Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles.

Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV gag mRNA, the Spike-SIVCT.745 (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with SSt+gag mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to SSt mRNA alone. Furthermore, mice immunized with SSt+gag mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.

A multiclade env-gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques.

The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian-human immunodeficiency virus (SHIV AD8). Thus, the multiclade env-gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine.

Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach.

OBJECTIVES: Trans-diagnostic approaches suggest that key cognitive and behavioural processes maintain symptoms across a wide range of mental health disorders. Fatigue is a common clinical feature of attention deficit hyperactivity disorder (ADHD) in adulthood; however, empirical data supporting its prevalence are lacking. This study aimed to collate outcomes from outpatient services to (1) investigate the prevalence of fatigue in adults with ADHD, (2) examine symptoms of ADHD in adults with chronic fatigue syndrome (CFS), and (3) consider secondary clinical characteristics common to both disorder groups. METHODS: Measures of self-reported fatigue were compared across groups of adults with ADHD (N = 243), CFS (N = 86), and healthy controls (HC) (N = 211) using a between-subjects cross-sectional design. Groups were also compared on secondary clinical measures of functional impairment, mood, anxiety, sleep, self-efficacy, and their beliefs about the acceptability of expressing emotions. RESULTS: The ADHD group were significantly more fatigued than HC with 62% meeting criteria for fatigue caseness. ADHD symptoms were significantly greater in the CFS group than in HC. ADHD and CFS groups did not differ significantly on measures of functional impairment, mood, and self-efficacy. No significant differences were detected on measures of anxiety when items relating to physical restlessness were removed from the analysis. CONCLUSIONS: Adults with ADHD experience greater fatigue than HC. Adults with CFS and ADHD share many trans-diagnostic clinical characteristics, including difficulties with low mood, anxiety, and reduced self-efficacy, which impact upon their overall functioning. Further research is required to investigate extraneous factors mediating fatigue severity in these clinical groups. PRACTITIONER POINTS: Fatigue is a common clinical feature of attention deficit hyperactivity disorder (ADHD) in adulthood. Evidence-based interventions for chronic fatigue syndrome could be adapted to address fatigue in ADHD in adults.

What's new in long-term care dining?

A number of long-term care facilities in North Carolina have adopted ways to improve the dining experience for long-term care residents. Wall murals and dining room themes help to create a pleasant atmosphere that also might stimulate resident imagination. Aroma therapies are also positive stimulants that increase the appetite and pleasure in eating. Flavor and food presentation are probably some of the most obvious modifications. We can all understand the desire to have our food taste and look good. There are probably even more ideas that could make eating in a nursing home more pleasant and home-like. Efforts Like these are critical to stemming weight loss among residents and also to maintaining resident independence to the extent possible. We hope more facilities across the state will use and build on these ideas as they try to maximize their residents' quality of life.

Does pollen competition reduce the cost of inbreeding?

We hypothesize that floral features promoting pollen competition in angiosperms may have evolved, in some cases, in response to selection generated by the negative effects of inbreeding, at least in plants with mixed-mating systems. Screening of haploid genotypes through pollen competition may purge recessive (or additive) deleterious alleles that are expressed in haploid pollen and hence may reduce the fitness cost of self-pollination, geitonogamy, or biparental inbreeding. We tested one prediction of this hypothesis, that offspring produced by more intense competition among self-pollen have higher fitness than offspring produced by less intense competition. Dalechampia scandens (Euphorbiaceae) flowers were pollinated with pollen from other flowers on the same plant (geitonogamous self-fertilization). Those flowers experiencing more intense pollen competition as a result of low pollen dispersion (positional variance) on the stigma produced heavier seeds and seedlings with faster-growing radicles than flowers experiencing less intense pollen competition (high pollen dispersion), as predicted by our hypothesis.