On February 17, El País reported that Brazil is experiencing the worst dengue epidemic in the last 90 years, with more than half a million patients and almost a hundred deaths from this disease. To face the crisis, health authorities decided to incorporate a vaccine into the dengue combat scheme.
The above makes Brazil the first country on the continent to use this health tool to combat the disease. The immunizer, purchased from the Japanese laboratory Takeda, began to be used in a clinical trial involving 20,000 people between 18 and 40 years old, who will receive two doses with an interval of three months between each one and will be followed for two years; well, although the drug has proven to be safe, it is not known for sure how it behaves in large population groups.
With this, the vaccine, which has already been marketed in the Brazilian private network since 2023, is now extended to the public health system.
The idea is to administer the six million doses acquired, prioritizing children over 10 years of age1 in the 541 cities with the highest incidence of cases. However, this is little for a country of 210 million inhabitants exposed to the disease.
A disease that spreads on a global scale
According to the WHO, in recent decades the number of reported cases of dengue has multiplied by 10, going from 500,000 to more than 5 million a year. The number of patients is probably between ten and twenty times greater.
During 2020 and 2022, a decrease in the number of reported cases was observed. However, last year we witnessed a peak that approached historical highs, with outbreaks in areas where it is not common. For example, in 2023, 43 cases were reported in France, 82 in Italy, and 3 in Spain, totaling 128 cases. So far this year, 312 cases have been diagnosed in the United States.
Although the state with the highest incidence is Florida, patients have also been reported far north of the subtropical belt in states such as Michigan, Illinois, New York, Montana, or Pennsylvania, close to Canada.
According to the UN agency, the Americas region, with 4.1 million cases, led the world in terms of reporting the disease, accounting for nearly 80% of the total cases. In the region, an incidence of 416 cases per 100,000 inhabitants was also observed, more than 6,000 serious cases and 2,049 deaths, for a fatality rate of 0.05 per thousand patients. Additionally, 45% of the reported cases were confirmed by laboratory studies.
Even though Cuba is not among the countries that reported the most cases nor those that reported the greatest number of serious illnesses or deaths to the international organization, on the island dengue is a recurring problem that the health authorities and, of course, the population have to confront. In fact, the incidence of the virus has sometimes been above 100 cases per 100,000 inhabitants.
Having a vaccine that prevents this disease is an old desire of Cuban scientists. Is this being worked on? How much progress has been made? How close is the country to having a dengue vaccine?
On the trail of the Cuban vaccine
Few diseases had as great an impact on Cuban public health during the second half of the 20th century as dengue. According to an article by Dr. Gustavo Kourí, one of the world authorities on this disease, the Dengue Type 2 epidemic that devastated the country from the end of May to October 1981 left a total of more than 344,000 patients, with weeks of close to 10,000 cases. Of that total, about 9,000 suffered a severe form of the disease.
According to the prominent virologist, 158 deaths were recorded, with a fatality rate of 0.46 per thousand patients, 101 of which were children. The ages where the highest number of deaths were concentrated were between 4 and 6 years old, which made this epidemic especially painful.
Since then, Cuban scientists such as Dr. Kourí and his wife, Dr. Mary Guzmán, together with a group of prominent researchers, have contributed to elucidating different characteristics of the virus and the pathogenesis of the disease it causes.
Their contributions have earned them important international awards, such as the 2022 L’Oreal for Dr. Guzmán, which she shared, among others, with last year’s Nobel Prize winner in Medicine and Physiology, Dr. Katalin Karikó, to whom we dedicate an article.
According to an article in Swissinfo, since 1992 Cuban scientists have been searching for a dengue vaccine. For more than two decades, different compounds have been tested that could lead to formulations capable of becoming a vaccine.
In 2006, a protein called Domain III caught the interest of the group of Cuban researchers from the Center for Genetic Engineering and Biotechnology (CIGB) and the Pedro Kourí Institute (IPK) who are working together in search of the immunizer. The compound’s ability to generate immunity against dengue in primates was encouraging. New results on this line of research were published in 2008 and 2009.
