The results indicate major genetic variation and simultaneous circulation of different strains, which increases the risk of epidemics and makes the creation of vaccines more difficult

Study outlines the evolutionary history of dengue virus type 2
2013-05-22

The results indicate major genetic variation and simultaneous circulation of different strains, which increases the risk of epidemics and makes the creation of vaccines more difficult.

Study outlines the evolutionary history of dengue virus type 2

The results indicate major genetic variation and simultaneous circulation of different strains, which increases the risk of epidemics and makes the creation of vaccines more difficult.

2013-05-22

The results indicate major genetic variation and simultaneous circulation of different strains, which increases the risk of epidemics and makes the creation of vaccines more difficult

 

By Karina Toledo

Agência FAPESP – A study published in the journal PLoS One has mapped the evolutionary history of one of the four dengue virus species transmitted to humans by the Aedes aegypti mosquito, dengue virus serotype 2 (DENV-2), in Brazil.

The results reveal simultaneous circulation of different lineages of DENV-2 throughout the country, which could be associated with a greater number of epidemic outbreaks and serious manifestations of the disease when compared to the three other types of dengue virus. The existence of greater genetic variability among DENV-2 has also been cited as the cause of poor success in vaccine testing.

To map the phylogenetic and phylogeographic diversity of the virus, or rather, its evolutionary path in different regions of the country, researchers from the São José do Rio Preto Medical School (Famerp), Universidade Federal de Juiz de Fora, and the Massachusetts Institute of Technology (MIT) completely sequenced 12 samples from DENV-2 patients treated in São José do Rio Preto during the 2008 epidemic. The data were compared to sample data from dengue genetics databases in Brazil and around the globe.

The study was coordinated by Mauricio Lacerda Nogueira from Famerp’s Virology Research Laboratory and received funding from FAPESP and the Minas Gerais Research Foundation (Fapemig), along with resources from the São José do Rio Preto Health Secretariat and the National Institute of Science and Technology on Dengue (INCT).

“In each of the four species of the viruses that cause dengue, there are different genotypes. Within each genotype, there are also genetic variations that we call DENV-2 clades or lineages. Our data show that three different lineages of DENV-2 entered Brazil in the last 30 years and that all of them belong to the American/Asian genotype,” explained Nogueira.

According to the researcher, there are six different genotypes of DENV-2. The American/Asian genotype, which is believed to have come from Vietnam via Cuba, predominates today throughout the American continent. “The existing American genotype was originally derived from a more aggressive version of the virus from Asia that was better adapted to the epidemiological conditions of the Americas,” he explained.

The researchers named the three different lineages of DENV-2 analyzed in the study BR1, BR2 and BR3. They differ genetically due to 37 amino acid alterations. These variations, according to Nogueira, are found the region of the virus genome that interacts most with the human immune system.

The results published in PLoS One indicate that the first introduction of the American/Asian genotype would have occurred from 1988 to 1989, possibly in Rio de Janeiro. This lineage, named BR1, would have circulated continuously in different regions of the country for at least 14 years.

From 1998 to 2000, introduction of the BR2 lineage is thought to have occurred, but it was restricted to the Northeast. Simultaneously, in 1999, BR3 appeared in the Southeast, reaching the North in 2001 and causing major epidemics in Rio de Janeiro and São Paulo from 2007 to 2008. BR3 surpassed the two other lineages in terms of the number of cases and serious manifestations.

Constant presence

“We conducted a similar study with DENV-1, published in 2012 in the Archives of Virology, where we showed that when a new lineage of the virus emerges, the previous strain disappears completely. However, in the case of DENV-2, there were periods in which there were two different clades circulating at the same time in the country, which makes the virus more dangerous. The greater genetic variability favors epidemics,” explained Nogueira.

It is not by chance, affirmed the researcher, that DENV-2 has been a constant presence in inland São Paulo, while the other serotypes have caused epidemics in specific years and later disappeared for long periods. “Upon analyzing the Health Ministry data, one can detect dengue type 2 every year in Brazil and in different regions,” he said.

There has been a consensus among specialists for some years now that once an individual is infected by one serotype of dengue, the individual will be immune to that species of the virus, even if they are infected by different genotypes and lineages. However, recent studies have raised some doubts among scientists.

In a 2012 article published in The Lancet, researchers from the Sanofi Pasteur Laboratory reported only partial success with the dengue tetravalent vaccine, which was tested in 4,000 children aged 4–11 in Thailand.

The efficiency rate for DENV-1, DENV-3 and DENV-4 serotypes ranged from 60% to 90%. However, the DENV-2 serotype almost totally resisted the effects of the vaccine. One of the reasons indicated in the study was the difference between the clades circulating in the Thai population and those used for immunization.

Other tests with the Sanofi vaccine are underway in 10 countries in Asia and Latin America, among which is Brazil, with a study including 31,000 children and adolescents. “We don’t know if the Brazilian results will be similar to those from Thailand. It could be, for example, that the vaccine works against DENV-2 and does not work against DENV-4. We need more studies to understand the evolution of the four serotypes, the lineage variations and how much this matters in terms of the immune response, the number of cases and the severity of the disease,” affirmed Nogueira.

For the researcher, however, the most probable scenario is that the results will indicate the need to develop specific vaccines for each country and region. “We have to know exactly what type of virus is circulating in a location to know what type of vaccine we need. Just as it is not possible to make a generic vaccine for the flu, we may also have to make different vaccines against dengue. However, we need more data on the ongoing trials to know for sure,” he stated.

With funding from the FAPESP and São José do Rio Preto’s City Hall, Nogueira also coordinates, a real-time dengue surveillance project to monitor what happens in the municipality, which is currently facing a major epidemic. “We have already registered 8,000 cases in 2013 alone, and our data indicate that more than 90% correspond to DENV-4, which is apparently less aggressive. The number of serious cases has not been that large,” he explained.

Between 2009 and 2010, the region faced a DENV-1 epidemic with more than 20,000 cases. With epidemics so close together caused by different viruses and the constant presence of DENV-2, the population’s risk of suffering repeated infections has increased, which has also increased the risk of serious manifestations, warns the researcher.

The article “Circulation of Different Lineages of Dengue Virus 2, Genotype American/Asian in Brazil: Dynamics and Molecular and Phylogenetic Characterization” (doi: 10.1371/journal.pone.0059422) can be read at www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0059422
 

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