ZIKA VIRUS (01): AMERICAS, RESEARCH, OBSERVATIONS

Posted on 02ND JAN 2018
tagged Zika Virus, Americas

A ProMED-mail post
http://www.promedmail.org
ProMED-mail is a program of the
International Society for Infectious Diseases
http://www.isid.org

In this update:
[1] Cases in various countries:
Americas
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Americas cumulative case numbers

North America
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USA
- Florida (Manatee county)
- Florida (Miami-Dade county)
- Texas (Hidalgo and Cameron counties)

Mexico and Central America
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Mexico
- Morelos
- Tamaulipas
- Sonora
Guatemala
Honduras

Caribbean
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Trinidad and Tobago

South America
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Argentina (Salta)
Brazil
- National
- Rio de Janeiro
Bolivia (Santa Cruz)
Peru (Ica)

Asia
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Singapore

Pacific
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Australia (Queensland)

Africa
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Angola
- National
- Luanda

Imported cases with little or no possibility of ongoing mosquito transmission
USA
- Case numbers mainland
- Territories and Commonwealth with local transmission

[2] Brain calcification unreliable
[3] Mutation and virulence
[4] prM protein of Zika virus and fetal microcephaly
[5] Blockage of neuron road
[6] Zika virus CNS paralysis
[7] Unfolded protein and microcephaly
[8] Development effects age 19-24 months
[9] Zika virus, microcephaly and other risks
[10] B- and T-cell response in a primary Zika virus infection
[11] Zika virus neuropathogenesis
[12] DNA vaccine trial
[13] Marmosets as models
[14] Vector mosquito review

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[1] Cases in various countries
Americas cumulative case numbers
As of 21 Dec 2017
http://www.paho.org/hq/index.php?option=com_content&view=article&id=1239...
Country / Locally acquired: suspected / Confirmed / Imported / Deaths / Confirmed congenital syndrome
North America:
Bermuda / 0 / 0 / 6 / 0 / 0
Canada / 0 / 0 / 544 / 0 / 1
USA / 0 / 226 / 5324 / 0 / 98

Latin America:
Mexico / 0 / 11 667 / 15 / 0 / 20

Central American Isthmus:
Belize / 2005 / 355 / 0 / 0 / 0
Costa Rica / 7763 / 2014 / 32 / 0 / 19
El Salvador / 11 778 / 51 / 0 / 0 / 4
Guatemala / 3907 / 1032 / 0 / 0 / 140
Honduras / 32 385 / 308 / 0 / 0 / 8
Nicaragua / 0 / 2795 / 3 / 0 / 2
Panama / 5646 / 1250 / 42 / 0 / 16

Latin Caribbean:
Cuba / 0 / 187/ 58 / 0 / 0
Dominican Republic / 4919 / 335 / 0 / 0 / 85
French Guiana / 10 500 / 483 / 10 / 0 / 1
Guadeloupe / 30 845 / 382 / 0 / 0 / 5
Haiti / 2955 / 5 / 0 / 0 / 1
Martinique / 36 680 / 21 / 0 / 0 / 5
Puerto Rico / 0 / 40 562 / 137 / 5 / 47
Saint Barthélemy / 1005 / 61 / 0 / 0 / 0
Saint Martin / 3283 / 200 / 0 / 0 / 1

Non-Latin Caribbean:
Anguilla / 31 / 23 / 1/ 0 / 0
Antigua and Barbuda / 540 / 25 / 2 / 0 / 0
Aruba / 1208 / 703 / 7 / 0 / 0
Bahamas / 531 / 25 / 3/ 0 / 0
Barbados / 715 / 150 / 0 / 0 / 1
Bonaire, St Eustatius and Saba / 235 / 437 / 0 / 0 / 0
Caymans / 237 / 30 / 11 / 0 / 0
Curacao / 4476 / 2049 / 0 / 0 / 0
Dominica / 1154 / 79 / 0 / 0 / 0
Grenada / 335 / 118 / 0 / 0 / 2
Guyana / 0 / 37 / 0 / 0 / 3
Jamaica / 7772 / 203 / 0 / 0 / 0
Montserrat / 18 / 5 / 0 / 0 / 0
Saint Kits and Nevis / 554/ 33 / 0 / 0 / 0
Saint Lucia / 822 / 50 / 0 / 0 / 0
Saint Vincent and the Grenadines / 508 / 83 / 0 / 0 / 0
Sint Maarten / 253 / 149 / 0 / 0 / 0
Suriname / 2768 / 724 / 0 / 4 / 4
Trinidad and Tobago / 0 / 718 / 1 / 0 / 17
Turks and Caicos / 203 / 25 / 3 / 0 / 0
Virgin Islands (UK) / 74 / 53 / 0 / 0 / 0
Virgin Islands (USA) / 1165 / 1024 / 2 / 0 / 0

