Dengue and Zika are both flaviviruses, are transmitted by the same mosquito (Aedes aegypti), and have similar symptoms. Almost half of the world’s population, about 4 billion people, live in areas with a risk of dengue. Dengue is often a leading cause of illness in areas with risk.
Much discussion and prior research has focused on how some patients with prior dengue infections can be at risk for developing severe dengue fever. Would the same be true for the impact of prior Zika infection on dengue patients?
In a new study, Brazilian researchers have shown that people who have had Zika do indeed run a higher risk of subsequently having severe dengue and being hospitalized.
Patients with a history of Zika infection had a 2.34 times higher risk of developing severe dengue and a 3.39 times higher risk of hospitalization compared to the controls (subjects with no dengue and no Zika history). Relatively advanced age (over 59) was also a higher risk factor for severe forms of dengue and hospitalization.
“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)
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.
Zika and Dengue Have Different Mechanism for Exacerbating Future Dengue Severity
Preliminary findings suggest that the mechanism is not the same one triggered in secondary dengue. The researchers did not find evidence of Zika virus antibody-dependent enhancement contributing to exacerbation of the subsequent dengue infection.
Dengue Antibody-Dependent Enhancement (ADE)
Infection by any of the four DENV serotypes may cause an acute febrile illness and lead to severe and potentially fatal clinical outcomes. While most patients recover from a self-limited illness, a small number progress to severe dengue disease. Potential outcomes of the secondary heterologous infections include an intense inflammatory response culminating in increased viral titers and exacerbated immune activation, a process known as ADE.
ADE occurs when non-neutralizing antibodies from a previous DENV infection bind to DENV in a subsequent heterotypic infection but cannot neutralize the virus. This results in the binding and entry of antibody-virus complexes to the Fcγ receptors (FcγR) on circulating monocytes, thus exacerbating clinical presentations manifested by hemodynamic changes, increased viremia, and proinflammatory cytokine profiles.
Zika T-Cell Activation
The science suggests that rather than ADE, the increase in dengue severity following a Zika infection may be due to activation of T cells, key parts of the immune system that help produce antibodies. 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.
Important Implications for Zika Vaccine Strategy
“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. 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,” Nogueira said.
In March 2023, a dengue vaccine produced by a Japanese company won approval from ANVISA, Brazil’s health surveillance agency, and this vaccine is now available from private clinics. Butantan Institute is developing an entirely indigenous dengue vaccine for distribution to public clinics . Development of a Zika vaccine is ongoing but at an earlier stage.
Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. (PLOS Pathogens – Aug 2023)
During recurrent infection, the antibody-mediated amplification of the disease severity sets a high bar to develop a vaccine against DENV. There is currently no such vaccination technique that can completely protect against all four serotypes in naive people. The most leading vaccine, a tetravalent live attenuated candidate (CYD-TDV), has received approval in certain dengue-prevalent nations; however, it has the unintended consequence of raising the risk of severe dengue in individuals who have never been infected by DENV. For the last ten years, our research group has been working on designing and production of monoclonal antibody (mAb) fragments and short peptide vaccines against DENV. Here, we deliberate the serotype-specific and cross-reactive epitopes and the therapeutic potential of the neutralizing and cross-reactivity antibodies targeted to these epitopes. After that, the mAbs developed against virus particle-like quaternary structure is described. Lastly, the insights on severe pathogenesis and ADE would provide extended knowledge to design future subunit vaccines and therapeutic mAbs. (Frontiers in Immunology – June 2023)
Serological cross-reactivity has proved to be a challenge to diagnose Zika virus (ZIKV) infections in dengue virus (DENV) endemic countries. Confirmatory testing of ZIKV IgM positive results by plaque reduction neutralization tests (PRNTs) provides clarification in only a minority of cases because most individuals infected with ZIKV were previously exposed to DENV. The goal of this study was to evaluate the performance of a ZIKV/DENV DUO IgM antibody capture ELISA (MAC-ELISA) for discriminating between DENV and ZIKV infections in endemic regions. (The American Journal of Tropical Medicine and Hygiene – Dec 2021)