Tuesday, April 26, 2016

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


More than two years ago, in Zika, Dengue & Unusual Rates Of Guillain Barre Syndrome In French Polynesia, we looked at the first reports of serious illness linked to the Zika virus, and speculation that it might be due to concurrent or prior infection with Dengue.

A few weeks later, in a Eurosurveillance report (see Zika Virus Infection Complicated By Guillain-Barré Syndrome), the authors wrote:

Our patient, like part of others who also presented a GBS, harboured serological markers of resolute dengue and recent ZIKA infections. This raises the hypothesis of a sequential arboviral immune stimulation responsible for such unusual clustering of GBS cases during concurrent circulation of ZIKA and two dengue serotypes. The risk of developing GBS would be consequently underlain by a specific sequence of DENV and ZIKA infections.

It is not so far-fetched an idea, as we see it sometimes in sequential dengue infections, in a phenomenon called ADE (Antibody Dependent Enhancement).

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.

When congenital birth defects began cropping up in Brazil last fall, the ADE theory was immediately suggested as a possible contributing factor, since Zika is genetically very similar to Dengue. 

You'll find a January discussion here, and in February Helen Branswell wrote Dengue could be the surprise culprit making Zika worse, researchers say.

While this is all still an unproven theory, if true, it offers hope that the risks of seeing severe fetal outcomes, or neuroinvasive disease, are less in regions where other flaviviruses are not endemic. 

Adding a bit more fuel to this hypothesis, we have a new paper - that while not yet published in a peer-reviewed journal - has been offered as a preview on the BioRxiv (Bio Archive) site, called:

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Background For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases endemic in the same regions. Recent reports of severe disease associated with ZIKV, including Guillain-Barre syndrome and severe fetal abnormalities, have greatly heightened awareness. Given its recent history of rapid spread in immune naive populations, it is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent Aedes mosquito vectors are found. 

Globally, dengue virus (DENV) is the most common mosquito-transmitted human flavivirus and is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through a mechanism known as antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. 

Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. However, response to DENV antibodies has not yet been investigated. 

Methodology / Principal Findings We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. 

Conclusions / Significance Our results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

Follow the above link to read the full PDF of the study.

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