Ratiometric Readout of Bacterial Infections via a Lyophilized CRISPR-Cas12a Sensor with Color-Changeable Bioluminescence.

The healthcare burden imposed by bacterial infections demands robust and accessible diagnostic methods that can be performed outside hospitals and centralized laboratories. Here, we report Pathogen Assay with Ratiometric Luminescence (PEARL), a sensitive and easy-to-operate platform for detecting pathogenic bacteria. The PEARL leveraged a color-changeable CRISPR-Cas12a sensor and recombinase polymerase amplification to elicit ratiometric bioluminescence responses to target inputs. This platform enabled robust and visualized identification of attomolar bacteria genome deoxyribonucleic acid according to the color changes of the reactions. In addition, the components of the color-changeable Cas12a sensor could be lyophilized for 3 month storage at ambient temperature and then be fully activated with the amplicons derived from crude bacterial lysates, reducing the requirements for cold-chain storage and tedious handling steps. We demonstrated that the PEARL assay is applicable for identifying the infections caused by Pseudomonas aeruginosa in different clinical specimens, including sputa, urines, and swabs derived from wounds. These results revealed the potential of PEARL to be used by untrained personnel, which will facilitate decentralized pathogen diagnosis in community- and resource-limited regions.

Nanoparticle-hydrogel composite as dual-drug delivery system for the potential application of corneal graft rejection.

Immune rejection remains the major cause of corneal graft failure. Immunosuppressants (such as rapamycin; RAPA) adjunctive to antibiotics (such as levofloxacin hydrochloride; Lev) are a clinical mainstay after corneal grafts but suffer from poor ocular bioavailability associated with severe side effects. In this study, we fabricated a Lev@RAPA micelle loaded cationic peptide-based hydrogel (NapFFKK) as a dual-drug delivery system by integrating RAPA micelles with Lev into a cationic NapFFKK hydrogel to potentially reduced the risk of corneal graft rejection. The properties of the resulting hydrogels were characterized using transmission electronmicroscopy and rheometer. Lev@RAPA micelles loaded NapFFKK hydrogel provided sustained in vitro drug release without compromising their inherent pharmacological activities. Topical instillation of Lev@RAPA micelles loaded NapFFKK hydrogel resulted in the great ocular tolerance and extended precorneal retention over 60 min, thus significantly enhancing the ocular bioavailability of both Lev and RAPA. Overall, such dual-drug delivery system might be a promising formulation for the suppression of corneal graft failure.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats.

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Multifunctional Additive Enables a "5H" PEO Solid Electrolyte for High-Performance Lithium Metal Batteries.

The solid-state battery with a lithium metal anode is a promising candidate for next-generation batteries with improved energy density and safety. However, the current polymer electrolytes still cannot fulfill the demands of solid-state batteries. In this work, we propose a "5H" poly(ethylene oxide) (PEO) electrolyte via introducing a multifunctional additive of tris(pentafluorophenyl)borane (TPFPB) for high-performance lithium metal batteries. The addition of TPFPB improves the ionic conductivity from 6.08 × 10-5 to 1.54 × 10-4 S cm-1 via reducing the crystallinity of the PEO electrolyte and enhances the lithium-ion transference number from 0.19 to 0.53 via anion trapping due to its Lewis acid nature. Furthermore, the fluorine and boron segments from TPFPB can optimize the composition of the solid-electrolyte interphase and cathode-electrolyte interphase, providing a high electrochemical stability window over 4.6 V of the PEO electrolyte along with significantly improved interface stability. At last, TPFPB can ensure improved safety through a self-extinguishing effect. As a result, the "5H" electrolyte enables the Li/Li symmetric cells to achieve a stable cycle over 2200 h at the current density of 0.2 mA cm-2 with a capacity of 0.2 mA h cm-2; the LiFePO4/Li full cells with a high LFP loading of 8 mg cm-2 exhibits decay-free capacity of 140 mA h g-1 (99% capacity retention) after 100 cycles; and the NCM811/Li cells exhibit a high capacity of 160 mA h g-1 after 50 cycles at 0.5 C. This work presents an innovative approach to utilizing a "5H" electrolyte for high-performance solid-state lithium batteries.

Development of Zn2+-controlled expression system for lactic acid bacteria and its application in engineered probiotics.

