Dengue is a public health priority in tropical and subtropical countries in Latin America and Asia, where it has become endemic and represents a threat to more than 2.5 billion people living in 128 countries. It has no specific treatment, but its timely detection and access to adequate care reduce the mortality rate to below 1%. In America, the number of people infected by this arbovirus increased fivefold between 2003 and 2013. Only during 2014 there were 909,000 infected on the continent and 370 deaths in Guatemala, Peru, Panama, Colombia, Brazil, Paraguay, the Dominican Republic and Martinique. Although it affects people of all ages and socio-economic backgrounds,the highest number of cases worldwide occurs in the highly mobile and social segment of the population made up of pre-adolescents and adults up to 45 years of age. An average of 100 million people contract this disease per year. Of these, 500,000 - particularly children - develop the severe form of dengue.
The associated problem is the impact it generates on the expenses of the health system and on the economic productivity of a country. Although it is not as deadly as other tropical diseases, for example malaria, it carries a heavy economic burden in the regions where it is prevalent, which constitutes a severe impact on the medical resources of governments, especially in countries with lower income per capita. A 2012 study, published in the American Journal of Tropical Medicine and Hygiene and carried out in eight countries in Latin America and Asia, indicated that in Puerto Rico alone, dengue fever had a cost of $ 37.8 million a year in care of health and loss of productivity. Meanwhile, the estimated average annual total cost associated with the disease was calculated at US $ 587 million.
In relative terms, the average cost to the economy of each country under study turned out to be 2.7 times higher in Asia than in Latin America, while hospitalization costs were 3.7 times higher than those generated by outpatient care. These calculations were considered conservative, considering only cases officially reported to health facilities, which are generally underreported. Nor were the costs associated with vector monitoring and control programs included. Attentive to these epidemiological and economic variables, the WHO has set the goal by 2020 to reduce the mortality of this communicable disease by 50% and the infection rate by 25%, using 2010 as a control base data.
The impact of a vaccine on the cost / effectiveness of the disease and its control
Since 1929, attempts have been made to use a vaccine to put a stop to the disease. The approval in 2015 of the first specific tetravalent immunogen developed by the French laboratory Sanofi Pasteur and marketed under the name Dengvaxia® by Mexico, and more recently by Brazil, allows a critically important advance for the public health of Latin America, the territory holder of the greatest burden of endemic dengue disease. Precisely this new vaccine, having all four serotypes, has the potential to significantly reduce the burden of this disease, which keeps the epidemiological transition polarized. And it is estimated that it will help the affected Latin American countries achieve the objective set by the WHO.
The two countries that have given the first approval to the vaccine face a complex epidemiological dilemma. Mexico is in ninth place in America with this ailment. According to the National Center for Epidemiological Surveillance (CENAVECE) of the Federal Government's Health Secretariat, the number of cases of classic dengue in Epidemiological Week 52 of 2015 decreased in relation to the peak of 44,565 confirmed cases that occurred in 2010, reaching 20,889 records nationwide, with 5,276 cases of hemorrhagic dengue (DH). This last data also meant a reduction of 6 thousand affected in relation to the cases reported in 2010.
Between 20 and 25% of dengue cases are experienced by people who have been infected on a new occasion by one of the various serotypes that circulate in the country, a circumstance that predisposes to the most serious forms of the disease. Statistics indicate that 60% of the records are located in the south-southwest area of the country, being the Federative States of Veracruz, Guerrero, Colima, Jalisco, Yucatán, Quintana Roo and Campeche the most affected in relative terms. (See diagram 1). In Yucatán, Tabasco, Morelos, Chiapas and Oaxaca, the simultaneous circulation of several serotypes of the dengue virus has been detected, while in the rest of the country the circulating serotype corresponds to Dengue 1.
For its part, Brazil, with 1.4 million cases of dengue registered this year, exhibits the highest registered outbreak in the history of the disease in Latin America. This country hopes to obtain a great health impact with the new alternative that configures the vaccine as a specific prevention instrument. Especially with respect to the 1,318 cases reported as severe hemorrhagic dengue, a figure that doubles the one that occurred in 2014. The viral serotypes most frequently identified in this country have been DENV-1 (93.4%) and DENV-4 (5.4 %), while DENV-2 and DENV-3 did not exceed 0.5% incidence, with which the vaccine ensures a wide possibility of coverage.
