Table of Contents TABLE OF CONTENTS ......................................................................................................................... 2 FIGURES ................................................................................................................................................ 3 TABLES .................................................................................................................................................. 3 ACKNOWLEDGEMENTS....................................................................................................................... 4 EXECUTIVE SUMMARY ........................................................................................................................ 5 INTRODUCTION ..................................................................................................................................... 7 Value Addition of the Project ............................................................................................................... 8 THAILAND COUNTRY PROFILE .......................................................................................................... 8 Brief Country Context .......................................................................................................................... 8 Burden of Disease Among the Thai Population .................................................................................. 9 Burden of disease for children under 5 years old ......................................................................... 10 COVID-19 Pandemic in Thailand ...................................................................................................... 11 SUMMARY OF THE NATIONAL IMMUNIZATION PROGRAM .......................................................... 15 Vaccines Included in the NIP ............................................................................................................ 16 Vaccine Delivery Challenges and Inequities ..................................................................................... 17 Adverse Events Following Immunization and Pharmacovigilance System ...................................... 18 VACCINE REGULATORY SYSTEM .................................................................................................... 19 Protocol for Registering New Vaccines ............................................................................................. 21 DOMESTIC VACCINE MANUFACTURING AND DISTRIBUTION CAPACITY.................................. 22 SWOT Analysis: Thailand’s contribution to the vaccine value chain in ASEAN.......................... 27 CONCLUSION ...................................................................................................................................... 28 REFERENCES ...................................................................................................................................... 29 ANNEX 1: Thailand NIP performance indicators, 2017-2021 ............................................................... 31 2 Figures Figure 1. Thailand age pyramid, 2020 .................................................................................................... 9 Figure 2. Causes of death in children under five years of age, Thailand, 2019 ................................... 11 Figure 3. ASEAN countries annual GDP growth, 2016-2020 ............................................................... 12 Figure 4. National COVID-19 vaccination coverage ............................................................................. 13 Figure 5. COVID-19 vaccine coverage by dose.................................................................................... 13 Figure 6. Thailand COVID-19 cases, deaths and vaccinations ............................................................ 14 Figure 7. COVID-19 deaths in Thailand ................................................................................................ 14 Figure 8. COVID-19 vaccination program for children and adolescents .............................................. 15 Figure 9. MoPH guidelines for COVID-19 vaccine administration ........................................................ 15 Tables Table 1. Top 10 disease morbidity rates in Thailand, 2019 .................................................................. 10 Table 2. Top 10 disease mortality rates in Thailand, 2019 ................................................................... 10 Table 3. National Immunization Program schedule in Thailand, 2022 ................................................. 16 Table 4. TFDA status as of June 2018 ................................................................................................. 20 Table 5. Thailand current manufacturers’ R&D projects and vaccine portfolios ................................... 22 3 Acknowledgements The Thailand case study was prepared by Mr. Stephane Guichard under the leadership of Dr. Ronald Mutasa, Practice Leader of Human Development. The report benefited from technical inputs from Dr. Ramana Gandham (Technical Advisor/former Lead Health Specialist), Dr. Andreas Seiter (Technical Advisor/ Industry Expert), Mr. Giles Newmarch (Senior Investment Officer, IFC), Ms. Ridhi Gupta (Investment Officer, IFC), Dr. Kwanpand Suddhi-Dhamakit (Senior Strategy Officer), Ms. Erin Sowers (Consultant), and Ms. Zinaida Korableva (Operations Analyst). The leadership, technical inputs and coordination support of the National Vaccine Institute, with special mention to Dr. Nakorn Premsri (Director), Dr. Wisit Tangkeangsirisin (Deputy Director), and Worrawich Boonyathisathan (Vaccine Technical Officer, International Affairs), is gratefully acknowledged. The information contained in this report draws heavily from interviews and consultations conducted with Thailand government officials and private sector representatives, including Vitoon Vonghangool (President), Pham Hong Thai (Chief Executive Officer), and Laurent Dapremont (Director Strategic Business Development) from BioNet Asia; Ponthip Wirachwong (Director, Biological Product Department) from GPO; Boorak Thawornrungroaj (Chief Executive Officer), Pipat Niyomkarn (Deputy Managing Director), and Panithan Phusetwong (Senior Manager Business Development) from GPO-MBP; Visit Sitprija (Director), Queen Saovabha Memorial Institute); Songpon Deechongkit (Managing Director), Siam Bioscience; and Onsiri Pitisuttithum (Medical Affairs Manager), Astra Zeneca Thailand. Ali Reza Khadem from WHO-Geneva also provided valuable insights. The Thailand case study is part of a larger regional study with the following components: global desk review, private sector landscape analysis, economic analysis, and country deep- dive case studies. Partnership and collaboration with the ASEAN Secretariat under the leadership of Dr. Ferdinal Fernando and Ms. Jennifer Dela Rosa, the UK Foreign, Commonwealth and Development Office, and the Global Financing Facility for Women, Children and Adolescents was essential to the successful completion of the study. Logistics support was provided by Pimon Iamsripong and Mae Myat Moe. The cover and report layout were designed by Kayleigh Ghiot. This report benefited from the valuable comments of peer reviewers Dr. Matthew Downham (Director, CEPI), Ms. Zeynep Kantur (Global Manager, Health, IFC), Dr. Lombe Kasonde (Senior Health Specialist), and Dr. Kayla Laserson (Deputy Director, Bill and Melinda Gates Foundation). The overall technical guidance provided by Daniel Dulitzky (Regional Director for Human Development), Farid Fezoua (Global Director, IFC) and Aparnaa Somanathan (Practice Manager, Health, Nutrition and Population) is gratefully acknowledged. 4 EXECUTIVE SUMMARY Thailand is a country of nearly 70 income countries, slowly became available million people, the fourth largest in Thailand in February 2021; by this time, among ASEAN nations. In 2002 it the emergence of highly-transmissible pioneered the establishment a National variants had led to dramatic increases in Health Security Office (NHSO) to COVID-19 cases and deaths, sparking ensure universal health coverage for public unease about the Government’s Thai people, including access to free, capacity to roll-out COVID-19 vaccines high-quality vaccines. A National and the country’s ability to produce them. Strategic Policy and Action Plan for Thailand’s vaccine campaign proceeded Vaccine Security has been in place in slowly until September 2021, when locally- Thailand since 2018 to ensure a manufactured COVID-19 vaccines became sustainable supply of vaccines and available, leading to a sharp increase in support the domestic vaccine industry. vaccine coverage; by the end of 2022, three-fourths of the population had Thailand’s National Immunization received two doses of vaccine. The Program was introduced in 1977 and procurement process for COVID-19 has achieved high vaccine coverage vaccines differs from that for NIP vaccines, rates (greater than 80 percent) over the as it is overseen by the National Vaccine past 20 years. The NIP schedule Institute Thailand (NVI), Department of currently includes 12 vaccines, including Diseases Control (DDC), and the MoPH for rotavirus, which was recently committee for private purchase of vaccine, introduced in 2020. with DDC responsible for distribution. Domestic production meets the yearly Universities and laboratories in requirement for BCG vaccine and Thailand have a long history of vaccine accounts for 50 percent of seasonal R&D, including for tropical diseases influenza vaccine; all other vaccines for (i.e. dengue) and pandemic influenza, the NIP are imported. Procurement of but the COVID-19 pandemic triggered NIP vaccines is overseen by the NHSO in an unprecedented level of interest in partnership with Siraraj Hospital, while vaccine development among import and distribution is managed by the stakeholders and policy makers. Two Government Pharmaceutical Organization university-based vaccine research centers (GPO), a public company. Thailand has along with the NVI and the four domestic four domestic vaccine manufacturers— vaccine manufacturers are working on one public, two public/private, and one COVID-19 vaccine R&D projects using private—all of which have upstream and different technology platforms, with several downstream vaccine manufacturing candidate vaccines in the final stage of capacity but in general lack full-spectrum clinical trials. The emphasis on COVID-19 production capacity. Thai vaccine vaccine R&D has led to reduced manufacturers have prioritized building prioritization