In this way, the concept of a quadrivalent vaccine candidate was built, that is, capable of protecting against the four serotypes of the dengue virus, one of the golden goals for any vaccine that aims to be effective against the disease and something already achieved by the Takeda laboratory, mentioned at the beginning of the article.
In 2014, a study was published according to which a formulation based on the combination of different proteins present in areas of the virus structure, including Domain III, had the capacity to generate an immunological (defensive) response of the organism against the pathogen, making it viable as a vaccine candidate.
The formula, called TetraDIIIC, was tested in 2015 in mice and non-human primates, obtaining encouraging results. In the following years, experiments were carried out to determine which doses allowed the best immunological response to be obtained in laboratory animals and the results were published in 2017, through several articles.
In 2019, a work in which the strategy of combining the vaccine candidate, TetraDIIIC, to which we have been referring, with another tetravalent candidate of attenuated viruses, known as TV005, developed by the U.S. National Institute of Allergy and Infectious Diseases.2 In this case, instead of the protein-based compound, a formulation containing weakened viruses of the four serotypes of dengue was used.
A new strategy?
In September 2022, national media briefly reported on the presentation by Dr.S. Gerardo Guillén Nieto — member of the team of researchers in charge of the development of the vaccine since the first published works and director of Biomedical Research at the CIGB — on “the Cuban strategy for the dengue vaccine” before the highest authorities of the country.
In March 2023, the CIGB reported through the X social media that the Cuban strategy to obtain a vaccine against this disease is based on recombinant proteins, but on this occasion, they were referring to the use of different structures than the one they were following with TetraDIIIC. According to the institution’s publication, it is “a very secure technological platform. We have a tetravalent candidate, based on proteins from the four dengue viruses, that we are evaluating at this moment.”
A month later, the aforementioned scientific institution announced that the vaccine candidate against dengue is currently in the “research-development stage.” According to the publication, the researchers “are beginning preclinical studies, where they are testing 2 different formulations, intending to determine which one will be taken to clinical studies,” that is, which one will be tested in humans.
On that same date, in an interview given to EFE and reproduced by Swissinfo, the CIGB research director explained that “instead of using the protein found in the virus membrane,” Cuban researchers “are experimenting with its non-structural proteins (which encode the genes of the virus).”
According to Guillén Nieto, what they are pursuing is to create a vaccine capable of strengthening the cell-mediated response in the person who receives it and not that of their antibodies. What does this mean?
The body’s immune response is made up of two fundamental branches: the humoral response and the cellular response. A humoral response is understood as the body’s way of dealing with toxins and infections through antibodies, which are proteins specifically designed against different antigens and transported by the blood, something like the infantry of the immune system.
They have the function of preventing the infection from entering the cells and multiplying. It is important to remember that viruses need the cellular apparatus to replicate.
Cellular immunity is focused on eliminating different enemies through the direct action of the cells of the immune system, such as T lymphocytes, which would be the motorized artillery and aviation of our defensive system. These cells have the ability to identify and eliminate infected cells, without attacking healthy ones or causing very little damage. It is a second line of defense against antibody-mediated immunity, which it completes and complements.
Does this new bet in the development of the Cuban vaccine mean abandoning years of research and starting a new path to obtain an efficient immunizer? What is this about? The answer is not clear. Based on more recent announcements, the Cuban team decided to put aside the line of research on the TetraDIIIC vaccine candidate.
In fact, since 2019, after intense activity in previous years with dozens of scientific articles on this line, the number of publications with the domain “Cuba dengue vaccine” on the Pubmed site decreased drastically, finding only 6 between 2020 and 2023. On the other hand, since that year, publications with the TetraDIIIC domain have not been collected on the same specialized site.
This may have to do with the safety profile of the Cuban candidate and may be related to what happened with Dengvaxia, the first approved dengue vaccine in the world, to which the CIGB research director refers in the Swissinfo publication.
Dengvaxia is an immunizer developed by a French pharmaceutical company based in the United States, Sanofi Pasteur. In 2017, after having vaccinated more than 733,000 minors in the Philippines, its administration was prohibited in that country, after the death of children with severe forms of the disease was recorded. Based on that, the FDA, the U.S. regulatory agency, ordered the suspension of all “sale, marketing, and marketing operations” of the product and “initiating an information campaign about the risks,” according to an article in El Mundo, generating a great deal of scandal with multiple implications.
