Perinatal Vaccination by Transamniotic Fetal mRNA Delivery: Immunization Against Human Cytomegalovirus in a Rodent Model

Purpose: Gestational cytomegalovirus (CMV) infection is a prevalent disease with significant fetal and neonatal morbidity. MRNA vaccines have emerged as powerful options for postnatal immunization against infections. It has been shown that mRNA delivered into the amniotic fluid reaches the fetal circulation via the placenta. We investigated whether transamniotic mRNA delivery could be a viable strategy for perinatal CMV immunization, first utilizing a rodent model. Methods: Pregnant Sprague Dawley dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 103) of either human CMV (hCMV) envelope glycoprotein B (hCMV-gB) antigen mRNA encapsulated in lipopolyplex (mRNA group; n = 56), or of the same lipopolyplex without mRNA (controls; n = 47) on gestational day 17 (E17; term = E21-22). Term placentas were screened for host production of hCMV-gB by protein immunoblotting. Serum hCMV-gB IgG antibodies were measured at term, and 7 (P7) and 14 (P14) days after birth by ELISA. Results: Overall fetal/neonatal survival was 86% (89/103). Immunoblotting showed hCMV-gB presence in term mRNA placentas (p = 0.008 vs. controls). No hCMV-gB IgG was detected in the serum of term fetuses (4 days following transamniotic delivery). However, significantly increased serum hCMV-gB IgG levels were present in mRNA pups at P7 (p = 0.008) and P14 (p = 0.006) when controlled by mRNA-free injections (11-19 days after transamniotic administration). Conclusions: Transamniotic fetal mRNA delivery of a human cytomegalovirus antigen can induce a humoral immune response extending into the neonatal period in a healthy rat model. Fetal mRNA vaccination via the minimally invasive transamniotic route may become a practical strategy for the prevention of perinatal infections. Level of Evidence: N/A (animal and laboratory study). Type of Study: Animal and Laboratory Study. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.