Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines

Abstract

Dengue is the most common arboviral disease caused by one of four distinct but closely related dengue viruses (DENV) and places significant economic and public health burdens in the endemic areas. A dengue vaccine will be important in advancing disease control. However, the effort has been challenged by the requirement to induce effective protection against all four DENV serotypes and the potential adverse effect due to the phenomenon that partial immunity to DENV may worsen the symptoms upon subsequent heterotypic infection. Currently, the most advanced dengue vaccines are all tetravalent and based on recombinant live attenuated viruses. CYD-TDV, developed by Sanofi Pasteur, has been approved but is limited for use in individuals with prior dengue infection. Two other tetravalent live attenuated vaccine candidates: TAK-003 by Takeda and TV003 by National Institute of Allergy and Infectious Diseases, have completed phase 3 and phase 2 clinical trials, respectively. This review focuses on the designs and evaluation of TAK-003 and TV003 vaccine candidates in humans in comparison to the licensed CYD-TDV vaccine. We highlight specific lessons from existing studies and challenges that must be overcome in order to develop a dengue vaccine that confers effective and balanced protection against all four DENV serotypes but with minimal adverse effects.

Progress and Development of Three Types of Live Attenuated Vaccines for Dengue Fever

“…Following injection, the researchers observed no significant adverse differences between DENV-infected and uninfected individuals. However, seroconversion rates were significantly higher in the uninfected compared to those infected with DENV [28]. This could also demonstrate that a single dose of TV003 is sufficient to induce protective immunity against dengue.…”

“…TV003 elicited higher DENV-3 viral loads, DENV-2, DENV-3 and DENV-4 antibodies, and a higher frequency of tetravalent responses in subjects previously infected with flavivirus [28]. Using the Dengue Human Challenge Model (DHCM), researchers determined that TV003 provided 100% protection against DENV-2 infection in a randomized, double-blind, placebo-controlled trial [28]. However, the model used in this study cannot be used to assess the efficacy and safety of vaccination in clinical trials.…”

“…Furthermore, there was no significant difference between TV003 and TV005 in terms of the occurrence of adverse events. TV003 elicited higher DENV-3 viral loads, DENV-2, DENV-3 and DENV-4 antibodies, and a higher frequency of tetravalent responses in subjects previously infected with flavivirus [28]. Using the Dengue Human Challenge Model (DHCM), researchers determined that TV003 provided 100% protection against DENV-2 infection in a randomized, double-blind, placebo-controlled trial [28].…”

Desafios Para O Desenvolvimento De Vacinas Contra a Dengue Na Atualidade: Uma Problemática Em Saúde Pública

“…Nessa perspectiva, os elevados índices de infecção global, as dificuldades no controle de vetores e a eficácia limitada da única vacina licenciada contra a dengue, a francesa Dengvaxia (CYD-TDV, Sanofi Pasteur), enfatizam a urgência de imunizantes adicionais eficazes (LIN et al, 2020). Em contrapartida, a complexidade das respostas imunes contra o vírus, as limitações de modelos humanos ou animais para testes e as estratégias de ensaio subótimas para a detecção da imunidade após infecção ou vacinação são alguns entraves a serem superados (HOU;YE;CHEN, 2022).…”

“…Outros entraves podem ser descritos: criação de teste confiável para determinar imunogenicidade de vacinas candidatas, consideração de que os mecanismos imunológicos são mutáveis ao longo do tempo após infecção natural ou vacinação e necessidade de vigilância pós vacinação(HOU;YE;CHEN, 2022). fundamental alinhar essas condições aos diferentes desenhos de vacinas contra a dengue no processo de produção e implementação de novos imunizantes.4 CONCLUSÃO À luz do exposto, apesar de bem estabelecidas as bases da Imunologia e da Virologia, há entraves importantes para o desenvolvimento de vacinas mais completas, eficazes e seguras contra a dengue.…”