Severe Dengue

Pictured: Takeda office in Massachusetts/iStock, hapabapa Takeda has voluntarily withdrawn the Biologics License Application for its dengue vaccine candidate TAK-003 following discussions with the FDA regarding additional data collection, the Japanese pharma company announced Tuesday. According to Takeda, it will not be able to address the regulator’s concerns within the current BLA review cycle. The company is currently assessing its future options and plans for TAK-003, as well as evaluating the requirements for a potential BLA resubmission in the U.S., a spokesperson told Fierce Pharma. The FDA accepted Takeda’s BLA for TAK-003 in November 2022 and put the application under Priority Review, which typically results in a decision within six months versus the standard 10-month review period. “We will continue to progress regulatory reviews and provide access for people living in and traveling to dengue-endemic areas while we work to determine next steps in the U.S.,” Gary Dubin, president of Takeda’s vaccines business unit, said in a statement. TAK-003 is a tetravalent live-attenuated vaccine candidate that can induce immunity for all four major dengue serotypes. In a large mid-stage trial, Takeda demonstrated that immunization with TAK-003 led to high antibody titers in children and teens, regardless if they were seropositive or seronegative at baseline. The immune response persisted for up to 48 months post-dose. Takeda followed up the Phase II data with the pivotal Phase III TIDES trial, which met its primary endpoint of overall vaccine efficacy. TIDES enrolled nearly 21,000 participants across several dengue-endemic areas in Latin America and Asia, who were enrolled at a 2:1 ratio to receive either TAK-003 or a placebo. The study’s primary endpoint is vaccine efficacy and safety calculated through 12 months after the second dose. TAK-003 had a vaccine efficacy of 80.2% against virologically confirmed dengue in the per-protocol analysis and a 95.4% efficacy rate against dengue leading to hospitalization. At the 17-month follow-up, TAK-003 had an efficacy rate of 90.4% against hospitalized dengue and 85.9% against dengue hemorrhagic fever. In a statement to Fierce Pharma, the Takeda spokesperson said that the FDA had previously reviewed and approved the trial design for TIDES, but during discussions with the company asked for more data that were beyond the scope of the study. TIDES is designed in accordance with “World Health Organization (WHO) guidance for a second-generation dengue vaccine, and it considered the need to achieve high levels of subject retention and protocol compliance in endemic regions,” Takeda said in a statement Tuesday. TAK-003 is approved in Thailand, Indonesia, Argentina, Brazil, the UK and the EU, where it is marketed under the brand name Qdenga. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Dengue is a mosquito-borne viral infection listed by WHO as top 10 threat for global health The government grant is awarded by Flanders Innovation & Entrepreneurship (VLAIO) GHENT, Belgium, June 28, 2023 (GLOBE NEWSWIRE) -- ExeVir Bio, a biotech company developing robust single domain antibody therapies for broad protection against infectious diseases, today announced it has been awarded a two-year R&D grant of EUR 1.6 million by Flanders Innovation & Entrepreneurship (VLAIO) for pre-clinical research towards prophylactic and therapeutic solutions for dengue. According to the WHO, dengue is one of the most important vector-borne viral diseases globally that is transmitted from mosquitoes to humans [1]. It is mainly spread by Aedes aegypti mosquitoes and, to a lesser extent, Aedes albopictus mosquitoes. In 2019, Dengue was listed by the WHO as a top ten global health threat [2]. It is caused by any of four dengue virus serotypes, each of which can cause dengue fever, and, in some cases, it can lead to deadly complications such as dengue hemorrhagic fever or dengue shock syndrome. The incidence of dengue has grown dramatically around the world in recent decades, fueled by climate change and urbanization leading to recent transmission in parts of mainland US and Europe. Dengue is a leading cause of fever in travelers returning to the US and Europe from endemic countries, and the incidence of dengue among travelers is generally underestimated [3][4]. The medical need remains very high as there are no specific antiviral therapeutics available for the disease, limiting the treatment options to relieving symptoms and preventing complications. While the current vaccines are a big step forward in protecting people, they are not 100% effective and cannot be used for all. ExeVir is leveraging its unique, modular llama-derived antibody (VHH) technology platform to generate multi-specific antibodies for prophylaxis and treatment against infectious diseases, such as dengue. ExeVir’s technology will enable cross-reactivity against all four serotypes, have a dual mode of action, and be prophylactic and therapeutic with a sufficiently long treatment