An Attenuated Cytomegalovirus Vaccine with a Deletion of a Viral Chemokine Gene Is Protective against Congenital CMV Transmission in a Guinea Pig Model

Development of a vaccine against congenital cytomegalovirus (CMV) infection is a public health priority, but CMVs encode immune evasion genes that complicate live virus vaccine design. To resolve this problem, this study employed guanosyl phosphoribosyl transferase (gpt) mutagenesis to generate a recombinant guinea pig CMV (GPCMV) with a knockout of a viral chemokine gene, GPCMV MIP (gp1). MIP deletion virus replicated with wild-type kinetics in cell culture but was attenuated in nonpregnant guinea pigs, demonstrating reduced viremia and reduced inflammation and histopathology (compared to a control virus with an intact GPCMV MIP gene) following footpad inoculation. In spite of attenuation, the vaccine was immunogenic, eliciting antibody responses comparable to those observed in natural infection. To assess its protective potential as a vaccine, either recombinant virus or placebo was used to immunize seronegative female guinea pigs. Dams were challenged in the early 3rd trimester with salivary gland-adapted GPCMV. Immunization protected against DNAemia (1/15 in vaccine group versus 12/13 in the control group, P<0.01). Mean birth weights were significantly higher in pups born to vaccinated dams compared to controls (98.7 g versus 71.2 g, P<0.01). Vaccination reduced pup mortality, from 35/50 (70%) in controls to 8/52 (15%) in the immunization group. Congenital GPCMV infection was also reduced, from 35/50 (70%) in controls to 9/52 (17%) in the vaccine group (P<0.0001). We conclude that deletion of an immune modulation gene can attenuate the pathogenicity of GPCMV while resulting in a viral vaccine that retains immunogenicity and demonstrates efficacy against congenital infection and disease

Blood Protein Concentrations in the First Two Postnatal Weeks That Predict Bronchopulmonary Dysplasia Among Infants Born Before the 28th Week of Gestation

Lung inflammation contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) and may be accompanied by a systematic inflammatory response. The objective of this study was to investigate the role of systemic inflammation in the development of BPD in a cohort of extremely low gestational age newborns (ELGANs) by examining the relationships between inflammation-associated proteins in neonatal blood samples and pulmonary outcomes. Proteins were measured in blood specimens collected on postnatal days 1–3, 5–8 and 12–15 from 932 ELGANs. Increased risk of BPD was associated with elevated blood concentrations of a variety of pro-inflammatory cytokines, adhesion molecules and proteases. Reduced risk was prominently associated with increased concentrations of one chemokine, RANTES. Elevations of inflammatory proteins associated with BPD risk occurred during the first days following birth, and inflammation intensified thereafter. Therefore, exposures that promote inflammation after the first postnatal days may be more critical in the pathogenesis of BPD. Fetal growth restriction, a known BPD risk factor, was not accompanied by proteins elevations and therefore does not appear to be mediated by systemic inflammation. By contrast, mechanical ventilation altered protein levels and may be associated with systemic inflammation