Analyzing the geographic impact in relative terms, the Southeast region is the one that registers the highest number of probable cases (922,662 cases; 64.1%) in relation to the total of the country, followed by the Northeast region (259,698 cases; 18.1%), the Center - West (176,557 cases; 12.3%), the South (52,007 cases; 3.6%) and the North (27,573 cases; 1.9%) (See diagram 2). Regarding the sequence of monthly distribution of cases, the maximum incidence peak took place in the month of April with 220.1 cases / 100,000 inhabitants, which was followed by a reduction in the month of May to 109.2 cases / 100,000 inh. This temporality also occurs in all regions of the country. 70% of dengue cases in Brazil are reported in people 9 to 13 years of age,population segment that contributes to the spread of the disease in communities by being socially active and highly mobile.
More than 29,000 volunteers received three doses of vaccine. The dengue endemic regions of Mexico (Morelos, Tamaulipas, Veracruz, and Yucatán) participated in all three phases of the clinical development program, as did Brazil. In Mexico, the children of 2 to 5 years studied, naive of infection, presented a seroconversion of 88 to 100%. Earlier, the same vaccine had been tested in children in another trial that was done in five Asian countries. It has been shown to have a good safety margin, and studies in Latin America certify that it makes it possible to curb the number of new confirmed virological symptomatic cases of dengue of any serotype by 56.5%. As drawbacks, it offers less protection to young children and is less effective against dengue 2 serotype, for which protection oscillates only 35%.
In a second Phase study, the vaccine obtained an overall reduction in cases of 60.8%. An ongoing 25-month and long-term Phase III analysis and combined efficacy article respectively, published in The New England Journal of Medicine in July 2015, states that it demonstrates consistent efficacy and long-term safety profile in the population. under study from 9 to 16 years of age, range in which said efficacy reaches a maximum point. In the combined efficacy analysis in this age group, Dengvaxia® was shown to reduce dengue caused by all four serotypes in two-thirds of the participants, and to prevent 8 out of 10 hospitalizations and up to 93% of severe dengue cases.
Upon receiving approval from COFEPRIS - Mexico's health risk protection agency - and allowing Dengvaxia® to be launched in that country, it became the first licensed vaccine in the world for the specific prevention of dengue. It will be available for application in Mexico starting in 2016. Its research and development process took 20 years, with an estimate of more than $ 1.6 billion dollars. The company now faces the unusual task of commercial deployment of this new vaccine, especially in low- and middle-income countries where health budgets are much lower than those of rich countries.
The only dengue vaccine production plant was recently installed by Sanofi in France, with an investment of more than 200 million Euros and will be able to produce one hundred million doses in its first stage. The company is in the phase of submitting Dengvaxia® for approval in 20 countries where the relative weight of dengue in the epidemiological profile is greater, and plans to submit it for European approval in 2016 and for approval by the US FDA in the year following.
As part of the regulatory approval in Mexico, COFEPRIS specially requested from the French pharmaceutical company a risk management plan designed especially for Mexico, which includes the electronic registry of the vaccinated population and the reporting of adverse reactions through sentinel medical centers located in endemic populations in which it is applied.
An old aphorism adaptable to this shot: Whoever strikes first strikes twice.
The approval of Dengvaxia® in two South American countries highlights the decision by Sanofi Pasteur, the company's vaccine division, to bypass European and US regulators, and bring the product directly to places where dengue is endemic. This represents an unusual strategy for the pharmaceutical industry, which typically launches products first in the developed world. Dengvaxia® is one of several new drugs and vaccines that the company relies on to offset a slowdown in its important diabetes business as a result of the loss of patents.
