A study led by researchers in Brazil shows that people infected with Zika have a higher risk of later developing severe dengue and being hospitalized. The finding is highly relevant to the development of a Zika vaccine.
According to the scientific literature, a second infection by any of the four known dengue serotypes is generally known to be more severe than the first, but so far no relationship between this fact and the occurrence of other diseases has been explored.
An article on the research has been published in the journal PLoS Neglected Tropical Diseases.
The authors concluded that exacerbation of dengue infection after Zika infection is different from two consecutive infections with dengue virus. While the viral load is high in the second dengue episode, the high levels of inflammatory cytokines are not seen in Zika.
Identification of other markers suggested that the cause of the exacerbation may be T cells, a key part of the immune system that help produce antibodies, a pathogenic immune response termed the “original antigenic signature”. The process involves so-called T-cell memory, a response in which T cells produced during a previous infection stimulate the production of more T cells to fight a new infection. Because these new cells are not specific for the virus, they trigger an excessive release of inflammatory cytokines, which attack the organism’s proteins and tissues, potentially leading to hemorrhage.
The researchers analyzed samples from 1,043 laboratory-confirmed dengue patients, identified as those with prior Zika and dengue infections. Cases occurred in 2019 in São José do Río Preto, a large city in the state of São Paulo, Brazil, which was considered hyperendemic for dengue because more than 70% of the population is infected with the disease. Its climate and geography favor the circulation of arboviruses throughout the year. There were dengue epidemics in 2010, 2013, 2015, 2016 and 2019, involving record numbers of serotype 2.
“We concluded that prior dengue infection was not a risk factor for exacerbations, possibly because patients were already on their third or fourth infection. However, prior Zika infection was important and a precipitating factor in second dengue episodes. This led us to suggest novel approaches and treatments for the disease. To renew our knowledge of the natural history,” Cassia Fernanda Estofolate Agenzia FAPESP, an infectious disease specialist at the São José do Rio Preto Medical School (FAMERP) and first author of the article, told
FAPESP supported the research through a research grant awarded to Estofolate, a postdoctoral fellowship for Alice Freitas Varciani, the second author of the article, and a thematic project grant for corresponding author Mauricio Lacerda Nogueira. Versiani and Lacerda are also affiliated with FAMERP.
“Our results confirmed the results of a previous study in Nicaragua with children with Zika. Later, when they had dengue, the risk of exacerbations increased. We showed the same thing. [risk of severe dengue increased by prior zika or dengue] For adults in Brazil. We have also shown that the ADE [antibody-dependent enhancement, in which, instead of providing protection, antibodies enhance viral entry into host cells and can exacerbate the disease] non-classical. This raises questions about the type and best timing of the Zika vaccine: For example, should it be administered with a dengue vaccine to avoid one after the other? There are several possibilities, which need to be understood, to ensure proper prescription. In Brazil, it is more important to give the dengue vaccine first because of the number of cases,” Nogueira said.
In November 2023, the number of dengue cases in Brazil surpassed the number notified in the 12 months of 2022, reaching 1,372,000, of which 1 million were confirmed between January and July (when the latest available bulletin was issued). The states of São Paulo and Minas Gerais had the most cases, according to the health ministry.
Regarding Zika, the latest number for 2023 is 4,773 possible cases, of which 1,725 have been confirmed. Bahia and Rio Grande do Norte had the most cases. Arboviral diseases are generally underreported, epidemiologists believe, because they are difficult to diagnose and because many people have mild symptoms and do not seek health services for treatment.
In 2016, when Zika outbreaks occurred in many parts of the world, there were more than 1.5 million in Brazil to 2.38 confirmed cases in the Americas. In 2019, there was a dengue epidemic in South America, with more than 3.13 million notified cases, four years after Zika first appeared on the continent.
In March 2023, a dengue vaccine produced by a Japanese company received approval from Brazil’s health surveillance agency ANVISA, and the vaccine is now available from private clinics. The Butantan Institute is developing a fully indigenous dengue vaccine for distribution in public clinics (Read more at agencia.fapesp.br/50764) Zika vaccine development is ongoing but at an early stage.
Dengue and Zika are both flaviviruses, transmitted by the same mosquito (Aedes aegypti), and have similar symptoms, often making diagnosis difficult. Dengue is more serious because it can cause bleeding and even death in addition to fever, headache, muscle and joint pain, rash and nausea.
Zika symptoms are mild, but the virus can cause serious problems in pregnant women and babies, such as microcephaly and possibly Guillain-Barré syndrome, a neurological disorder that leads to paralysis.
Experts have warned about this eds Global warming and climate change are causing mosquitoes and their infections to appear in temperate regions. Deforestation also contributes to the increase in cases as biodiversity hotspots have more mosquito predators.
The study was conducted using samples from suspected dengue patients confirmed by RT-PCR. The samples were assessed for past history of dengue and Zika infection using an enzyme-linked immunosorbent assay (ELISA) developed by the FAMERP group in partnership with Lee Gehrke’s laboratory at the Massachusetts Institute of Technology (MIT), USA. The test was specifically developed to eliminate the high cross-reactivity between flaviviruses observed in commercial kits available in the market.
The analysis showed that patients with a history of Zika infection had a 2.34 times higher risk of severe dengue and a 3.39 times higher risk of hospitalization compared to controls (subjects without dengue and no history of Zika). Relatively advanced age (over 59 years) was a high risk factor for dengue and hospitalization.
With years of research behind them, Nogueira and his group published a study in 2021 showing that prior dengue infection in pregnant women infected with the Zika virus did not increase the risk of giving birth to a baby with microcephaly (microcephaly).Read more at agencia.fapesp.br/36370)
Estofolete has now embarked on a new phase of research, extending the study period to cover dengue cases notified in 2022 and changing the serotype. “The goal is not only to answer questions about severity, but to know whether the process we identified is the same for all dengue serotypes because it affects other factors and processes. We don’t have a lot of knowledge about the Zika vaccine,” he said.