Andean Area:
Bolivia / 2636 / 806 / 4 / 0 / 14
Colombia / 98 803 / 9927 / 0 / 0 / 248
Ecuador / 3954 / 2397/ 15 / 0 / 14
Peru / 7366 / 1530 / 22 / 0 / 0
Venezuela / 60 146 / 2413 / 0 / 0 / 0

[Brazil and] Southern Cone:
Brazil / 231 725 / 137 288 / 0 / 11 / 2952
Argentina / 539 / 278 / 41 / 0 / 5
Chile / 0 / 0 / 34 / 0 / 0
Paraguay / 705 / 20 / 0 / 0 / 2
Uruguay / 0 / 0 / 1 / 0 / 0

Totals, Americas / 583 144 / 223 336 / 6318 / 20 / 3715

[Maps showing the location of the affected islands and countries in the Americas mentioned above and below can be accessed at
http://healthmap.org/promed/p/35574;
North America: . - Mod.TY]

Pacific
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Australia (Queensland). 29 Nov 2017. (conf) 1 imported case ex Cuba. There is concern that local _Aedes aegypti_ could become infected from imported cases and initiate transmission.
http://www.townsvillebulletin.com.au/news/dengue-and-zika-virus-threat-f...

[HealthMap/ProMED-mail map
Queensland, Australia: http://healthmap.org/promed/p/285 - Mod.TY]

Africa
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Angola
- National. 1 Dec 2017. (WHO reported) As of 29 Nov 2017, a total of 42 cases of microcephaly have been reported, of which 39 occurred in live births and 3 were in stillbirths. Most of the cases (39, 93 per cent) originated from Luanda Province, especially in the southern part of the city. The other cases came from Zaire province (1 case), Moxico province (1), and Benguela province (1). A total of 15 blood specimens were collected either from the newborns or their mothers and sent to the National Public Health Institute laboratory. To date, all the specimens have tested negative for Zika virus by polymerase chain reaction (PCR).
http://apps.who.int/iris/bitstream/10665/259557/1/OEW48-2504122017.pdf

[Since all 15 blood samples tested negative by PCR, these cases must be termed suspected.

HealthMap/ProMED-mail map
Angola: http://healthmap.org/promed/p/165. - Mod.TY]

- Luanda. 1 Dec 2017. (conf) 2 cases, 1 adult febrile case, 1 stillborn malformed fetus; microcephaly apparently increasing but no proof of Zika virus infection.
http://apps.who.int/iris/bitstream/10665/259557/1/OEW48-2504122017.pdf

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Imported cases with little or no possibility of ongoing mosquito transmission
USA
- Case numbers mainland. Zika virus disease in the United States, 1 Jan-20 Dec 2017
http://www.cdc.gov/zika/geo/united-states.html
State / Symptomatic cases / Viremic blood donors
Alabama 3 / 3
Alaska 1 / 0
Arizona 2 / 0
Arkansas 0 / 0
California 46 / 4
Colorado 6 / 0
Connecticut 0 / 0
Delaware 0 / 0
District of Columbia 2 / 0
Florida 92 / 5
Georgia 2 / 0
Hawaii 2 / 0
Idaho 0 / 0
Illinois 7/ 0
Indiana 2 / 0
Iowa 1 / 0
Kansas 2 / 0
Kentucky 2 / 0
Louisiana 1 / 5
Maine 1 / 0
Maryland 10 / 1
Massachusetts 9 / 0
Michigan 7 / 0
Minnesota 6/ 0
Mississippi 2 / 0
Missouri 2 / 0
Montana 0 / 0
Nebraska 1 / 0
Nevada 1 / 0
New Hampshire 0/ 0
New Jersey 11 / 0
New Mexico 0 / 0
New York 61 / 1
North Carolina 5 / 0
North Dakota 0 / 0
Ohio 3 / 0
Oklahoma 1 / 0
Oregon 5 / 0
Pennsylvania 6/ 1
Rhode Island 3 / 0
South Carolina 2 / 0
South Dakota 0 / 0
Tennessee 1 / 0
Texas 44 / 2
Utah 4 / 0
Vermont 3 / 0
Virginia 6 / 0
Washington 13 / 0
West Virginia 1/ 1
Wisconsin 4 / 0
Wyoming 2 / 0
Totals 385 / 23

- Territories and Commonwealth with local transmission
Symptomatic / Blood donors
American Samoa 72 / 0
Puerto Rico 494 / 6
US Virgin Islands 45/ 0
Total 611 / 6

[A map of the USA showing the states and territories mentioned above can be accessed at http://www.mapsofworld.com/usa/. - Mod.TY]

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[2] Brain calcification unreliable
Date: Fri 13 Oct 2017
Source: BMJ journal [edited]
http://www.bmj.com/content/359/bmj.j4188.long

ref: Petribu NCL, Aragao MFV, van der Linden V, et al. Follow-up brain imaging of 37 children with congenital Zika syndrome: case series study.
BMJ. 2017; 359: j4188. doi: 10.1136/bmj.j4188
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Abstract
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Objective. To compare initial brain computed tomography (CT) scans with follow-up CT scans at one year in children with congenital Zika syndrome, focusing on cerebral calcifications.

