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A key success in vaccine development for congenital infection by Cytomegalovirus (CMV): a major cause of infant brain damage

A research team led by Duke Health says it has found a key marker that will help speed up successful cytomegalovirus (CMV) vaccine designs, the world's most common congenital infection and a leading cause of infant brain injury.

This research appear in Science Translational Medicine. "Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans"

The researchers identify an immune surrogate that demonstrates when the requisite antibodies protecting against CMV infection have been released by a vaccine. This result is now being used for the screening of possible vaccines.

The most common infectious cause of infant brain damage and posttransplant complications worldwide is human cytomegalovirus (CMV). Despite the high global disease burden, the production of infection prevention vaccines remains hindered by difficulties in producing protective immunity. A soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB / MF59), which achieved 50 percent safety in several historical phase 2 clinical trials, is the most successful CMV vaccine candidate tested to date, write the investigators.

The immune responses elicited by the vaccine that conferred this defence have remained uncertain. In populations of CMV-seronegative adolescent and postpartum women who received the gB / MF59 vaccine, we studied the humoral immune correlates of defence from CMV acquisition. We found that gB / MF59 immunisation in adolescent and postpartum vaccines elicited different CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses, with heterologous CMV strain neutralisation observed predominantly in adolescent vaccines.

Using penalised multiple logistic regression study, we established that serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen was correlated with defence against primary CMV infection in both cohorts, indicating that IgG binding to cell-associated gB is an immune correlate of vaccine effectiveness. To support this, we identified gB-specific monoclonal antibodies that are differentially recognised as soluble or cell-associated gB, revealing that cell-associated and soluble gB structural variations are important to the generation of protective immunity. Our findings illustrate the significance of native, cell-associated gB conformation in the potential design of the CMV vaccine.

For over 20 years, CMV has been recognised as a top priority for vaccine production, but we remain without an approved vaccine. Senior author Sallie Permar, MD, a professor in the departments of Pediatrics, Immunology, Molecular Genetics and Microbiology, and Pathology at the Duke University School of Medicine, said that this work provides a way to ensure that current and prospective vaccine candidates promote an efficient immune response.

In the United States alone, we are more than responsible for the development of vaccinations to protect against this virus, which infects 40,000 babies a year, with a third of these children suffering permanent hearing loss, brain damage or neurodevelopmental delays, Permar added.

Permar and colleagues, including lead author Jennifer A. Jenks, a candidate for MD / PhD at Duke, investigated immune responses that protected women who obtained the investigational protein vaccine gB / MF59 against CMV infections. The CMV protein "gB" used by the virus to penetrate human cells was the key component of this vaccine.

An immune response that could stop CMV from entering host cells was expected to be produced by the investigational vaccine. In several Phase 2 clinical trials, it was around 50 percent effective in preventing CMV infection, but an appropriate CMV vaccine should be at least 70 percent effective.

The researchers found that the presence of antibodies in the blood that bind to the target protein gB when it is presented on a cell surface, but not to gB when it is in its soluble, free-floating form used in the gB / MF59 vaccine, was correlated with defence against CMV infection.

This finding indicates that potential vaccines for CMV should be formulated to target the gB conformation that is suitable. In addition, the existence of these antibodies can be used to predict the possible efficacy of future candidate vaccines, the researchers say.

This is an important immunological endpoint for the production and assessment of vaccines,' Jenks said. This could serve as a proxy for antiviral function assessment and could assist in the evaluation of vaccines in preclinical and early-phase clinical trials.'

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