Journal of Vaccine Research 2024, Vol.14, No.4, 170-182 http://medscipublisher.com/index.php/jvr 171 development, the research synthesizes current knowledge, highlighting key challenges and exploring future directions in the field. By examining the latest clinical trial data, regulatory considerations, and implementation strategies, the study offers valuable insights for researchers, policymakers, and healthcare providers involved in dengue prevention and control. 2 Historical Context and Initial Developments 2.1 Early efforts in vaccine development The quest to develop a dengue vaccine has a long and challenging history, dating back to the mid-20th century when the global burden of dengue began to escalate. Initial attempts at vaccine development were primarily focused on inactivated virus vaccines, which were common at the time for other viral diseases (Pinheiro-Michelsen et al., 2020). However, these early efforts were hindered by the complexity of the dengue virus, which exists in four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). A vaccine needed to provide balanced immunity across all four serotypes to be effective, a requirement that was not met by the early inactivated vaccines. Additionally, there were concerns about the potential for antibody-dependent enhancement (ADE), where a vaccine might exacerbate the severity of dengue in individuals who were subsequently infected by a different serotype (Guy et al., 2016). Despite these challenges, the foundational work conducted during this period laid the groundwork for future vaccine candidates. Early research also highlighted the need for a live-attenuated vaccine that could mimic natural infection more closely and potentially provide long-lasting immunity without the risk of ADE (Guy et al., 2011). These insights were critical in shaping the direction of subsequent vaccine development efforts. 2.2 Development of live-attenuated vaccines Live-attenuated vaccines use a weakened form of the virus that is still capable of inducing an immune response but is not virulent enough to cause severe disease. This approach was believed to offer a more balanced immune response across the four dengue serotypes, a critical requirement for any effective dengue vaccine. One of the earliest and most notable efforts in this area was the development of the tetravalent dengue vaccine (CYD-TDV) by Sanofi Pasteur. This vaccine, based on a chimeric yellow fever vaccine backbone, was designed to include the envelope proteins from each of the four dengue serotypes, thus inducing immunity against all serotypes (Guy et al., 2011). Early trials of this vaccine showed promise, demonstrating good immunogenicity and a favorable safety profile in both flavivirus-naïve and seropositive individuals. Another significant effort was the development of TAK-003 by Takeda, which is a live-attenuated vaccine based on a DENV-2 backbone. This vaccine was designed to elicit a broad immune response by including genetic material from the other three serotypes. Early trials of TAK-003 demonstrated strong immunogenicity and an acceptable safety profile, providing hope that it could overcome some of the challenges faced by earlier candidates (de Silva and White, 2023). 2.3 Lessons from early clinical trials The early clinical trials of live-attenuated dengue vaccines provided invaluable lessons that have shaped the current landscape of dengue vaccine development. The most significant lesson was the recognition of the critical role that pre-existing immunity plays in vaccine efficacy and safety. For example, the CYD-TDV vaccine showed high efficacy in seropositive individuals but posed safety concerns for seronegative recipients, particularly children under 9 years old (Tricou et al., 2020). This outcome highlighted the need for careful consideration of the target population in vaccine deployment strategies (Hadinegoro et al., 2015). Furthermore, these trials underscored the importance of long-term follow-up to fully understand the safety and efficacy of dengue vaccines. The observation of increased hospitalization rates for severe dengue in certain populations several years after vaccination with CYD-TDV prompted a reevaluation of vaccine strategies and highlighted the need for post-licensure monitoring (Wichmann et al., 2017).
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