The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 spike ...protein
. Cellular immune responses, particularly CD8
T cell responses, probably contribute to protection against severe SARS-CoV-2 infection
. Here we show that cellular immunity induced by current vaccines against SARS-CoV-2 is highly conserved to the SARS-CoV-2 Omicron spike protein. Individuals who received the Ad26.COV2.S or BNT162b2 vaccines demonstrated durable spike-specific CD8
and CD4
T cell responses, which showed extensive cross-reactivity against both the Delta and the Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron spike-specific CD8
T cell responses were 82-84% of the WA1/2020 spike-specific CD8
T cell responses. These data provide immunological context for the observation that current vaccines still show robust protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantially reduced neutralizing antibody responses
.
Microbial communities have numerous potential applications in biotechnology, agriculture, and medicine. Nevertheless, the limited accuracy with which we can predict interspecies interactions and ...environmental dependencies hinders efforts to rationally engineer beneficial consortia. Empirical screening is a complementary approach wherein synthetic communities are combinatorially constructed and assayed in high throughput. However, assembling many combinations of microbes is logistically complex and difficult to achieve on a timescale commensurate with microbial growth. Here, we introduce the kChip, a droplets-based platform that performs rapid, massively parallel, bottom-up construction and screening of synthetic microbial communities. We first show that the kChip enables phenotypic characterization of microbes across environmental conditions. Next, in a screen of ∼100,000 multispecies communities comprising up to 19 soil isolates, we identified sets that promote the growth of the model plant symbiont Herbaspirillum frisingense in a manner robust to carbon source variation and the presence of additional species. Broadly, kChip screening can identify multispecies consortia possessing any optically assayable function, including facilitation of biocontrol agents, suppression of pathogens, degradation of recalcitrant substrates, and robustness of these functions to perturbation, with many applications across basic and applied microbial ecology.
Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these ...populations are therefore limited.
To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern.
An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection.
SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants.
This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants.
In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.
Engineering the utilization of non-native substrates, or synthetic heterotrophy, in proven industrial microbes such as Saccharomyces cerevisiae represents an opportunity to valorize plentiful and ...renewable sources of carbon and energy as inputs to bioprocesses. We previously demonstrated that activation of the galactose (GAL) regulon, a regulatory structure used by this yeast to coordinate substrate utilization with biomass formation during growth on galactose, during growth on the non-native substrate xylose results in a vastly altered gene expression profile and faster growth compared with constitutive overexpression of the same heterologous catabolic pathway. However, this effort involved the creation of a xylose-inducible variant of Gal3p (Gal3pSyn4.1), the sensor protein of the GAL regulon, preventing this semi-synthetic regulon approach from being easily adapted to additional non-native substrates. Here, we report the construction of a variant Gal3pMC (metabolic coordinator) that exhibits robust GAL regulon activation in the presence of structurally diverse substrates and recapitulates the dynamics of the native system. Multiple molecular modeling studies suggest that Gal3pMC occupies conformational states corresponding to galactose-bound Gal3p in an inducer-independent manner. Using Gal3pMC to test a regulon approach to the assimilation of the non-native lignocellulosic sugars xylose, arabinose, and cellobiose yields higher growth rates and final cell densities when compared with a constitutive overexpression of the same set of catabolic genes. The subsequent demonstration of rapid and complete co-utilization of all three non-native substrates suggests that Gal3pMC-mediated dynamic global gene expression changes by GAL regulon activation may be universally beneficial for engineering synthetic heterotrophy.
•Engineering utilization of non-native substrates by Saccharomyces cerevisiae is time-consuming.•Engineered Gal3p called metabolic coordinator (Gal3pMC) activates the galactose regulon in a substrate-independent manner.•Molecular modeling studies support that Gal3pMC can activate the galactose regulon without substrate bound.•Activation of galactose regulon is beneficial for growth on structurally diverse non-native substrates.•Gal3pMC enables concurrent utilization of, and rapid growth on, multiple lignocellulose-derived sugars.
