Hadley Young

 Introduction. Zika Virus (ZIKV) is a flavivirus spread by Aedes mosquitoes and transmitted sexually and trans-placentally.³ First discovered in 1947 in Uganda, the recent ZIKV epidemic began in Brazil in 2015.³ Beyond flu-like symptoms, ZIKV has been linked to microcephaly and Guillian-Barre’ syndrome.¹ Treatment is presently supportive and preventative, but current research is exploring specific antibodies including EDE1 C8 and C10 that bind and neutralize the E protein of ZIKV.⁴ The process of cell entry and mechanism of neutralization related to the E protein is thought to distinguish ZIKV from other flaviviruses and is vital to the development of future therapeutic strategies.² Methods. In the studies, mice were utilized as animal models to test the ZIKV E protein interaction with specific antibodies. Monoclonal antibodies were screened with bilayer interferometry for neutralization of ZIKV and cross-neutralization of other flaviviruses.⁴ Interferon knockout mice were treated with antibodies and neutralization outcomes were analyzed using crystallization and X-ray structures, pH adjustments with Cryo-EM, and antigenic cartography.^4-6 Results. EDE1 antibodies like C8 and C10 more strongly neutralized ZIKV than EDE2 antibodies like B7 and A11.⁴ Interaction with EDE1 antibodies required an E dimer to bind to the central ß-strand, which is highly conserved in flaviviruses. EDE1 antibodies locked the entire viral surface and the E protein raft to prevent structural rearrangement required for fusion of ZIKV with the membrane.^4,6 The EDE1 treated mice all survived, mostly exhibited no signs of illness, and gained more weight than ZIKV infected mice.⁵ Additionally, LALA variants increased therapeutic antibody safety by eliminating antibody-dependent enhancement.⁶ Conclusions. ZIKV and flaviviruses like DENV have geographical overlap and close to 60% similarity in sequence homology.⁵ Moreover, DENV has multiple drugs in late phases of clinical trials that could be cross-protective against ZIKV.⁵ The success of the ZIKV neutralizing antibodies EDE1 C8 and C10 in vitro and in vivo is a first step to thwarting ZIKV complications during pregnancy.⁵ Since fusion is a fundamental step in ZIKV infection, the EDE1 antibodies, especially LALA variants, could be great therapeutic candidates for ZIKV by blocking structural rearrangements of fusion.⁶ Emphasis on LALA mutated EDE1 antibodies offers promise for development of therapeutics for ZIKV and presents the potential for a universal vaccine encompassing all the flaviviruses. Most importantly, these LALA variant antibodies may offer immediate advantageous immune prophylaxis in pregnant women at risk of contracting ZIKV.⁴

1. Duca LM, Beckham JD, Tyler KL, Pastula DM. Zika Virus Disease and Associated Neurologic Complications. Current Infectious Disease Reports. 2017;19(1): 1-8.
2. Hasan SS, Miller A, Sapparapu G, et al. A human antibody against Zika virus crosslinks the E protein to prevent infection. Nature Communications. 2017;8:14722-14730.
3. Shuaib W, Stanazai H, Abazid AG, Mattar AA. Re-Emergence of Zika Virus: A Review on Pathogenesis, Clinical Manifestations, Diagnosis, Treatment, and Prevention. Am J Med. 2016;129(8):879.e7-879.e12.
4. Barba-Spaeth G, Dejnirattisai W, Rouvinski A, et al. Structural basis of potent Zika–dengue virus antibody cross-neutralization. Nature. 2016;539(7628):314-334.
5. Swanstrom JA, Plante JA, Plante KS, et al. Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus. mBio. 2016;7(4).
6. Zhang S, Kostyuchenko VA, Ng T-S, et al. Neutralization mechanism of a highly potent antibody against Zika virus. Nature Communications. 2016;7:13679-13686.