Sanofi had warned its investors that they should not expect significant growth in their shares for two years, due to increasing competition facing its best-selling Lantus® long-acting insulin glargine. Revenues from the commercialization of this product, which had grown 20% annually between 2007 and 2011, slowed down to an annual rate of 6.5% between 2012 and 2016. And from 2015, sales will probably begin to fall further, given the imminent arrival of its biosimilars. Pharmaceutical market analysts already estimate that the vaccine could be priced at € 20 per dose (three need to be applied at six-month intervals) and generate $ 1.4 billion in annual revenue for Sanofi by 2020, becoming its next blockbuster.
This and other issues make some scientists wary of the vaccine issue. In Scientific American it is argued that there is still no adequate blood test to establish what constitutes immunity to dengue, as occurs with the flu or yellow fever vaccine. It is necessary to know more about aspects of the immune system that protect against dengue. Especially because certain individuals are less vulnerable to disease after multiple exposures to the virus. It is also not known exactly how much virus is necessary to develop effective immunity against the disease. In addition, researchers from the Institute of Biological Sciences of the University of São Paulo argue that this vaccine does not activate the response of a type of defense cell (T lymphocytes) against dengue,which could reduce its effectiveness.
The company's plan is to make dengue the next preventable disease and vaccinate as many people as possible within five years, at which time it estimates its first competition will appear after the patent expires. What Sanofi Pasteur intends is that the vaccine is initially integrated into the basic vaccination scheme of Mexico, something that would suppose a captive and safe market that will later be followed, by cascade effect, other affected countries. By the time the patent has expired, the laboratory trusts that it has consolidated the supply contracts with all the countries in the world that suffer from dengue and have adopted the vaccine.
But the commercial war between laboratories is already in the future. In addition to the chimera vaccine, there are five others in the research phase. Two have already passed Phase II. One developed at the Butantan Institute of Brazil (although it is the result of a primary investigation of the National Institutes of Health of the United States from a genetically modified variety of dengue virus so that the individual develops antibodies against the serotypes of the disease, causing a response similar to that of infected people who have managed to neutralize the virus) and the other by the Japanese company Takeda. These are attenuated virus vaccines, and it is expected that they will be available by 2018. In addition, there are three others under development in Phase I different from that of Sanofi Pasteur,since they have inactivated virus or are the result of DNA recombination or modification by viral vectors (a tool of molecular biology used to introduce certain genetic material into a host cell). These innovations correspond to GlaxoSmithKline and Merck and the United States Army Medical Research Center separately.
The CEO of Sanofi Pasteur has recently admitted that a price has yet to be agreed with the Mexican government. I note that this is being analyzed, but it will be accessible. And what the company does not want is to launch the vaccine on the market with a price and when it is available in at least ten countries, lower it by half. Hence, they want to offer it at an appropriate price for all countries where it is endemic, reflecting the savings generated in other instances of disease control, prevention, and care.
The annual cost of dengue treatment is estimated at about US $ 9 billion globally, and prevention strategies such as mosquito nets and insecticides add an additional US $ 6 to US $ 9 billion. In Mexico alone, the prevention, control, outpatient care and hospitalization of patients with dengue in the public and private sector exceeds US $ 328 million annually. Of that total, approximately U $ 190 million correspond to pure spending by the Secretary of Health, which must assist 60% of confirmed cases, equivalent to 2.5% of its total budget. The second in expense is the IMSS, with more than 25% of the cases.
The current Mexican government has also invested more than 230 million pesos in the purchase of material to combat the dengue-transmitting mosquito, but resources are always insufficient to eliminate breeding sites. For its part, the estimated cost to face the disease in Brazil is US $ 1.2 billion per year, which is equivalent to an average of US $ 448 per hospitalized case and US $ 173 per outpatient case. To this must be added indirect losses such as the drop in labor productivity as a result of the acute episode and convalescence.
To be sure, the incremental cost / effectiveness of a vaccine, as in this case, is far from being questioned. Even more so if it does not exceed once the GDP / capita of the country to which it is intended for commercialization. Only the Secretary of Health of the Mexican government estimates that it could save US $ 65 million per year in costs associated with dengue care.
