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As COVID-19 vaccines roll out across the world, researchers are hoping it could inject new momentum into the search for safe and effective vaccines against dengue fever. Could new vaccine technologies, including mRNA vaccine platforms, offer fresh hope?<\/p>\n
It\u2019s now five years since Sanofi Pasteur introduced the first dengue vaccine, Dengvaxia, to the world in 2015. In December 2018, the European Medicines Agency (EMA) approved Dengvaxia<\/a> to prevent dengue in people aged between nine and 45 living in endemic areas with a documented prior infection. In May 2019, the US Food and Drug Administration (FDA) approved Dengvaxia<\/a> to prevent dengue in children aged between nine and 16 living in endemic areas with a documented prior infection. Dengvaxia is also approved for use in several endemic countries in Latin America and Asia.<\/p>\n Other vaccines that could prevent dengue are advancing at pace. Amongst other things, Takeda recently announced that its TAK-003 vaccine is on track for regulatory filing very shortly. And Brazil\u2019s Instituto Butantan is expected to announce the results of its phase III trial of TAV003 in the first half of 2021. Various other TV003\/TV005 trials are in progress or have recently completed.<\/p>\n We last took a look at the dengue vaccine pipeline<\/a> back in February 2018. Let\u2019s see how it has progressed over the last three years.<\/p>\n \u00a0<\/p>\n Takeda\u2019s TAK-003 (also known as TDV) dengue vaccine is the most advanced vaccine candidate currently in the pipeline. Takeda recently told Reuters<\/a> that TAK-003 \u201cis on track for regulatory filing in Asia, Latin America, and the European Union by the end of fiscal 2020\u201d.<\/p>\n TAK-003 is based on a live-attenuated DENV-2 (dengue serotype 2) virus, which provides the genetic \u2018backbone\u2019 for all four dengue serotypes. The tetravalent dengue vaccine candidate is given in two doses, three months apart.<\/p>\n Takeda began its phase III Tetravalent Immunization against Dengue Efficacy Study<\/a> (TIDES) trial of TAK-003 back in September 2016. The on-going study, which is taking place in eight dengue-endemic countries in Latin America and Asia, completed enrolment of 20,100 children and adolescents ages 4 through 16 within seven months. The study aims to test how well the vaccine prevents dengue and the long-term side effects of the vaccine in children.<\/p>\n The primary results Takeda announced<\/a> in November 2019 showed TAK-003 to be well-tolerated and to offer protection against dengue. The results revealed the vaccine\u2019s efficacy (its ability to prevent dengue) 12-months after participants\u2019 second dose, finding it to be 80% overall \u2013 82% in participants who had not previously contracted dengue and 75% in participants who had previous contracted dengue. In other words, the vaccine protects whether or not a person has previously had dengue.<\/p>\n The Lancet published the trial\u2019s secondary results<\/a> \u2013 the results from an 18-month follow-up \u2013 in March 2020. These showed an overall efficacy of 73%. In its press release, Takeda announced a 70% vaccine efficacy for DENV-1, 95% for DENV-2 and 49% for DENV-3. It had insufficient data for DENV-4.<\/p>\n TV003\/TV005<\/em><\/p>\n Developed by the US-government funded NIAID (National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health (US NIH)), TV003 and TV005 are variations of the same live-attenuated and recombinant vaccine, except that the former has ten times more of the DENV-2 component than the latter. Both are intended to be given as a single dose.<\/p>\n NIAID has licensed TV003\/TV005 to several manufacturers for further development. These include Instituto Butantan in Brazil; VaBiotech in Vietnam; Panacea Biotec, Serum Institute of India and Indian Immunologicals in India; Medigen Biotech in Taiwan; and Merck in the US, Canada, China, Europe, and Japan. Its goal is to ensure market access through cheaper domestic production in key dengue-endemic regions.<\/p>\n While TV003\/TV005 remains behind TAK-003 in development, progress is moving forward and looking positive. Brazil\u2019s Instituto Butantan began a large phase III community-based trial<\/a> of TAV003 in February 2016. The on-going trial includes almost 17,000 adults and children from a number of urban areas across Brazil that have dengue transmission. The institute expects to complete the trial to assess the vaccine\u2019s safety and efficacy in the first half of 2021.<\/p>\n One significant advantage of the vaccine is that it is given in a single dose, making it especially attractive to travellers since this is more convenient and can be given at short notice.