of R&D for tropical and/or strong, collaborative relationships with endemic disease vaccines, though the universities, biotech companies, vaccine industry is sufficiently dynamic to laboratories and other vaccine accommodate a broadened focus going manufacturers for technology transfer and forward. In terms of COVID-19 vaccine capacity building. production, Siam Bioscience Thailand, a public/private entity, is producing Thailand reported its first case of AstraZeneca COVID-19 vaccine via a COVID-19 in January 2020 and its first technology transfer contract initiated in death two months later. Rapidly- 2020 with AstraZeneca UK. The vaccine is implemented public health and social distributed in Thailand, ASEAN countries, measures successfully controlled and globally. disease spread in the initial phase of the pandemic. Safe and efficacious COVID-19 vaccines, first produced in and delivered to the populations of high 5 The National Regulatory Authority in Thailand achieved WHO Maturity Level 3 in 2021, demonstrating the presence of Thailand has a dynamic systems that ensure the safety of vaccines produced and used in the country. vaccine R&D Manufacturers and stakeholders interviewed for this study reported that environment in which substantial financial and human strong partnerships resource investments must be made in order for vaccine R&D, manufacturing exist between the and regulatory systems to keep pace with the Government’s goals for public and private vaccine security. Stakeholders reported additional challenges as well, including sector and the vaccine limited dialogue between vaccine manufacturers and vaccine security manufacturing stakeholders that undermines long-term planning efforts, barriers in access to industry plays an financing among public institutions that causes delays in infrastructure active role. improvement initiatives, and a lack of transparency in Government-led initiatives, which has eroded public and private sector trust in Government institutions. 6 Introduction COVID-19 has had a devastating effect on the ASEAN region, which has recorded over 27 million cases of the virus. Access to COVID-19 vaccination has significantly reduced the spread of the disease and limited the number of severe COVID-19 cases, but it has also impacted routine immunization coverage. Countless strategies have been developed to ensure vaccine equity, which were swiftly translated from political assessment to practical action; however, they failed to address the sustained growth of the COVID-19 pandemic and the emergence of variants of concerns, requiring ongoing vaccine booster doses. The pandemic revealed weaknesses in ASEAN's regional vaccine capacity, including in research and development, manufacturing infrastructure and human resources, which made the region particularly vulnerable during COVID-19 surges, as it was highly dependent on vaccine imports. Despite the existence of an established framework for ASEAN collaboration on vaccines, there has been minimal coordination between member states to collectively procure COVID- 19 vaccines. Initial consultations with various stakeholders involved in vaccination and equitable access in the ASEAN region highlighted several gaps related to ensuring a sustained supply of quality vaccines throughout the life cycle, as well as several critical areas that require immediate attention. The political commitment to address these issues has been shaped by the evolving pandemic scenarios. The ASEAN Vaccine Security and Self-Reliance (AVSSR) initiative was launched just before the COVID-19 pandemic began and was agreed upon and endorsed by the region's ten leaders during the 34th ASEAN Summit in November, 2019. Future regional strategies, policies and plans must ensure consistency with this important ASEAN initiative. To accelerate the sustainability of regional vaccine capacity in accordance with the AVSSR milestone (2021-2025), ASEAN should collaborate with development partners who can offer adequate levels of manufacturing expertise, market analysis, financial capability, and technical assistance, including global players like WHO, UNICEF, and World Bank, among others. Moreover, the ASEAN alliance is committed to assisting ASEAN members in fighting pandemics and facilitating recovery from economic instability, particularly by advancing vaccine research and development and building manufacturing capacity. To optimize this favorable environment, ASEAN member states now need to share and collectively discuss their challenges, competencies, and actual capabilities in the vaccine and biopharmaceutical areas to find the best ways to achieve the goal of regional vaccine security and self-reliance in vaccine research, development and manufacturing. In addition, the nations should work to identify pooled procurement mechanisms—especially for non-vaccine-producing middle income countries (MICs) that have limited access to donor funding and procurement facilities like UNICEF and COVAX—to enable them to bid for larger vaccine volume, thus strengthening negotiating power for affordable vaccine prices, for example for PCV and HPV vaccines which are the most expensive among NIP vaccines and are produced by few manufacturers. While some evidence on regional vaccine manufacturing capacity for ASEAN exists, there has been limited research on the technical, operational, financing and strategic partnership opportunities that exist in the region and might be leveraged to advance regional vaccine security. To address this knowledge gap, the ASEAN Vaccine Development and Manufacturing Research Project was initiated by the UK Foreign, Commonwealth and Development Office (UK FCDO), the World Bank, International Finance Corporation, and Global Financing Facility 7 for Women, Children and Adolescents. This project complements the AVSSR Initiative and the Coalition for Epidemic Preparedness Innovations (CEPI) 2021 plan, and supports the November 2019 declaration of ASEAN leaders on regional vaccine security and self-reliance. Value Addition of the Project This regional analytical activity will contribute to knowledge on the technical, operational, and financial viability of and strategic partnerships required among ASEAN countries to strengthen coordinated investments in the vaccine value chain. Five ASEAN members states—Indonesia, Malaysia, Philippines, Thailand and Vietnam—were engaged to conduct detailed analyses of their country’s current vaccine system, including current processes related to procurement and distribution, manufacturing capabilities (current or potential), and regulatory systems related to domestic vaccine registration, quality and safety oversight of production, and post-marketing surveillance. The country teams also consulted with high- level stakeholders from government, regulatory agencies, academia, private sector and civil society to identify relative strengths and critical weaknesses in each country’s technical and human resource capacity to respond to vaccine manufacturing needs in the future. This document is the deep dive into Thailand’s capacity for vaccine R&D and production. Thailand Country Profile Brief Country Context Among Upper Middle Income Countries (UMIC) around the world, Thailand is recognized for its strong health care system. The country was ranked fifth globally and first in Asia on the Global Health Security Index in December 2021 (Bell and Nuzzo, 2021). In the region, Thailand pioneered the establishment of a National Health Security Office (NHSO) in 2002 to ensure universal health coverage (UHC), which includes a national strategic policy and action plan for vaccine security in which all Thai people have equal access to quality vaccines at no cost to the patient. Thailand has a National Vaccine Committee (NVC), which was established by the National Vaccine Security Act of 2018; it is chaired by the Prime Minister, vice-chaired by the Minister of Health, and includes representatives from government agencies and experts in related fields. The NVC established the National Strategic Policy and Action Plan for Vaccine Security, which has four major objectives: 1. to improve the effective management system for a sustainable supplies of vaccines; 2. to support networking on vaccine research and development, production, and regulatory control; 3. to enhance and strengthen the domestic vaccine industry in all aspects, from research and development to marketing; 4. to support vaccine-related resource management, including human resource development, knowledge transfer, financing of infrastructure, and enhanced networking. 8 Figure 1. Thailand age pyramid, 2020 > 80 70-74 60-64 female 50-54 male Age group 40-44 30-34 20-24 10-14 0-4 10% 5% 0% 5% 10% Percentage pop. Source: World Bank Open Data Thailand is a country with a land area of 510,890 square kilometers, of which 93 percent is rural (2010). The country shares borders with Myanmar, Laos, Cambodia and Malaysia. Thailand has a total population of just under 70 million inhabitants, the fourth-largest among ASEAN member states. It has an annual population growth rate of 0.3 percent with a near even division between males and females in the population. The age pyramid is shown in Figure 1. Thailand is divided into five regions—the city of Bangkok plus the Central, Northern, Northeastern, and Southern regions—and 77 provinces, 928 districts, 7,425 subdistricts, and 74,948 villages. Nearly sixty percent of the population lives in the Northeastern and Central regions (32 percent and 25 percent, respectively). Bangkok is the largest city in Thailand with 6 million inhabitants; slightly more than one-third of the population lives in urban areas. Burden of Disease Among the Thai Population In 2019, the World Bank reported that 77 percent of deaths in Thailand were attributable to non-communicable diseases, including: ischemic heart disease (leading cause of death), stroke, chronic kidney disease, and a number of cancers (IHME, n.d). 