Human antibodies targeting Zika virus NS1 provide protection against disease in a mouse model

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Zika virus (ZIKV) is a mosquito-borne flavivirus causing severe human diseases like microcephaly and Guillain-Barré syndrome.
• Current treatments and vaccines for ZIKV infection are unavailable, necessitating the development of novel therapeutic strategies.

Purpose of the Study:

• To isolate and characterize human monoclonal antibodies (mAbs) targeting the ZIKV non-structural protein 1 (NS1).
• To evaluate the potential of these NS1-specific mAbs in preventing ZIKV infection and disease.

Main Methods:

• Isolation and characterization of four ZIKV NS1-specific mAbs from an infected patient.
• In vitro assessment of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent enhancement (ADE) of ZIKV infection.
• In vivo efficacy studies using a lethal ZIKV challenge model in Stat2 knockout mice, comparing wild-type and Fc-function-deficient mAbs.

Main Results:

• The characterized mAbs were non-neutralizing but could engage FcγR without inducing ADE in vitro.
• Monoclonal antibody AA12 demonstrated significant Fc-dependent protection against lethal African and Asian ZIKV strains in Stat2^-/- mice.
• Fc-dependent effector functions were crucial for the in vivo protective efficacy of mAb AA12.

Conclusions:

• The ZIKV NS1 protein is a viable target for therapeutic antibody development.
• Fc-mediated effector functions are critical for the protective activity of anti-ZIKV antibodies.
• NS1-specific mAbs, like AA12, represent a promising avenue for ZIKV countermeasures.