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Science Corner

DENGUE: PREVENTABLE AND TREATABLE SOON?

By: Herman Kosasih

Historically, dengue-like illnesses occurred almost simultaneously in Asia, Africa and North America around 200 years ago. The term ‘dengue’ originated from the Swahili phrase Ka-dinga pepo, which translates to “cramp-like seizure.” It wasn’t until 1943 that Ren Kimura and Susumu Hotta successfully isolated the virus (DENV) during an epidemic in Nagasaki. Subsequently, the epidemiology of dengue underwent significant changes.

Since the first dengue report in Indonesia in 1968, the disease’s epidemiology experienced dynamic transformations. The number of provinces reporting dengue cases increased from two to encompassing all provinces. Incidence rates gradually climbed from 1 per 100,000 people in 1968 to 40 per 100,000 people in 2020, with several peaks reaching 70-100 per 100,000 people every 6-8 years. However, the case fatality rate (CFR) dropped from 40% in 1968 to 0.7% in 2020.

Although the CFR has significantly decreased, den-gue remains endemic in over 125 countries, predominantly in tropical and subtropical regions, causing an estimated 390 million infections annually worldwide, with 96 million being clinically apparent. The WHO’s goal, outlined in the 2021-2030 Global Strategy for Dengue Prevention and Control, is to reduce the CFR to 0% and the incidence rate by 25%. Considering the substantial advancements in dengue prevention and treatment, which we will briefly discuss here, there is hope that after 80 years since its discovery, dengue will soon become a preventable and treatable disease.

What is Dengue?

Dengue is a febrile illness caused by the dengue virus, a member of the flavivirus genus. It is transmitted by mosquitoes, specifically Aedes aegypti or Aedes albopictus. There are four serotypes of the DENV: DENV-1, DENV-2, DENV-3, and DENV-4. These serotypes interact differently with antibodies, leading to their classification as distinct types. The DENV is a positive-sense RNA virus, meaning it can be directly translated into proteins. The genome encodes ten genes (Figure 1) that is translat-ed into ten proteins.

The diameter of the DENV is 50 nm. The core of the virus contains the nucleocapsid, which consists of the viral genome and the C proteins. Surrounding the nucleocapsid are the viral envelope and membrane proteins. The seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) play essential roles in viral replication and assembly.

Infection with one serotype of the DENV provides long-term protection against reinfection with the same serotype but only transient cross-protection against other serotypes. Therefore, people living in dengue-hyperendemic areas where multiple serotypes circulate are at risk of experiencing multiple infections.

Clinical Classification and disease severity

DENV infection can range from asymptomatic or mild febrile illness to severe disease (life-threatening shock syndrome). The clinical classification of symptomatic DENV infection has undergone revisions. Initially, it was classified into den-gue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) (WHO, 1997). However, this classification has been criticized for its emphasis not on the most crucial feature of severe dengue, which is plasma leakage leading to shock. A re-evaluation in 2009 introduced a classification based on the presence of warning signs and severe dengue. The focus of this scheme is to recognize the warning signs early for management decisions. It was also criticized because the criteria for severe dengue was not clear. The concept of expanded dengue syndrome that includes patients with severe organ involvement (liver, kidney, brain, or heart) but without evidence of plasma leakage was then proposed by the WHO South-East Asia Regional Office in 2011. As there are several classifications, institutions/countries may use different classification.

Several factors can influence disease severity in dengue infection. These include the specific serotype or genotype of the virus, secondary infection with a different serotype, age of infants, nutritional status, and genetic factors such as race, specific HLA genes, blood group, and various gene polymorphisms. However, conflicting findings exist regarding some of these factors.

Progress in Treatment

Current treatment for DENV is supportive, managing fever, bleeding, plasma leakage, and shock. While no direct antiviral therapy exists, successful approaches have led to a decrease in mortality rates. However, to further reduce incidence and CFR, effective antiviral drugs that can be used for prophylaxis and for reducing the viral load, duration of viremia and severity are needed. Previous clinical trials with drugs like chloroquine, lovastatin, balapiravir, and celgosivir did not yield significant results. A promising molecule inhibitor, JNJ-1802, blocks the formation of the viral replication by inhibiting complex formation between NS3 and NS4B, has shown positive results in a Phase 2a DENV-3 human challenge study. Participants receiving JNJ-1802 had a lower proportion of detectable DENV-3 RNA, shorter duration of symptoms, and reduced viral load compared to the control group. Larger studies involving all DENV serotypes will be conducted to further evaluate its effectiveness.

Progress in prevention

Wolbachia-Infected Mosquito Deployments for the Control of Dengue

Wolbachia-infected mosquito deployments have shown promising results as a novel strategy for dengue control. This approach involves releasing A. aegypti mosquitoes infected with Wolbachia, a bacterium that makes the mosquitoes less susceptible to DENV infection. A trial conducted in Yogyakarta, Indonesia, demonstrated the effectiveness of this method. Over a two-year trial period, the intervention clusters had a lower incidence of symptomatic dengue compared to the control clusters. The efficacy of Wolbachia in protecting against DENV infection was 77.1% (95% CI 65.3-84.9) and was similar across all four DENV serotypes. Furthermore, the efficacy in preventing hospitalization due to dengue was 86.2% (95% CI 66.2-94.3). Following the successful trial, the deployment was expanded to neighboring districts (Bantul and Sleman). The MoH in Indonesia has issued a decree (No 1341/2022) to conduct a pilot project for dengue control using Wolbachia-infected mosquitoes in five cities: West Jakarta, Bandung, Semarang, Bon-tang, and Kupang.