1 That same year, among diseases under surveillance, the highest morbidity rate was reported for acute diarrhea, while acute respiratory infections ranked third (influenza) and fourth (pneumonia) (Table 1). The mortality rates for these two diseases were also among 1 Institute for Health Metrics and Evaluation, Thailand country profile page. 9 the highest nationally: pneumonia had a mortality rate 0.350 per 100,000 inhabitants in 2019, while influenza had a mortality rate of 0.042 per 100,000 inhabitants (Table 2). Table 1. Top 10 disease morbidity rates in Thailand, 2019 Diseases Cases Deaths Morbidity rate (/100,000 pop.) 1. Acute diarrhea 1078923 9 1622.77 2. Pyrexia of unknown origin 604781 3 909.63 3. Influenza 396363 28 596.16 4. Pneumonia 256555 233 385.88 5. D.H.F (total) 131157 142 199.23 6. Food poisoning 110736 1 166.55 7. H. Conjunctivitis 84389 0 126.93 8. Hand, foot and mouth 67355 1 101.31 9. Chickenpox 47126 0 70.88 10. STI (total) 40527 0 61.56 Source: MoPH Epidemiological Surveillance Report, 2019 Table 2. Top 10 disease mortality rates in Thailand, 2019 Diseases Cases Deaths Mortality rate (/100,000 pop.) 1. Pneumonia 256555 233 0.350 2. D.H.F (total) 131157 142 0.214 3. Melioidosis 2819 81 0.122 4. Leptospirosis 2170 30 0.045 5. Influenza 396363 28 0.042 6. Tuberculosis 13886 27 0.041 7. Streptococcus suis 377 29 0.044 8. Measles 6614 21 0.032 9. Acute diarrhea 1078923 9 0.014 10. Encephalitis (total) 894 7 0.011 Source: MoPH Epidemiological Surveillance Report, 2019 Burden of disease for children under 5 years old In the twenty year period between 1990 and 2019, the mortality rate for children under 5 fell by a factor of 2.5, from 22 deaths per 1,000 population to 8.7. The leading causes of death among children under five in 2019 were perinatal; lower respiratory infections ranked fourth among children in this age group 2 (Figure 2). In 2010, the Bureau of Epidemiology reported that pneumonia-associated morbidity rates among children under 5 years of age decreased from 5.6 percent to 1.6 percent from 1993 to 2009; likewise mortality rates decreased from 9.57 to 1.74 per 100,000 population in that same period, achieving national targets for both 2 Our World in Data. https://ourworldindata.org/grapher/causes-of-death-in-children-under-5?country=~THA 10 measures. However, substantial underreporting was acknowledged as data was pulled exclusively from public sector health care facilities. Pneumonia-associated morbidity and mortality among Thai children has decreased dramatically since the turn of the millennia thanks to improved surveillance and case management and the introduction of the Hib vaccine in 2019 3; nonetheless, among cases of lower respiratory infection, pneumonia represents a significant proportion of hospital admissions and deaths among young children. Figure 2. Causes of death in children under five years of age, Thailand, 2019 Source: Our World in Data In 2019, UNICEF reported that 0.9 percent of Thai children under the age of five died as a result of diarrheal diseases. Studies conducted in Thailand have shown that 43 to 56 percent of diarrhea-related hospital admissions among children under five are due to Rotavirus infection (Jiraphongsa et al., 2005; Sutra et al., 2012). These studies, along with further disease burden assessments and cost benefit analyses, led the Government in 2020 to introduce the Rotavirus vaccine into the national immunization schedule. COVID-19 Pandemic in Thailand Thailand was the first country in ASEAN—and the first outside of China—to report a case of COVID-19 in January 2020; it was also the first to report a death two months later. In the absence of a vaccine in the early stage of the pandemic, and to control the spread of the virus, the Government of Thailand promptly issued strong community-based contact tracing and Public Health and Social Measures (PHSM). A state of emergency was declared on March 26, 2020 until May of that year, though it was later extended through the end of July. The Center for COVID-19 Situation Administration (CCSA) was established on March 16, 2020. Under the leadership of the Prime Minister, it is charged with leading the country in the fight against COVID-19 and coordinating and reporting on the implementation of control measures, which have included: a ban on foreigners entering the country, a mandatory 14- day quarantine for any travelers entering Thailand, and the restriction of mass gatherings and travelling between provinces. All public venues were closed in Bangkok from April 2020; beginning in May, all schools were closed except for international private schools, and the start of the new academic year was postponed until July 2020. 3WHO New and Underutilized Vaccine Introduction, Thailand. https://immunizationdata.who.int/pages/indicators-by- category/new_and_under_utilized_vaccines_introduction.html?ISO_3_CODE=THA&YEAR= 11 Like many countries throughout the world, COVID-19 exacted a heavy toll on the Thai economy, causing a contraction of the GDP. In 2020, Thailand reported negative 6.10 percent GDP growth, the second most severe contraction in the region behind the Philippines. ASEAN country GDP growth from 2016-2020 is shown in Figure 3. Figure 3. ASEAN countries annual GDP growth, 2016-2020 15% 10% 5% 0% -5% -10% -15% 2016 2017 2018 2019 2020 Source: World Bank Open Data As described, PHSM measures were critical in the early stage of the pandemic to contain the spread of the disease. From January to May 2021, five COVID-19 vaccines were given TFDA approval for emergency use (Box 1), allowing the Ministry of Public Health (MoPH) to begin a mass vaccination campaign; other COVID-19 vaccines were subsequently registered, with detailed information available on the Thai Food and Drugs Administration (TFDA) website4. Deliveries of COVID-19 vaccine began arriving in Thailand in February 2021, enabling MoPH to initiate vaccination of priority groups including frontline HCWs in the public and private sector, individuals over 60 years of age, individuals with underlying conditions, and officials involved in disease control whose line of work involved contact with confirmed cases. SINOVAC vaccine was used at first, followed by imported Astra Zeneca and later locally- manufactured Astra Zeneca vaccine when Siam Bioscience received TFDA approval. Box 1. COVID-19 vaccines approved for emergency use in Thailand 1. January 2021: Astra Zeneca AZD1222, a recombinant ChAdOx1 adenoviral vector vaccine manufactured first by ATALENT ANAGNI S.R.L, Italy, then with South Korea Bio Co Ltd, and then by April/May 2021, with Siam Bioscience Thailand. Vaccines manufactured in South Korea and Thailand were registered as additional production sites with identical registration numbers. Vaccine from the company in Italy and South Korea are imported by Astra Zeneca Thailand. 2. February 2021: Coronavac, a Vero cell inactivated vaccine manufactured by Sinovac Life Sciences Co. Ltd China and imported through GPO Thailand. This vaccine was licensed for use in Thailand before it was WHO EUL listed. WHO finalized the assessment for EUL in June 2021. 3. March 2021: ad26-Cov2-S Recombinant, replication-incompetent adenovirus type 26 (Ad26) vectored vaccine manufactured by Janssen-Cilag NV, Leiden in Netherlands and imported by Janssen-Cilag Thailand. 4. May 2021: mRNA-1213 later renamed SPYKEVAX, an mRNA-based vaccine encapsulated in lipid nanoparticle manufactured by Rovi Pharmaceutical Industrial Services S.A. Spain (joint venture with Moderna). Two additional production sites were added in November 2022 with Baxter Pharmaceutical Solutions, LLC and Catalent Indiana LLC both located in Bloomington Indiana, USA. 5. 4 May 2021: Information COVILO, about vaccines a vero approved forcell inactivated use in vaccine Thailand can be found onmanufactured by Beijing the Thai Food and Drug Institute Administration, of Biological Medicines Regulation Division https://www.fda.moph.go.th/sites/drug/SitePages/Vaccine_SPC-Name.aspx website atCo., Products Ltd. and imported by Biogenetech Co. Ltd. In Thailand. 12 COVID-19 vaccine coverage ramped up starting in June 2021 for all ASEAN countries. Because it had access to locally-manufactured vaccine, Thailand saw a sharp increase in vaccine coverage from September 2021 (14 percent) to December 2021 (61 percent) (Figure 4). In Thailand, the combination of PHSM and increasing vaccination rates enabled the country to control the number of new infections and avoid overloading hospitals and ICUs with severe cases despite several waves of infection due to emerging variants of concern (Figure 5). As of early May 2022, the total cumulative number of reported COVID-19 cases in Thailand was 4.29 million with nearly 29,000 deaths (Figure 7). Figure 4. National COVID-19 vaccination coverage Figure 4: Source: Thailand Center for COVID-19 Situation Administration (CCSA). https://www.thaigov.go.th/news/contents/details/29299 The Government of Thailand has expanded vaccine eligibility and added booster doses to the immunization schedule as supply has become available. The TFDA authorized the use of Pfizer-BioNTech mRNA pediatric formulation for children ages 5-11 in January 2022; it has also provided COVID-19 vaccination to the estimated 2.9 million migrant workers who live in Thailand (International Labour Organization, 2019). Despite these efforts, regional variation in coverage rates is evident, with the rate of two-dose vaccination ranging from 45 percent in some rural areas to nearly 100 percent in Bangkok. Figure 5. COVID-19 vaccine coverage by dose Source: Thailand CCSA. https://www.thaigov.go.th/news/contents/details/29299 13 Figure 6. Thailand COVID-19 cases, deaths and vaccinations Source: Thailand CCSA. https://www.thaigov.go.th/news/contents/details/29299 Figure 7. COVID-19 deaths in Thailand Source: WHO Thailand, 2022. Among the numerous challenges of vaccinating against COVID-19 has been the use of multiple vaccines with different technological platforms, which have had to be wisely combined to ensure the highest level of protection. MoPH issued detailed guidelines for the vaccination of 5-17 year olds including recommended vaccines for booster doses; similar guidance was given for adults. These recommendations are displayed below in Figures 8 and 9. 