Why was this vaccine unsafe? Everything seems to indicate that it is due to a phenomenon known as antibody-dependent amplification (ADA), which is characteristic of this disease. When a person is infected by a virus of one of the four dengue serotypes, say 1, the infection is usually asymptomatic or very mild.
However, if a person becomes infected in the future with a virus of any of the other serotypes, then there is a possibility that instead of a banal infection, a severe form of the disease will appear, which can lead to death. This happens because antibodies, that first line of defense, instead of protecting the body against infection, induce an exaggerated response.
Returning to Dr. Guillén Nieto’s interview, “Cuba seeks to make the vaccine in a different way” and, according to the expert, “it is the only country that is trying to do it this way,” experimenting with non-structural proteins, that is, they are not part of the virus envelope, but are encoded by its genes.
So that it is understood, the virus is known as a “virion” when it has not infected the cell. The virion is DNA or RNA (genetic information) that encodes the proteins responsible for the activity of the virus, covered by different molecules that make up a structure called capsid. These molecules are known as capsomers and are responsible for protecting the viral core.
Non-structural proteins are contained in the genetic information carried by the virus and have different functions. Viruses need the cell’s assembly machinery to reproduce or replicate.
This would avoid ADA or immunoamplification, as the phenomenon is also known, generating an important cellular response that would prevent severe forms of dengue. According to the CIGB research director, what is sought is that the “cellular response is sufficient to protect (from the four serotypes). We are going to have a safety guarantee, but it remains to be demonstrated whether we are going to be sufficiently effective to protect against the disease.”
In the near future, there will surely be more information on this topic. At the moment, there is a precedent for a 2014 publication in which antigenicity (the ability to produce an immune response in the body) and immunogenicity were studied, which is related to the immunological memory of the recombinant non-structural protein 3 (NS3) of dengue.
Be that as it may, it is a fact that Cuban scientists have worked for decades to obtain a vaccine against the four serotypes of the dengue virus. The path has been complex, not only for the island’s researchers but for all those who have tried to find the precious formulation.
As we saw, there are only two approved vaccines in the world: Dengvaxia, from a French laboratory, whose safety problems have considerably limited its marketing, and Qdenga, as the Japanese vaccine is also known, whose cost per dose, according to an Argentine newspaper, is 52 dollars. Qdenga manufacturers cannot meet the demand of a country like Brazil,3 much less that of nearly 50% of the world’s population exposed to the virus.
In this way, the strategy of having a nationally produced compound in Cuba would be extraordinary from many points of view. Firstly, the country would greatly reduce the costs of immunizing its population. On the other hand, it would enter a market of billions of people in the world who are exposed to dengue throughout the tropical and subtropical belt, which would bring obvious economic benefits.
However, the achievement of a Cuban antigen against dengue will take time. To give you an idea, only phase III studies last between 3 and 5 years in the case of vaccine candidates against this disease and are the last step in the long process of research and development of an immunizer, which in the conditions in Cuba, according to CIGB authorities, are made more complex by U.S. regulations.
But the longest path begins with the first step, no matter how many times it is necessary to take it.
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Notes:
1 Children are one of the most important risk groups for dengue, with one of the highest mortality rates, as was the case in the 1981 Cuban epidemic.
2 This research was jointly conducted by Cuban researchers from CIGB and IPK, Vietnamese researchers from the Center for Vaccine Research POLYVAC and the vaccine production company VABIOTECH. Through the latter, the license was obtained for the use of the vaccine candidate being developed by the National Institute of Health (NIH) of the United States. The U.S. side obtained from this investigation valuable information about the use of its candidate in conjunction with other preparations in a strategy that may be novel and useful. This is an example of international cooperation in the field of science.
3 As it is a vaccine made from attenuated viruses, producing this type of immunizer is much more complex than producing recombinant protein or RNA vaccines. Due to the country’s demand, the Japanese do not have the capacity to produce the 420 million dengue vaccines that a nation like Brazil needs.
