Evaluation of a Zika virus-like particle-based vaccine in a highly penetrant non-human primate model of congenital infection

Abstract

Zika virus (ZIKV) is an arthropod-borne Orthoflavivirus that caused a major outbreak in Central and South America in 2015–16. During that outbreak, ZIKV infection during pregnancy was associated with high rates of adverse outcomes, including miscarriage and a spectrum of neurological birth defects collectively termed congenital Zika syndrome (CZS). Ten years later, there are still no licensed ZIKV vaccines, underscoring the need for robust experimental models to evaluate vaccine efficacy against congenital disease. Here, we evaluated a highly pathogenic nonhuman primate pregnancy model for its ability to assess vaccine-mediated protection using a Zika virus-like particle (VLP) vaccine as a test platform. First, non-pregnant rhesus macaques (RM) were vaccinated with a prime-boost method to compare control, VLP alone, and VLP plus Alhydrogel (alum) adjuvant. Vaccination plus alum elicited strong neutralizing antibody responses and reduced viral dissemination compared to controls. Next, we evaluated the vaccine’s protective efficacy against adverse pregnancy complications. Two cohorts of female RM were vaccinated with ZIKV-VLP adjuvanted with alum or alum alone prior to time-mated breeding. At gestational day (GD) 30 (mid first trimester), pregnant animals were challenged with ZIKV-DAK 41524, an African-lineage strain previously shown to induce frequent first-trimester pregnancy loss. Within the vaccinated cohort, two of three animals reached the study endpoint of GD 90 with no observed adverse pregnancy outcomes. One vaccinated animal experienced early pregnancy loss despite the absence of detectable virus in fetal or placental tissues. In the sham vaccine control pregnancy cohort, severe adverse outcomes included miscarriage and hydrops fetalis with widespread viral RNA and placental pathology in two animals. These results support a high risk of early pregnancy loss following African-lineage ZIKV-DAK 41524 infection in RM. This model can be further used to understand the complexities of placental immunological features underlying miscarriage following ZIKV infection.