14 Figure 8. COVID-19 vaccination program for children and adolescents Source: MoPH Press Briefing 21 March 2022 Figure 9. MoPH guidelines for COVID-19 vaccine administration Source: MoPH Press Briefing 21 March 2022 Summary of the National Immunization Program The National Immunization Program (NIP) was introduced in Thailand in 1977. It has a long history of high immunization coverage rates, achieving greater than 80 percent coverage for more than twenty years. The coverage of essential health services in Thailand is among the highest in the region at 83 percent, though studies show that there are pockets of low immunization coverage, especially among children of migrant workers (Pinna et al., 2020) and in some provinces in the Southern region (UNICEF, 2021). In Thailand, immunization 15 services are provided free of charge through a network of 9,800 health promotion hospitals and primary health care facilities as well as 771 community hospitals that provide secondary health services—including vaccinations—at the district level. The private sector provides immunization services as well: at the provincial level, 10-15 percent of all vaccinations are given by private sector providers, while in Bangkok the percentage is closer to 30 percent. Immunization services are financed by the National Health Insurance Plan (NHIP), which was established in 2002. The Advisory Committee on Immunization Practices (ACIP) was established in 1970 to advise MoPH on vaccine priorities, new introductions and the recommended vaccination schedule; in 2001 it was integrated into the National Vaccine Committee to form the National Immunization Technical Advisory Group (Rattanavipapong et al., 2020), which continues to advise the MOPH on vaccine introductions and practices. MoPH introduces a new vaccine into the NIP once TFDA provides regulatory approval. The Thai government’s measures to fight COVID-19 enabled the country to control the spread of the diseases and rapidly reduce the COVID-19 case fatality rate while having a limited impact on childhood immunization coverage, which is a remarkable achievement. Though DTP3 vaccination coverage decreased slightly from 99 percent in 2017 to 97 percent in 2021, and measles 2nd dose coverage—given to children at two-and-a-half years of age— decreased by 10 percent in 2021, coverage rates remained well higher than among other countries in the ASEAN region. Additional information on Thailand NIP performance indicators is included in Annex 1. Vaccines Included in the NIP Thailand’s immunization schedule currently includes 12 vaccines to be administrated to different age groups (Table 3). Several new and underutilized vaccines were recently introduced into the immunization program, including: rotavirus vaccine in 2020, pentavalent DPT-HepB-Hib vaccine in 2019, HPV vaccine in 2017, and the seasonal influenza vaccine in 2008 (WHO, n.d.-b) 5. Thailand is the only country among ASEAN member states that has introduced seasonal influenza vaccine into the NIP. Table 3. National Immunization Program schedule in Thailand, 2022 Vaccine Age of administration BCG At birth HepB At birth and 1 month (newborn from HepB carrier mother) DTP-HepB-Hib 2 months, 4 months and 6 months OPV 2 months, 4 months, 6 months, 1.5 years and 4 years IPV 4 months MMR 9 months and 2.5 years DTP 1.5 years and 4 years 5 WHO Vaccine Introduction in Thailand. https://immunizationdata.who.int/pages/vaccine-intro-by-country/tha.html?YEAR 16 Td School children in grade 6 (12 years) and pregnant women at 1st contact, + 1 month, +6 months (depending on vaccination history) JE LAV 1 year and 2.5 years HPV Grade 5 girls (2 doses, 6 months apart) Rotavirus 2 months, 4 months, and 6 months Meningitis ACWY 9 months to 55 years (priority group: pilgrims from Thailand and travellers to 135 conj. epidemic areas). Vaccine Delivery Challenges and Inequities Since the inception of the NIP in Thailand, the vaccine supply chain system has gone through several reforms. Prior to 2002, the pharmacy unit within the Bureau of General Communicable Diseases in MOPH was in charge of budgeting, procuring and distributing vaccines. Following health care reform in 2002, the budget for NIP vaccines was based on the capitation payment under the universal health coverage scheme managed by NHSO, which was established that same year. In 2009, the NHSO and the Department of Diseases Control (DDC) in MoPH launched a pilot project to outsource vaccine supply management to the Government Pharmaceutical Organization (GPO). The project was successful, and since 2010, NHSO has been in charge of the vaccine procurement process while GPO imports and distributes the vaccine in the country. To monitor vaccine distribution, GPO introduced and manages a vendor-managed inventory system (VMI) (PATH, 2011). Although it is a vaccine-producing country, Thailand imports most of the vaccines for the NIP. In 2017-18, the country procured a total of 33.6 million doses of vaccine for the NIP, 19 percent of which were locally-produced. Domestic vaccine production meets the yearly requirements for BCG; domestic production also accounted for nearly 50 percent of seasonal influenza vaccine procured in 2017 and 20 percent in 2018. In 2017, the MoPH reported a total vaccine procurement expenditure of US$41.82 million; in 2018, the total expenditure was approximately USD 56 million 6. The difference in budget spending between 2017 and 2018 may be due to late purchase of vaccines for use in the following year; an analysis of vaccine spending for three consecutive years would provide more details, but data is not available. Thailand is an upper-middle income country and as such has limited access to donor funding; it must fully finance vaccine procurement for NIP, including the COVID-19 vaccine. Thailand did not join the COVAX facility. The uninterrupted supply of vaccine is the cornerstone of NIP efforts to reach and maintain high immunization coverage. However, studies have shown that vaccine shortages occur in many countries, including MICs. The Global Vaccine Action Plan (2011-2020) targeted a two- thirds reduction in the number of countries reporting national-level vaccine stock-outs by 2020 (WHO, 2013). According to WHO/UNICEF Joint Reporting Form data, vaccine shortages 6WHO Immunization Expenditure, Thailand page. Available online at: https://immunizationdata.who.int/pages/indicators-by- category/finance.html?ISO_3_CODE=THA&YEAR= 17 occurred in Thailand on two separate occasions: for HPV vaccine in 2018 and 2019, and for measles-containing vaccine (MMR) in 2019. An analysis of vaccine stock-outs for the period 2011-2015 showed that 39 percent of stock- outs globally were attributable to a government funding delay (Lydon et al., 2017). Though no analysis was conducted in Thailand on the causes of the HPV and MMR shortages of 2018 and 2019, the country could consider establishing multi-year procurement agreements with manufacturers as a general strategy to ensure adequate vaccine supply. The establishment of such long-term agreements may require policy changes, however, as the current government financial rules do not allow for funding commitments beyond the duration of the fiscal year. Procurement delays can also result from incorrect vaccine specifications in bid documents, which Thailand experienced in 2019. A delay of this nature may highlight a lack of interagency collaboration among TFDA and other involved parties during the preparation of marketing authorization documents and product specifications. Adverse Events Following Immunization and Pharmacovigilance System Another important element of achieving and maintaining high immunization coverage is the capacity of the NIP to detect, manage, report and investigate Adverse Events Following Immunization (AEFI). Strong post-marketing vaccine safety surveillance enables the program to build public confidence in immunization and to mitigate safety concerns when serious AEFIs are reported in the media. The National AEFI Experts Review Committee was established in Thailand in 2004 by MoPH/DDC decree 166/2547; sub-national AEFI committees were established throughout the country between 2010 and 2013. The National AEFI guideline was revised in 2019 and is now on the 5th edition. The AEFI surveillance system is integrated in the Health Product Vigilance Center (HPVC) within the Thai Food and Drugs Administration (TFDA). The AEFI system in Thailand was recognized as high-performing during the 2019 South-East Asia Regional workshop on inter-country expert review of selected AEFI cases (MacDonald et al., 2020). The AEFI monitoring system for COVID-19 vaccines is strongly anchored in the routine vaccine safety surveillance system while also responsive to COVID-19-specific requirements. In the beginning of the pandemic, WHO provided advice to COVAX on vaccine efficacy and safety of products listed in EUL for one year only, due to the lack of post-marketing safety data; TFDA provided COVID-19 vaccine regulatory approval for one year as well. The decision to extend regulatory approval is based on a reassessment of vaccine products once additional post-marketing safety and efficacy data becomes available, including among people with comorbidities, pregnant women, and younger or older age groups not usually included in clinical trial (CT) population samples. All NRAs including the EMA and USFDA granted one- year regulatory approval under emergency use based on clinical trial phase 3 data and risk- benefit analysis. To continuously monitor the safety profile of a vaccine, it is essential to have strong, collaborative mechanisms between NIP, MoPH and DDC, the Department of Epidemiology, TFDA, and manufacturers to update vaccine safety information, especially for the COVID-19 vaccine with which large swaths of the population were vaccinated in a short period of time. The relief of having a COVID-19 vaccine was tempered by false allegations of vaccine safety 18 shared by the media and in social networks, making it even more essential to continuously monitor and communicate safety and efficacy data. Strengthening collaboration among ASEAN vaccine safety specialists would help to scientifically document and inform the public about vaccine safety, but this has not yet happened due to limited collaboration within ASEAN countries and with the WHO Global Advisory Committee on Vaccine Safety (GACVS). Additionally, regional collaboration could provide additional expertise and help to reinforce the findings of AEFI causality assessments conducted by the Thailand AEFI committees and others ASEAN counterparts. NVI’s leadership role in the AVSSR could position it to spearhead a collaborative mechanism for ASEAN vaccine causality experts to review selected cases when necessary (e.g. during outbreaks or pandemic situations) with inputs from the WHO Global Advisory Committee on Vaccine Safety (GACVS). Vaccine Regulatory System The Thai Food and Drugs Administration (TFDA) within MoPH is the National Regulatory Agency in Thailand. Within TFDA, the Bureau of Drug Control manages the regulatory system, market authorization, market control and surveillance, licensing of products, regulatory inspection and clinical trials authorization, and monitoring and data analysis, while the Technical and Planning Division undertakes the pharmacovigilance function. TFDA is supported by two other departments in MoPH: the Department of Medical Sciences (within the Institute of Biological