Design. Case series study.

Setting. Barão de Lucena Hospital, Pernambuco state, Brazil.

Participants. 37 children with probable or confirmed congenital Zika syndrome during the microcephaly outbreak in 2015 who underwent brain CT shortly after birth and at one year follow-up.

Main outcome measure. Differences in cerebral calcification patterns between initial and follow-up scans.

Results. 37 children were evaluated. All presented cerebral calcifications on the initial scan, predominantly at cortical-white matter junction. At follow-up the calcifications had diminished in number, size, or density, or a combination in 34 of the children (92 per cent; 95 per cent confidence interval 79 per cent-97 per cent), were no longer visible in one child, and remained unchanged in 2 children. No child showed an increase in calcifications. The calcifications at the cortical-white matter junction which were no longer visible at follow-up occurred predominately in the parietal and occipital lobes. These imaging changes were not associated with any clear clinical improvements.

Conclusion. The detection of cerebral calcifications should not be considered a major criterion for late diagnosis of congenital Zika syndrome, nor should the absence of calcifications be used to exclude the diagnosis.

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communicated by:
ProMED-mail rapporteur Mary Marshall

[Many previous reports of lesions in fetuses and neonates infected with Zika virus mention cerebral calcifications. The report above indicates that cerebral calcification in infants may disappear after a year and at a year may no longer be a reliable diagnostic criterion. - Mod.TY]

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[3] Mutation and virulence
Date: Wed 20 Sep 2017
Source: Journal of Virology [edited]
http://jvi.asm.org/content/91/23/e01348-17.long

[ref: Annamalai AS, Pattnaik A, Sahoo BR, et al. Zika virus encoding non-glycosylated envelope protein is attenuated and defective in neuroinvasion. J Virol. 2017 Sep 20. pii: JVI.01348-17. doi: 10.1128/JVI.01348-17. [Epub ahead of print]
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Abstract
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Zika virus (ZIKV), a mosquito-transmitted flavivirus, responsible for sporadic outbreaks of mild and febrile illness in Africa and Asia, re-emerged in the last decade causing serious human diseases including microcephaly, congenital malformations, and Guillain-Barré syndrome. Although genomic and phylogenetic analyses suggest that genetic evolution may have led to enhanced virulence of ZIKV, experimental evidence supporting the role of specific genetic changes in virulence is currently outstanding. One sequence motif, VNDT, containing an N-linked glycosylation site in the envelope (E) protein, is polymorphic, being absent in many of the African isolates while present in all isolates from the recent outbreaks. In the present study, we interrogated the role of this sequence motif and glycosylation of the E protein in pathogenicity of ZIKV. We first constructed a stable full-length cDNA clone of ZIKV in a novel linear vector from which infectious virus was recovered. The recombinant ZIKV generated from the infectious clone, which contains the VNDT motif, is highly pathogenic and causes lethality in a mouse model. In contrast, recombinant viruses from which the VNDT motif is deleted or from which N-linked glycosylation site is mutated by single amino acid substitution, are highly attenuated and non-lethal. The mutant viruses replicate poorly in the brain of infected mice when inoculated subcutaneously but replicate well following intracranial inoculation. Our findings provide the first evidence that N-linked glycosylation of the E protein is an important determinant of ZIKV virulence and neuroinvasion.

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communicated by:
Roland Hübner
Superior Health Council
Brussels
Belgium

[It will be interesting to learn if other Zika virus isolates from the Americas also has the VNDT motif. A recent study suggests that the ZIKV African lineage is more toxic and causes more potent brain damage than the Asian lineage (http://dev.biologists.org/content/144/22/4114.long). - Mod.TY]

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[4] prM protein of Zika virus and fetal microcephaly
Date: Fri 17 Nov 2017
Source: Science journal [edited]
http://science.sciencemag.org/content/358/6365/933

ref: Yuan L, Huang XY, Liu ZY, et al. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science. 2017; 358(6365): 933-6. doi: 10.1126/science.aam7120. Epub 2017 Sep 28.
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Abstract
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Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution [Ser139 -->Asn139 (S139N)] in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.

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[An important question has been: why was microcephaly not recognized in Zika virus infection prior to the outbreak in French Polynesia in 2013? The answer may be that that the S139N substitution arose before the 2013 outbreak. However, relative virulence may depend as well on the clade and isolate tested. - Mod.TY]

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[5] Blockage of neuron road
Date: Thu 9 Nov 2017
Source: Virology Blog [edited]
http://www.virology.ws/2017/11/09/zika-virus-blocks-the-neuron-road-2/

The authors think it is likely that Zika virus disruption of glial fibers during embryonic development contributes to microcephaly: if neurons cannot migrate to the pial surface, the neocortex will be thinner. Zika virus infection also inhibits the proliferation of progenitor cells that line the ventricular surface, which is likely a contributing factor to microcephaly. Other embryonic brain cells are infected with Zika virus, and these could play a role in microcephaly. Furthermore, there are other effects of Zika virus infection on the developing brain, including calcifications, hypoplasia (reduced cell density), lissencephaly (smooth brain), ventriculomegaly (enlarged ventricle), and brainstem dysfunction.