Experimental data highlight the potential benefits and health system cost savings related to surgical prehabilitation; however, adequately powered randomized controlled trial (RCT) data remain ...nascent. Emerging prehabilitation services may be informed by early RCT data but can be limited in informing real-world program development. Pragmatic trials emphasize external validity and generalizability to understand and advise intervention development and implementation in clinical settings. This paper presents the methodology of a pragmatic prehabilitation trial to complement emerging phase III clinical trials and inform implementation strategies.
This is a pilot pragmatic clinical trial conducted in a large academic hospital in Toronto, Ontario, Canada to assess feasibility of clinical implementation and derive estimates of effectiveness. Feasibility data include program referral rates, enrolment and attrition, intervention adherence and safety, participant satisfaction, and barriers and facilitators to programming. The study aims to receive 150 eligible referrals for adult, English-speaking, preoperative oncology patients with an identified indication for prehabilitation (
., frailty, deconditioning, malnutrition, psychological distress). Study participants undergo a baseline assessment and shared-decision making regarding the intervention setting: either facility-based prehabilitation or home-based prehabilitation. In both scenarios, participants receive an individualized exercise prescription, stress-reduction psychological support, nutrition counseling, and protein supplementation, and if appropriate, smoking cessation program referrals. Secondary objectives include estimating intervention effects at the week prior to surgery and 30 and 90 days postoperatively. Outcomes include surgical complications, postoperative length of stay, mortality, hospital readmissions, physical fitness, psychological well-being, and quality of life. Data from participants who decline the intervention but consent for research-related access to health records will serve as comparators. The COVID-19 pandemic required the introduction of a 'virtual program' using only telephone or internet-based communication for screening, assessments, or intervention was introduced.
This pragmatic trial will provide evidence on the feasibility and viability of prehabilitation services delivered under usual clinical conditions. Study amendments due to the COVID-19 pandemic are presented as strategies to maintain prehabilitation research and services to potentially mitigate the consequences of extended surgery wait times.
Bacillus Calmette–Guérin (BCG) remains the only approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next-generation TB vaccines typically use a murine aerosol model ...with a supraphysiologic challenge dose. Here, we show that the protective efficacy of a live attenuated Mycobacterium tuberculosis (Mtb) vaccine ΔLprG markedly exceeds that of BCG in a low-dose murine aerosol challenge model. BCG reduced bacterial loads but did not prevent establishment or dissemination of infection in this model. In contrast, ΔLprG prevented detectable infection in 61% of mice and resulted in anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low-dose challenge model, which showed serum IL-17A, IL-6, CXCL2, CCL2, IFN-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low-dose murine challenge model.
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•ΔLprG reduces detectable infection in mice after single 1 MID50 challenge•ΔLprG prevents infection dissemination after single 1 MID50 challenge•Repeated 1 MID50 challenge facilitates correlates of ΔLprG vaccine protection
Immunology; Medical Microbiology
Despite the availability of several effective SARS-CoV-2 vaccines, additional vaccines will be required for optimal global vaccination. In this study, we investigate the immunogenicity and protective ...efficacy of the GBP510 protein subunit vaccine adjuvanted with AS03, which has recently been authorized for marketing in South Korea under the trade name SKYCovione
. The antigen in GBP510/AS03 is a two-part recombinant nanoparticle, which displays 60 receptor binding domain (RBD) proteins of SARS-CoV-2 Spike on its surface. In this study we show that GBP510/AS03 induced robust immune responses in rhesus macaques and protected against a high-dose SARS-CoV-2 Delta challenge. We vaccinated macaques with two or three doses of GBP510/AS03 matched to the ancestral Wuhan strain of SARS-CoV-2 or with two doses of GBP510/AS03 matched to the ancestral strain and one dose matched to the Beta strain. Following the challenge with Delta, the vaccinated macaques rapidly controlled the virus in bronchoalveolar lavage and nasal swabs. Binding and neutralizing antibody responses prior to challenge correlated with protection against viral replication postchallenge. These data are consistent with data with this vaccine from the phase 3 clinical trial.
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