Products), which is the National Control Laboratory (NCL) for laboratory access and lot release functions; and the Department of Disease Control (within the Bureau of Epidemiology) for the detection and investigation of AEFI cases including causality assessment conducted by an expert group. The TFDA is funded by the government based on the Annual Expenditure Budget Act and fees collected according to the Order of the Head of the National Council for Peace and Order No.77/2559. In June 2018, the WHO conducted a formal review of the TFDA regulatory system using the standard Global Benchmarking Tool (GBT). The GBT is globally recognized as a standard tool for NRA benchmarking; it is comprised of 280 indicators and sub-indicators (below) developed over several years of extensive consultations with NRAs in HICs, MICs and LICs. 1. Regulatory system with 62 sub-indicators; 2. Registration and market authorization with 31 sub-indicators; 3. Pharmacovigilance with 25 sub-indicators; 4. Market surveillance and control with 26 sub-indicators; 5. Licensing of premises with 20 sub-indicators; 6. Regulatory inspections with 29 sub-indicators; 7. Laboratory access and testing with 34 sub-indictors; 8. Clinical trial oversight with 30 sub-indicators 9. Lot release with 23 sub-indicators WHO benchmarking of the TFDA was conducted with regulatory experts from the Therapeutic Goods Administration (TGA) Australia, the National Agency for Drugs and Food 19 Control (NADFC) Indonesia, the Agenzia Italiana del Farmaco (AIFA) Italy, the Center for Biologics Evaluation and Research (CEBER), United States Food and Drugs Administration, the medicine evaluation board in the Netherlands, and experts from WHO. The status of the TFDA benchmarking is summarized in Table 4. Table 4. TFDA status as of June 2018 Key features of the TFDA Reported data 1. Types of health products and / or technologies regulated by the National Human, veterinary and traditional medicines Regulatory Authority (NRA) according to available national legislation 2. Budget allotment in 2017 (U$) US$ 26.25 million 3. Total number of employees in the TFDA at central level 288 4. Percentage of staff with post-graduate 28.77% Pharmacists, 44% (all staff) (Master’s/Diploma/specialization/Doctorate 5. Number of medicines with current valid registration 41,211 6. Number of licensed manufacturing plants 398 7. Number of Marketing Authorization Holders with registered medicines Manufacturers: 443, Exporters: 924, Total: 1,367 8. Number of notifications of adverse drug events received per million 614.28 inhabitants in 2017 9. Percentage of serious ADR 15-20% 10. Number of request for clinical trials of medicines received by TFDA in 2017 252 Source: World Health Organization, Regional Office for South-East Asia, 2021. In vaccine producing countries, the NRA GBT is used to assess the maturity level of the regulatory system; a maturity level of 3 or above enables manufacturers to submit vaccines for WHO pre-qualification. The vaccine regulatory performance findings in Thailand identified four regulatory functions with a maturity level score below 3: registration and marketing authorization (ML 1); licensing of premises (ML 1); clinical trial oversight (ML 1); and pharmacovigilance and regulatory inspection (ML 2). The highest score (ML 4) was reported for the laboratory access and testing function. The major issues found during the assessment included: 1. Parallel structures/units (market authorization and registration) • Inconsistency in process and outcome (different staff and advisory committees as well as competency of reviewers) • Inadequate internal communication and transparency • Inadequate QMS coverage • Human resources • Imbalance between fixed term and temporary staff • Use of too many external experts • Inadequate systematic and needs driven training program 2. Enforcement • Lengthy and time consuming processes • Hierarchical and involvement of many layers • Exclusion of public sector in some areas 20 3. Performance measurement • Some KPIs are not able to properly measure the performance of regulatory functions. • KPIs should be considered as tools to measure and improve the performance of regulatory functions. 4. Enforcement of regulatory oversight on distribution channels 5. Inadequate communication and transparency with regards to regulatory oversight on clinical trials 6. Regulatory preparedness to address crises: lack of a comprehensive crisis management system that is supported by legal framework and regulatory processes In countries that produce WHO pre-qualified vaccines, WHO does not assign a maturity level immediately after completion of the assessment; instead, it allows four to six months for the NRA to implement the Corrective and Preventive Action (CAPA) plan. In Thailand, WHO monitored progress on implementing CAPA measures through regular communications with the TFDA, and in June 2021 it officially granted an overall maturity level 3 to the TFDA. In doing so, vaccine manufacturer GPO-MBP was able to keep the JE-LAV (IMOJEV- MD) vaccine in the list of WHO pre-qualified vaccines (WHO, 2021). The TFDA is built on several strengths, including the ability to select and recruit staff with a high level of relevant knowledge. A website is maintained in Thai and in English that provides a significant amount of information to external stakeholders regarding TFDA activities 7. Additionally, Thailand has a well-established Quality Management System that obtained ISO 9001:2015 certification in January 2018. The TFDA is funded by the government to implement all regulatory functions, however, the budget allocation for the Bureau of Drug Control (12.2 percent of the total TFDA budget, which was US$26 million for 2018) is considered insufficient to effectively and efficiently perform all regulatory activities. Fees and charges were introduced in 2017 to recoup some regulatory costs, but this is not enough for a country with plans to invest in vaccine production. Protocol for Registering New Vaccines Thailand’s marketing authorization (MA) function and its legal framework are laid out in Chapter 10, Section 79 of Drug Act B.E. 2510. Ministerial Ordinance No 18 B.E. 2525, issued under Drug Act B.E.2510, defines the legal provisions and regulations related to MA activities; the application form and credential certificate of drug registration are listed under the Ministerial Notification. TFDA notification B.E 2551 provides definitions for type of marketing authorization, CTD format according to the International Consortium on Harmonization (ICH), and CTD format according to ASEAN Pharmaceutical Harmonization on Registration for modern medicines, referred as ASEAN CTD (ACTD). The TFDA has implemented the ACTD, though its requirements are just a minimum standard for submission of medicinal products of different categories; the licensing of biologicals and vaccines requires additional information that is listed in the full package of ACTD or ICH CTD. 7 Vaccine information for Thailand can be found at: https://www.fda.moph.go.th/sites/drug/SitePages/Vaccine.aspx 21 The authority and independence of the TFDA was challenged in the early days of the COVID- 19 pandemic, as the usual mechanisms for granting marketing authorization were overruled in an effort to vaccinate citizens as quickly as possible. This situation was not unique to Thailand but nonetheless highlighted a lack of transparency in the Government decision- making process. Domestic Vaccine Manufacturing and Distribution Capacity Thailand has four domestic vaccine manufacturers: one in the public sector (QSMI), two public/private manufacturers (Siam Bioscience; GPO-MBP), and one in the private sector (BioNet Asia). Although all four have upstream and downstream capacity, few products are fully manufactured in Thailand, and the vaccines in the companies’ portfolios include many imported vaccines, either as bulk product to be formulated in Thailand, or as finished product ready for distribution. A complete listing of manufacturers’ current R&D projects and vaccine portfolios is summarized in Table 5. The overall production capacity of three of the vaccine manufacturers—BioNet Asia, GPO- MBP and QSMI—is generally limited and/or insufficient to meet NIP vaccine requirements, though QSMI produces sufficient BCG vaccine to meet demand for the NIP. GPO-MBP produces seasonal influenza vaccine that is supplied to the NIP, though not the full amount that is required each year. The remaining vaccine doses required for the NIP are imported and distributed by GPO as part of the NHSO contractual arrangement for NIP imported vaccines. Table 5. Thailand current manufacturers’ R&D projects and vaccine portfolios 8 Company Highlights of collaboration with Upstream/downstream Other vaccine Partners and manufacturers, universities and vaccine production products business model R&D institutes BioNet Asia Co Ltd. Liaoning Chengda Biotechnology Co., The bulk vaccine product TetraFlu™ Quadrivalent Prefilled syringe single Established in 2001. Private sector with Ltd China to manufacture a imported from Liaoning, fill Influenza vaccine dose (0.5 ml). operations in Europe, Asia and Australia. The chromatographically purified cell- and finish in QSMI facility Manufacturer Adimmune vaccine production facility is located in culture rabies vaccine. BioNet Asia is Co. Taiwan. Adimmune Ayuthaya. The company has a long history of providing the know-how to QSMI to partnership with BioNet collaborations and partnerships with manufacture the vaccine. Asia responsible for universities, biotech companies, laboratories marketing the vaccine in and manufacturers. Southeast Asian markets. BioNet can import bulk The company operates as a Contract vaccine to fill and finish in Development Manufacturing Organization (CDMO). BioNet Asia facility. In March 2022, BioNet, Technovalia, In 2015-2016, faculty of medicine of In September 2016, TFDA bOPV Bivalent type 1 and Imported finished Sypharma announced the establishment of Siriraj Hospital and faculty of Tropical granted market authorization 3 Oral Polio vaccine. products from BioFarma. Genetis, the first Australian Vaccine Medicines Mahidol University for clinical for Pertagen™, in October Manufacturer: Biofarma Bionet provided technical Development and Manufacturing Hub for trial phase II/III of two acellular Pertussis 2016, for Boostagen™ a (Indonesia) support to Biofarma to mRNA, DNA and recombinant vaccines. vaccines (aP standalone and TdaP combined tetanus, reduced increase production, Genetis will operate as an independent combined vaccines) and chemically- diphtheria toxoid and formulate fill and finish Vaccine Hub offering Contract Development detoxified Adacel Tdap vaccine were recombinant acellular products and to receive Manufacturing Services and Product conducted in Bangkok. vaccine. Pertagen is with WHO PQ which started in Development Expertise for mRNA, DNA and recombinant vaccines NRA approval SG. Both 2001. BioNet also products are fully provided bulk OPV to manufactured by BioNet Asia. Biofarma in Indonesia and SII in India. 