--
communicated by:
ProMED-mail

[The report provides an interesting overview of neuronal movement in the developing fetal brain and the effects of Zika virus infection on that movement. - Mod.TY]

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[6] Zika virus CNS paralysis
Date: Mon 20 Nov 2017
Source: Nature Microbiology journal [edited]
https://www.nature.com/articles/s41564-017-0060-z?WT.mc_id=COM_NMicro_17...

Jurado KA, Yockey LJ, Wong PW, et al. Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. Nat Microbiol. 2017 Nov 20. doi: 10.1038/s41564-017-0060-z. [Epub ahead of print]
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Abstract
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Zika virus (ZIKV) is an emerging, mosquitoborne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly and Guillain-Barré syndrome as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis, meningoencephalitis, and fatal encephalitis. Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1-/-) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. We also find that antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood-brain barrier breakdown and T-cell-mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

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[7] Unfolded protein and microcephaly
Date: Mon 11 Dec 2017
Source: Nature Neuroscience journal [edited]
https://www.nature.com/articles/s41593-017-0038-4

ref: Gladwyn-Ng I, Cordón-Barris L, Alfano C, et al. Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly. Nat Neurosci. 2018; 21(1): 63-71. doi: 10.1038/s41593-017-0038-4.
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Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice.

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ProMED-mail

[Interestingly, a recent publication raises doubts about Zika virus causality of microcephaly. The author quantified and compared the prevalence of all and severe microcephaly in Brazil, during and before 2015-2016, to assess whether an outbreak has occurred, used time series analysis to evaluate if the presumed outbreak was linked to a previous outbreak of ZIKV infections, and quantitatively synthesized published data from observational studies testing this association. The results of this study indicated that the prevalences of microcephaly in 2015-2016 were similar or lower than background levels (prevalence ratio [PR]) for all microcephaly. Changes in the number of cases of ZIKV infections at times matching 11-18 weeks of pregnancy were not followed by changes in the number of microcephaly cases. In observational studies, the prevalence of microcephaly was not significantly increased in newborns of Zika-infected. In conclusion, existing evidence is insufficient to claim maternal ZIKV infection causes microcephaly. Although a public health response seems sensible, it should be consistent with existing knowledge and consider risks, potential benefits and harm, and competing priorities (https://www.sciencedirect.com/science/article/pii/S10472797173028310. It will be interesting to see if there are rebuttals of the conclusion, taking into consideration the clinical and experimental evidence of teratogenic effects from Zika virus infection of fetuses in the included and previous reports posted on ProMED-mail. - Mod.TY]

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[8] Development effects age 19-24 months
Date: Fri 15 Dec 2017
Source: CDC. MMWR Morb Mortal Wkly Rep. 2017; 66(49); 1347-51 [edited]
http://dx.doi.org/10.15585/mmwr.mm6649a2

ref: Satterfield-Nash A, Kotzky K, Allen J, et al. Health and development at age 19-24 months of 19 children who were born with microcephaly and laboratory evidence of congenital Zika virus infection during the 2015 Zika virus outbreak -- Brazil, 2017. MMWR Morb Mortal Wkly Rep. 2017; 66(49): 1347-51. doi: 10.15585/mmwr.mm6649a2.
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The Brazilian MOH, the State Health Secretariat of Paraíba, and CDC collaborated on a follow-up investigation of the health and development of children in northeastern Brazil who were reported to national surveillance with microcephaly at birth. In this study, 19 children with microcephaly at birth and laboratory evidence of Zika virus infection were assessed through clinical evaluations, caregiver interviews, and review of medical records. At follow-up (ages 19-24 months), most of these children had severe motor impairment, seizure disorders, hearing and vision abnormalities, and sleep difficulties. Children with microcephaly and laboratory evidence of Zika virus infection have severe functional limitations and will require specialized care from clinicians and caregivers as they age.

The families of 278 previously studied children residing in the ZODIAC [Zika outcomes and development in infants and children] investigation catchment area were eligible for inclusion; 122 children were enrolled, including 19 who were aged less than 24 months and who had both microcephaly at birth and laboratory evidence of Zika virus infection. Among the 19 children, 11 had a blood specimen that tested positive for Zika virus-specific IgM antibodies and neutralizing antibodies against Zika virus, and eight had only neutralizing antibodies against Zika virus. Among the 8 with neutralizing antibodies only, 7 had at least one test for other congenital infections; one had a positive toxoplasma immunoglobulin G (IgG) antibody result and one had positive rubella virus and cytomegalovirus IgG results. Both had negative IgM antibody results for these infections; the 1st had brain imaging findings consistent with congenital Zika virus infection and the 2nd had no record of imaging.

