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AZD1222 (ChAdOx1-nCov19): An intramuscular injection vaccine development and reproductive toxicity study in female CD-1 mice

Richard Stebbings, Shaun Maguire, Gillian Armour, Christopher Jones, Joanne Goodman, Anna Karin Maguire, Chi Man Tang, Vicky Skellett, Jayne Harris

Clinical Pharmacology & Safety Sciences, AstraZeneca, Cambridge, UK

The COVID-19 Vaccine AstraZeneca (AZD1222, also known as ChAdOx1-nCov19) is a recombinant replication-deficient chimpanzee adenovirus (ChAd) expressing the SARS-CoV-2 spike (S) surface glycoprotein (Folegatti, et al. Lancet. 2020;396:467–478). The aim of this preliminary study was to evaluate the effects of AZD1222 on the fertility and reproductive processes of the female CD-1 mouse during embryofetal development (EFD) and littering phases to support administration of AZD1222 to pregnant and lactating women.

AZD1222 was administered by intramuscular injection on 2 occasions to each dam (0.07 mL/occasion) at half the standard human dose. During the EFD phase, 16 female mice were given AZD1222 on Day 1 (13 days prior to pairing for mating) at 2.5×10¹⁰ viral particles (VP) and on Gestation Day (GD) 6 at 2.59×10¹⁰ VP. For the littering phase, 15 female mice were given AZD1222 on GD 6 and on GD 15 at 2.59×10¹⁰ VP. Groups of 16 females acted as controls in both phases, receiving buffer instead. The following were assessed: clinical observations, body weights, food consumption, dermal scoring, mating performance, fertility indices, gestation duration, litter performance, litter survival indices, litter and pup weights, immunogenicity (dams, fetuses, and pups), gravid uterus weights and corrected maternal body weights (EFD phase only), examinations of pregnancies with fetal weights and examinations (visceral and skeletal examination, EFD phase only), and dam and pup gross pathology. There were no AZD1222-related effects seen for dams in-life or at the site of injection or for female reproduction, fetal, or pup survival, and there were no abnormal gross pathology findings in pups or dams in the EFD or littering phases. There were no AZD1222-related fetal visceral or skeletal findings.

Antibody response to S-glycoprotein was measured in dams, fetuses, and pups during lactation. All serum samples from control animals were below the limit of quantification (0.25 AU/mL) for the immunogenicity assay and were considered seronegative. In AZD1222 EFD phase dams, immunogenicity results indicated an antibody response to S-glycoprotein, with seroconversion of all vaccinated animals occurring prior to mating. Antibody responses to S-glycoprotein were maintained from Day 14 (mean [SD] antibody concentration 354.9 [142.5] AU/mL) through GD 7, the day after the second dose (788.1 [531.1] AU/mL), and both dams and pooled fetal samples were seropositive by GD 17.5 (184.1 [96.5] and 91.0 [53.9] AU/mL, respectively). In AZD1222 littering phase dams, antibodies to S-glycoprotein were observed on GD 15 in all vaccinated animals, before the second dose (55.8 [47.8 AU/mL]). This response was maintained at Lactation Day (LD) 14 for all dams (155.1 [116.9] AU/mL), and pooled samples from pups at LD 14 were seropositive (266.2 [196.9] AU/mL), with greater anti–S-glycoprotein antibody levels in pups on LD 14 compared with fetal samples on GD 17.5.

To conclude, intramuscular administration of AZD1222 to CD-1 female mice during the EFD and littering phases was well tolerated. Anti–S-glycoprotein antibody responses were raised in all dams following administration of AZD1222, and these responses were maintained throughout the gestational and lactation periods. Seropositivity of fetuses, indicative of placental anti–S-glycoprotein antibody transfer, was confirmed; seropositivity of pups, suggestive of lactational transfer, was also confirmed. There were no AZD1222-related effects seen for dams in-life including at the injection site or for female reproduction, fetal or pup survival, and there were no abnormal gross pathology findings in pups or in dams and no fetal visceral or skeletal findings.

Funding source, AstraZeneca and Biomedical Advanced Research and Development Authority