Evolution of protection after maternal immunization for respiratory syncytial virus in cotton rats

Abstract

Maternal anti-respiratory syncytial virus (RSV) antibodies acquired by the fetus through the placenta protect neonates from RSV disease through the first weeks of life. In the cotton rat model of RSV infections, we previously reported that immunization of dams during pregnancy with virus-like particles assembled with mutation stabilized pre-fusion F protein as well as the wild type G protein resulted in robust protection of their offspring from RSV challenge. Here we describe the durability of those protective responses in dams, the durability of protection in offspring, and the transfer of that protection to offspring of two consecutive pregnancies without a second boost immunization. We report that four weeks after birth, offspring of the first pregnancy were significantly protected from RSV replication in both lungs and nasal tissues after RSV challenge, but protection was reduced in pups at 6 weeks after birth. However, the overall protection of offspring of the second pregnancy was considerably reduced, even at four weeks of age. This drop in protection occurred even though the levels of total anti-pre-F IgG and neutralizing antibody titers in dams remained at similar, high levels before and after the second pregnancy. The results are consistent with an evolution of antibody properties in dams to populations less efficiently transferred to offspring or the less efficient transfer of antibodies in elderly dams.

The Respiratory Syncytial Virus G Protein Enhances the Immune Responses to the RSV F Protein in an Enveloped Virus-like Particle Vaccine Candidate

“…The presence of G (H/G) in the VLPs did not make a statistically significant difference in the levels of total anti-pre-fusion F IgG antibodies induced using either mutant stabilized pre-F as target (Figure 4, panels A, B). As we have previously noted, however, the levels of total anti-pre- F IgG antibodies detected with the soluble UC-3 F protein target were consistently slightly higher than the levels detected with the soluble DS Cav1 F protein target, but the differences were not statistically significant (36).…”

“…One was the soluble version of the DS-Cav1 mutant F protein. The other was a soluble version of another mutant stabilized, but uncleaved pre-fusion F protein which we have characterized previously, UC-3 pre-fusion F protein (20, 32, 35, 36). Inclusion of the UC-3 F target was because we have detected differences between the two targets in assessing induced anti-RSV antibodies (20, 32, 36).…”

“…Inclusion of the UC-3 F target was because we have detected differences between the two targets in assessing induced anti-RSV antibodies (20,32,36).…”

“…One was the soluble version of the DS-Cav1 mutant F protein. The other was a soluble version of another mutant stabilized, but uncleaved pre-fusion F protein which we have characterized previously, UC-3 pre-fusion F protein (20,32,35,36).…”

Correlative outcomes of maternal immunization against RSV in cotton rats

“…Our previous studies in the cotton rat model of maternal immunization using a novel virus-like particle (VLP) vaccine candidates assembled with different pre-fusion RSV F proteins along with the RSV G attachment protein showed that maternal vaccination improves protection in young animals (at 4 weeks after birth). 20 Here, we show that maternal vaccination also protects litters from lung pathology and cytokine gene expression early on, but not later in life as maternal antibodies in the litter wane. Importantly, we find that maternal vaccination results in an increase in mRNA expression for IL-6 and IFNγ in the lung when RSV infection occurs later in the life of the litters, and when protection from RSV by matAbs wanes or cannot be detected, correlating with the modulation of the litter’s response to RSV in their lung.…”