Wednesday, July 06, 2016

PLoS Currents: Another In Vitro Study Suggests Previous Dengue Exposure May Exacerbate Zika Severity


Our first hint that severe Zika virus infection might be mediated by either a concurrent or previous Dengue infection came in 2014 when we started getting reports of an outbreak of Dengue and Zika in French Polynesia, and a simultaneous increase in Guillain-Barre cases (see Zika, Dengue & Unusual Rates Of Guillain Barre Syndrome In French Polynesia).

 In February 2014, the ECDC wrote:
The reported complications in French Polynesia are not confirmed to be caused by ZIKAV infections. However, there is a temporal association with the simultaneous outbreaks of ZIKAV and dengue. It is important to determine the cause of this increase and a possible association with the ongoing transmission of DENV-1, DENV-3 and ZIKAV.

The following month (see Eurosurveillance: Zika Virus Infection Complicated By Guillain-Barré Syndrome) researchers raised the possibility that the 20-fold increase in GBS in French Polynesia might be due to `sequential arboviral immune stimulation'.

And while this had never been documented with Zika before, it made a certain amount of sense, in that we've seen this sort of thing before with sequential dengue infections. 

There are 4 distinct, but closely related, serotypes of the Dengue virus, and the first infection of any serotype is usually mild. The patient recovers with lifetime immunity, but remains susceptible to the other three serotypes.

When infected a second time,the host’s immune system - which already has neutralizing antibodies against the first DENV infection - misidentifies the second DENV infection as the first strain.
Rather than creating new neutralizing antibodies to fight the infection, it deploys its existing cross reactive, but non-neutralizing (read: ineffective) antibodies to the field of battle.

This is called ADE (Antibody Dependent Enhancement), and over the past 6 months it has been increasingly suggested as one of the reasons why Zika virus infections in the Americas - areas which have been hit hard by Dengue over the past decade - are unusually severe.

The plausibility of this idea is bolstered by the fact that Zika is in the same family of viruses (Flaviviridae), and is genetically very close to the Dengue branch.

So much so that diagnostic tests can have difficulty differentiating between the two infections.

Over the past 6 months we've revisited the idea several times, including:

Nature Immunology: Previous Dengue Infection May Make Zika Infection Worse

Dengue & Zika: Does What Goes Around, Come Around?

It's an elegant theory, and would help explain the sudden shift in Zika virulence when it arrived in the Americas, but it too early to consider it established fact.

That said, we've another in vitro study, published yesterday in PloS Currents, that looks at the effect of DENV serotype 2-derived monoclonal antibodies (4G2) on Zika virus infection of vero cells. 
Their findings support the plausibility of preexisting Dengue antibodies exacerbating a Zika infection, and the authors raise the possibility that other Flavivirus infections (including Japanese Encephalitis & Yellow Fever), might have similar ADE impacts. 

Follow the link below to read the full study.  

Utility of a Dengue-Derived Monoclonal Antibody to Enhance Zika Infection In Vitro
July 5, 2016 · Research Article   

Anu Susan Charles, Rebecca C. Christofferson


Introduction: Zika virus (ZIKV) has emerged in dengue (DENV) endemic areas, where these two related flaviviruses continue to co-circulate. DENV is a complex of four serotypes and infections can progress to severe disease. It is thought that this is mediated by antibody dependent enhancement (ADE) whereby antibodies from a primary DENV infection are incapable of neutralizing heterologous DENV infections with another serotype. ADE has been demonstrated among other members of the Flavivirus group.

Methods: We utilize an in vitro ADE assay developed for DENV to determine whether ZIKV is enhanced by a commonly available DENV serotype 2-derived monoclonal antibody (4G2).

Results: We show that ZIKV infection in vitro is enhanced in the presence of the 4G2 mAb.

Discussion: Our results demonstrate that ADE between ZIKV and DENV is possible and that the 4G2 antibody is a useful tool for the effects of pre-existing anti-DENV antibodies during ZIKV infections.


While 4G2 is DENV2-derived, it is broadly used as an anti-flavivirus monoclonal antibody22,23. Thus, it cannot be ruled out that ZIKV could be enhanced by other closely related flaviviruses such as Japanese Encephalitis or Yellow Fever. As the scientific community pushes to fill the gaps in our ZIKV knowledge base, elucidating the potential for interaction with DENV is critical. Understanding the methods and tools available for such investigations is important to move the field of ZIKV research forward. Hence, our results demonstrate not only the utility of a widely available tool for ZIKV research, but also provides further insight into the potential for a role of pre-existing Flavivirus antibody in ZIKV pathogenesis.

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