![\"\"](\"https:\/\/revistapesquisa.fapesp.br\/wp-content\/uploads\/2020\/01\/054-059_Butantan_275-1-800px.jpg\")
PDBE <\/span><\/a> A representation of the dengue virus, which has four serotypesPDBE <\/span><\/p><\/div>\n The partnership was made possible by the fact that Butantan and MSD both based their vaccines on a set of genetically modified dengue virus strains developed by a team led by Stephen Whitehead of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH). When international collaborations to develop the vaccine were initiated, the NIH established geographical domains for each partner in advance.<\/p>\n The vaccine developed by Butantan, designated as Butantan-DV, is made of live attenuated viruses, as is MSD\u2019s. It has the advantage of being tetravalent, meaning it provides protection against all four dengue virus types. Butantan\u2019s clinical trials have been designed to evaluate product adequacy for a broad age bracket, from 2 to 59 years. The vaccine has thus far been shown to be safe, causing only a few adverse reactions similar to those caused by other vaccines. No other dengue vaccine developed from NIH-licensed material is at such an advanced clinical trial stage. In late 2015, Sanofi Pasteur launched Dengvaxia, the only commercially available vaccine against dengue, which was developed with a different technology from the NIH. However, the French company\u2019s product has several drawbacks: it has a relatively low efficacy rate (60%), can cause adverse reactions, and is contraindicated for people who have never had dengue.<\/p>\n The collaboration between Butantan and MSD began to take shape shortly after the Brazilian-developed vaccine passed Phase 2 clinical trials, demonstrating that it was safe and effectively stimulated the immune system to produce antibodies against the four dengue fever viruses. Although the trials have already been completed, the results have yet to be published. \u201cThe paper on this study has been recently submitted for publication and we are awaiting a response,\u201d explains Alexander Precioso, director of Butantan\u2019s Clinical Trials Division. \u201cPublishing the Phase 2 trials is not a condition for moving to Phase 3. A clinical trial is approved at the health-surveillance and ethics level.\u201d After being successfully tested for safety and toxicity in Phase 1, a vaccine (or drug) candidate must undergo Phase 2 testing, which covers additional safety aspects, and a therapeutic study involving a small but increasing number of participants to determine whether the product fulfills its intended purpose. Phase 3 consists of a trial, usually multicenter in nature, with a large number of volunteers across varying age profiles to determine efficacy and confirm the vaccine or drug\u2019s safety profile.<\/p>\n The dengue vaccine is being tested on 17,000 Brazilian volunteers aged 2 to 59 years<\/p><\/blockquote>\n While still pending publication in a scientific journal, the results of the Phase 2 Butantan vaccine trials, which included 300 volunteers recruited by the University of S\u00e3o Paulo School of Medicine (FM-USP), have been reported to the MSD and other companies and institutions at scientific meetings, conferences, and events. \u201cThe Phase 2 studies were extremely promising and caught our attention,\u201d says Guilherme Leser, director of government affairs and access at MSD Brazil. \u201cWe promptly initiated discussions with Butantan about the possibility of a collaboration, as Brazil had the highest prevalence of dengue cases globally at that time. The country was experiencing outbreaks of the disease in the southeast and northeast, and the large number of cases allowed Butantan to get a head start on Phase 3 clinical studies, the last stage, to evaluate the vaccine\u2019s efficacy.\u201d In 2015, and 2016, Brazil recorded approximately 1.5 million cases of dengue. In 2017 and 2018, the number dropped to approximately 240,000.<\/p>\n The Phase 3 Butantan vaccine trial, which has a goal of covering 17,000 people over a five-year follow-up period, is well underway and near completion. The trial divided volunteers into three age brackets: 2 to 7, 8 to 17, and 18 to 59 years. Only the youngest age group, the hardest to recruit for clinical trials, has yet to reach the target number of participants. The difficulty in recruiting this group of volunteers is explained by both the surprisingly small number of dengue cases in the last two years and the need for parental permission for children to participate in the study. \u201cThere is some evidence that the 2019 epidemic will be larger than the 2018 epidemic,\u201d says Esper Kall\u00e1s, a professor at FM-USP and coordinator of one of the 16 trial centers. \u201cAt the end of 2018, dengue cases in S\u00e3o Paulo already exceeded the estimates for the period. Because epidemics reach a maximum peak in February, we\u2019ll likely be seeing a very large number of cases next season.