"Why Dengue Vaccine Prioritizes Previously Infected Individuals: Understanding Risks and Strategy"

CYD-TDV, the first licensed dengue vaccine, is a live recombinant tetravalent vaccine administered in three doses at six-month intervals. It's recommended for individuals aged 9–45 years or 9–60 years in dengue-endemic regions. However, only those individuals with previous exposure should receive the vaccine, therefore, pre-vaccination screening for previous dengue infection is essential (source: WHO).

One crucial consideration is that the dengue vaccine should not be given to children and adults, who have not had a previous dengue infection because it may increase the risk of severe dengue and hospitalization if infected afterwards.

For effective vaccination, children/adults, require three doses of the dengue vaccine. The second dose should be administered six months after the first, and the third dose six months after the second. This schedule ensures optimal protection against dengue. The dengue vaccine can be given alongside other vaccines, without interrupting other usual vaccination schedules. However, it is not recommended for travellers.

The dengue virus is a single-stranded positive sense RN virus, with four serotypes dengue virus 1 (DEN-1), dengue virus 2 (DEN-2), dengue virus 3 (DEN-3), and dengue virus 4 (DEN-4). Clinical manifestations of dengue can be categorized into two types: dengue fever, predominantly observed in adults during primary infection with the virus, and dengue hemorrhagic fever(DHF), which can potentially progress to dengue shock syndrome (DSS) if infected secondarily.

A secondary DENV infection results when a person previously infected with one serotype is exposed to a different serotype, and is the single most important risk factor for severe dengue disease.

Severe clinical manifestations of DHF/DSS are more prevalent in infants and there is an approximately fourfold higher mortality rate compared to other age groups. Infants born to dengue-immune mothers, if infected for the first time, may lead to severe DHF/DSS. The reason is, that the person infected with one serotype develops immunity against that specific serotype and if the same person is later infected with a different serotype of dengue virus, particularly within a relatively short time, the immune response can work against them leading to complications. Severe disease in dengue virus infections, known as severe dengue or dengue hemorrhagic fever (DHF), after secondary infection with Dengue, is associated with a phenomenon called "antibody-dependent enhancement" (ADE). 

Antibody-dependent enhancement (ADE) occurs when antibodies generated in response to the first infection recognize and bind to the new serotype of the dengue virus. Still, instead of neutralizing it, they facilitate its entry into cells via Fc receptors on immune cells. This can lead to increased viral replication and more severe disease outcomes.              

             

Severe dengue can manifest as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), characterized by severe bleeding, plasma leakage, and organ impairment. These complications are more likely to occur in secondary infections with a different dengue serotype due to ADE.

Due to all these reasons, developing a safe vaccine against dengue has always been challenging. 

As primary dengue virus infection does not give long-term protection to re-infection with the other three viral serotypes. This is against the general rule that a vaccine will need to induce protective responses against all four serotypes.

If the individual previously uninfected with the dengue virus gets vaccinated, the subsequent natural infection with Dengue may develop into complications, possibly by ADE, as they have been primed but not protected by the dengue vaccine.

Dengue Vaccine trials have shown better efficacy in individuals who had previously been infected with the dengue virus, implying that the vaccine can boost pre-existing dengue virus immunity but is poor at producing a protective immune response in uninfected but vaccinated individuals.

The challenge lies in developing vaccines that can stimulate the immune system to produce antibodies and cellular responses effective against each serotype without causing immune enhancement, leading to more severe disease upon subsequent infections. Achieving durable protection against all four serotypes is crucial for the success of dengue vaccines, particularly in regions where multiple serotypes co-circulate and contribute to the burden of dengue fever. Therefore, extensive research and testing are required to ensure that candidate vaccines meet these complex requirements before they can be widely implemented in endemic populations.