Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine

Abstract

BNT162b2 is a vaccine developed to prevent coronavirus disease 2019 (COVID-19). BNT162b2 is a lipid nanoparticle formulated nucleoside-modified messenger RNA (mRNA) encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein locked in its prefusion conformation. A developmental and reproductive toxicity study was conducted in rats according to international regulatory guidelines. The full human BNT162b2 dose of 30 μg mRNA/dose (>300 times the human dose on a mg/kg basis) was administered intramuscularly to 44 female rats 21 and 14 days prior to mating and on gestation days 9 and 20. Half of the rats were subject to cesarean section and full fetal examination at the end of gestation, and the other half were allowed to deliver and were monitored to the end of lactation. A robust neutralizing antibody response was confirmed prior to mating and at the end of gestation and lactation. The presence of neutralizing antibodies was also confirmed in fetuses and offspring. Nonadverse effects, related to the local injection site reaction, were noted in dams as expected from other animal studies and consistent with observations in humans. There were no effects of BNT162b2 on female mating performance, fertility, or any ovarian or uterine parameters nor on embryo-fetal or postnatal survival, growth, physical development or neurofunctional development in the offspring through the end of lactation. Together with the safety profile in nonpregnant people, this ICH-compliant nonclinical safety data supports study of BNT162b2 in women of childbearing potential and pregnant and lactating women.

Keywords: BNT162b2; COVID-19 vaccine; Developmental toxicity; Fertility; Pregnancy; Rat.

Fig. 1

Overview of the study design. Female rats were administered four intramuscular injections (2 prior to cohabitation with the males and 2 during gestation) of saline (control) or BNT162b2 (44/group). On each dosing day, animals were administered the full human dose (30 μg mRNA/dose) by intramuscular injection into the quadriceps muscle. Approximately half the rats (n = 22/group) underwent cesarean section on gestation day (GD) 21. The remaining rats (n = 22/group) were allowed to deliver naturally, and the maternal animals and offspring were followed through to the end of weaning. Blood was collected for measurement of antibody response in maternal animals prior to the first dose, at mating, end of gestation, and end of lactation. Blood was collected from fetuses at the end of gestation and from the littered offspring at the end of lactation.

Fig. 2

Functional antibody response against SARS-CoV2, as measured by microneutralization titer (MNt), over time after administration of saline (control) or BNT162b2 to female rats. See methods section for details on the method. MNt in dams were measured just prior to cohabitation for the mating phase, at the end of gestation on GD21, and at the end of lactation on LD 21. There were no detectable titers in females prior to first dose (data not shown). MNt in offspring were measured on GD 21 (fetuses) and PND 21 (pups). Titer data for each individual animal are shown with their respective means.

Fig. 3

Body weight of female rats (n = 44/group) following administration of saline (control) or BNT162b2 during the premating, gestation, and lactation phases. Significant decrease compared to control (p < 0.05) indicated by (*).