\u201d<\/p>\n The 16 trial centers in Brazil are working to recruit the required number of volunteers. \u201cTo demonstrate that the vaccine is effective, we need to document 100 cases of the disease among volunteers, but we have yet to reach that number,\u201d explains Kall\u00e1s. One-third of the volunteers are in the control group, which is given an innocuous preparation, and two-thirds receive the actual vaccine. When one hundred patient targets were reached, the researchers opened the files of the participants who were infected and identified which group they were in. If almost all the patients with active cases received the placebo, this will be a very strong indication that the vaccine is effective. However, the clinical trial will not be complete if and when this occurs. It will also need to evaluate the protection offered by the vaccine against each serotype of the virus\u2014in Brazil, most cases of dengue are types 2 and 3 across the different profiles of patients who have or have not been infected.<\/p>\n Butantan Institute<\/span><\/a> A step in the production of the dengue vaccine at ButantanButantan Institute<\/span><\/p><\/div>\n \u201cMSD is now starting Phase 2 studies on its vaccine. We have not yet established which countries and populations we want to include in the Phase 3 trials,\u201d says Leser of Merck. \u201cWe hope to recruit significant numbers of people who have been exposed to different dengue serotypes, such as type 4, which occurred infrequently in Butantan\u2019s studies.\u201d<\/p>\n The collaboration agreement is mutually beneficial. The advanced stage at which the Brazilian partner\u2019s vaccine program finds itself means the resulting data and experience in producing the vaccine can help to accelerate Merck\u2019s program. Conversely, the US company\u2019s experience in developing, producing, and trialing new vaccines can expedite the final manufacturing phase and clinical trials at Butantan. Although based on the same virus preparation engineered at the NIH, the two vaccines will need separate regulatory approvals.<\/p>\n The Butantan and MSD vaccines have different formulations. The Brazilian institute developed a multidose vaccine initially designed for vaccination campaigns such as those periodically organized by the Brazilian Ministry of Health. MSD is looking to serve a more fragmented global market, with demand substantially coming from people traveling to tropical areas. The company would therefore focus on the production of single-dose vials. The World Health Organization (WHO) estimates that 390 million dengue virus infections occur per year. Should either of the partners in the collaboration decide to shift course, they have agreed to continue to share their experience in production techniques without charging additional royalties.<\/p>\n Sanofi Pasteur \/ Gabriel Lehto<\/span><\/a> Sanofi\u2019s Dengvaxia vaccine has limited efficacy and can only be received by people who have already been infected with the dengue virusSanofi Pasteur \/ Gabriel Lehto<\/span><\/p><\/div>\n According to Covas, the funds provided by MSD can be used toward developing the dengue vaccine and accelerating some stages of the process. \u201cThe process of demonstrating the efficacy of the vaccine obviously cannot go any faster, but the process of building and expanding the needed infrastructure can,\u201d says Precioso. Finding the best way to apply the funds will be at Butantan\u2019s discretion. \u201cThey will also be used toward development and innovation in general,\u201d he says. The agreement with MSD accommodates potential collaborations involving other vaccines currently produced at Butantan, such as vaccines against hepatitis A and HPV<\/a>. Through its partnership with MSD, the institute hopes to tap into global markets, especially in low-income and developing countries.<\/p>\n There are still many questions to be explored in the field of dengue research. Alongside the yet-to-be-published Phase 2 clinical trials and the ongoing Phase 3 trial, there is other research that is currently other research on Butantan dengue vaccines being conducted. Kall\u00e1s\u2019s laboratory at USP, for example, is investigating the extent to which the product activates a cellular immune response without involving the production of antibodies. \u201cI hope my research provides an understanding of which immune markers indicate whether a person is protected against dengue, an aspect that currently remains unclear,\u201d explains Kall\u00e1s.<\/p>\n Published in January 2019<\/p>\n