Sustained early postnatal humoral and cellular immunity against human cytomegalovirus after transamniotic fetal mRNA vaccination in a rodent model.

Abstract

PURPOSE: We sought to examine the humoral and cellular immune responses to transamniotic fetal mRNA vaccination against a human cytomegalovirus (hCMV) antigen over time in early postnatal life in a rodent model. METHODS: Seven pregnant Sprague Dawley dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 82) of a custom-made mRNA encoding for hCMV envelope glycoprotein-B (hCMV-gB) antigen encapsulated by a lipid-polymer composite on gestational day 17 (E17; term = E21-22). At three time points between 1 and 3 months after birth, serum levels of antigen-specific hCMV-gB IgG antibodies were measured by ELISA. In addition, host spleen lymphocytes were incubated with or without challenge with the hCMV-gB antigen, followed by flow cytometry of culture supernatants to assess T-cell response. RESULTS: Overall neonatal survival was 44 % (36/82), with no significant differences between the groups. Antigen-specific hCMV-gB antibodies were present in the serum at all time points, albeit decreasing significantly from 1 to 3 months postnatally (p = 0.029). Spleen lymphocytes from vaccinated pups showed significantly increased production of IFN-&#x3b3;, IL-2, TNF-&#x3b1;, GM-CSF, and IL-6 following antigen-specific challenge (p = 0.021 to <0.001 vs. non-challenged cells). Cellular response increased significantly over time (p = 0.043 to <0.001), indicating a maturing Th1 response. CONCLUSIONS: Transamniotic fetal mRNA delivery of a human cytomegalovirus antigen can induce a lasting adaptive cell-mediated immune response, while also exhibiting continued antigen-specific immunoglobulin production extending into the early 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. TYPE OF STUDY: Animal and laboratory study.