Ginsenoside Rb2-based inactivation enables a Zika vaccine that maintains pregnancy and protects offspring against virus.

The development of safe and effective inactivated vaccines against Zika virus (ZIKV) is hampered by limitations of conventional chemical inactivants. This study identifies ginsenoside Rb2 (G-Rb2), a natural plant-derived compound, as a novel and effective viral inactivant. G-Rb2 potently inactivated high-titer ZIKV under optimized conditions (200 μM, 37 °C) without cytotoxicity. Mechanistic investigations revealed that G-Rb2 disrupts the integrity of the viral envelope, thereby exposing and facilitating the degradation of the viral genome, a mode of action distinct from traditional cross-linking agents. The G-Rb2-inactivated ZIKV vaccine, formulated with adjuvant, demonstrated an excellent safety profile in susceptible AG6 mice, inducing no detectable viremia or pathogenicity. In immunocompetent mice, it elicited robust ZIKV-specific neutralizing antibodies and T-cell responses. Immunization conferred complete protection against a subsequent lethal ZIKV challenge, preventing viremia, weight loss, mortality, and pathological damage in the brain and testes. Crucially, maternal vaccination ensured successful pregnancy outcomes, protecting immunized pregnant dams and ensuring the birth of healthy offspring that were resistant to lethal challenge via transferred maternal antibodies. These findings establish G-Rb2 as a promising candidate for developing a novel, safe, and effective inactivated ZIKV vaccine with the critical ability to block mother-to-fetus transmission.