On Wednesday, December 12, 2018, Brazil's Butantan Institute signed a collaboration agreement with Merck Sharp & Dohme (MSD) to develop dengue vaccines. The São Paulo State research institution and pharmaceutical company will exchange information on proprietary processes and clinical trials that are at different stages of development.
The vaccine developed by Butantan Institute with São Paulo Research Foundation - FAPESP's support is currently in the last phase of trials involving humans, with 17,000 volunteers participating. MSD's vaccine is in Phase I clinical trials, involving a small group of participants.
For this reason, MSD will pay Butantan Institute US$ 101 million for access to information about its vaccine production process and the ongoing clinical trials until the partners reach the same level of development. From then on they will collaborate freely, although each partner will end up producing its own vaccine.
"It is great to see that a project that was initiated from studies funded by FAPESP over nearly 20 years is now becoming a product that within a few years may enter the global market. It is an unprecedented fact in the life of Brazilian research institutions and represents a victory of a way of thinking about the interaction between the public and private sectors that will certainly bring many benefits in the future", said Marco Antonio Zago, president of FAPESP and health secretary of the State of São Paulo, at the signing ceremony of the agreement.
"It's a win-win relationship, in which MSD will be able to accelerate its development program thanks to Butantan Institute's know-how and the data from its dengue vaccine clinical trials, while the institute will be financially compensated for this," told Fábio de Carvalho Groff, who manages Butantan Institute's Technological Innovation Unit.
The agreement also allows for exclusive licensing by MSD of patents relating to the dengue vaccine developed by Butantan Institute, even if the company decides not to use them fully or partially. If MSD wins patents on its technology during the development of its own vaccine, Butantan Institute will have access to them free of charge. MSD will not be able to market its own vaccine in Brazil and will pay Butantan Institute royalties on any sales of its vaccine elsewhere.
"The agreement will also enable Butantan Institute to accelerate clinical studies of its dengue vaccine and introduce part of its know-how into a vaccine marketed abroad by MSD, receiving royalties on any sales," Groff said.
One of the factors that motivated the collaboration agreement between Butantan Institute and MSD is that the dengue vaccines they are developing are both based on a formulation created by the National Institutes of Health (NIH) in the United States.
NIH research centers have managed to modify strains of all four dengue virus serotypes for use as the basis of a vaccine. These attenuated viral strains differ sufficiently from the virus not to cause the disease and are capable not just of triggering protection through antibodies but also of stimulating specific cells of the immune system that preserve a memory of infection by dengue.
An initial frozen liquid formulation of these strains - not yet a market-ready vaccine - has been tested experimentally by the NIH in animals and humans. The results were satisfactory.
In 2009 Butantan Institute obtained a license to use these attenuated viral strains to develop a vaccine for distribution only in Brazil. In 2014 MSD was granted a license to use them to develop a vaccine for distribution in the United States, Canada, China, Japan, and the European Union, among other countries, not including Brazil.
Patent and efficacy
For the past several years Butantan Institute has been developing a lyophilized vaccine based on all four dengue serotypes. This is a freeze-dried powder that can be stored in a refrigerator and has to be diluted before being administered. In September 2015 the institute applied to the United States Patent & Trademark Office (USPTO) for a patent on the process it has developed using the strains supplied by the NIH. The patent was awarded in June 2018.
Because the viral strains they used to develop the vaccine were the same as those used by colleagues at the NIH in the United States, Butantan Institute's researchers were authorized by ANVISA, Brazil's national health surveillance agency, to begin a Phase II clinical trial designed to show that the vaccine is safe and capable of activating an immune response.
"We made swift progress with development of the vaccine precisely because we began with Phase II," said Alexander Precioso, who heads Butantan Institute's clinical trial and drug surveillance division.
On completing Phase II, the institute at once applied to ANVISA for permission to conduct a Phase III trial. This was in 2013. Permission was granted in 2015. The Phase III trial must prove that the vaccine is tetravalent, i.e. effective against all four dengue virus serotypes.
Once it has demonstrated the vaccine's efficacy, the institute will apply to ANVISA to register the vaccine so that it can be distributed free of charge as part of Brazil's national immunization program.
"So far all the data collected in both Phase II and Phase III confirms that the vaccine is safe, causing very few adverse reactions similar to those caused by other vaccines," Precioso said. "Preliminary results also show that a single dose is sufficient to stimulate the immune system and protect vaccinees against all four types of dengue."
However, the researchers have experienced setbacks in this third and last phase of clinical trials, which began in 2016 and is being conducted at 14 clinical research centers in all five regions of Brazil.
The number of dengue cases in Brazil has fallen in recent years, and circulation of the virus is very low, delaying finalization of the clinical trials. Moreover, participants aged 2-6 are still being recruited. This is the hardest age group to recruit for clinical trials.
"The difficulty of recruiting this age group is due to the need for parents to give permission for their children to participate as volunteers, and most are reluctant to do so," Precioso said.
"However, we've vaccinated a large number of children in this age group, and we expect to have the minimum number of volunteers required within a few months."
Phase III trials require 17,000 volunteers divided into three age groups - 2-6, 7-17, and 18-59. Butantan Institute has recruited 15,500 to date.
All these groups have to be monitored for five years to prove the vaccine's efficacy against infection by dengue virus, so estimates of the time it could take to complete development of the vaccine vary from six to 15 years.
"Development of vaccines is classically estimated to take between six and 15 years, typically closer to the latter. Between 12 and 15 years is most frequently considered the amount of time taken to develop a new vaccine," Precioso said.
Besides Butantan Institute and MSD, other players that are developing dengue vaccines include pharmaceutical companies Sanofi, with Dengvaxia, and Takeda.
Butantan Institute's vaccine and these candidates differ in several ways. A single dose of Butantan Institute's vaccine is effective whereas the others require two or even three doses. It is tetravalent. And it can be administered to children and older adults, whereas there are candidates that are valid only for specific age groups.