Dengue and vaccine. The tree cannot not let you see the forest
Dengvaxia® is not a perfect vaccine. It appears to be less effective in children under the age of nine, particularly those under the age of six whose immune systems are especially vulnerable and would be part of the group most in need of immunization. And it also has a significantly lower efficacy for dengue 1 and 2 than for dengue 3 and 4. Hence, it is not enough to inject doses, but vaccination will have to be one of the strategies of governments to combat the disease, also bearing in mind that there may not be enough budget for vaccines.
Other diseases, such as Chikungunya and the Zika virus, are also transmitted by mosquitoes and do not yet have a vaccine, so nonspecific prevention continues and will continue to be the fundamental strategy. The latter condition - which causes dengue-like symptoms - has been linked to newborns of infected mothers who were born with abnormally small heads, known as microcephaly. Epidemiologists have detected an alarming and inexplicable spike in these cases in the northeast of Brazil.
Control of the larvae, as well as the vector of the transmitting agent, has historically failed. Not only in Mexico and Brazil, but in all countries where dengue is an endemic issue. As a disease typical of the tropics, and particularly of rainy seasons, it is a disease that spreads to new areas of contagion due to the movement of viral serotypes, strains and genotypes from one region to another. And also due to the adaptation of the transmitting mosquito to different ecological environments, resulting from the increase in air travel to endemic areas of America and Asia, from climate change and from the unsanitary conditions, lack of services and poverty in which millions of people live. within large urban and suburban areas in multiple countries.
It is essential that the tree (the vaccine) does not cover the forest (the external factors of health / disease). The causes of the increase in dengue vary between regions, but their common denominator is the weight of social determinants and negative externalities. The most important include the lack of control to avoid the presence of mosquitoes, demographic changes, uncontrolled urbanization often accompanied by poor housing and floodplains, lack of adequate water, sewage and sewage supplies, inappropriate waste management and garbage and the increase in travel and commerce. The same occurs with insufficient public health services in towns and cities with deteriorating structures and scarce human resources.
Beyond the cost / effectiveness and the health benefit that its use will undoubtedly bring, the dengue vaccine should not be seen as a sanitary panacea. The pandemic responds to a large extent to cultural, economic, health and social issues, as is the case with other vector-borne diseases. Even with climate change, which causes excess rain and its accumulation in inappropriate places that favor the appearance of larvae.
The question between health and disease is a conflict between man with himself and with different determining factors, which are not within the reach of being modified exclusively by people as individuals. The latter require adequate dissemination and communication to be identified in the first instance and subsequently transformed. The disease risks that people face do not depend exclusively on biology or genetics, but also on factors present in the context in which people are born, live and work. Hence the need to anticipate actions, looking for causes in the social environment of family groups.
The vaccine, its impact in terms of reducing the incidence of cases and especially mortality due to the hemorrhagic form of dengue, is a very important step to raise levels of prevention. And at the same time, it is to be estimated that its cost / effectiveness is adequate compared to the expenses demanded by the care of those affected by the ailment and the weight that this has in the productive structure of the country. Especially when it comes to fragile or flimsy economies and intensive labor. Those on the poorest and most vulnerable spectrum of society get sicker. That is to say, those who have the least economic resources and the least capacities to achieve adequate social protection.
This disease, like others that have as intermediaries vectors that reproduce in unfavorable habitat conditions, must also be analyzed and resolved from the point of view of inequities. In other words, how unequally the risks and vulnerability are distributed, with the intention of trying to reestablish the social fabric that gives rise to unnecessary, systematic and unjust conditions. The vaccine is a specific prevention instrument as well as an element that makes inclusion, since its provision does not admit inequalities of any kind. But dengue, like other mosquito-borne diseases, finds in neighborhoods without water supply, without pipes or sewers, without proper garbage management systems or disposal of disused tires, an ideal habitat to grow.And its inhabitants are exposed to being bitten by vectors more frequently, so they will have a high risk of contracting these diseases. If these populations also have little access to health services, they face a situation of greater vulnerability to any complication that may occur.
In conclusion. The economic evaluation of the vaccine will surely determine its cost effectiveness compared to the alternative of treating confirmed cases, and even the most serious and life-threatening. But non-specific prevention is also essential to combat these diseases, and ultimately, it continues to be everyone's responsibility.
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