Of this group, 11 children screened positive for nonfebrile seizures, indicating possible seizure disorder (table 2, table 3 [tables available at the source URL above]). Caregivers reported that 8 children were previously hospitalized, including 6 hospitalized for bronchitis/pneumonia, and that 10 children had frequent sleeping difficulties and 9 had eating or swallowing challenges. There were 13 children with an impaired response to auditory stimuli; 4 children had retinal abnormalities and 11 had an impaired response to visual stimuli. There were 15 children who did not pass the ASQ-3 age interval questionnaire designed for a child aged 6 months; 15 children had a global score below 40 on the HINE, indicating severe motor impairment, including 14 who had findings consistent with cerebral palsy. Outcomes including feeding challenges, sleeping difficulties, severe motor impairment, vision and hearing abnormalities, and seizures tended to co-occur. All children had at least one of these outcomes, 12 had 3-5 of these outcomes, and 2 had all 6 outcomes; 4 children (infant no.s 16, 17, 18, and 19) (table 2) had typical growth and development at follow-up and might have been misclassified at birth.

This report expands on initial findings by demonstrating that specific outcomes, such as severe motor impairment and impaired visual and auditory response to stimuli, affect the majority of children with evidence of congenital Zika virus infection and microcephaly and become more apparent as these children age. Approximately 3/4 of young children affected by Zika virus infection in this analysis had at least 3 of the specified co-occurring outcomes. Many of the initial findings identified at birth remain present at ages 19-24 months, and these children are falling far behind in achievement of age-appropriate developmental milestones, indicating the need for long-term follow-up and support.

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communicated by:
ProMED-mail rapporteur Mary Marshall

[The human tragedy resulting from teratogenic effects of Zika virus infections is serious and will be long-term. The adverse social and economic consequences on families, especially those living under marginal conditions, are serious and continuous. - Mod.TY]

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[9] Zika virus, microcephaly and other risks
Date: Mon 11 Dec 2017
Source: The Lancet journal [edited]
http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(17)30727-2.pdf

ref: de Araújo TVB, Ximenes RAA, Miranda-Filho DB, et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect Dis. 2017. pii: S1473-3099(17)30727-2. doi: 10.1016/S1473-3099(17)30727-2. [Epub ahead of print]
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Summary
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Background: A Zika virus epidemic emerged in northeast Brazil in 2015 and was followed by a striking increase in congenital microcephaly cases, triggering a declaration of an international public health emergency. This is the final report of the 1st case-control study evaluating the potential causes of microcephaly: congenital Zika virus infection, vaccines, and larvicides. The published preliminary report suggested a strong association between microcephaly and congenital Zika virus infection.

Methods: We did a case-control study in 8 public maternity hospitals in Recife, Brazil. Cases were neonates born with microcephaly, defined as a head circumference of 2 SD below the mean. In each case, 2 controls without microcephaly by expected date of delivery and area of residence. We tested the serum of cases and controls and the CSF of cases for detection of Zika virus genomes with quantitative RT-PCR and for detection of IgM antibodies with capture-IgM ELISA. We also tested maternal serum with plaque reduction neutralisation assays for Zika and dengue viruses. We estimated matched crude and adjusted odds ratios with exact conditional logistic regression to determine the association between microcephaly and Zika virus infection.

Findings: We screened neonates born between 15 Jan and 30 Nov 2016, and prospectively recruited 91 cases and 173 controls. In 32 (35 per cent) cases, congenital Zika virus infection was confirmed by laboratory tests and no controls had confirmed Zika virus infections. 69 (83 per cent) of 83 cases with known birth weight were small for gestational age, compared with 8 (5 per cent) of 173 controls. The overall matched odds ratio was 73.1 (95 per cent CI 13.0-infinity) for microcephaly and Zika virus infection after adjustments. Neither vaccination during pregnancy or use of the larvicide pyriproxyfen was associated with microcephaly. Results of laboratory tests for Zika virus and brain imaging results were available for 79 (87 per cent) cases; within these cases, 10 were positive for Zika virus and had cerebral abnormalities, 13 were positive for Zika infection but had no cerebral abnormalities, and 11 were negative for Zika virus but had cerebral abnormalities.

Interpretation: The association between microcephaly and congenital Zika virus infection was confirmed. We provide evidence of the absence of an effect of other potential factors, such as exposure to pyriproxyfen or vaccines (tetanus, diphtheria, and acellular pertussis, measles and rubella, or measles, mumps, and rubella) during pregnancy, confirming the findings of an ecological study of pyriproxyfen in Pernambuco and previous studies on the safety of Tdap vaccine administration during pregnancy.

