Risk of Zika microcephaly correlates with features of maternal antibodies

Robbiani, Davide F.; Olsen, Priscilla C.; Costa, Federico; Wang, Qiao; Oliveira, Thiago Y.; Nery, Nívison; Aromolaran, Adeolu; Rosário, Mateus Santana do; Sacramento, Gielson Almeida do; Cruz, Jaqueline S.; Khouri, Ricardo; Wunder, Elsio A.; Mattos, Adriana; Freitas, Bruno de Paula; Sarno, Manoel; Archanjo, Gracinda; Daltro, Dina; Carvalho, Gustavo B. S; Pimentel, Kleber; Siqueira, Isadora Cristina de; Almeida, João Ricardo Maltez de; Henriques, Daniele Freitas; Lima, Jaime; Vasconcelos, Pedro Fernando da Costa; Schaefer-Babajew, Dennis; Azzopardi, Stephanie; Bozzacco, Leonia; Gazumyan, Anna; Belfort, Rubens; Alcântara, Ana P; Moreira, Lícia Maria Oliveira; Araujo, Katiaci; Reis, Mitermayer Galvão dos; Keesler, Rebekah I.; Coffey, Lark L.; Tisoncik-Go, Jennifer; Gale, Michael; Rajagopal, Laksmi; Waldorf, Kristina M. Adams; Dudley, Dawn M.; Simmons, Heather A.; Mejía, Andrés; O’Connor, David H.; Steinbach, Rosemary J.; Haese, Nicole; Smith, Jessica L.; Lewis, Anne D.; Colgin, Lois M.A.; Roberts, Victoria H. J.; Frias, Antonio E.; Kelleher, Meredith A.; Hirsch, Alec J.; Streblow, Daniel N.; Rice, Charles M.; MacDonald, Margaret R.; Almeida, Antônio Raimundo Pinto de; Rompay, Koen K. A. Van; Ko, Albert Icksang; Nussenzweig, Michel C.

doi:10.1084/jem.20191061

“…Conversely, antibodies to ZIKV that are maternally acquired cause more severe disease in mice infected with dengue (47). Finally, features of the antibodies that increase ZIKV infection in in vitro ADE assays correlate with an enhanced risk of Zika microcephaly in humans and brain pathology in macaque (22). Thus, even though preliminary epidemiologic studies in humans do not show ADE of ZIKV (48), the potential for enhancement is a safety concern for ZIKV vaccine development that clinical trials need to address.…”

Section: Discussionmentioning

confidence: 97%

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

Rompay¹,

Coffey²,

Kapoor

³

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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“…Conversely, antibodies to ZIKV that are maternally acquired cause more severe disease in mice infected with dengue (49). Finally, features of the antibodies that increase ZIKV infection in in vitro ADE assays correlate with an enhanced risk of Zika microcephaly in humans and brain pathology in macaque (22). Thus, the potential for enhancement is a safety concern for ZIKV vaccine development that clinical trials need to address.…”

Section: Discussionmentioning

confidence: 99%

“…One of the potential issues with vaccination is that active immunization regimens require time to induce protective immunity and therefore vaccination after conception may be ineffective in preventing fetal disease in the setting of an active outbreak. In addition, there is concern about vaccine-mediated enhancement because features of maternal antibodies that enhance ZIKV infection in vitro are associated with an increased risk of human microcephaly and other neurologic defects in humans and macaques (22). Thus, there is a need to develop strategies to limit maternal and fetal pathology that are rapid, effective, and safe.…”

mentioning

confidence: 99%

A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques

Rompay

¹

,

Coffey

²

,

Kapoor

³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and 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 (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three 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.

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“…Not only was this shown to occur in conventional antigen presenting cells, dependent on the Fc gamma receptors, DENV antibodies can also enhance uptake of ZIKV in the syncytiotrophoblasts, and fetal endothelial cells of the placenta in a mechanism dependent on the fetal neonatal Fc Receptor, FcRN (27). In support of the role of antibody dependent enhancement of ZIKV pathology in vivo in humans, mothers with antibodies that were highly enhancing to ZIKV were shown to have fetuses (or children) with more severe microcephaly phenotypes (68). This pathological influence of DENV immunity during subsequent ZIKV infection may be specific for the context of pregnancy, since epidemiologic studies in humans suggest that ZIKV infection rates may be reduced in DENV immune non-pregnant individuals (69).…”

Section: Flavivirus Cross-reactive Antibody Responsesmentioning

confidence: 97%

Cross-Reactive Immunity Among Flaviviruses

Rathore

¹

,

John

²

2020

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Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping geographical distributions, coupled with increases in vaccination coverage, increase the likelihood of exposure to multiple flaviviruses. Depending on the antigenic properties of the viruses to which a person is exposed, flavivirus cross-reactivity can be beneficial or could promote immune pathologies. In this review we describe our knowledge of the functional immune outcomes that arise from varied flaviviral immune statuses. The cross-reactive antibody and T cell immune responses that are protective versus pathological are also addressed.

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Risk of Zika microcephaly correlates with features of maternal antibodies

Cited by 43 publications

References 59 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

A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques

Cross-Reactive Immunity Among Flaviviruses

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