SARS-CoV-2 mRNA-based vaccines in the Aicardi Goutières Syndrome.

Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.

Do not transform food systems on the backs of the rural poor.

Even prior to COVID, there was a considerable push for food system transformation to achieve better nutrition and health as well as environmental and climate change outcomes. Recent years have seen a large number of high visibility and influential publications on food system transformation. Literature is emerging questioning the utility and scope of these analyses, particularly in terms of trade-offs among multiple objectives. We build on these critiques of emerging food system transformation approaches in our review of four recent and influential publications from the EAT-Lancet Commission, the IPCC, the World Resources Institute and the Food and Land Use Coalition. We argue that a major problem is the lack of explicit inclusion of the livelihoods of poor rural people in their modeling approaches and insufficient measures to ensure that the nature and scale of the envisioned changes will improve these livelihoods. Unless livelihoods and socioeconomic inclusion more broadly are brought to the center of such approaches, we very much risk transforming food systems to reach environmental and nutritional objectives on the backs of the rural poor.

Pathogen-sugar interactions revealed by universal saturation transfer analysis.

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an "end-on" manner. uSTA-guided modeling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.

Do not transform food systems on the backs of the rural poor

Even prior to COVID, there was a considerable push for food system transformation to achieve better nutrition and health as well as environmental and climate change outcomes. Recent years have seen a large number of high visibility and influential publications on food system transformation. Literature is emerging questioning the utility and scope of these analyses, particularly in terms of trade-offs among multiple objectives. We build on these critiques of emerging food system transformation approaches in our review of four recent and influential publications from the EAT-Lancet Commission, the IPCC, the World Resources Institute and the Food and Land Use Coalition. We argue that a major problem is the lack of explicit inclusion of the livelihoods of poor rural people in their modeling approaches and insufficient measures to ensure that the nature and scale of the envisioned changes will improve these livelihoods. Unless livelihoods and socioeconomic inclusion more broadly are brought to the center of such approaches, we very much risk transforming food systems to reach environmental and nutritional objectives on the backs of the rural poor.

Seizing the moment: now is the time for integrated global surveillance of antimicrobial resistance in wastewater environments.

Antimicrobial resistance (AMR) is a growing global health threat that requires coordinated action across One Health sectors (humans, animals, environment) to stem its spread. Environmental surveillance of AMR is largely behind the curve in current One Health surveillance programs, but recent momentum in the establishment of infrastructure for monitoring of the SARS-CoV-2 virus in sewage provides an impetus for analogous AMR monitoring. Simultaneous advances in research have identified striking trends in various AMR measures in wastewater and other impacted environments across global transects. Methodologies for tracking AMR, including metagenomics, are rapidly advancing, but need to be standardized and made modular for access by LMICs, while also developing systems for sample archiving and data sharing. Such efforts will help optimize effective global AMR policy.

Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses.

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.

Development of a COVID-19 Vaccine Readiness Kit for Veterans With Rheumatologic Diseases on Immunomodulators: A Quality Improvement Project.

BACKGROUND: The advent of multiple safe and effective vaccines to prevent SARS-CoV-2 infection represents a major step in resolving the COVID-19 global pandemic. Vaccination of individuals with rheumatologic diseases on immunomodulators represents an additional challenge because data suggest that certain immunomodulators may impact vaccine efficacy. METHODS: At a large, predominantly rural Midwestern Veterans Affairs rheumatology clinic, an interprofessional group of investigators conducted a quality improvement project to develop a COVID-19 vaccine readiness kit, consisting of patient education materials and a readiness questionnaire to help guide veteran decision-making. Using a Lean Six Sigma approach and the DMAIC (Define-Measure-Analyze-Improve-Control) framework, the investigators identified customer values, needs, and barriers to participation. Return rates and responses from the questionnaire were tracked over 28 days. RESULTS: One hundred seventy-nine veterans were identified and mailed kits; 129 (73%) returned the questionnaire within 28 days. Ninety-seven percent of those opted to hold immunomodulators after at least 1 administration of the vaccine; 3.1% were not interested in vaccination. Veterans voiced satisfaction at the simplicity of the process, comprehensibility of materials, and the clarity of communication. CONCLUSIONS: The Lean Six Sigma approach, systematically focusing on identifying the values, needs, and barriers of veterans on immunomodulators, was critical to high participation rates from veterans. This approach is cost-effective for resource-poor settings, audiences without access or familiarity to digital content, and rural settings separated by large geographic distances.