Threshold regression models are a diverse set of non-regular regression models that all depend on change points or thresholds. They provide a simple but elegant and interpretable way to model certain kinds of nonlinear relationships between the outcome and a predictor. The R package chngpt provides both estimation and hypothesis testing functionalities for four common variants of threshold regression models. All allow for adjustment of additional covariates not subjected to thresholding. We demonstrate the consistency of the estimating procedures and the type 1 error rates of the testing procedures by Monte Carlo studies, and illustrate their practical uses using an example from the study of immune response biomarkers in the context of Mother-To-Child-Transmission of HIV-1 viruses. chngpt makes several unique contributions to the software for threshold regression models and will make these models more accessible to practitioners interested in modeling threshold effects.

Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis.

Significance: The CDC estimates that every hour, a child is born in the United States with permanent neurologic disability resulting from human cytomegalovirus (HCMV) infection—more than is caused by Down syndrome, fetal alcohol syndrome, and neural tube defects combined. A maternal vaccine to block transmission of HCMV to the developing fetus is a necessary intervention to prevent these adverse outcomes. The gB/MF59 vaccine is the most successful tested clinically to date, achieving 50% reduction in HCMV acquisition. This manuscript establishes the function and epitope specificity of the humoral response stimulated by this vaccine that may explain the partial vaccine efficacy. Understanding the mechanism of gB/MF59-elicited protective immune responses will guide rational design and evaluation of the next generation of HCMV vaccines.

Significance: Congenital cytomegalovirus (CMV) is the leading infectious cause of childhood hearing loss and brain damage worldwide. Yet, despite its high prevalence and ranking as a top priority for vaccine development, the immune correlates of protection that could guide vaccine development remain undefined. Using a novel nonhuman primate model of congenital CMV transmission, we demonstrate a critical role for maternal CD4 ⁺ T cells in the induction of protective maternal immune responses that prevent fetal demise. In addition to establishing placental CMV transmission for the first time (to our knowledge) in nonhuman primates, this study reveals an association between delayed maternal virus-specific neutralizing antibody responses and severe fetal outcome, providing insight into the mechanism by which maternal CD4 ⁺ T cells impact congenital CMV disease.