Introduction The coronavirus disease (COVID-19) pandemic provided an impetus to rapidly advance research and development (R&D) of vaccines. In less than a year after the discovery of SARS-CoV-2, more than one hundred vaccine candidates had entered preclinical testing and more than ten vaccine candidates, comprising a range of available vaccine technologies, were already in phase 3 clinical testing. This rapid vaccine development relied on decades of prior research, much of which was publicly funded in developed economies. Global inequities in access to the most effective COVID-19 vaccines and vaccine technologies have raised interest in strengthening vaccine R&D more broadly. Investments should focus on diverse vaccine platforms, capacity building, and collaborative networks. Keys to developing effective vaccines tailored to local needs include strengthening trial ecosystems, aligning regulatory frameworks, and promoting equitable access. This article is the third installment of the "vaccine manufacturing and regulatory systems strengthening" series. It is ideal to read the first and second pieces before proceeding with this one. Analysis Decisions on vaccine platform choice should be context-specific. Various vaccine technologies or platforms are available to help the body defend against pathogens (Table 1). While mRNA-based vaccines were the fastest to be developed and the most effective against SARS-CoV-2, the technology is not a solution for all pathogens. Each vaccine platform has its advantages and limitations, and choosing one depends on factors such as the pathogen, immune response, outbreak situation, cost, and ease of manufacturing. The understanding of how the human body defends against different pathogens often guides vaccine technology selection. The two major protective, vaccine-induced immune components include: 1) neutralizing antibodies in the blood that can block infection and 2) immune T cells that kill infected cells. For example, the immune system combats bacterial infections through T-cell-dependent antibodies targeting the outer bacterial polysaccharide coating. As a result, most bacterial vaccines use polysaccharide conjugate vaccine technologies. Tackling pandemic versus endemic pathogens requires vastly different vaccine development considerations. During a pandemic, rapid vaccine development technologies, such as mRNA, are critical. However, for vaccines against endemic pathogens, priorities may shift to long-term immunity and cost-effectiveness. When developing vaccines in or for populations in low-resource settings, cost and manufacturing complexity are key considerations. Furthermore, up-to-date knowledge of the major circulating pathogen strains—both locally and globally—and their associated epidemiology should inform vaccine development. Investment in a range of vaccine platforms is critical for maximizing success. As countries tackle a vast range of emerging infectious diseases, experts recommend judicious R&D investments in a variety of platforms, as well as innovations in manufacturing. The “portfolio approach” by the Coalition for Epidemic Preparedness Innovations (CEPI) is a case in point. It refers to the deliberate investment in a diverse range of vaccine platforms. Portfolio diversification enhances overall success by ensuring that different platforms do not share the same features and risks of failure. Investment in early-stage R&D is instrumental for understanding how vaccine candidates provide protection and for generating evidence to support early go/no-go decisions in vaccine development. All vaccine R&D investments require a comprehensive assessment to evaluate market demand, barriers to access, and expected public health impact. For example, GAVI’s vaccine investment analysis framework aims to understand and capture the full value of vaccines, including social, economic, and population health benefits. CEPI’s 100-day mission proposes to build a global vaccine library to promote coordinated investments and a global collaborative network for rapid content sharing. This initiative aims to build a library of vaccine prototypes and incorporate AI tools to forecast virus variants for high-priority diseases before their emergence. Accelerating vaccine development requires multi-stakeholder effort. The COVID-19 pandemic highlighted the possibility of drastically shrinking clinical development timelines by combining clinical trial phases and using adaptive trial designs. The use of immune correlates of protection (CoP)—i.e., immune parameters responsible for vaccine-induced protection—also enabled the rapid licensure of several COVID-19 vaccines. This was achieved through bridging studies, where immunology results from completed clinical trials were extrapolated to different populations. Fundamental research on high-priority pathogens is therefore crucial for establishing and validating CoP for future pandemic pathogens. Newer methods, such as controlled human challenge models, offer further potential to provide rapid insights into protection and safety. Regulatory agility during the pandemic facilitated the expedited development of safe and high-quality vaccines. Similarly, regional and global collaboration in