A global approach to HIV-1 vaccine development

Summary A global human immunodeficiency virus-1 (HIV-1) vaccine will have to elicit immune responses capable of providing protection against a tremendous diversity of HIV-1 variants. In this review, we first describe the current state of the HIV-1 vaccine field, outlining the immune responses that are desired in a global HIV-1 vaccine. In particular, we emphasize the likely importance of Env-specific neutralizing and non-neutralizing antibodies for protection against HIV-1 acquisition and the likely importance of effector Gag-specific T lymphocytes for virologic control. We then highlight four strategies for developing a global HIV-1 vaccine. The first approach is to design specific vaccines for each geographic region that include antigens tailor-made to match local circulating HIV-1 strains. The second approach is to design a vaccine that will elicit Env-specific antibodies capable of broadly neutralizing all HIV-1 subtypes. The third approach is to design a vaccine that will elicit cellular immune responses that are focused on highly conserved HIV-1 sequences. The fourth approach is to design a vaccine to elicit highly diverse HIV-1-specific responses. Finally, we emphasize the importance of conducting clinical efficacy trials as the only way to determine which strategies will provide optimal protection against HIV-1 in humans

Hanging Out, Messing Around, and Geeking Out

The tenth-anniversary edition of a foundational text in digital media and learning, examining new media practices that range from podcasting to online romantic breakups. Hanging Out, Messing Around, and Geeking Out, first published in 2009, has become a foundational text in the field of digital media and learning. Reporting on an ambitious three-year ethnographic investigation into how young people live and learn with new media in varied settings—at home, in after-school programs, and in online spaces—it presents a flexible and useful framework for understanding the ways that young people engage with and through online platforms: hanging out, messing around, and geeking out, otherwise known as HOMAGO. Integrating twenty-three case studies—which include Harry Potter podcasting, video-game playing, music sharing, and online romantic breakups—in a unique collaborative authorship style, Hanging Out, Messing Around, and Geeking Out combines in-depth descriptions of specific group dynamics with conceptual analysis. Since its original publication, digital learning labs in libraries and museums around the country have been designed around the HOMAGO mode and educators have created HOMAGO guidebooks and toolkits. This tenth-anniversary edition features a new introduction by Mizuko Ito and Heather Horst that discusses how digital youth culture evolved in the intervening decade, and looks at how HOMAGO has been put into practice. This book was written as a collaborative effort by members of the Digital Youth Project, a three-year research effort funded by the John D. and Catherine T. MacArthur Foundation and conducted at the University of California, Berkeley, and the University of Southern California

Effect of Fungicide Applications on Grain Sorghum ( Sorghum bicolor

Field studies were conducted in the upper Texas Gulf Coast and in central Louisiana during the 2013 through 2015 growing seasons to evaluate the effects of fungicides on grain sorghum growth and development when disease pressure was low or nonexistent. Azoxystrobin and flutriafol at 1.0 L/ha and pyraclostrobin at 0.78 L/ha were applied to the plants of two grain sorghum hybrids (DKS 54-00, DKS 53-67) at 25% bloom and compared with the nontreated check for leaf chlorophyll content, leaf temperature, and plant lodging during the growing season as well as grain mold, test weight, yield, and nitrogen and protein content of the harvested grain. The application of a fungicide had no effect on any of the variables tested with grain sorghum hybrid responses noted. DKS 53-67 produced higher yield, greater test weight, higher percent protein, and N than DKS 54-00. Results of this study indicate that the application of a fungicide when little or no disease is present does not promote overall plant health or increase yield

Activation of Coagulation and Proinflammatory Pathways in Thrombosis with Thrombocytopenia Syndrome and Following COVID-19 Vaccination

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15-19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.National Institutes of Health (U.S.) (AI055332)National Institutes of Health (U.S.) (AI060354)National Institutes of Health (U.S.) (AI078526)National Institutes of Health (U.S.) (AI084794)National Institutes of Health (U.S.) (AI095985)National Institutes of Health (U.S.) (AI096040)National Institutes of Health (U.S.) (AI100148)National Institutes of Health (U.S.) (AI10063)Bill & Melinda Gates Foundation (OPP1033091)Bill & Melinda Gates Foundation (OPP1033115)Bill & Melinda Gates Foundation (OPP1040741)Bill & Melinda Gates Foundation (OPP1040753)Ragon Institute of MGH, MIT, and HarvardStavros S. Niarchos FoundationHoward Hughes Medical Institute (Investigator

Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization

Replication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent Ad serotype 26 (rcAd26) vectors by adding the E1 region back into a replication-incompetent Ad26 vector backbone with the E3 or E3/E4 regions deleted. We assessed the effect of vectorization on the replicative capacity of the rcAd26 vaccines. Attenuation occurred in a stepwise fashion, with E3 deletion, E4 deletion, and human immunodeficiency virus type 1 (HIV-1) envelope (Env) gene insertion all contributing to reduced replicative capacity compared to that with the wild-type Ad26 vector. The rcAd26 vector with E3 and E4 deleted and containing the Env transgene exhibited 2.7- to 4.4-log-lower replicative capacity than that of the wild-type Ad26 in vitro. This rcAd26 vector is currently being evaluated in a phase 1 clinical trial. Attenuation as a result of vectorization and transgene insertion has implications for the clinical development of replication-competent vaccine vectors