8 Information provided by vaccine manufacturers during in-depth interviews. 22 Company Highlights of collaboration with Upstream/downstream Other vaccine Partners and manufacturers, universities and vaccine production products business model R&D institutes In 2018, collaborative project with In- The R&D project is to create a TT single dose. Imported finished product Cell-Art (ICA), a French tech company single component pentavalent Manufacturer: Biofarma for Asian market mostly. specializing in nano-carrier, and the dengue-Zika vaccine Institute Pasteur Paris France (GFMI-IP) preventing antibody- to develop a Nanotaxi formulated DNA dependent enhancement vaccine to induce strong immune phenomenon. response against dengue virus. ChulaCov19 vaccine developed by • ChulaCov19 BNA159 mRNA Equirab in vial of 100 IU Imported finished Chulalongkorn University Vaccine vaccine is the lipid Manufacturer: Bharat products for BSV Research Center and manufactured by nanoparticles (LNPs)- Serums and Vaccines Ltd. BioNet Asia with Moderna’s Asian encapsulated mRNA-based Mumbai India. Distributor Zuellig Pharma Thailand. • CT I/II expected date of completion May 2023. CT batch production BioNet (30,000 ds for CT3). BioNet Asia in collaboration with With needle-free injection Telethon Kids Perth Children’s Hospital made by Pharmajet to inject in Australia, University of Sydney, and the vaccine. For delivery into Technovalia is developing a DNA the skin (intradermally) a vaccine to protect against SARS CoV-2 device called "Tropis" will be virus, called COVIGEN, used, and for delivery into the muscle (intramuscularly) a device called "Stratis" will be used. CTI is being conducted in Australia with an expected date of completion June 30, 2023 The Coalition for Epidemic Production of clinical trial Preparedness Innovations (CEPI) material, and analytical awarded BioNet Asia with a grant of development. $16.9 million to support preclinical studies and phase I/II clinical trials. Bionet-Asia is collaborating for this R&D project with Penn University in Australia and IVI in S. Korea. to engineer a COVID-19 vaccine that provides broad, variant-proof protection against SARS- CoV-2 and other betacoronaviruses. Government Pharmaceutical Organization COVID-19 NVD-HXP-S non replicating GPO plant in Saraburi JE LAV vaccine IMOJEV- • Although WHO Pre- (GPO) and GPO-MBP viral vector. GPO with Center for province use for production of MD. Vaccine substance Qualified since 2014, the Vaccine Development (CVD), Mahidol CT batches. CT I/II imported from SANOFI vaccine never been GPO is a state enterprise operating under the University, Icahn School of Medicine at completion date May 2023. (USA), formulated and fill awarded for supply to Ministry of Public Health. It was founded in Mount Sinai (ISMMS) – Medical School finish in GPO-MBP UN procurement agency. accordance with the GPO Act of 1966 New York City, the University of Texas production facility. • The vaccine is used in (B.E.2509). The main responsibility of GPO is at Austin (UTA) and PATH. Thailand and was to support the nation’s public health works by exported to Australia producing and supplying medicines and (Queensland), Malaysia medical supplies. GPO is a member of the DCVMN and PIC/S for GMP enforcement. (Sarawak), Brunei, Philippines, Hong Kong, Macau, South Korea, Indonesia, Myanmar, The Government Pharmaceutical Vietnam, Cambodia, Organization-Merieux Biological Products Co Taiwan, Bangladesh and (GPO-MBP) is a joint venture between GPO the vaccine is under (40%), Sanofi (49%) and the Thai crown (2%) registration in Sri-Lanka to make vaccines, especially children's and Israel. vaccines, for the Thai population. COVID-19 inactivated recombinant This R&D project is in pre- Pandemic seasonal The production capacity using cell based technology at the clinical trial stage. influenza and avian of the plant is 2 million preclinical level developed in influenza vaccine doses per annum; in case collaboration with Faculty of Medicine production capacity using of pandemic, capacity can Siriraj Hospital, Mahidol University. egg-based technology in be increased to 10 million Saraburi provinces. GPO doses. plans to use this production facility for the production of the 2 cell- culture technologies COVID-19 vaccine. In collaboration with the Center for Pre-clinical phase. • NHSO has contractual • Vaccines for the National Vaccine Development, Mahidol arrangement with GPO Immunization Program. University a live Chimeric JE based on for the importation of the SA 14/14/2 strain using cell/based vaccine for the NIP culture technology is being developed in including their distribution. order to replace the inactivated SMB JE • The GPO vaccine previously manufactured by GPO. distribution include 11 antigens: tuberculosis (BCG vaccine), hepatitis 23 Company Highlights of collaboration with Upstream/downstream Other vaccine Partners and manufacturers, universities and vaccine production products business model R&D institutes B, diphtheria, tetanus, pertussis, poliomyelitis (OPV and IPV vaccine), measles, mumps, rubella, Japanese encephalitis (JE), influenza vaccine and human Papilloma Virus (HPV vaccine). Collaborating with the National Centre The prototype will be injected In mid-2021, GPO-MBP • National pandemic for Genetic Engineering and into eggs and incubated to started discussions with response plan. Biotechnology (BIOTEC) under the allow for replication. This Sinovac about providing a • GPO-MBP has made National Science and Technology research project is in large supply of vaccine but available fill-finish Development Agency (NSTDA) vaccine preclinical stage. there was a conflict of capacity for 5m doses for R&D by splicing SARS-CoV2 RNA into interest because GPO- immediate use by any of genes of an inactivated influenza virus. MBP is 49% owned by the companies in Sanofi. The contract was Thailand when they have handed over to GPO to drug substance ready. handle independently and finalize the deal for 2m doses. In collaboration with WHO Pandemic Manufacturing site used for seasonal influenza and avian influenza the production of vaccine vaccine production were developed with batch for clinical trial of the capacity with 2 million doses per year COVID-19 NVD-HXP-S and capacity to ramp up production to vaccine. 10 million for pandemic. In collaboration with CVD Mahidol and CT phase II was completed US army to develop a chikungunya vaccine. HPV vaccine production project under HPV is imported to supply the discussion with a Chinese company for NIP. tech transfer. This project is an undertaking of GPO and it is under NVI consideration. A joint venture with France's Sanofi There are plans to build Pasteur includes an 8 year plan to production facilities. upgrade the production facility in Thailand for DTap-HepB vaccine manufacturing. Queen Saovabha Memorial Institute (QSMI) Liaoning Chengda Biotechnology Co., Waiting for the new plant and Manufacturing BCG Production meets NIP was established in 1922 initially for the Ltd China and BioNet Asia to tech transfer for upstream requirements development and production of anti-snake manufacture a chromatographically process. Agreement expected venoms, then for BCG vaccine in 1953. purified cell-culture rabies vaccine. at the end of 2022. Today, QSMI is responsible for packaging and Downstream production has distributing the bulk of vaccine, serums and been working for 10 years. other biomaterials and sterilization liquid; conducting research and providing services in scientific tests; services concerning rabies; Chulalongkorn University VRC, CU • CU Enterprise, for clinical JE (completed process giving suggestions about bites from venomous Enterprise and KinGenBiotech (CDMO) trial batches (CT phase I validation, but terminated animals; tropical diseases; and giving vaccine for protein subunit COVID-19 vaccine done with QSMI, COVID already). TFDA rejected the injections to people. QSMI is member of the development. protein subunit). With submission. Tech transfer DCVMN. capacity for clinical trial from China to do (phase I/II only) batches downstream. 5,000. • CTI completed but unsatisfactory results. The vaccine is being reformulated for CTI w/ expected completion date June 2022. • Approached by Chula VRC for phase III clinical trial for mRNA COVID-19, but limitation on capacity. Rabies imported from Domestic market, 500,000 China does/year. Siam Bioscience, a private/public sector Currently, there is no ongoing Siam Bioscience produces Upstream and company, is one of 25 companies selected by collaboration for Vaccine R&D and Astra Zeneca ChAdOx1- downstream production AstraZeneca to license its COVID-19 viral production. S/nCoV-19 recombinant processes. End-to-end vector vaccine. Siam Bioscience is a vaccine through a manufacturing takes biopharmaceuticals manufacturer founded in technology transfer around 120 days to 2009 through the King’s Fund, which was set initiated in 2020 with complete each drug up by the Late King Rama IX to improve AstraZeneca UK. Siam substance lot. Drug health and wellbeing. AstraZeneca audited Bioscience Co. operates product lots are converted Siam Bioscience during Q2 of 2020. as Contracting from drug substance daily 24 Company Highlights of collaboration with Upstream/downstream Other vaccine Partners and manufacturers, universities and vaccine production products business model R&D institutes Management Organization with output of 700,000 (CMO) producing vaccine doses per day. Siam upon the request of Astra Bioscience is producing Zeneca Thailand. Astra 200 million doses of Astra Zeneca Thailand places Zeneca vaccine per year. orders with Siam The overall contract is for Bioscience to produce the 200m doses to supply to vaccine. The vaccine is Thailand, ASEAN then dispatched according countries, and the to Astra Zeneca Maldives. distribution plans TFDA is a member of PIC/S and all vaccine manufacturers in Thailand comply with GMP PIC/S 9 and international standards. In addition, GMP compliance in the GPO-MBP facility is periodically reviewed by