window. Dr. Torsten Mummenbrauer, CEO of ExeVir, said: “We’re delighted with this support from the Flemish Government as it will help us with our research into using our powerful VHH technology to combat global health threats from infectious diseases beyond COVID-19.” Alongside this dengue R&D project, ExeVir remains committed to its pioneering work in developing COVID-19 solutions for the millions of immunocompromised people who remain at high risk of severe morbidity or death from COVID-19 as they do not generate the same level of antibodies as immunocompetent people and could benefit from new multi-specific antibodies. References [1] https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue[2] https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019[3] https://www.cdc.gov/mmwr/volumes/69/wr/mm6906a1.htm[4] https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2022.27.2.2001937 About VLAIO Flanders Innovation & Entrepreneurship (Agentschap Innoveren & Ondernemen - VLAIO) is a Flemish Government agency that stimulates and supports R&D activities by innovative entrepreneurs and companies. More information: https://www.vlaio.be/en About ExeVir Bio ExeVir Bio is a clinical stage biotechnology company developing single-domain antibody based therapeutics focusing on infectious diseases. The company is harnessing its llama-derived antibody (VHH) technology platform to generate multi-specific antibodies for prophylaxis and treatment of infectious diseases. ExeVir’s initial focus is on prevention of COVID-19 for the immunocompromised patient population, including active chemotherapy, immunosuppressive drugs, solid organ transplantation, hematological malignancies, and AIDS patients, where there remains a high unmet need due to the limitations of current vaccines and therapeutic approaches. ExeVir’s COVID-19 pipeline includes XVR012, a combination product of XVR013 and XVR014, a bi-specific single-domain-based antibody construct which targets two conserved epitopes in the S1 subunit. Together they target several S1 and S2 epitopes in one product. XVR021 is targeting dengue and XVR031 is for pandemic preparedness. ExeVir has demonstrated it can progress its candidates from research to the clinic in under one year, execute on Phase 1a and Phase 1b studies, and conduct scale-up manufacturing. Leveraging this extensive experience, its XVR012 asset is being developed to start First in Human clinical trial in 2024. VHHs are smaller in size than whole antibodies, giving them access to hidden epitopes that traditional monoclonal antibodies are unable to reach with potential for deeper tissue penetration and simpler, more cost-effective manufacturing. VHHs can be linked together like building blocks into a single molecule to tackle different epitopes or act through different mechanisms of actions at once, to address the “arms race” in more complex and co-evolving infectious diseases. ExeVir is a spin out of VIB, the leading Belgium-based life sciences research institute. It is backed by strong investors including Fund+, which led the series A of EUR 42 million, together with an international consortium including UCB Ventures, SFPIM, V-Bio Ventures, VIB, Wallonie Entreprendre, Noshaq, Vives IUF and SambrInvest. ExeVir has received support from VLAIO, the SPW-Recherche and the European Union, leading to a total of EUR 18 million in non-dilutive funding. In 2023, ExeVir secured an option for EUR 25 million venture debt financing from the European Investment Bank. Find out more on ExeVir’s LinkedIn or on ExeVir’s website

For mosquito-borne diseases such as dengue fever, the abundance of the insects in places where people gather has long served as the main barometer for infection risk. A new study, however, suggests that the number of 'hidden' infections tied to a place, or cases of infected people who show no symptoms, is the key indicator for dengue risk. For mosquito-borne diseases such as dengue fever, the abundance of the insects in places where people gather has long served as the main barometer for infection risk. A new study, however, suggests that the number of "hidden" infections tied to a place, or cases of infected people who show no symptoms, is the key indicator for dengue risk. PNAS Nexus published the research led by scientists at Emory University, which drew from six years of data collected in the Amazonian city of Iquitos, Peru. The results found that 8% of human activity spaces in the study accounted for more than half of infections during a dengue outbreak. And these "super spreader" spaces were associated with a predominance of asymptomatic cases, or 74% of all infections. "Our findings show that any public health intervention that focuses on responding to symptomatic cases of dengue is going to fail to control an outbreak," says Gonzalo Vazquez-Prokopec, first author of the study and an Emory associate professor of environmental sciences. "Symptomatic cases represent only the tip of the iceberg." Co-authors of the research include Uriel Kitron, Emory