Spotlight
Dengue Antibody
and Zika: Friend or
Foe?
Anna P. Durbin1,*
Zika virus is a mosquito-borne Fla-
vivirus related to dengue that is
rapidly spreading through the
Americas. This outbreak is occur-
ring in dengue-endemic areas
where the population has acquired
antibodies to dengue. Recent stud-
ies reveal that preexisting dengue
antibodies may have opposite
effects on Zika infection, transmis-
sion, and clinical outcome. Dis-
cerning these effects is critical to
a better understanding of Zika
pathogenesis and the prevention
of future outbreaks.
Zika and Dengue Infections
Before 2015, Zika virus had caused small
outbreaks in Africa, parts of Asia, and
French Polynesia. Subsequently, it has
spread dramatically throughout South
and Central America, with ongoing circu-
lation being reported in 67 countries and
territories as of July 2016. Zika virus
causes an asymptomatic infection in
approximately 80% of those infected
and when symptomatic the resultant ill-
ness is generally mild, comprising low-
grade fever, pruritic rash, myalgias, and
non-purulent conjunctivitis [1]. The excep-
tion to this is congenital Zika infection,
which can result in devastating conse-
quences for the fetus including death,
microcephaly, and other brain abnormali-
ties [2]. The association between Zika
virus infection during pregnancy and
microcephaly led the World Health Orga-
nization to declare Zika a Public Health
Emergency of International Concern. In
addition to microcephaly, increasing num-
bers of cases of GuillainBarr syndrome
(GBS) have also been reported during the
current epidemic; however, a causal link Recently there have been several papers
between Zika infection and GBS has yet to evaluating the effect of preexisting DENV
be made. antibody on Zika infection [79]. These
studies are important as the current Zika
Zika is a mosquito-borne virus and is a epidemic is occurring in areas where den-
member of the Flavivirus genus of the gue is endemic. Plasma collected from
Flaviviridae family. Phylogenetic analysis dengue patients during the convalescent
has determined that Zika is most closely phase of their illness was able to bind to
related to Spondweni virus, with which it both DENV and Zika virus but was poorly
shares approximately 70% nucleotide neutralizing for Zika in the majority of
identity overall. By comparison, it shares patients [7]. Interestingly, plasma from
approximately 60% nucleotide identity three samples strongly neutralized Zika.
with Japanese encephalitis virus, West By contrast, pooled convalescent serum
Nile virus, and dengue virus (DENV) [3]. was able to enhance Zika infection of the
This relatedness with DENV has compli- monocyte cell line U937 by more than
cated the serologic diagnosis of Zika. Per- 100-fold. Monoclonal antibodies gener-
sons who have previously been exposed ated from DENV-infected patients were
to DENV and who are subsequently also evaluated and many were found to
infected with Zika virus mount an anam- crossreact with Zika, some of which
nestic response to DENV making it difcult caused enhancement of Zika infection of
to denitely determine which virus was the U937 cells while others were able to neu-
etiologic agent. In addition, these crossre- tralize Zika and prevent ADE. The two
active antibodies may play a role in trans- monoclonal antibodies that highly neutral-
mission of Zika and possibly in its clinical ized Zika virus were previously demon-
outcome. strated to be broadly crossreactive and
highly neutralizing against all four DENV
Antibody-Mediated Enhancement serotypes (EDE1 C8 and EDE1 C10) [9].
of Infection These antibodies are directed against
There are four DENVs and infection with quaternary epitopes in the E dimer and
one DENV serotype is thought to confer are thought to be induced by sequential
long-lived protection against symptomatic heterotypic dengue infection [10].
reinfection with that same serotype. Only Although more severe dengue is associ-
short-term protection is conferred against ated with a second, heterotypic dengue
the other DENV serotypes; indeed, more infection, the broad immunity induced by
severe disease is associated with second, the second infection appears to protect
heterotypic DENV infections, presumably against illness induced by third and fourth
by the phenomenon of antibody-mediated dengue infections. It is unclear whether
enhancement of infection (Figure 1). This this broad protection is mediated by highly
phenomenon occurs when crossreactive neutralizing antibodies such as the EDE1
non-neutralizing antibody is able to bind to antibodies but this is an area of active
the virus and allow entry of the virusanti- investigation.
body complex through Fcg receptors on
monocytes and macrophages [4], leading Concluding Remarks
to higher virus titers. Antibody-dependent Although dengue antibody can enhance
enhancement (ADE) of infection has been Zika infection in vitro, there has been no
well documented for DENV [5]. In addition, epidemiologic evidence of enhanced Zika
ADE across different Flavivirus groups has illness during the current epidemic.
been demonstrated in vitro for several a- Enhancement of Zika infection by preex-
viviruses, including Zika [6]. Despite this, isting dengue antibody may, however,
ADE leading to more severe disease has contribute to more procient transmission
been described only for dengue and het- of Zika by mosquitoes and may affect the
erologous DENV antibody. ability of Zika to infect and replicate within
Trends in Immunology, October 2016, Vol. 37, No. 10 635
 Dengue virus transmission is ongoing. These studies
provide a good opportunity to investigate
the effects of dengue immunity on both
the cellular and the humoral immune
response to Zika infection. It is critical to
determine whether preexisting Flavivirus
antibody, particularly dengue antibody,
is contributing to the clinical outcome or
Dengue anbodies transmission of Zika in the current epi-
demic, to better control the outbreak
and to address future outbreaks.
No eect 1
Anbody Center for Immunization Research, Department of
International Health, Johns Hopkins Bloomberg School of
dependent
Public Health, Baltimore, MD, USA
enhancement
Neutralizaon *Correspondence: adurbin1@jhu.edu (A.P. Durbin).
http://dx.doi.org/10.1016/j.it.2016.08.006

Zika virus References

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virus infections with distinct serotypes (blue, red) usually lead to the production of serotype-specic antibodies in Rio de Janeiro preliminary report. N. Engl. J. Med.
(blue, red). These antibodies can confer protection against the same serotype (green lines) but may enhance Published online March 4, 2016. http://dx.doi.org/
infection by other serotypes (red arrow). Serial infections can lead to the production of broadly crossreactive, 10.1056/NEJMoa1602412
highly neutralizing antibodies (pink) that confer protection against multiple serotypes. In the case of Zika virus 3. Ye, Q. et al. (2016) Genomic characterization and phyloge-
infection, dengue-specic antibodies may do nothing, may lead to enhanced infection of Fcg receptor-bearing netic analysis of Zika virus circulating in the Americas. Infect.
Genet. Evol. 43, 4349
cells, or may protect against infection, depending on the antibody. Broadly crossreactive, highly neutralizing
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enhancement in peripheral blood leukocytes from immune
human beings. Proc. Soc. Exp. Biol. Med. 151, 136139
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