WHO in order for the JE LAV IMOJEV vaccine to remain on the list of WHO pre-qualified products. GPO-MBP is also marketing the JE LAV vaccine in Hong Kong, Macau, South Korea, Taiwan and other countries within the ASEAN. Several BioNet Asia vaccines received EU market approval and approval in other Southeast Asian countries— including Singapore and Australia—both of which have stringent regulatory systems. All Thai vaccine manufacturers have high standards for quality assurance/quality control and GMP compliance, and with the TFDA at Maturity Level 3, vaccines manufactured in Thailand are of assured quality. Except for Siam Bioscience which exclusively produces Astra Zeneca COVID-19 vaccine, Thailand’s vaccine manufacturers have extensive experience in vaccine R&D, as reported in the MoPH/NVI ASEAN Baseline Vaccine Survey (ASEAN Secretariat, 2019). This experience has positioned them to undertake R&D to develop locally-engineered COVID-19 vaccines. There are currently seven ongoing R&D projects for COVID-19 vaccine in Thailand, several in early pre-clinical stages and one in clinical trial phase 3. These projects have benefited from effective public/private collaboration in particular with Chulalongkorn and Mahidol Universities, which are involved in most of the projects. The National Vaccine Institute in MoPH plays a key role in coordinating vaccine R&D, collaborating in clinical trials, and reviewing public sector company proposals for technology transfer. Both Siam Bioscience and BioNet Asia operate as Contract (Development and) Manufacturing Organizations (CDMO/CMO). Siam Bioscience is currently under contract with Astra Zeneca UK to produce its COVID-19 vaccine. Astra Zeneca Thailand provides the manufacturer with purchase orders (PO), and once the vaccine is produced, Siam Bioscience delivers it to Astra Zeneca Thailand which in turn delivers the vaccine to the MoPH, countries within and outside Asia, and to international procurement agencies like UNICEF and PAHO. Under the current contractual arrangement, Siam Bioscience does not participate in discussions around vaccine allocations and does not have ongoing R&D projects, although the company submitted an EOI to WHO to acquire mRNA technology. 9 PIC/S is the acronym used to describe both the Pharmaceutical Inspection Convention (PIC) and the pharmaceutical Inspection Co- operation Scheme (PIC Scheme) operating together in parallel. The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is a non-binding, informal co-operative arrangement between Regulatory Authorities in the field of Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. PIC/S aims at harmonizing inspection procedures worldwide by developing common standards in the field of GMP and by providing training opportunities to Inspectors. 25 BioNet Asia operates as a Contract Development Manufacturing Organization (CDMO) and is currently supporting several collaborations with various manufacturers to develop vaccines and upgrade their production facilities. BioNet Asia is a leading member of an R&D consortium composed of universities from the US and Thailand as well as the International Vaccine Institute in South Korea. Within the consortium, BioNet Asia provides engineering know-how and produces clinical trial vaccine batches of virus like particles (VLP) forming multivalent mRNA vaccine. The company has also been operating as a consulting company to provide technical support and technology access to several vaccine manufacturers in the region, including Bio Farma in Indonesia, Serum Institute of India (SII), and Panacea and Bharat (both in India) around the production and formulation of oral polio and pentavalent vaccines. In addition, BioNet provides emerging vaccine manufacturers with network access to technologies, sources of bulk materials, manufacturing capacities and supply platforms with the goal of production self-sufficiency and maximizing existing idle vaccine capacities. Vaccine Manufacturing Challenges All four vaccine manufacturers report difficulties procuring excipients and ingredients to manufacture vaccines as well as disposable items for vaccine production, such as bioreactor filters. All raw materials and items are imported from the US and EU except for vaccine vials, which some manufacturers report procuring from a supplier in Indonesia. The scale of difficulty to procure raw materials and disposable items depends on the annual volume of vaccine produced by the manufacturer. Siam Bioscience, with the largest quantity of vaccine doses manufactured, reported that vaccine production requires not less than 200 ingredients, bio-process materials and other disposable supplies to complete formulation and manufacturing. Many of these ingredients have specific supply chain requirements, and with many vaccine manufacturers competing simultaneously to procure these products, the supply is not assured. This high global demand with limited suppliers puts a substantial strain on the supply chain. Siam Bioscience identifies the “supply strain” as the main threat to its current Astra Zeneca vaccine production efforts in Thailand. BioNet Asia procures excipients and ingredients in large quantities to sustain vaccine manufacture for several months; however, this strategy requires substantial storage capacity, which is costly. The other two manufacturers import vaccine in bulk, which is then formulated and bottled; with less quantity of vaccine produced upstream and downstream, these smaller vaccine manufactures face fewer difficulties in procuring excipients, ingredients and disposable materials. BioNet Asia, QSMI, GPO and Siam Bioscience are members of the Developing Country Vaccine Manufacturers Network (DCVMN); the collaborative enterprise between GPO and MBP (GPO-MBP) is not a member of the network. Vaccine manufacturers in Thailand acknowledge the usefulness of trainings organized by DCVMN, for example on quality control, self-audit and bio-setting, and recognize DCVMN as a reliable source of knowledge and information exchange among manufacturers. However, several manufacturers suggested that DCVMN could go beyond knowledge exchange into practical collaboration (i.e. learning by doing) and help to facilitate partnerships for R&D and production. 26 In general, vaccine industry stakeholders expressed a lack of collaboration within the ASEAN, although ASEAN leaders have talked for many years about strengthening partnerships. For example, the harmonization of regulatory pathways for vaccines among the ASEAN countries has not yet resulted in a comprehensive market authorization procedure common to all ASEAN countries. SWOT Analysis: Thailand’s contribution to the vaccine value chain in ASEAN Strengths Weaknesses • Good collaboration between public & private • Upstream vaccine production is limited with sectors with strong participation of universities only two vaccines manufactured in Thailand in vaccine R&D. being used in the NIP, the rest are imported. • Manufacturers are very active in vaccine R&D • Price to remain competitive is challenging, for COVID-19 vaccine and other vaccines e.g.: with vaccine manufacturers in India and chikungunya, HPV, Dengue, JE Chimeric vaccine. China manufacturing large portfolio of • Production of novel vaccine e.g. recombinant vaccine and quantities at low costs. acellular pertussis (BioNet Asia) and COVID-19 • Concentration of R&D projects for COVID-19 subunit with novel approach and technology vaccine at the expense of other vaccines using plants. that are in short supply or needed for • Vaccine manufacturing is in compliance with diseases specific to the region e.g. rotavirus, stringent regulatory requirements for QA/QC typhoid, dengue. and GMP. • Vaccine production capacity for pandemic influenza is available. • Production of WHO pre-qualified vaccine (JE LAV). Opportunities Threats • Government support for National Vaccine • Government financial support has not yet Security materialized to meet national ambition for • The MoPH/National Vaccine Institute (NVI) are vaccine security. involved in vaccine clinical trials and help • The dynamic of regional and international coordinate vaccine security agenda among vaccine markets is not well analyzed, ASEAN countries through the ASEAN Vaccine monitored and understood in Government Security and Self-Reliance (AVSSR) institutions. • WHO benchmarking of the Thai FDA was • Public sector companies do not have the conducted in 2018 and reached Maturity level 3. same access to financing as private sector • Network of universities and scientists are well companies. Public sector companies’ versed in vaccine R&D and in collaborating with financing involves lengthy process for vaccine manufacturers. project review and allocation of funds, • Thailand is centrally located in South Asia with especially for upgrading production capacity. airport hub for the flights in the region and • Government National Vaccine Security plans beyond. focus on domestic production and not enough on the regulatory system which needs human and financial resources to keep up with manufacturers production plans using new and more sophisticated 27 vaccines and technologies. • Lack of dialogue between public/private manufacturers and national governments within the ASEAN. Conclusion Thailand has a dynamic vaccine R&D environment in which strong partnerships exist between public and private sectors and the vaccine manufacturing industry plays an active role. Collaborative relationships with external strategic partners have also been nurtured to facilitate technology transfer, coordinated by the National Vaccine Institute (NVI). The country has an ambitious agenda for development and manufacture of new generation vaccines focusing on future pandemics and neglected tropical diseases, but in order to meet it, significant investment is required to build human resource capacity in full-spectrum of vaccine development and manufacturing, and to maintain the NRA’s Maturity Level 3 status. Thailand’s NVI has a strong track record of bringing together key stakeholders domestically and regionally and is well-positioned to use its experience to spearhead initiatives with nearer-term outputs. For example, at the national level, NVI could foster consultative arrangements between the domestic vaccine industry, university-based scientists with vaccine R&D experience, and NRA program managers through Expressions of Interest (EOI), Requests for Proposal (RFP), and other mechanisms to address current vaccine access challenges for NIP and pandemic response in line with the National Vaccine Security strategy. These consultations would contribute to fine tuning cost/benefit production versus imports of vaccines and provide the rationale for accelerating R&D and production of selected vaccines. At the regional level, the NVI has facilitated the AVSSR through undertaking the ASEAN vaccine baseline survey in 2017 and developing the AVSSR regional strategic and operational plan. Thailand through NVI could take the lead regionally on encouraging enhanced collaboration among ASEAN nations to promote vaccine R&D and strengthen AEFI causality assessments. It could also work with international partners like WHO Global Advisory Committee on Vaccine Safety to build the vaccine safety profile of locally manufactured and other vaccines used in NIP and pandemic response, thus helping to build public confidence. There is also a great need to further discuss with ASEAN partners post-pandemic strategies for COVID-19 and seasonal influenza vaccine programs, and to initiate a shared procurement mechanism through which countries jointly negotiate prices and select suppliers to use during national procurement efforts. The pandemic vaccine response is replete with lessons learned that are just beginning to be captured. During COVID-19 response, manufacturers gained invaluable knowledge about pandemic vaccine production cycles and good storage practices, among other insights, which should be used to inform future preparedness strategies for pandemic vaccine deployment. 