--
communicated by:
Roland Hübner
Superior Health Council
Brussels
Belgium

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[10] B- and T-cell response in a primary Zika virus infection
Date: Thu 21 Dec 2017
Source: PLoS Neglected Tropical Diseases journal [edited]
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006000

ref: Ricciardi MJ, Magnani DM, Grifoni A, et al. Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naive individual during the 2016 outbreak in Miami, FL. PLoS Negl Trop Dis. 2017; 11(12): e0006000. doi: 10.1371/journal.pntd.0006000. [Epub ahead of print]
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Abstract
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Zika virus (ZIKV) is a mosquitoborne flavivirus of significant public health concern. In the summer of 2016, ZIKV was 1st detected in the contiguous United States. Here we present one of the 1st cases of a locally acquired ZIKV infection in a dengue-naive individual. We collected blood from a female with a maculopapular rash at day (D) 5 and D7 post onset of symptoms (POS) and we continued weekly blood draws out to D148 POS. To establish the ontogeny of the immune response against ZIKV, lymphocytes and plasma were analyzed in a longitudinal fashion. The plasmablast response peaked at D7 POS (19.6 per cent of CD19+ B-cells) and was undetectable by D15 POS. ZIKV-specific IgM was present at D5 POS, peaked between D15 and D21 POS, and subsequently decreased. The ZIKV-specific IgG response, however, was not detected until D15 POS and continued to increase after that. Interestingly, even though the patient had never been infected with dengue virus (DENV), cross-reactive IgM and IgG binding against each of the 4 DENV serotypes could be detected. The highest plasma neutralization activity against ZIKV peaked between D15 and D21 POS, and even though DENV binding antibodies were present in the plasma of the patient, there was neither neutralization nor antibody dependent enhancement (ADE) of DENV. Interestingly, ADE against ZIKV arose at D48 POS and continued until the end of the study. CD4+ and CD8+ T-cells recognized ZIKV-NS2A and ZIKV-E, respectively. The tetramer positive CD8+ T-cell response peaked at D21 POS with elevated levels persisting for months. In summary, this is the 1st study to establish the timing of the ontogeny of the immune response against ZIKV.

Author summary
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Zika virus (ZIKV) is an emerging viral disease that has the potential to negatively impact future generations by causing birth defects in [fetuses of] infected pregnant mothers. While there have been many studies performed in animal models of ZIKV infection, there have only been a limited number of reports studying the immune responses in humans. Ricciardi et al analyzed the immune response of a primary ZIKV infection in a dengue virus (DENV) naive individual during the 2016 outbreak in Miami, Florida. B- and T-cell responses were assessed over multiple time points. Cross-reactive antibodies against DENV, a virus that the patient was never infected with, were generated during the ZIKV infection, but these antibodies failed to neutralize any of the DENV serotypes. Furthermore, while these DENV-cross-reactive antibodies might be expected to cause antibody dependent enhancement (ADE) of DENV infection, they did not. Interestingly, ADE of ZIKV infection was seen at approximately 1.5 months after infection. Together, these results establish the timing of the ontogeny of the immune response against a primary ZIKV infection in a DENV-naive individual.

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[Although these results are based on the response of a single individual, they likely can be extrapolated to other Zika virus infected individuals who have not had previous dengue virus infection. Confirmatory studies of other similar individuals would be of interest, especially as they relate to ADE. - Mod.TY]

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[11] Zika virus neuropathogenesis
Date: Sat 16 Dec 2017
Source: The Journal of Infectious Diseases [edited]
https://academic.oup.com/jid/article/216/suppl_10/S897/4753684

ref: Muñoz LS, Parra B, Pardo CA; Neuroviruses Emerging in the Americas Study. Neurological implications of Zika virus infection in adults. J Infect Dis. 2017; 216(suppl_10): S897-S905. doi: 10.1093/infdis/jix511.
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Abstract
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The 2015-2016 epidemic of Zika virus (ZIKV) in the Americas and the Caribbean was associated with an unprecedented burden of neurological disease among adults. Clinically, Guillain-Barré syndrome (GBS) predominated among regions affected by the ZIKV epidemic, but the spectrum of neurological disease in the adults appears broader as cases of encephalopathy, encephalitis, meningitis, myelitis, and seizures have also been reported. A para-infectious temporal profile of ZIKV-associated GBS (ZIKV-GBS) has been described in clinical studies, which may suggest a direct viral neuropathic effect. However, ZIKV neuropathogenesis has not yet been fully understood. Mechanisms for ZIKV-GBS and other neurological syndromes have been hypothesized, such as adaptive viral genetic changes, immunological interactions with other circulating flaviviruses, and host and factors. This review summarizes the current evidence on ZIKV-associated neurological complications in the adults.

