Dengue virus has four serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) and while infection by one serotype results in lifelong immunity against that specific serotype, infection by a different dengue serotype results in increased infectivity and more severe clinical manifestations such as dengue haemorrhagic fever and dengue-shock syndrome. This kind of aggravation of the infection when infected for the second time by a different dengue virus serotype is called antibody-dependent enhancement (ADE).
Zika virus tends to circulate in areas that are endemic to dengue infection, and most people who get infected with Zika virus are likely to be already infected with at least one of the four serotypes of dengue. It is not clearly known if previous infection with any of the four dengue virus serotypes worsens the subsequent infection with Zika virus.
Monkeys and patients with previous dengue infection did not show antibody-dependent enhancement when infected with Zika
Earlier studies have proposed out that people infected with any of the four serotypes of dengue virus are at increased risk of Zika infectivity and clinical manifestation due to ADE.
In vitro studies
But two studies published recently have shown that this is not true. A study published recently in the journal Nature Communications, found four rhesus macaques with pre-existing dengue virus immunity showed typical antibody-dependent enhancement with Zika during in vitro studies. Samples were tested at periodical intervals for up to 2.5 years after infection with dengue.
Monkeys show contradicting results
But tests carried out on monkeys (in vivo) produced completely different results. Compared with monkeys that were not already infected with dengue virus, the four monkeys that had pre-existing infection with dengue did not show any increase in the amount of Zika virus or have the disease worsened. In fact, previous exposure to dengue led to a reduction in the amount of Zika virus and faster clearance of Zika virus compared with monkeys that had no pre-infection with dengue virus. There were changes in the immune response induced by Zika virus but that did not lead to increased infectivity or severity of Zika disease.
“Results from our work may suggest that pregnant women with previous exposure to dengue virus may have limited Zika viremia [amount of virus] and less tendency to have invasion of the central nervous system,” the authors conclude.
Confirmation in patients
Results of another study carried out in Zika-infected patients with pre-existing dengue infection also did not show increased infectivity or severity of Zika disease. The results published in the journal Clinical Infectious Diseases were based on 65 patients with acute febrile illness (45 patients positive for Zika and 20 patients positive for dengue type-2) between January and June 2016.
To understand the link between ADE in patients with previous dengue infection and subsequent infection with dengue type-2 or Zika, the researchers studied the viral loads and cytokine profiles during acute infection.
A ‘cytokine storm’ arises from overly expressed immunological response when people are reinfected with another serotype of dengue virus. An increase in about 10 cytokines indicates the occurrence of severe dengue and poor outcomes.
Of the 10 cytokines studied, except one all the other nine cytokines showed significantly lower levels in dengue patients who were previously infected with dengue; but the authors note that the study had “low power to detect biologically-realistic differences” in dengue virus load.
In the case of patients with Zika infection, the researchers did not see increased infectivity or severity of disease whether patients were previously infected with dengue or not. All Zika-infected patients recovered after receiving recommended supportive therapy.
“Our focus now is to continue to evaluate this cohort to determine whether primary infection by dengue does, in fact, provide protective benefits in secondary infections by Zika and by other dengue serotypes,” the authors write.