Beta and γ human herpesviruses (HHV)—which latently infect Americans at an annual cost of at least $4 billion—are responsible for acute infections, multiple forms of cancer, autoimmune disease and birth defects. The β-HHV subfamily includes human cytomegalovirus (CMV) and roseoloviruses. The γ-HHV subfamily includes Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV). Of these, EBV and CMV clinically impact the largest proportion of the US population. EBV causes significant disease in adolescents and young adults as the cause of infectious mononucleosis. EBV can later cause lymphomas, gastric and nasopharyngeal cancer, the autoimmune disease multiple sclerosis (MS), and lymphoproliferative disease in transplant patients. CMV is the leading cause of congenital birth defects, as in-utero infection can result in permanent hearing loss or more profound neurodevelopmental impairments that disproportionately impact socioeconomically disadvantaged children. CMV infection is linked to educational achievement gaps in disadvantaged populations.

The America’s SHIELD program application was submitted in response to a funding opportunity posted by the Advanced Research Projects Agency for Health (ARPA-H) in support of its Antigens Predicted for Broad Viral Efficacy through Computational Experimentation (APECx) Program. The primary awardee on the award is Erica Ollmann Saphire, PhD, Professor, President & CEO Center for Autoimmunity and Inflammation, Center for Cancer Immunotherapy, Center for Sex-based Differences in the Immune System, Center for Vaccine Innovation La Jolla Institute for Immunology (LJI). Co-PI is Jimmy Gollihar, PhD, Professor of Pathology and Genomic Medicine and Head of the Antibody Discovery & Accelerated Protein Therapeutics laboratory at Houston Methodist. Previous HHV vaccine efforts focused on one or more viral glycoproteins or complexes involved in entry, but HHVs have large DNA genomes encoding more than 10 surface glycoproteins and nearly 200 other genes for which we lack crucial information. The sheer number of possible vaccine antigens made traditional technologies untenable. In addition, it’s still unclear which conformations or combinations of these antigens are needed for robust immunity. The prior focus on neutralization of cell-free virus entry also ignores the needs of the >100 million Americans already latently infected who remain at risk of HHV-associated disease. Through the SHIELD program, researchers will develop an integrated sequence-, phylogeny-, structure-, and immunologically driven computational toolkit for antigen engineering with the potential to transform vaccine development against a myriad of pathogens with the potential to cause cancer. They will apply the toolkit to major public health and economic threats to Americans, the β- and γ-HHV.