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communicated by:
ProMED-mail

[GBS may not be the only neurological consequence of Zika virus infection. Interestingly, there is one case of a 17 year old boy who was transferred to a psychiatric emergency ward for evaluation of a 1st-episode psychosis. He had no significant health history or previous psychiatric history; 10 days prior to admission, he suddenly presented paranoid delusions and vivid auditory, somatic, and olfactory hallucinations. He showed intense anxiety and panic-like symptoms, alternating with moments of inadequate behavioral disinhibition. Symptoms also included sleeplessness, increased speech production, vocal mannerisms and refusal to eat. A distinct period of altered mood was negated. To the best of the author's knowledge, this is the 1st report in which psychiatric symptoms were the only complication of acute ZIKV infection. There is much evidence of psychiatric symptomatology in viral infections. Dengue-related manic and psychotic episodes have been described in which symptoms suggesting encephalitis or encephalopathy were not seen -- thus supporting flavivirus' role in inducing purely behavioral symptoms. Cases in which DENV infections have led to neuropsychiatric complications are numerous, well established in the literature and more commonly diagnosed than in regular clinical practice (http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462017000...).

Although this is just one case, it does indicate that clinicians need to be aware of the possibility of the occurrence of psychosis following Zika virus infections. - Mod.TY]

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[12] DNA vaccine trial
Date: Mon 4 Dec 2017 [ahead of print]
Source: The Lancet journal [edited]
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33105-7/fulltext

ref: Gaudinski MR, Houser KV, Morabito KM, et al. Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials. Lancet. 2017. pii: S0140-6736(17)33105-7. doi: 10.1016/S0140-6736(17)33105-7. [Epub ahead of print]
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Summary
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Background: The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed 2 new DNA vaccines expressing premembrane and envelope Zika virus structural proteins.

Methods: We did 2 phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in 3 centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18-35 years in VRC19 and 18-50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov [http://clinicaltrials.gov/], numbers NCT02840487 [http://clinicaltrials.gov/show/NCT02840487] and NCT02996461 [http://clinicaltrials.gov/show/NCT02996461].

Findings: VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and 2 in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46 per cent] of 80 participants in VRC 319 and 36 [80 per cent] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27 per cent] and 18 [22 per cent], respectively, in VRC 319 and 17 [38 per cent] and 15 [33 per cent], respectively, in VRC 320). For VRC5283, 14 of 14 (100 per cent) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials.

Interpretation: VRC5283 was well tolerated and has advanced to phase 2 efficacy testing.

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communicated by:
ProMED-mail rapporteur Mary Marshall

[DNA vaccine is an interesting approach for Zika virus vaccine development. This vaccine looks promising after having successfully completed phase 1 trials. Results of phase 2 efficacy trials are awaited with considerable interest. Interestingly, in a test of a different vaccine, healthy adults mounted strong immune responses after receiving an investigational whole inactivated Zika virus vaccine in 3 phase 1, placebo-controlled, double-blind trials. The findings were published on 4 Dec 2017 in The Lancet http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33106-9/fulltext.

There are also questions about the durability of Zika virus vaccination protection beyond the peak response. Investigators reported that a single immunization with an adenovirus vector-based vaccine, as well as 2 immunizations with a purified inactivated virus vaccine, afforded robust protection against ZIKV challenge in rhesus monkeys at 1 year after vaccination. In contrast, 2 immunizations with an optimized DNA vaccine, which provided complete protection at peak immunity, resulted in reduced protective efficacy at 1 year that was associated with declining neutralizing antibody titers to subprotective levels. These data define a microneutralization log titer of 2.0 to 2.1 as the threshold required for durable protection against ZIKV challenge in this model. Moreover, their findings demonstrated that protection against ZIKV challenge in rhesus monkeys is possible for at least 1 year with a single-shot vaccine. http://stm.sciencemag.org/content/9/420/eaao4163. - Mod.TY]

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[13] Marmosets as models
Date: Thu 7 Dec 2017
Source: Scientific Reports journal [edited]

[These experiments represent an interesting 1st step in testing marmosets as a non-human primate model for Zika virus infections. The authors indicate that none of the marmosets had had fever, rash, conjunctivitis, diarrhea, or postural abnormalities suggestive of joint and/or muscle pain, despite being infected. Further testing in a larger number of marmosets, including pregnant females, would be of interest. Interestingly, samples from sera and oral swabs from 15 marmosets (_Callithrix jacchus_) and 9 capuchin-monkeys (_Sapajus libidinosus_) captured in Ceará state in Brazil were tested for Zika virus. Samples were positive by real time PCR and sequencing of the amplified product from a capuchin monkey showed 100 per cent similarity to other ZIKV from South America. This is the 1st report on ZIKV detection among free-living neotropical primates (https://www.biorxiv.org/content/early/2016/04/20/049395), and raises concern about the establishment of a sylvan (forest) transmission cycle that would lead to endemicity in nature. - Mod.TY]

