Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates

Dudley, Dawn M.; Rompay, Koen K. A. Van; Coffey, Lark L.; Ardeshir, Amir; Keesler, Rebekah I.; Bliss‐Moreau, Eliza; Grigsby, Peta L.; Steinbach, Rosemary J.; Hirsch, Alec J.; MacAllister, Rhonda; Pecoraro, Heidi L.; Colgin, Lois M.A.; Hodge, Travis; Streblow, Daniel N.; Tardif, Suzette D.; Patterson, Jean L.; Tamhankar, Manasi; Seferovic, Maxim D.; Aagaard, Kjersti M.; Martín, Claudia Sánchez San; Chiu, Charles Y.; Panganiban, Antonito T.; Veazey, Ronald S.; Wang, Xiaolei; Maness, Nicholas J.; Gilbert, Margaret H.; Bohm, Rudolf P.; Waldorf, Kristina M. Adams; Gale, Michael; Rajagopal, Lakshmi; Hotchkiss, Charlotte E.; Mohr, Emma L.; Capuano, Saverio; Simmons, Heather A.; Mejía, Andrés; Friedrich, Thomas C.; Golos, Thaddeus G.; O’Connor, David H.

doi:10.1038/s41591-018-0088-5

Cited by 94 publications

(114 citation statements)

References 29 publications

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“…ZIKV infection of pregnant macaques is associated with fetal demise and neuropathology (11)(12)(13). To evaluate the effect of anti-ZIKV antibodies on fetal development and health in pregnant primates, we performed timed breeding experiments and challenged the dams 3 times with 10 3 PFU of ZIKV subcutaneously on gestational days (GD) 30, GD 60 and GD 90, which corresponds to 1 st and 2 nd trimester (normal gestation of rhesus macaques is ~165 days) (21).…”

Section: Resultsmentioning

confidence: 99%

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A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

Rompay¹,

Coffey²,

Kapoor

et al. 2020

Preprint

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Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmissionand fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement in vitro (ADE) and extend their half-lives. Here we report on prophylactic co-administration of the Fc-modified antibodies to pregnant rhesus macaques challenged 3 times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV. Significance statement:Zika virus (ZIKV) infection during pregnancy can cause fetal abnormalities. Vaccines against ZIKV are under development, but because of potential safety concerns due to disease enhancing antibodies, and the time required by active immunization to induce protective antibodies, there is a need to explore alternative strategies. Recombinant monoclonal antibodies can be modified to prevent enhancement of infection, and thus could be an efficacious and safe alternative to vaccines to confer rapid protection. We show that prophylactic administration of two engineered antibodies, Z004 and Z021, to pregnant macaques partially protects against fetal neurologic damage and limits vertical transmission of ZIKV.

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Section: Resultsmentioning

confidence: 99%

“…The rate of adverse outcomes varies but can surpass 40% in some regions (7)(8)(9)(10). Similar consequences are observed in macaques, where experimental infection during gestation can lead to fetal neuropathology and demise (11)(12)(13).…”

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confidence: 83%

A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

Rompay¹,

Coffey²,

Kapoor

et al. 2020

Preprint

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“…Established animal models of ZIKV infection during pregnancy that result in vertical transmission include non-human primates (NHP) and type-1 interferon/interferon receptor deficient mice. In NHP models, first trimester infection most frequently results in fetal demise and reduced fetal development even in asymptomatic mothers, while second trimester infections tend to produce fetuses with higher viral loads but greater fetal viability [8][9][10]. In all NHP models, fetal pathology ranges from mild to severe manifestations, consistent with Congenital Zika Syndrome (CZS) seen in humans [11][12][13][14][15][16].…”

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confidence: 87%

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

Schwarz

Oliveira

Bonfante

et al. 2020

Viruses

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Zika virus (ZIKV) is an arbovirus that causes birth defects, persistent male infection, and sexual transmission in humans. The purpose of this study was to continue the development of an ovine ZIKV infection model; thus, two experiments were undertaken. In the first experiment, we built on previous pregnant sheep experiments by developing a mid-gestation model of ZIKV infection. Four pregnant sheep were challenged with ZIKV at 57-64 days gestation; two animals served as controls. After 13-15 days (corresponding with 70-79 days of gestation), one control and two infected animals were euthanized; the remaining animals were euthanized at 20-22 days post-infection (corresponding with 77-86 days of gestation). In the second experiment, six sexually mature, intact, male sheep were challenged with ZIKV and two animals served as controls. Infected animals were serially euthanized on days 2-6 and day 9 post-infection with the goal of isolating ZIKV from the male reproductive tract. In the mid-gestation study, virus was detected in maternal placenta and spleen, and in fetal organs, including the brains, spleens/liver, and umbilicus of infected fetuses. Fetuses from infected animals had visibly misshapen heads and morphometrics revealed significantly smaller head sizes in infected fetuses when compared to controls. Placental pathology was evident in infected dams. In the male experiment, ZIKV was detected in the spleen, liver, testes/epididymides, and accessory sex glands of infected animals. Results from both experiments indicate that mid-gestation ewes can be infected with ZIKV with subsequent disruption of fetal development and that intact male sheep are susceptible to ZIKV infection and viral dissemination and replication occurs in highly vascular tissues (including those of the male reproductive tract).Viruses 2020, 12, 291 2 of 23 and negative gestational outcomes when infection occurs during pregnancy. In humans, ZIKV is believed to result in trimester-specific effects to the fetus [2][3][4][5][6][7]. Established animal models of ZIKV infection during pregnancy that result in vertical transmission include non-human primates (NHP) and type-1 interferon/interferon receptor deficient mice. In NHP models, first trimester infection most frequently results in fetal demise and reduced fetal development even in asymptomatic mothers, while second trimester infections tend to produce fetuses with higher viral loads but greater fetal viability [8][9][10]. In all NHP models, fetal pathology ranges from mild to severe manifestations, consistent with Congenital Zika Syndrome (CZS) seen in humans [11][12][13][14][15][16]. While NHP models of ZIKV infection during pregnancy recapitulate human infection, other outbred host models can serve as surrogates when ethical and economic constraints create obstacles to the use of NHP.Sheep offer a unique animal model for translational biomedical research, and have long been used as a model for human pregnancy and fetal development due to longer gestation and comparably staged rates of fetal d...

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“…The most severe consequences of infection are manifest in fetuses, which can develop devastating developmental aberrations, including microcephaly, collectively referred to as congenital Zika syndrome (Brasil et al, 2016; Del Campo et al, 2017). Infection of macaques, a natural host of ZIKV, during pregnancy frequently leads to fetal demise (Dudley et al, 2018), and in some non-human primate models, prenatal and early postnatal infection is associated with fetal and infant neuropathology and persistent functional and behavioral abnormalities (Coffey et al, 2018; Mavigner et al, 2018). …”

Section: Introductionmentioning

confidence: 99%

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

et al. 2018

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SUMMARY Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.

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Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates

Cited by 94 publications

References 29 publications

A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

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