NPJ Vaccines · 14 authors, 5 centres
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ZF2001, a protein subunit COVID-19 vaccine, showed no adverse effects on female fertility, embryo-fetal development, or postnatal development in Sprague-Dawley rats in two nonclinical studies. Strong binding and neutralizing antibody responses were confirmed in dams and transferred to fetuses/offspring. These results support the use of ZF2001 in maternal immunization campaigns, including in women of childbearing potential.
**Background:** ZF2001 is a protein subunit COVID-19 vaccine targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, adjuvanted with aluminium hydroxide. It has been approved for emergency use in several countries, but pregnant and lactating women were excluded from initial clinical trials. Given the increased risk of severe COVID-19 in pregnancy, nonclinical developmental and reproductive toxicity (DART) studies are essential to support use in these populations. This paper reports two DART studies in Sprague-Dawley rats conducted according to ICH S5 (R3) guidelines.
**Methods:** Study 1 (embryo-fetal developmental toxicity, EFD) used 144 virgin female rats assigned to four groups: blank control (sodium chloride), adjuvant control (aluminium hydroxide), ZF2001 25 μg/dose, and ZF2001 50 μg/dose. Rats received three intramuscular doses on days 21 and 7 before mating and on gestation day (GD) 6. Main study cohort (n=24/group) underwent caesarean section on GD 20; immunogenicity cohort (n=12/group) had blood collected for antibody analysis. Study 2 (pre- and postnatal developmental toxicity, PPND) used 56 virgin female rats assigned to two groups: blank control and ZF2001 25 μg/dose (n=28/group). Rats received four intramuscular doses: 7 days before mating, GD 6, GD 20, and postnatal day (PND) 10. Pregnant rats (16/group) delivered naturally, and F1 offspring were monitored from PND 0 to postnatal week 11, including physical/reflex development, behavioral tests (autonomous activity via TopScan, modified Irwin’s evaluation), and reproductive performance. Antibody responses (RBD-binding IgG and pseudovirus neutralizing antibodies) were measured in dams and offspring.
**Key Results:** In both studies, no vaccine-related adverse effects were observed in dams except for local injection site reactions (khaki-yellow nodular deposits in muscle fibers) attributed to the aluminium adjuvant. In Study 1, body weight and food intake in the ZF2001 50 μg/dose group were significantly higher at some time points (e.g., body weight on GD 20: 4.3% higher vs adjuvant control, 6.8% higher vs blank control; body weight gain GD 0–20: up to 11.8% and 15.7% higher; food consumption on GD 19: 9.7% and 15.3% higher), but these were considered nonadverse. Female fertility indices (mating index, pregnancy rate, fertility index) were unaffected. Caesarean section data showed no differences in corpora lutea, implantation sites, resorptions, live fetuses, sex ratio, fetal body weight/length, or tail length. Placental weight was higher in ZF2001 groups vs blank control (p<0.05) but not vs adjuvant control (p>0.05), and not considered adverse. Fetal external, visceral, and skeletal examinations revealed no treatment-related malformations; one spontaneous malformation (exencephaly) occurred in the 50 μg/dose group and one in blank control, considered normal background. In Study 2, maternal delivery parameters (parturition rate, gestation length, pups per litter, live pups per litter) were similar between groups. Offspring survival rates at birth (99.5% control vs 99.0% ZF2001), on PND 4 (97.0% vs 98.5%), and during lactation (100% both) were comparable. No effects on physical development (auricle separation, incisor eruption, fur appearance, eye opening, pinna unfolding), reflex development (plane correction, negative geotaxis, auditory startle, aerial righting, pupillary reflex), or sexual development (vaginal opening, preputial separation) were observed. Autonomous activity and modified Irwin’s behavioral assessment showed no differences. Reproductive performance of F1 offspring (mating index, pregnancy rate, fertility index, caesarean section data) was unaffected. Antibody responses: In Study 1, all ZF2001-vaccinated dams had high anti-RBD-binding IgG titers (GMT ~10^6) on the day before cohabitation and GD 20, and antibodies were detected in F1 pups on GD 20, indicating placental transfer. In Study 2, high binding and neutralizing antibody titers were present in dams on GD 20 and PND 21, and in F1 pups on PND 21 and PND 70, confirming transfer via placenta and lactation. No antibodies were detected in control groups.
**Clinical Implications:** These nonclinical DART studies demonstrate that ZF2001 has no adverse effects on female fertility, embryo-fetal development, or postnatal development in rats at doses up to 50 μg/dose (≥50-fold human dose by body weight). Strong antibody responses and passive transfer to offspring suggest potential for maternal immunization to protect neonates. The results support clinical trials and use of ZF2001 in pregnant and lactating women, and have already supported marketing approval in China and Uzbekistan. However, the authors note that species differences limit direct extrapolation, and real-world clinical data are needed to confirm safety in pregnant women.