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[14] Vector mosquito review
Date: Thu 16 Nov 2017
Source: PLoS Neglected Tropical Diseases journal [edited]
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005933

ref: Epelboin Y, Talaga S, Epelboin L, Dusfour I. Zika virus: an updated review of competent or naturally infected mosquitoes. PLoS Negl Trop Dis. 2017; 11(11): e0005933. doi: 10.1371/journal.pntd.0005933. eCollection 2017 Nov
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Abstract
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Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) that recently caused outbreaks in the Americas. Over the past 60 years, this virus has been observed circulating among African, Asian, and Pacific Island populations, but little attention has been paid by the scientific community until the discovery that large-scale urban ZIKV outbreaks were associated with neurological complications such as microcephaly and several other neurological malformations in fetuses and newborns. This paper is a systematic review intended to list all mosquito species studied for ZIKV infection or for their vector competence. We discuss whether studies on ZIKV vectors have brought enough evidence to formally exclude other mosquitoes than _Aedes_ species (and particularly _Aedes aegypti_) to be ZIKV vectors. From 1952 to 15 Aug 2017, ZIKV has been studied in 53 mosquito species, including 6 _Anopheles_, 26 _Aedes_, 11 _Culex_, 2 _Lutzia_, 3 _Coquillettidia_, 2 _Mansonia_, 2 _Eretmapodites_, and 1 _Uranotaenia_. Among those, ZIKV was isolated from 16 different _Aedes_ species. The only species other than _Aedes_ genus for which ZIKV was isolated were _Anopheles coustani_, _A. gambiae_, _Culex perfuscus_, and _Mansonia uniformis_. Vector competence assays were performed on 22 different mosquito species, including 13 _Aedes_, 7 _Culex_, and 2 _Anopheles_ species with, as a result, the discovery that _A. aegypti_ and _Aedes albopictus_ were competent for ZIKV, as well as some other _Aedes_ species, and that there was a controversy surrounding _Culex quinquefasciatus_ competence. Although _Culex_, _Anopheles_, and most of _Aedes_ species were generally observed to be refractory to ZIKV infection, other potential vectors transmitting ZIKV should be explored.

Author summary
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The 1st isolation of Zika virus (ZIKV) in mosquitoes was made in 1948 in _Aedes africanus_. Over the next years, knowledge about ZIKV increased, with detection of the virus in primates, including humans and several other mosquito species. Most of these species were collected in Africa during arbovirus surveillance studies and belong to the genus _Aedes_, and today, 20 mosquito species have been identified that can be naturally infected by ZIKV. Although field studies are essential to have an overview of potential mosquito vectors of ZIKV during outbreaks or involved in the maintenance of the sylvatic cycle, laboratory studies are needed to assess the capacity of a species to transmit the virus to a new host. Since 2015, corresponding to the beginning of the outbreak in Brazil, vector competence studies have multiplied and confirmed that the mosquito _A. aegypti_, known to transmit dengue fever and chikungunya viruses, was also the main vector of ZIKV. This review aims to highlight the studies conducted from several laboratories about mosquito species naturally infected or tested for their vector competence for ZIKV.

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communicated by:
ProMED-mail

[Mere isolation of Zika virus from field-caught mosquitoes does not prove that they are competent vectors of this virus in nature. Laboratory virus transmission studies are required to prove or discard vector competence. As the authors point out, _A. aegypti_ is the main vector mosquito. Results of susceptibility and competence studies of _Culex quinquefasciatus_ are conflicting, but most indicate that this species is refractory to infection or transmits the virus inefficiently. Although _A. aegypti_ is considered the main Zika virus vector, a recent study indicated that _A. albopictus_ mosquitoes given a 2nd, virus-free blood meal a couple of days later became much more infectious than mosquitoes given a single blood meal (https://medicalxpress.com/news/2017-11-extra-blood-invasive-asian-tiger....).

[The incidence of Zika virus infections has been declining over the past 12 months in the Americas, but likely has become endemic in many localities there and will not disappear. - Mod.TY]

See Also
2017
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Zika virus (21): Americas, research, observations 20171009.5367967
Zika virus (20): Americas, Asia, research, observations 20170925.5339356
Zika virus (19): Americas, research, observations 20170917.5322171
Zika virus (18): Americas, research, observations 20170908.5303860
Zika virus (17): Americas, research, observations 20170830.5283102
Zika virus (16): Americas, Asia, research, observations 20170819.5261363
Zika virus (15): Americas, research, observations 20170701.5144254
Zika virus (14): Americas, Asia, research, observations 20170623.5127418
Zika virus (13): Americas, research, observations 20170617.5112404
Zika virus (12): Americas, Asia, research, observations 5099103
Zika virus (11): Americas, research, observations 20170604.5083731
Zika virus (10): Americas, Asia, Middle East, research 20170529.5069572
Zika virus (09): Americas, Asia, Europe, research, observations 20170517.5043638
Zika virus (08): Americas, Asia, research, observations 20170501.5005629
Zika virus (07): Americas, PAHO/WHO 20170429.5003908
Zika virus (06): Americas, Pacific, Asia, Africa, research 20170416.4974439
Zika virus (05): Americas, Pacific, Asia, research, observations 20170326.4927523
Zika virus (04): Americas, Asia Europe, research, observations 20170320.4912123
Zika virus (03): Americas, research 20170309.4888510
Zika virus (02): Americas, Asia, Africa, Pacific, research, observations 20170217.4846633
Zika virus (01): Americas, Asia, Africa, research 20170117.4772206
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