What is dengue fever?

Dengue virus (DENV) is a single positive-strand RNA virus belonging to Flaviviridae family. The structure of the dengue virus is roughly spherical, with a diameter of approximately 45-55 nm. There are four circulating dengue virus (DENV) serotypes, namely DENV-1, DENV-2, DENV-3 and DENV-4.

The four DENV serotypes cause two clinical types of Dengue in humans: dengue fever and severe dengue, through mosquito bites and are endemic worldwide, especially in Asia and Latin America, with 3.9 billion people at risk for infection and up to 400 million infections each year, most often affecting children. Recovery from infection with one serotype of the dengue virus gives life-long homologous immunity to that serotype but only temporary and partial immunity to the other serotypes. Pre-existing antibodies can aggravate disease during subsequent infection with a different serotype or vaccination via the mechanism of antibody-dependent enhancement (ADE) of DENV replication.

                Figure 1: Schematic representation of ADE effect in DENV replication (Image from Reference 5)

Dengue fever has spread rapidly around the world in recent years. It is currently endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific region, with Asia accounting for about 70% of the global disease burden. The global incidence of dengue has grown dramatically, with the number of dengue cases reported to the World Health Organization has increased more than sevenfold over the past 20 years. It is estimated that 100 million to 400 million DENV infections occur each year causing approximately half of the world's population is at risk.

The spread of dengue virus has become a serious public health problem and a major disease burden in tropical and subtropical regions. Statistical studies have shown that the elderly, infants and pregnant women, accompanied by diabetes, hypertension, coronary heart disease, peptic ulcer, asthma, chronic kidney disease and chronic liver disease and other underlying diseases, accompanied by immunodeficiency, are at high risk of severe dengue fever. In 2019, the World Health Organization has identified dengue fever as one of the top ten global health threats.

Sanofi and Takeda have entered vaccine research and development, and the "optimal solution" is still being explored…

Dengvaxia®(CYD-TDV) developed by Sanofi Pasteur, obtained its first license in Mexico, the Philippines and Brazil in December 2015 for use in individuals aged 9 to 45 to prevent disease caused by four serotypes of dengue virus. The product is the world's first approved dengue vaccine and has now been approved by regulators in 19 countries.

The vaccine is a live attenuated vaccine, which combines the non-structural genes of yellow fever virus with the structural genes of four serotypes of dengue virus by recombinant technology. Full vaccination requires three doses with an interval of six months, and a time span of one year.

In November 2017, Sanofi Pasteur released new follow-up data from the Dengvaxia clinical trial showing that trial participants who were considered seronegative at the time of their first vaccination had a higher risk of severe dengue infection and hospitalization for dengue infection than unvaccinated participants. Dengvaxia is currently only available to people with at least 1 previous documented dengue virus infection due to the substantially increased risk of severe dengue fever in seronegative people following vaccination. The follow-up of clinical trials for this vaccine is still in progress.

Figure 2: Dengvaxia (Image from Reference 6)

Qdenga ® (TAK-003) developed by Takada, was approved and marketed in Indonesia in August 2022 for people aged 6 to 45 to avoid dengue infection of any serotype. The vaccine is an attenuated live vaccine, which combines the non-structural genes of serotype 2 with the structural genes of serotype 1, 3 and 4 by recombinant technology. Among them, the viral strain DENV-2 used as the backbone was originally derived from DENV-2 (16681) PDK53 developed by Mahidol. The vaccine requires two doses, administrated three months apart, and does not require pre-vaccination testing.

The approval of Qdenga is based on the data from the ongoing clinical phase 3 TIDES trial, that is the patient outcomes at 3 years post-vaccination. Data analysis showed that Qdenga continued to protect vaccinees from dengue illness and hospitalization for 3 years after vaccination, regardless of whether participants had previously been infected with dengue fever. However, it is worth noting that in seronegative people, the protection rate of Qdenga against DENV-3 and DENV-4 is negative, which means that Qdenga may also face the same challenge of ADE as Dengvaxia. Therefore, clinical data with longer follow-up are needed to support limited use in some populations.

Figure 3: Dengue Vaccine TKA-003 (Image from Reference 7)

Prophylactic + therapeutic: natural fully human monoclonal antibody drug

In 2018, China State authority promulgated “Guidelines for Clinical Diagnosis and Treatment of Dengue Fever in China, in which it clearly pointed out that “To translate human monoclonal neutralizing antibodies for clinical use” is one of the issues to be resolved at present.

In principle, human monoclonal neutralizing antibodies have great potential to avoid many problems in vaccine development. Trinomab has developed a strategy to develop a broadly neutralizing monoclonal antibody or a cocktail of monoclonal antibodies that can not only be effective in neutralizing four serotypes of DENV, but also can avoid the occurrence of ADE. Thus, human monoclonal neutralizing antibody drugs can be developed as therapeutic measures for prevention and treatment of Dengue infection for people who are not protected by vaccines.

Trinomab Uses Human Monoclonal Antibody Research and Development Platform to Study Dengue Monoclonal Antibody Drugs

In response to such clinical needs and industry challenge, Zhuhai Trinomab Biotech Co., Ltd. (Hereinafter referred to as Trinomab), a clinical stage biopharmaceutical company with a global expansion perspective, dedicates its effort to gnaw down this "hard bone".

Trinomab Biotech Co., Ltd. is mainly engaged in R&D of novel fully native human mAb drugs. The core technology of the company is known as the fourth-generation antibody technology HitmAb®, a proprietary technology platform featuring differentiated advantages and high efficiency for the discovery of fully native human mAbs as therapeutics against infectious diseases, autoimmune disorders, malignant tumors and other human diseases.

Trinomab plans to make full use of the advantages of HitmAb® platform to develop “efficient, safe and accessible” fully human anti-dengue virus neutralizing antibody drugs, and formally enter the field of dengue monoclonal antibodies. At present, Trinomab has reached a strategic cooperation agreement with The Eighth Affiliated Hospital of the Guangzhou Medical University and also formally launching the development of fully human anti-dengue neutralizing antibody related products.

Dr. HUAXIN LIAO, Chairman and CTO of Trinomab, said, “There is still an unmet clinical need for the prevention and treatment of dengue fever. Natural human monoclonal antibody drug developed by Trinomab is expected to overcome ADE problem of Dengue vaccines. We are expected to benefit patients and solve social and public health problems through natural human monoclonal antibodies against dengue fever with broad spectrum, high specificity and affinity.”

References:

1. World health organization. Dengue and severe dengue. 2022.

2. Sri Rezeki Hadinegoro, … CYD-TDV Dengue Vaccine Working Group. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. NEJM, 2015.

3. Luis Rivera, … Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003). Clin Infect Dis, 2022.

4. Zhang Fuchun, He Jianfeng, et al. Guidelines for the diagnosis and treatment of dengue in China. Chinese Journal of Internal Medicine, 2018.57(9),642-648.

5. Whitehead SS, etal. Prospects for a dengue virus vaccine. Nat Rev Microbiol. 2007 Jul;5(7):518-28.

6. Sanofi Pasteur. Meeting Non-FDA Briefing Document- Dengvaxia- Tetravalent, Live-Attenuated Viral Vaccine against Dengue Serotypes 1, 2, 3 and 4. Vaccines and Related Biological Products Advisory Committee, March 6 - 7, 2019.

7. Adam T Waickman, etal. Assessing the Diversity and Stability of Cellular Immunity Generated in Response to the Candidate Live-Attenuated Dengue Virus Vaccine TAK-003. Front Immunol. 2019 Jul 31;10:1778.