Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimmers as HIV-1 vaccine candidates.

Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.

Pediatric-Specific Hazard Vulnerability Analysis: The Missing Component of Regional and Hospital-Based Preparedness.

Though children comprise a large percentage of the population and are uniquely vulnerable to disasters, pediatric considerations are often omitted from regional and hospital-based emergency preparedness. Children's absence is particularly notable in hazard vulnerability analyses (HVAs), a commonly used tool that allows emergency managers to identify a hazard's impact, probability of occurrence, and previous mitigation efforts. This paper introduces a new pediatric-specific HVA that provides emergency managers with a quantifiable means to determine how a hazard might affect children within a given region, taking into account existing preparedness most relevant to children's safety. Impact and preparedness categories within the pediatric-specific HVA incorporate age-based equipment and care needs, long-term developmental and mental health consequences, and the hospital and community functions most necessary for supporting children during disasters. The HVA allows emergency managers to create a more comprehensive assessment of their pediatric populations and preparatory requirements.

Evaluation of a DNA Aß42 vaccine in adult rhesus monkeys (Macaca mulatta): antibody kinetics and immune profile after intradermal immunization with full-length DNA Aß42 trimer.

BACKGROUND: Aggregated amyloid-ß peptide 1-42 (Aß42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer's disease (AD). Although active immunization against Aß42 peptide was successful in AD mouse models and led to removal of plaques and improved memory, a similar clinical trial in humans (Aß42 peptide immunization with QS-21 adjuvant) was stopped in phase II, when 6% of the treated patients developed encephalitis. Currently ongoing passive immunizations with the injection of preformed monoclonal antibodies against different epitopes within the Aß1-42 peptide, which do not lead to activation of the immune system, have shown some effects in slowing AD pathology. Active DNA Aß42 immunizations administered with the gene gun into the skin are noninflammatory because they activate a different T-cell population (Th2) with different cytokine responses eliciting a different humoral immune response. We present our findings in rhesus macaques that underwent the DNA Aß42 immunization via gene gun delivery into the skin. METHODS: Six rhesus monkeys received two different doses of a DNA Aß42 trimer vaccine. The humoral immune response was analyzed from blood throughout the study, and cellular immune responses were determined in peripheral blood mononuclear cells (PBMCs) after three and six immunizations. RESULTS: DNA Aß42 trimer immunization led to high titer antibody responses in the nonhuman primate (NHP) model. Antibodies generated in the rhesus monkeys following DNA Aß42 immunization detected amyloid plaques consisting of human Aß42 peptide in the brain of the triple-transgenic AD mouse model. T-cell responses showed no interferon (IFN)-γ- and interleukin (IL)-17-producing cells from PBMCs in Enzyme-Linked ImmunoSpot assays after three immunization time points. At six immunization time points, IFN-γ- and IL-17-producing cells were found in immunized animals as well as in control animals and were thus considered nonspecific and not due to the immunization regimen. IFN-γ and IL-17 secretion in response to Aß42 peptide restimulation became undetectable after a 3-month rest period. CONCLUSIONS: Intradermal DNA Aß42 immunization delivered with the gene gun produces a high antibody response in NHPs and is highly likely to be effective and safe in a clinical AD prevention trial in patients.

Assisted Reproductive Technologies (ART) with baboons generate live offspring: a nonhuman primate model for ART and reproductive sciences.

Human reproduction has benefited significantly by investigating nonhuman primate (NHP) models, especially rhesus macaques. To expand the Old World monkey species available for human reproductive studies, we present protocols in baboons, our closest Old World primate relatives, for assisted reproductive technologies (ART) leading to live born offspring. Baboons complement rhesus by confirming or modifying observations generated in humans often obtained by the study of clinically discarded specimens donated by anonymous infertility patient couples. Here, baboon ART protocols, including oocyte collection, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), preimplantation development to blastocyst stage, and embryo transfer techniques are described. With baboon ART methodologies in place, motility during baboon fertilization was investigated by time-lapse video microscopy (TLVM). The first ART baboons produced by ICSI, a pair of male twins, were delivered naturally at 165 days postgestation. Genetic testing of these twins confirmed their ART parental origins and demonstrated that they are unrelated fraternal twins not identicals. These results have implications for ART outcomes, embryonic stem cell (ESC) derivation, and reproductive sciences.