate the next influenza pandemic. The mission of Biomedical Advanced Research and Development Authority (BARDA) is to develop medical countermeasures against pandemics, including influenza and other health security threats.Areas covered. Despite considerable gains in pandemic vaccine preparedness since 2009, old and new challenges threaten the pandemic influenza response capabilities of the U.S. Government: insufficient U.S.-based vaccine production, two-dose vaccination regimen, logistically complex adjuvanted formulation, and sustained surge manufacturing capacity despite no commercial market for pandemic vaccines. Although the coronavirus disease 2019 (COVID-19) pandemic has re-exposed these gaps in preparedness and response, previous investments into flexible influenza vaccine technologies proved to be critical to accelerate COVID-19 vaccine development.Expert opinion. BARDA addresses these challenges by implementing a pandemic influenza vaccine strategy with two key goals: 1) accelerating vaccine development and production (faster) and 2) improving vaccine performance (better). This strategy involves an end-to-end approach, including increasing manufacturing and fill-finish capacity; improving release testing speed; and funding clinical trials to improve current vaccine utilization. As demonstrated by the COVID-19 response, continued investments into this pandemic influenza vaccine strategy will further enhance the ability to respond to future emerging pandemic pathogens.

Rapid development and deployment of high-volume vaccines for pandemic response.

Overcoming pandemics, such as the current Covid-19 outbreak, requires the manufacture of several billion doses of vaccines within months. This is an extremely challenging task given the constraints in small-scale manufacturing for clinical trials, clinical testing timelines involving multiple phases and large-scale drug substance and drug product manufacturing. To tackle these challenges, regulatory processes are fast-tracked, and rapid-response manufacturing platform technologies are used. Here, we evaluate the current progress, challenges ahead and potential solutions for providing vaccines for pandemic response at an unprecedented scale and rate. Emerging rapid-response vaccine platform technologies, especially RNA platforms, offer a high productivity estimated at over 1 billion doses per year with a small manufacturing footprint and low capital cost facilities. The self-amplifying RNA (saRNA) drug product cost is estimated at below 1 USD/dose. These manufacturing processes and facilities can be decentralized to facilitate production, distribution, but also raw material supply. The RNA platform technology can be complemented by an a priori Quality by Design analysis aided by computational modeling in order to assure product quality and further speed up the regulatory approval processes when these platforms are used for epidemic or pandemic response in the future.