Progress in vaccine development:

An effective dengue vaccine should provide long-lasting protection against all four DENV types (tetravalent immunity) due to the severe disease potential and short-lived cross-protection between serotypes.

Vaccine development efforts began in the 1920s using methods such as attenuation with ox-bile and chemical treatments. Advances in tissue culture and recombinant DNA technology have greatly contributed to vaccine development. Currently, several candidate vaccines are in clinical trials. TDENV PIV is a tetravalent purified inactivated vac-cine undergoing phase I trials. V180 is a recombinant subunit vaccine which has completed phase I trials with favorable tolerability. A monovalent DNA plasmid vaccine showed moderate immunogenicity in early studies. The furthest along in development are three live attenuated vaccines, CYD-TDV (Dengvaxia), TAK-003 (Takeda), and TV-003 (Butantan), using mutation and/or chimeric approaches. The structure of these chimeric vaccines is illustrated in Figure 3 below.

CYD-TDV is a yellow fever 17D-dengue chimeric vaccine comprising four strains where the prM and E proteins from each DENV type replace the equivalent proteins in a yellow fever 17D backbone virus. The vaccine demonstrated an efficacy of 57% to 61% against virologically confirmed dengue of any severity caused by any DENV serotype and 80% to 95% efficacy against severe dengue or hospitalization. Efficacy varied by serotype, with rates of 75% for DENV-3 and DENV-4, 50% for DENV-1, and 35% to 42% for DENV-2. However, further analysis revealed that the vaccine increased the risk of severe illness and hospitalization in individuals without previous dengue exposure. Therefore, the WHO recommended the CYD-TDV (Dengaxia) vaccine for individuals aged 9 to 45 years with confirmed prior dengue infection. The mechanisms underlying the vaccine’s efficacy in seropositive individuals and the increased risk in seronegative individuals are still uncertain due to limited monitoring and analysis of immune profiles in the vaccinated population.

TAK-003 is a tetravalent vaccine based on an attenuated laboratory-derived DENV-2 virus, which provides the genetic backbone for all four of the viruses in the vaccine The other three virus strains are chimeras generated by replacing the preM and E genes of TDV-2 with those from wild-type DENV-1, DENV-3, and DENV-4 strains.

A phase 3 clinical trial involving >20,000 children aged 4 to 16 years in Asia and Latin America showed that after 18 months follow-up, the vaccine had an overall efficacy of 73.3% and a 90.4% efficacy against hospitalized dengue cases. The vaccine demonstrated higher efficacy in individuals who were seropositive at baseline compared to seronegative individuals (76.1% versus 66.2%). Efficacy by serotype was 69.8% DENV-1, 95.1% DENV-2, and 48.9% DENV-3. The efficacy against DENV-1 and DENV-2 was similar in participants with baseline seronegative or positive, but for DENV-3, efficacy was only among seropositive individuals (61.8%). DENV-4 efficacy was difficult to measure due to insufficient data. The incidence of serious adverse events (SAEs) was similar in the vaccine and placebo groups. TAK-003 appears to be effective in both seropositive and seronegative individuals and has the potential to reduce the burden of severe dengue. However, further evaluation of efficacy and safety, particularly for DENV-3 and DENV-4, is needed.

TV-003 is a live attenuated tetravalent dengue vaccine composed of three attenuated DENV strains with deletions in the 3′ untranslated region and a fourth component that is a chimeric virus with prM and E proteins from DENV-2 replacing those of DENV-4 in the DENV4 30 background. The vaccine was developed by the US-NIAID and licensed to Instituto Butantan in 2009.

A phase 3 study of this single-dose vaccine was initiated in Brazil in 2016, enrolling 16,235 participants aged 2-59 years. Over a two-year follow-up period, the vaccine demonstrated an overall efficacy of 79.6% in preventing dengue illness, with no cases of severe dengue reported. Among seropositive participants at baseline, the efficacy was 89.2%, while in seronegative participants, it was 73.5%. Efficacy against DENV-1 and DENV-2 was 89.5% and 69.6%, respectively, but no data on efficacy against DENV-3 and DENV-4 were available due to limited circulation in Brazil during the study period. However, a previous phase 2 study indicated that 80% of volunteers produced antibodies against all four serotypes.

SAEs related to the vaccine occurred in less than 0.1% of participants within 21 days after vaccination. The frequency of AEs was similar across age groups and among participants previously exposed to dengue or not. Instituto Butantan signed a partnership with MSD in 2018 for further development and MSD plans to conduct a large phase 3 trial in Asia.

The Indonesian Food and Drug Authority (BPOM) approved Dengvaxia in August 2016 and Qdenga in August 2022. Although the Indonesian Pediatric and Internal Medicine Societies recommended it for individuals aged 6 to 45, the government has not included it in the routine national vaccination program. They are waiting for the Indonesia Technical Advisory Group of Immunization (ITAGI) recommendation.

Summary

Progress has been made in understanding and addressing DENV due to its widespread facilitated by human behaviors and global climate change. However, efforts in understanding DENV’s pathogenesis, disease management, prevention, and treatment have resulted in a reduction in global case fatality rates. Achieving the WHO’s 2030 target of reducing the burden and incidence of dengue by 25% compared to 2010/2020 and eliminating deaths is becoming more feasible. Advancements in mosquito control, vaccine development, and antiviral discovery hold promise in making dengue preventable and treatable.

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