professor of environmental sciences; Lance Waller, professor of biostatistics and bioinformatics at Emory's Rollins School of Public Health; and scientists from University of California-Davis, Tulane University, San Diego State University, University of Notre Dame, North Carolina State University and the U.S. Naval Medical Research Unit in Lima, Peru. Dengue fever is caused by a virus transmitted by the bite of a female Aedes aegypti mosquito. When the insect takes a blood meal from a human infected with dengue, the virus begins replicating within the mosquito. The virus may then spread to another person that the mosquito bites days later. This species of mosquito feeds exclusively on human blood, has a limited flight range of about 100 meters and thrives in sprawling urban areas of the tropics and subtropics. Its preferred habitat is inside homes, where it rests on the backs of furniture and at the bases of walls. Even the little bit of water held by an upturned bottle cap can serve as a nursery for its larvae. Vazquez-Prokopec is pioneering new mosquito-borne disease interventions, including tapping spatiotemporal data to track, predict and control outbreaks of pathogens transmitted by Aedes aegypti. The mosquito spreads the Zika, chikungunya and yellow fever viruses in addition to dengue. Around 500,000 cases of dengue occur annually around the world, according to the World Health Organization. The disease is caused by four distinct but closely related serotypes of the dengue virus. Infected people may have some immunity that prevents them from experiencing any noticeable effects while others may be severely debilitated for a week or more by symptoms such as extreme aches and pains, vomiting and rashes. Dengue hemorrhagic fever, the most severe form of the disease, causes an estimated 25,000 deaths annually worldwide. Iquitos, a city of nearly 500,000 people on the edge of the Amazon rainforest in Peru, is a dengue hotspot. For more than a decade, Vazquez-Prokopec and colleagues have mapped patterns of human mobility and dengue spread in Iquitos. "For diseases that are directly spread from one person to another, like COVID-19, what matters is who you were near," he says. "But in the case of dengue, what matters most is where you went." For the current study, the researchers wanted to determine the role of asymptomatic cases. People without symptoms may continue to go about their daily routines, unknowingly infecting any mosquitoes that bite them, which can then later spread the virus to more people. The study involved 4,600 people in two different neighborhoods. They were surveyed three times a week about their mobility. This data was used to map "activity spaces," such as residences, churches and schools. The study participants were also regularly surveilled to determine if they experienced any dengue symptoms. Blood analyses confirmed a total of 257 symptomatic cases of dengue during the six-year study period. That led to investigations of other participants whose activity spaces overlapped with the symptomatic cases. More than 2,000 of these location-based contacts were confirmed by blood tests to have dengue infections and more than half of them reported not having any noticeable symptoms. The results pinpointed the role of asymptomatic "super spreaders" in a dengue outbreak. A small number of the activity spaces, or 8%, were linked to more than half of the infections and most of the cases associated with those places were asymptomatic. The comprehensive, one-of-a-kind study broke down the virus infections by serotype and measured the amount of mosquitoes in the activity spaces. "We found that the mosquito numbers in a location alone is not a predictor of the risk of infection," Vazquez-Prokopec says. Instead, risk prediction for a location requires a cascade of circumstances: a high number of asymptomatic cases frequenting the location combined with high levels of mosquitos and high numbers of people who are not immune to the particular serotype of dengue virus that is circulating. "That's the complicated nature of this virus," Vazquez-Prokopec says. "We have underestimated the role of asymptomatic cases in spreading dengue." Generally, about 50 to 70% of dengue cases are asymptomatic, making detection by public health officials impractical, and the current study reveals that asymptomatic cases are tied to a third of transmission. "The lesson is that we need to focus on prevention of dengue outbreaks," Vazquez-Prokopec says. "The interventions for dengue for decades have been reactive. Simply reacting by closing a net around reported cases of the disease, however, will fail to contain an outbreak because that's missing the super spreaders." The study was funded by the U.S. National Institute of Allergy and Infectious Diseases, Bill and Melinda Gates Foundation, University of Notre Dame, Defense Threat Reduction Agency, Military Infectious Disease Research Program and the Armed Forces Health Surveillance Branch Global Emerging Infections Systems research program.