Reintervention Burden and Vessel Growth After Surgical Reimplantation of a Pulmonary Artery During Childhood.

Children requiring reimplantation of a branch pulmonary artery (PA) are at risk for postoperative stenosis and impaired growth of the reimplanted PA. Outcomes and risk factors for reintervention and impaired growth are incompletely described. We reviewed data on patients who underwent reimplantation of a branch PA between 1/1/99 and 5/1/15 at a single center. The primary outcome was reintervention to treat postoperative stenosis. The secondary outcome was "catch-up" growth (faster diameter growth of the affected PA compared with the unaffected PA from the preoperative to follow-up measurements.). Twenty-six patients were identified with a total follow-up of 102.2 patient-years (median 2.5 years). Diagnoses included LPA sling (n = 12) and isolated PA of ductal origin with (n = 7) or without (n = 7) tetralogy of Fallot (ToF). All had primary repair of the anomalous PA. Seventeen (65%) had reintervention with median time to first reintervention of 69 (range 1-1005) days and median of 1.5 (range 1-6) reinterventions. 94% of reinterventions were transcatheter (53% balloon and 41% stent angioplasty). Patients with reintervention were younger (hazard ratio 0.75 per log-day, p = 0.02) and lower weight (hazard ratio 0.18 per log-kg, p = 0.02) at initial repair. Of the 18 with PA growth data, 8 (44%) had catch-up growth. There were no identified differences between those who did and did not demonstrate catch-up growth. Despite a practice of primary reimplantation and aggressive postoperative reintervention, these results suggest that changes in strategy are needed or that there are intrinsic patient factors that have more influence on longer-term reimplanted PA growth.

Synthetic DNA approach to cytomegalovirus vaccine/immune therapy.

There is no licensed vaccine or cure for human cytomegalovirus (CMV), a ubiquitous ß-herpes virus that infects 60-95 % of adults worldwide. Infection is a major cause of congenital abnormalities in newborns, contributes to development of childhood cerebral palsy and medulloblastoma, can result in severe disease in immunocompromised patients, and is a major impediment during successful organ transplantation. While CMV has been increasingly associated with numerous inflammatory diseases and cancers, only recently has it been correlated with increased risk of heart disease in adults, the number-one killer in the USA. These data, among others, suggest that subclinical CMV infection, or microinfection, in healthy individuals may play more of a causative role than an epiphenomenon in development of CMV-associated pathologies. Due to the myriad of diseases and complications associated with CMV, an efficacious vaccine would be highly valuable in reducing human morbidity and mortality as well as saving billions of dollars in annual health-care costs and disability adjusted life years (DALY) in the developing world. Therefore, the development of a safe efficacious CMV vaccine or immune therapy is paramount to the public health. This review aims to provide a brief overview on aspects of CMV infection and disease and focuses on current vaccine strategies. The use of new synthetic DNA vaccines might offer one such approach to this difficult problem.

Induction of broad cytotoxic T cells by protective DNA vaccination against Marburg and Ebola.

Marburg and Ebola hemorrhagic fevers have been described as the most virulent viral diseases known to man due to associative lethality rates of up to 90%. Death can occur within days to weeks of exposure and there is currently no licensed vaccine or therapeutic. Recent evidence suggests an important role for antiviral T cells in conferring protection, but little detailed analysis of this response as driven by a protective vaccine has been reported. We developed a synthetic polyvalent-filovirus DNA vaccine against Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SUDV). Preclinical efficacy studies were performed in guinea pigs and mice using rodent-adapted viruses, whereas murine T-cell responses were extensively analyzed using a novel modified assay described herein. Vaccination was highly potent, elicited robust neutralizing antibodies, and completely protected against MARV and ZEBOV challenge. Comprehensive T-cell analysis revealed cytotoxic T lymphocytes (CTLs) of great magnitude, epitopic breadth, and Th1-type marker expression. This model provides an important preclinical tool for studying protective immune correlates that could be applied to existing platforms. Data herein support further evaluation of this enhanced gene-based approach in nonhuman primate studies for in depth analyses of T-cell epitopes in understanding protective efficacy.

Vaccination with synthetic constructs expressing cytomegalovirus immunogens is highly T cell immunogenic in mice.

There is no licensed vaccine or cure for human cytomegalovirus (CMV), a ubiquitous ß-herpesvirus infecting 60-95% of adults worldwide. Infection can cause congenital abnormalities, result in severe disease in immunocompromised patients, and is a major impediment during successful organ transplantation. In addition, it has been associated with numerous inflammatory diseases and cancers, as well as being implicated in the development of essential hypertension, a major risk factor for heart disease. To date, limited data regarding the identification of immunogenic viral targets has frustrated CMV vaccine development. Based upon promising clinical data suggesting an important role for T cells in protecting against disease in the transplantation setting, we designed a novel panel of highly-optimized synthetic vaccines encoding major CMV proteins and evaluated their immune potential in murine studies. Vaccination induced robust CD8+ and CD4+ T cells of great epitopic breadth as extensively analyzed using a novel modified T cell assay described herein. Together with improved levels of CMV-specific T cells as driven by a vaccine, further immune evaluation of each target is warranted. The present model provides an important tool for guiding future immunization strategies against CMV.

A highly optimized DNA vaccine confers complete protective immunity against high-dose lethal lymphocytic choriomeningitis virus challenge.

Protection against infection is the hallmark of immunity and the basis of effective vaccination. For a variety of reasons there is a great demand to develop new, safer and more effective vaccine platforms. In this regard, while 'first-generation' DNA vaccines were poorly immunogenic, new genetic 'optimization' strategies and the application of in vivo electroporation (EP) have dramatically boosted their potency. We developed a highly optimized plasmid DNA vaccine that expresses the lymphocytic choriomeningitis virus (LCMV) nucleocapsid protein (NP) and evaluated it using the LCMV challenge model, a gold standard for studying infection and immunity. When administered intramuscularly with EP, robust NP-specific cellular and humoral immune responses were elicited, the magnitudes of which approached those following acute LCMV infection. Furthermore, these responses were capable of providing 100% protection against a high-dose, normally lethal virus challenge. This is the first non-infectious vaccine conferring complete protective immunity up to 8 weeks after vaccination and demonstrates the potential of 'next-generation' DNA vaccines.