sharing manufacturing processes and vaccine safety and efficacy data further accelerated vaccine R&D. Therefore, continued data sharing, harmonization of regulatory requirements and resolving intellectual property issues will lead to faster availability of new vaccines during emergencies. Limited infrastructure, funding, technical expertise, operational and manpower limitations currently hamper trials in resource-limited countries. Equitable vaccine access may be facilitated through international public-private partnerships in vaccine development and technology transfer. Understanding the magnitude and extent of knowledge and expertise gaps in these countries is important for guiding capacity building initiatives. Affordability dictates the success of vaccine development programs in resource-limited countries. Innovative strategies are essential in ensuring financial sustainability of vaccine R&D in lower-resourced countries. Design and discovery of new and improved vaccine technologies usually require decades of investment in basic scientific research, which is mostly sustainable in high-resource settings. To level the playing field, initiatives such as the WHO mRNA transfer hub and private and philanthropic joint ventures like Hilleman laboratories are working to make new vaccine technologies more accessible to lower-resource countries through technology transfer mechanisms. Additionally, vaccine clinical trials require significant financial investments for setting up infrastructure, capacity development and clinical trial implementation. As a solution, WHO recently set up the Global Clinical Trials Forum to strengthen the clinical trial ecosystem in the Global South and promote domestic financing of clinical trials. Table 1: Major Vaccine Platforms and Considerations for Development in Resource-Constrained Settings Vaccine Platform Advantages Challenges Live-attenuated Robust long-term immunity and protection Can be used as mucosal vaccines Technically easy to manufacture Relatively inexpensive Appropriate for endemic and emerging pathogens Vaccine design requires prior knowledge on pathogen attenuation Safety concerns in immunocompromised Requires well-regulated cold chain Biosafety manufacturing requirements Not appropriate for pandemic pathogens Inactivated Relatively safe Technically easy to manufacture Relatively inexpensive Appropriate for seasonal and pandemic pathogens Elicits weak immune responses Requires adjuvants Requires large amounts per dose Requires multiple booster doses Viral vector Strong immune responses (including cellular immunity) Good safety profile Appropriate for endemic, emerging and pandemic pathogens Pre-existing immunity to vector can interfere with vaccine immune responses Requires cold chain Associated with some adverse events Virus-like particle Strong immune responses Inherent adjuvating properties Easy to scale up production Good safety profile Appropriate for endemic, emerging and pandemic pathogens Some challenges in manufacturing and assembly Challenges in stability and quality Requires multiple booster doses Subunit Recombinant protein Strong humoral responses Easy to scale up production Technically easy to manufacture Good safety profile Relatively inexpensive Appropriate for endemic, emerging and pandemic pathogens Frequently low cellular immunity May struggle with long term immunity Requires adjuvants Requires multiple booster doses Conjugate polysaccharide Strong vaccines against bacteria Long-term antibody responses Can be used as mucosal vaccines Good safety profile Relatively inexpensive No CD8 T cell responses Require multiple booster doses Nucleic acid DNA Induces cellular immunity Long-term vaccine stability Very little cold chain requirements Relatively inexpensive Requires special medical devices for vaccine delivery Weak immune responses and protection Possibility of genetic integration Very little real-world evidence mRNA Strong immune responses (including cellular immunity) Rapid vaccine development Rapid manufacturing Good safety profile Appropriate for pandemic pathogens Associated with some inflammatory adverse reactions Not appropriate for intranasal vaccines Not appropriate for polysaccharide bacterial vaccines Requires multiple booster doses Requires cold chain Expensive or high cost per dose Recommendations Prior to determining the path for vaccine design and development, a thorough understanding of the pathogen, vaccine technologies, immune correlates of protection, outbreak scenarios, and costs must be considered. Invest in a diverse portfolio of vaccines. Conduct a systematic gap analysis to identify areas requiring guidance and develop tailored programs to strengthen the ecosystem for resource-limited countries. Develop the capacity to implement various strategies for accelerating clinical trials. Create downstream collaborative, multi-stakeholder networks to encourage transparent data-sharing on manufacturing processes, vaccine safety and efficacy data, to align regulatory requirements and resolve intellectual property issues. NOTE: The ADB-CoRE Vaccine Regulation Project aims to inform the ADB Human and Social Development Sector Group on the vaccine regulatory landscape in Asia and the Pacific, focusing on Bangladesh, India, Indonesia, Republic of Korea, and Singapore. Initiated in 2022, it has facilitated public-private vaccine stakeholder engagements among ADB developing member countries and produced country-specific and regional vaccine landscape analysis and recommendations. This article reflects a collaborative effort, with insights from Prof. Silke Vogel and Prof. John Lim of Duke-NUS Medical School, and Dr. Jae Kyoun Kim, Dr. Ye Xu, and Dr. Patrick Osewe of the Asian Development Bank. Resources A. Postigo. 