28 References ASEAN Secretariat. 2019. Report of the ASEAN Baseline Survey (AVBS) 2017: Current Situation and Gap Analysis. Jakarta: ASEAN Secretariat. Available online at https://asean.org/wp- content/uploads/2021/10/Agd-6.3.a.i_AVBS_Final_23082019.pdf. Bell JA and Nuzzo JB. 2021. Global Health Security Index: Advancing Collective Action and Accountability Amid Global Crisis, 2021. Available online at www.GHSIndex.org Institute for Health Metrics and Evaluation (IHME). (n.d.) Thailand country profile page. Retrieved September 1, 2022, from https://www.healthdata.org/thailand. International Labour Organization. 2019. Triangle in ASEAN Quarterly Briefing Note, Thailand, July-September, 2019. Available online at https://www.ilo.org/wcmsp5/groups/public/--- asia/---ro-bangkok/documents/genericdocument/wcms_614383.pdf Jiraphongsa C et al. 2005. Epidemiology and Burden of Rotavirus Diarrhea in Thailand: Results of Sentinel Surveillance. The Journal of Infectious Diseases 2005; 192:S87–93. Lydon et al. 2017. Vaccine stockouts around the world: Are essential vaccines always available when needed? Vaccine 35 (2017): 2121–2126. MacDonald et al. 2020. Lessons on causality assessment and communications from the 2019 South-East Asia Regional (SEAR) workshop on inter-country expert review of selected Adverse Events Following Immunization (AEFI) cases. Vaccine 2020 Jul 6; 38(32):4924-4932. Our World in Data. (n.d.) Causes of death in children under 5, Thailand, 2019. Retrieved online from https://ourworldindata.org/grapher/causes-of-death-in-children-under- 5?country=~THA PATH, World Health Organization, Health Systems Research Institute, Mahidol University. 2011. An Assessment of Vaccine Supply Chain and Logistics Systems in Thailand. Seattle: PATH. Available online at https://www.path.org/resources/an-assessment-of-vaccine-supply- chain-and-logistics-systems-in-thailand/ Pinna et al. 2020. Along Thailand-Myanmar Border: Compliance with Global Vaccine Action Plan (2011-2020). Vaccines 2020, 8(1), 68. Available online at https://doi.org/10.3390/vaccines8010068. Rattanavipapong et al. 2020. Comparing 3 Approaches for Making Vaccine Adoption Decisions in Thailand. International Journal of Health Policy Management, 2020 Oct; 9(10): 439-447. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719214/. Sutra et al. 2012. Burden of Acute, Persistent and Chronic Diarrhea, Thailand, 2010. J Med Assoc Thai 2012; 95 (Suppl. 7): S97-S107. Thailand Food and Drug Administration, Medicines Regulation Division. (n.d.) Vaccines. Retrieved online from https://www.fda.moph.go.th/sites/drug/SitePages/Vaccine.aspx 29 Thailand Ministry of Public Health, Department of Disease Control. 2019. Annual Epidemiological Surveillance Report 2019. Retrieved online from https://apps- doe.moph.go.th/boeeng/download/MIX_AESR_2562.pdf. UNICEF. 2021. Children in far south of Thailand lag behind in nutrition, immunization and learning, NSO and UNICEF survey finds. Retrieved online from https://www.unicef.org/thailand/press-releases/children-far-south-thailand-lag-behind- nutrition-immunization-and-learning-nso-and. World Bank Open Data. Indicator: GDP growth (annual %) – East Asia and Pacific. Available online at https://data.worldbank.org/indicator/NY.GDP.MKTP.KD.ZG?locations=4E World Bank Open Data. Population Indicators, Thailand. Retrieved online 27 April 2022. https://data.worldbank.org WHO. (n.d.-a). Immunization Expenditure, Thailand. Retrieved online from https://immunizationdata.who.int/pages/indicators-by- category/finance.html?ISO_3_CODE=THA&YEAR= WHO. (n.d.-b). New and underutilized vaccine introduction, Thailand. Retrieved online from https://immunizationdata.who.int/pages/indicators-by- category/new_and_under_utilized_vaccines_introduction.html?ISO_3_CODE=THA&YEAR= WHO. (n.d.-c). Vaccine Introduction in Thailand. Retrieved online from https://immunizationdata.who.int/pages/vaccine-intro-by-country/tha.html?YEAR WHO. 2013. Global Vaccine Action Plan, 2011-2020. Available online at: https://www.who.int/publications/i/item/global-vaccine-action-plan-2011-2020 WHO. 2021. Thailand’s vaccine regulatory system reaches WHO’s second highest level. Retrieved online from https://www.who.int/thailand/news/detail/06-10-2021-thailand-s- vaccine-regulatory-system-reaches-who-s-second-highest-level WHO, Regional Office for South East Asia. 2020. Factsheet 2020 Thailand Expanded Program on Immunization. Available online at: www.who.int/southeastasia/health- topics/immunization. WHO Thailand. 2022. WHO Thailand Weekly Situation Update No. 234. https://cdn.who.int/media/docs/default-source/searo/thailand/2022_05_04_tha-sitrep-234- covid-19.pdf?sfvrsn=30d828f0_1 30 Annex 1: Thailand NIP performance indicators, 2017-2021 31 Year NIP performance indicators Vaccine Financing and Procurement Policy Vaccine Coverage Vax shortage % of vaccine self-financed (Gov Procurement policy WUENIC expenditure on vaccine) THAILAND 2017 BCG 99% No 100% (41,824,976 THB) 100% locally manufactured QSMI HepB birth dose 99% No Imported with NHSO responsible for procurement and GPO for DTP contain. Vax. 1st ds 99% No domestic distribution DTP contain. Vax. 3rd ds 99% No Hib 3rd ds N/A N/A HepB 3rd ds 99% No OPV 3rd ds 99% No IPV contain. Vax. 1st ds 93% No PCV last ds N/A N/A Rota last ds N/A N/A Meas. Contain. Vax 1st ds 99% No Rubella/containing vaccine 1st ds 99% No Meas. Contain. Vax 2nd ds 95% No Rotavirus 1st ds N/A N/A Rotavirus last ds N/A N/A HPV 1st ds by 15 yrs fem. N/A N/A HPV last ds by 15 yrs fem N/A N/A Influenza child age N/A N/A 32 Year NIP performance indicators Vaccine Financing and Procurement Policy Vaccine Coverage Vax shortage % of vaccine self-financed (Gov Procurement policy WUENIC expenditure on vaccine) Influenza elderly N/A N/A 2018 BCG 99% No 100% (1,830,985,770 THB) 100% locally manufactured QSMI HepB birth dose 99% No Imported with NHSO responsible for procurement and GPO for DTP contain. Vax. 1st ds 99% No domestic distribution DTP contain. Vax. 3rd ds 97% No Hib 3rd ds N/A No HepB 3rd ds 99% No OPV 3rd ds 99% No IPV contain. Vax. 1st ds 95% No PCV last ds N/A N/A Rota last ds N/A N/A Meas. Contain. Vax 1st ds 96% No Rubella/containing vaccine 1st ds 96% No Meas. Contain. Vax 2nd ds 87% No Rotavirus 1st ds N/A No Rotavirus last ds N/A No HPV 1st ds by 15 yrs fem. N/A Yes HPV last ds by 15 yrs fem N/A Influenza child age 4% No Mix procurement policy w/ locally produced GPO and imported from Influenza elderly 21% No EU and or USA 33 Year NIP performance indicators Vaccine Financing and Procurement Policy Vaccine Coverage Vax shortage % of vaccine self-financed (Gov Procurement policy WUENIC expenditure on vaccine) 2019 BCG 99% No N/A 100% locally manufactured QSMI HepB birth dose 99% No Imported with NHSO responsible for procurement and GPO for DTP contain. Vax. 1st ds 99% No domestic distribution DTP contain. Vax. 3rd ds 97% No Hib 3rd ds N/A No HepB 3rd ds 97% No OPV 3rd ds 97% No IPV contain. Vax. 1st ds 97% No PCV last ds N/A N/A Rota last ds N/A N/A Meas. Contain. Vax 1st ds 96% No Rubella/containing vaccine 1st ds 96% No Meas. Contain. Vax 2nd ds 87% Yes Rotavirus 1st ds N/A N/A Rotavirus last ds N/A N/A HPV 1st ds by 15 yrs fem. N/A Yes HPV last ds by 15 yrs fem N/A Influenza child age 23% no Mix procurement policy with locally produced GPO and Influenza elderly 92% imported from EU and or USA 2020 BCG 99% No N/A 100% locally manufactured QSMI 34 Year NIP performance indicators Vaccine Financing and Procurement Policy Vaccine Coverage Vax shortage % of vaccine self-financed (Gov Procurement policy WUENIC expenditure on vaccine) HepB birth dose 99% No Imported with NHSO responsible for procurement and GPO for DTP contain. Vax. 1st ds 99% No domestic distribution DTP contain. Vax. 3rd ds 97% No Hib 3rd ds N/A No HepB 3rd ds 97% No OPV 3rd ds 97% No IPV contain. Vax. 1st ds 97% No PCV last ds N/A N/A Rota last ds N/A N/A Meas. Contain. Vax 1st ds 96% No Rubella/containing vaccine 1st ds 96% Meas. Contain. Vax 2nd ds 87% No Rotavirus 1st ds N/A N/A Rotavirus last ds N/A N/A HPV 1st ds by 15 yrs fem. N/A N/A HPV last ds by 15 yrs fem N/A N/A Influenza child age 23.5% No Mix procurement policy with locally produced GPO and Influenza elderly 110% No imported from EU and or USA Imported with NHSO responsible for procurement and GPO for 2021 BCG 99% No N/A 35 Year NIP performance indicators Vaccine Financing and Procurement Policy Vaccine Coverage Vax shortage % of vaccine self-financed (Gov Procurement policy WUENIC expenditure on vaccine) HepB birth dose 99% No domestic distribution DTP contain. Vax. 1st ds 99% No DTP contain. Vax. 3rd ds 97% No Hib 3rd ds N/A No HepB 3rd ds 97% No OPV 3rd ds 97% No IPV contain. Vax. 1st ds 97% No PCV last ds N/A N/A Rota last ds N/A N/A Meas. Contain. Vax 1st ds 96% No Rubella/containing vaccine 1st ds 96% No Meas. Contain. Vax 2nd ds 87% No Rotavirus 1st ds 71% No Rotavirus last ds 71% No HPV 1st ds by 15 yrs fem 80% No HPV last ds by 15 yrs fem N/A N/A Influenza child age N/A N/A Mix procurement policy with locally produced GPO and Influenza elderly N/A N/A imported from EU and or USA 36 37