A 3-D Stability Analysis of Lee Harvey Oswald in the Backyard Photo

Fifty years have passed since the assassination of U.S. President Kennedy. Despite the long passage of time, it is still argued that the famous backyard photo of Oswald, holding the same type of rifle used to assassinate the President, is a fake. These claims include, among others, that Oswald’s pose in the photo is physically implausible. We describe a detailed 3-D stability analysis to determine if this claim is warranted

Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge

The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1β in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques

Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV

Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization, reduced risk of infection was associated IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, and via vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE immunized animals. Thus while route independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc-activity via distinct innate effector cells and antibody isotypes. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes, pointing to critical correlates of immunity that may support the rational design of a protective vaccine against HIV.Bill & Melinda Gates Foundation (OPP1032817)Bill & Melinda Gates Foundation (OPP1114729)National Institutes of Health (U.S.) (R37 AI080289)National Institutes of Health (U.S.) (R01 AI102291)National Institutes of Health (U.S.) (P01 AI120756)National Institutes of Health (U.S.) (R01 AI131975)National Institutes of Health (U.S.) (R01 AI102660

Antibody Fab‐Fc properties outperform titer in predictive models of SIV vaccine‐induced protection

Abstract Characterizing the antigen‐binding and innate immune‐recruiting properties of the humoral response offers the chance to obtain deeper insights into mechanisms of protection than revealed by measuring only overall antibody titer. Here, a high‐throughput, multiplexed Fab‐Fc Array was employed to profile rhesus macaques vaccinated with a gp120‐CD4 fusion protein in combination with different genetically encoded adjuvants, and subsequently subjected to multiple heterologous simian immunodeficiency virus (SIV) challenges. Systems analyses modeling protection and adjuvant differences using Fab‐Fc Array measurements revealed a set of correlates yielding strong and robust predictive performance, while models based on measurements of response magnitude alone exhibited significantly inferior performance. At the same time, rendering Fab‐Fc measurements mathematically independent of titer had relatively little impact on predictive performance. Similar analyses for a distinct SIV vaccine study also showed that Fab‐Fc measurements performed significantly better than titer. These results suggest that predictive modeling with measurements of antibody properties can provide detailed correlates with robust predictive power, suggest directions for vaccine improvement, and potentially enable discovery of mechanistic associations