2022. Vaccine Research and Development (R&D) in the Asia-Pacific: The Economics of Vaccine R&D and Policy Recommendations to Overcome Market Failures and Promote R&D Cooperation. Economic and Social Commission for Asia and the Pacific. B.A. Williams et al. 2023. Outlook of Pandemic Preparedness in a Post-COVID-19 World. NPJ Vaccines. 8 (1). p. 178. M.J. Hogan and N. Pardi. 2022. mRNA Vaccines in the COVID-19 Pandemic and Beyond. Annu Rev Med. 73. pp. 17–39. M. Saville et al. 2022. Delivering Pandemic Vaccines in 100 Days—What Will It Take? Cambridge, MA: New England Journal of Medicine. M. Shrotri et al. 2021. An Interactive Website Tracking COVID-19 Vaccine Development. Lancet Glob Health. 9 (5). pp. e590–e2. N.C. Kyriakidis et al. 2021. SARS-CoV-2 Vaccines Strategies: A Comprehensive Review of Phase 3 Candidates. NPJ Vaccines. 6 (1). p. 28. R. Rappuoli, E. De Gregorio, and P. Costantino. 2019. On the Mechanisms of Conjugate Vaccines. Washington, DC: National Academy Press. pp. 14–6. S.J. Kent et al. 2022. Disentangling the Relative Importance of T Cell Responses in COVID-19: Leading Actors or Supporting Cast? Nat Rev Immunol. 22 (6). pp. 387–97. OECD. 2021. Enhancing Public Trust in COVID-19 Vaccination: The Role of Governments. Paris. Ask the Experts Uttara Soumyanarayanan Senior Education Associate, Centre of Regulatory Excellence, Duke-NUS Medical School Dr. Uttara Soumyanarayanan’s work focuses on supporting capacity-building and regulatory system-strengthening initiatives by the center. She leads the preparation, content creation, and facilitation of training programs for regulatory professionals from industry, regulatory authorities, and other healthcare professionals across the region. Follow Uttara Soumyanarayanan on Rukie de Alwis Deputy Director, Center for Outbreak Preparedness, Duke-NUS Medical School Assistant Professor Rukie de Alwis is a viral immunologist and vaccinologist with two decades of research experience, spanning basic vaccine-induced immune responses to preclinical and phase 2 clinical trials. Her current role involves working with LMIC countries in the Asian region to strengthen health security against infectious diseases. Follow Rukie de Alwis on Wei Chuen Tan-Koi Lead of Regulatory Systems Strengthening, Centre of Regulatory Excellence, Duke-NUS Medical School Assistant Professor Wei Chuen Tan-Koi focuses on health policy research and capacity building in biomedical innovation and regulatory science. She was formerly regulatory consultant and team lead of the Regulatory Research and Risk Communication teams at Singapore’s Health Sciences Authority. Follow Wei Chuen Tan-Koi on Eduardo P. Banzon Director, Human and Social Development Sector Office, Sectors Group, Asian Development Bank Dr. Eduardo Banzon provides technical leadership for health and collaborates with other sector offices and other departments to develop and maintain health policies, strategies, and operational plans in alignment with ADB’s Strategy 2030. He has over 26 years of experience, showcasing his extensive experience in a range of organizations focused on health and public health management, including as Philippine Health Insurance Corporation president and CEO. He has also worked with the WHO, World Bank, University of the Philippines, and Ateneo University Graduate School of Business. Dinesh Arora Principal Health Specialist, Human and Social Development Sector Office, Sectors Group, Asian Development Bank Dr. Dinesh Arora is a medical doctor specializing in public health and economics. He has more than 20 years of experience leading transformational public sector projects in South Asia, the Middle East, and North Africa. At ADB, he manages a diverse, bank-wide portfolio, including knowledge work and transformational projects on climate and health, human resources for health management, health sector assessments, pandemic preparedness, adult vaccination, vaccine therapeutics and diagnostics manufacturing and regulatory strengthening, early childhood development projects, and “One Health” initiatives. Ben Coghlan Former Senior Health Specialist, Human and Social Development Sector Office, Sectors Group, Asian Development Bank Dr. Ben Coghlan is a former senior health specialist with ADB’s Health Team. He is a public health physician and medical epidemiologist focused on strengthening health systems to address major public health challenges in Asia and the Pacific. His work has covered COVID-19, climate and environmental change, aging and non-communicable diseases, the digital transformation of health care, and universal health coverage. Leave your question or comment in the section below: View the discussion thread.