SÃO PAULO.- A study led by Brazilian researchers shows that people who have had the Zika virus run a higher risk of subsequently having 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 known to be typically more severe than the first, but until now no correlation between this fact and the occurrence of other diseases had been investigated.
The study is published in the journal PLOS Neglected Tropical Diseases.
The mechanism that exacerbates dengue infection following a case of Zika differs from that of two consecutive infections by the dengue virus, the authors conclude. The viral load is higher in the second dengue episode, with high levels of inflammatory cytokines not seen in Zika.
Detection of other markers suggested that the increase in severity may be due to activation of T cells, key parts of the immune system that help produce antibodies, in a pathogenic immune response that has been termed the "original antigenic sin."
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 combat a new infection. Because these new cells are not specific to 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, identifying those with prior Zika and dengue infections. The cases occurred in 2019 in São José do Rio Preto, a large city in São Paulo state, Brazil, considered hyperendemic for dengue since more than 70% of the population has had the disease. Its climate and geography favor the circulation of arboviruses throughout the year. Dengue epidemics occurred there in 2010, 2013, 2015, 2016 and 2019, with a record number of cases involving serotype 2.
"We concluded that a prior dengue infection was not a risk factor for severity, probably because the patients were already into their third or fourth infection. Prior Zika infection, however, was important and an aggravating factor in a second dengue episode. This led us to suggest novel mechanisms and renew our knowledge of the natural history of the disease," Cássia Fernanda Estofolete, an infectious disease specialist at the São José do Rio Preto Medical School (FAMERP) and first author of the article, told Agência FAPESP.
"Our findings confirmed the results of a previous study involving children who had Zika in Nicaragua. Later, when they had dengue, the risk of severity increased. We showed the same thing [risk of severe dengue increased by prior Zika or dengue] for adults in Brazil. We also showed that ADE [antibody-dependent enhancement, in which—instead of providing protection—antibodies enhance viral entry into host cells and can exacerbate the disease] is non-classical," said corresponding author Maurício Lacerda Nogueira.
"This raises questions about the type of Zika vaccine that should be used and the optimal timing: should it be administered with a dengue vaccine in order to avoid this problem of one following the other, for example? There are various possibilities, which need to be understood to ensure correct prescription. In Brazil, it's still more important to give the dengue vaccine first because of the number of cases," added Nogueira.