<\/p>\n \u00a0<\/p>\n NIAID is also sponsoring a clinical trial of TV003\/TV005 in countries such as Thailand and Bangladesh. The phase II trial of TV003 in Thailand<\/a> was completed in October 2018, and the phase II trial of TV005 in Bangladesh<\/a> was completed in February 2020. In parallel, a phase II trial in Brazil of TV003<\/a> that Butantan Institute is sponsoring is expected to complete in December 2020.<\/p>\n Elsewhere, the Medigen Biotech phase II trial of TV003<\/a> in healthy adults in Taiwan completed in May 2019. According to Medigen<\/a>, the vaccine showed great safety and participants produced an immune response against all four dengue serotypes in participants whatever their age \u2013 from 20 to 70.<\/p>\n And the National Taiwan University Hospital is currently recruiting for a phase II trial of TV005<\/a> to determine the candidate vaccine\u2019s safety and ability to elicit an immune response in people aged 50 to 70.<\/p>\n PIV emerged from a collaboration between GlaxoSmithKline (GSK), Walter Reed Army Institute of Research (WRAIR) and Fiocruz. TDENV-PIV is a purified inactivated vaccine, meaning it is made up of dead purified components of the dengue virus with an \u2018adjuvant<\/a>\u2018 (a substance that helps boost the body\u2019s immune reaction). Like TDV, TDENV-PIV is given in two doses, in this case, four weeks apart.<\/p>\n The collaboration completed its phase II trial on 140 adults in the US<\/a> in March 2018. The trial\u2019s main objective was to evaluate and refine TDENV-PIV further. The trial results show<\/a> participants tolerated the vaccinate well and that the vaccine is best given with a boost one month and six months after the initial vaccination.<\/p>\n While we mentioned in our last update<\/a> that GSK might be developing a DPIV vaccine candidate from the knowledge gained from this collaboration, there is no mention of a dengue vaccine in its pipeline<\/a>.<\/p>\n \u00a0<\/p>\n Merck\u2019s V180 is a recombinant subunit dengue vaccine, meaning it only contains essential antigens and not all the other molecules that make up the virus. It is intended to be administered in three doses, one month apart. Merck\u2019s phase I trials<\/a> in the US and Australia tested different doses of the vaccine candidate in combination with different \u2018adjuvants\u2019. Published results show<\/a> that the vaccine formulations did induce a modest amount of antibodies against dengue serotype 1 in most participants that waned over time.<\/p>\n Also in phase, I, the US Naval Medical Research Center (NMRC) has evaluated its DNA vaccine (a technique using genetically engineered DNA to stimulate the body\u2019s immune system) in combination with an adjuvant. While TVDV, as it is known, targets all four dengue serotypes, an earlier phase I trial evaluated its DENV-1 component, which is known as D1ME100.<\/p>\n KM Biologics (formerly Kaketsuken) completed a phase I trial of its KD-382<\/a> live attenuated tetravalent dengue vaccine in Australia in June 2020 after completing preclinical trials in Japan in 2018. The trial assessed the safety and tolerability of KD-382 in healthy adults aged between 18 and 65 who had not previously contracted dengue. It also evaluated the participants\u2019 immune response over 57 days.<\/p>\n Meanwhile, the Serum Institute of India is currently recruiting in Australia<\/a> for its phase I trial of its Dengusiil<\/a> dengue vaccine candidate. This trial will assess the safety and tolerability of a single dose of Dengusiil in healthy adults aged between 18 to 45. It will assess participants\u2019 immune response to Dengusiil over six months.<\/p>\n Other developments<\/strong><\/p>\n Excitingly, an article published in Frontiers in Immunology<\/a> in 2019 describes how an mRNA vaccine induced a potent immune response and protection against DENV-1 in mice. A more recent article published in Molecular Therapy<\/a> describes an mRNA vaccine candidate that elicited a strong immune response and partial protection against DENV-2 in mice. \u201cThese results form the foundation for further development of a tetravalent DENV vaccine based on mRNA technology,\u201d it concludes.<\/p>\n In addition to the mRNA vaccine candidates mentioned above, several other novel developments are progressing:<\/p>\n The dengue fever vaccine pipeline is continuing to make great steps forward, developing a variety of vaccines to help combat this terrible disease.<\/p>\n Additional sources:<\/strong><\/p>\n http:\/\/www.who.int\/research-observatory\/monitoring\/processes\/health_products\/en\/<\/a><\/p>\n http:\/\/www.who.int\/immunization\/research\/vaccine_pipeline_tracker_spreadsheet\/en\/<\/a><\/p>\n https:\/\/www.precisionvaccinations.com\/<\/a><\/p>\n https:\/\/www.sciencedirect.com\/science\/article\/pii\/S0264410X17311647<\/a><\/p>\n<\/div>\nPhase III trials<\/strong><\/h2>\n
TAK-003<\/em><\/h3>\n
Phase II trials<\/strong><\/h2>\n
TV003\/TV005<\/em><\/h3>\n
TDENV-PIV<\/em><\/h3>\n
Phase I trials<\/strong><\/h2>\n