CodonBERT large language model for mRNA vaccines.

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties, including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs, which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods, including on a new flu vaccine data set.

Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella.

Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity.

Zoonotic pathogens and diseases detected in Vietnam, 2020-2021.

Vietnam has been identified as a country at high-risk for emergence and re-emergence of zoonotic diseases. The government of Vietnam recognized five priority zoonoses, including highly pathogenic avian influenza, rabies, leptospirosis, anthrax, and Streptococcus suis, and established a framework for One Health investigation and response to these diseases. From July 2020 to February 2021, quantitative data of zoonoses were collected from an online survey in 61 of 63 provinces based on either clinical diagnosis or laboratory confirmation. The responses were followed up by using in-depth interviews, and scientific literatures on zoonoses in Vietnam during 2010 to 2020 were reviewed. A total of 234 human health professionals and 95 animal health professionals responded to the survey. The proportion of clinical-based respondents was higher than laboratory-based respondents in both human health (130/234, 55.6%) and animal health (65/95, 68.4%) sectors. There were differences in the reported frequency of zoonoses between human and animal health professionals, and between clinical-based and laboratory-based respondents. Rabies was the most serious zoonotic disease based on the number of human cases and the geographic distribution. No human cases of avian influenza infection have been reported since 2015, although the H5 subtype viruses have been found in poultry. Besides, some bacterial, fungal, and parasitic zoonoses were detected in both humans and animals. Out of the 75 zoonoses identified, we recommend that the original five prioritized zoonoses, plus 24 additional zoonoses, should be targeted for future prevention, detection, and control under One Health approach in Vietnam.

Pan-SARS neutralizing responses after third boost vaccination in non-human primate immunogenicity model.

The emergence of SARS-CoV-2 variants, especially Beta and Delta, has raised concerns about the reduced protection from previous infection or vaccination based on the original Wuhan-Hu-1 (D614) virus. To identify promising regimens for inducing neutralizing titers towards new variants, we evaluated monovalent and bivalent mRNA vaccines either as primary vaccination or as a booster in nonhuman primates (NHPs). Two mRNA vaccines, D614-based MRT5500 and Beta-based MRT5500ß, tested in sequential regimens or as a bivalent combination in naïve NHPs produced modest neutralizing titers to heterologous variants. However, when mRNA vaccines were administered as a booster to pre-immune NHPs, we observed a robust increase in neutralizing titers with expanded breadth towards all tested variants, and notably SARS-CoV-1. The breadth of the neutralizing response was independent of vaccine sequence or modality, as we further showed either MRT5500 or recombinant subunit Spike protein (with adjuvant) can serve as boosters to induce broadly neutralizing antibodies in the NHPs primed with MRT5500. The data support the notion that a third vaccination is key to boosting existing titers and improving the breadth of antibodies to address variants of concern, including those with an E484K mutation in the Receptor Binding Domain (RBD) (Beta, Gamma).

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

Prevalence and Outcomes of Pericardial Effusion in Kidney Transplant Candidates.

Pericardial disease is a recognized manifestation of cardiovascular disease in the end-stage renal disease (ESRD) population, and can manifest as pericardial effusion, though the prognosis of pericardial disease in ESRD patients is unclear. In the modern era of renal replacement therapy, little is known about the prevalence and the implications of pericardial effusion in ESRD patients, its echocardiographic characteristics, and risk factors. We conducted a retrospective chart review on subjects > than 18 years of age with known ESRD who were undergoing outpatient evaluation for renal transplantation at Mayo Clinic Arizona between January 2001 and December 2015 and had baseline echocardiogram completed within 3 months of their initial evaluation. Patients with moderate sized pericardial effusions or larger were identified. The pericardial effusion cohort was age and gender matched with a cohort of patients with ESRD without pericardial effusion in a 1:2 fashion. 54 patients with moderate or greater sized pericardial effusion out of 2,820 patients that fit our inclusion criteria, corresponding to a prevalence of 1.9%. A total of 41 patients or 75.9%, had a moderate sized effusion. A total of 13 patients, or 24.1% had a large sized effusion, 7 of whom had tamponade physiology on echocardiography. The presence and size of the effusion was not predictive for worse outcomes. Hemodialysis duration was protective, but no other factors were predictive or protective in the development of moderate sized or larger pericardial effusions, including echocardiographic parameters.

Accounting for the effect of degree of milling on rice protein extraction in an industrial setting.

The by-products of rice milling (BRM), which are predominately rice bran, are a potential source of soluble protein that has been underexploited due to difficulties in extraction. Significant advances have been made understanding how protein content changes with degree of milling (DOM) at the laboratory scale. However, these results cannot be compared due to the lack of information on how DOM affects protein extractability in industrially produced BRM. The colorimetry or particle size analysis may estimate milling degree in industrial scale, and protein extractability changes due to a series of abrasive milling passes. Both colorimetry and particle size could differentiate the industrial abrasive passes and correlated with the amount of bran/protein present. Both the 1st and 2nd pass of milling were suitable sources for the extraction. While the relative amount of protein extracted in each fraction changed, the protein profile of the major fractions was conserved between mill passes.

Lineage overwhelms environmental conditions in determining rhizosphere bacterial community structure in a cosmopolitan invasive plant.

Plant-microbe interactions play crucial roles in species invasions but are rarely investigated at the intraspecific level. Here, we study these interactions in three lineages of a globally distributed plant, Phragmites australis. We use field surveys and a common garden experiment to analyze bacterial communities in the rhizosphere of P. australis stands from native, introduced, and Gulf lineages to determine lineage-specific controls on rhizosphere bacteria. We show that within-lineage bacterial communities are similar, but are distinct among lineages, which is consistent with our results in a complementary common garden experiment. Introduced P. australis rhizosphere bacterial communities have lower abundances of pathways involved in antimicrobial biosynthesis and degradation, suggesting a lower exposure to enemy attack than native and Gulf lineages. However, lineage and not rhizosphere bacterial communities dictate individual plant growth in the common garden experiment. We conclude that lineage is crucial for determination of both rhizosphere bacterial communities and plant fitness.Environmental factors often outweigh host heritable factors in structuring host-associated microbiomes. Here, Bowen et al. show that host lineage is crucial for determination of rhizosphere bacterial communities in Phragmites australis, a globally distributed invasive plant.