Lactococcus lactis and Streptococcus thermophilus are considered as ideal chassis of engineered probiotics, while food-grade genetic tools are limited in those strains. Here, a Zn2+-controlled gene expression (ZICE) system was identified in the genome of S. thermophilus CGMCC7.179, including a transcriptional regulator sczAst and a promoter region of cation transporter czcD (PczcDst). Specific binding of the SczAst to the palindromic sequences in PczcDst was demonstrated by EMSA analysis, suggesting the regulation role of SczAst on PczcDst. To evaluate their possibility to control gene expression in vivo, the sczAst-PczcDst was employed to drive the expression of green fluorescence protein (GFP) gene in L. lactis NZ9000 and S. thermophilus CGMCC7.179, respectively. Both of the transformants could express GFP under Zn2+ induction, while no fluorescence without Zn2+ addition. For optimal conditions, Zn2+ was used at a final concentration of 0.8 mM in L. lactis and 0.16 mM in S. thermophilus at OD600 close to 0.4, and omitting yeast extract powder in the medium unexpectedly improved GFP expression level by 2.2-fold. With the help of the ZICE system, engineered L. lactis and S. thermophilus strains were constructed to secret cytokine interleukin-10 (IL-10) with immunogenicity, and the IL-10 content in the supernatant of the engineered L. lactis was 59.37 % of that under the nisin controlled expression system. This study provided a tightly controlled expression system by the food-grade inducer Zn2+, having potential in development of engineered probiotics.

Nano Self-Assemblies of Caffeic Acid-Fibronectin Mimic a Peptide Conjugate for the Treatment of Corneal Epithelial Injury.

Rapid corneal re-epithelialization is important for corneal wound healing. Corneal epithelial cell motility and oxidative stress are important targets for therapeutic intervention. In this study, we covalently conjugated the antioxidant caffeic acid (CA) with a bioactive peptide sequence (PHSRN) to generate a CA-PHSRN amphiphile, which was formulated into nanoparticular eye drops with an average size of 43.21 ± 16 nm. CA-PHSRN caused minimal cytotoxicity against human corneal epithelial cells (HCECs) and RAW264.7 cells, exhibited an excellent free radical scavenging ability, and remarkably attenuated reactive oxygen species (ROS) levels in H2O2-stimulated HCECs. The antioxidant and anti-inflammatory activities of CA-PHSRN were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The results show that CA-PHSRN treatment effectively prevented LPS-induced DNA damage and significantly reduced the levels of LPS-induced pro-inflammatory cytochemokines (i.e., iNOS, NO, TNF-α, IL-6, and COX-2) in a dose-dependent manner. Moreover, using a rabbit corneal epithelial ex vivo migration assay, we demonstrated that the proposed CA-PHSRN accelerated corneal epithelial cell migration and exhibited high ocular tolerance and ocular bioavailability after topical instillation. Taken together, the proposed CA-PHSRN nanoparticular eye drops are a promising therapeutic formulation for the treatment of corneal epithelial injury.

Supramolecular nanofiber of indomethacin derivative confers highly cyclooxygenase-2 (COX-2) selectivity and boosts anti-inflammatory efficacy.

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications.

Potentiating the Immune Responses of HBsAg-VLP Vaccine Using a Polyphosphoester-Based Cationic Polymer Adjuvant.

Virus-like particle (VLP)-based vaccines are required to be associated with a suitable adjuvant to potentiate their immune responses. Herein, we report a novel, biodegradable, and biocompatible polyphosphoester-based amphiphilic cationic polymer, poly(ethylene glycol)-b-poly(aminoethyl ethylene phosphate) (PEG-PAEEP), as a Hepatitis B surface antigen (HBsAg)-VLP vaccine adjuvant. The polymer adjuvant effectively bound with HBsAg-VLP through electrostatic interactions to form a stable vaccine nanoformulation with a net positive surface charge. The nanoformulations exhibited enhanced cellular uptake by macrophages. HBsAg-VLP/PEG-PAEEP induced a significantly higher HBsAg-specific IgG titer in mice than HBsAg-VLP alone after second immunization, indicative of the antigen-dose sparing advantage of PEG-PAEEP. Furthermore, the nanoformulations exhibited a favorable biocompatibility and in vivo tolerability. This work presents the PEG-PAEEP copolymer as a promising vaccine adjuvant and as a potentially effective alternative to aluminum adjuvants.

Elastin-like recombinamer-mediated hierarchical mineralization coatings on Zr-16Nb-xTi (x = 4,16 wt%) alloy surfaces improve biocompatibility.

The biocompatibility of biomedical materials is vital to their applicability and functionality. However, modifying surfaces for enhanced biocompatibility using traditional surface treatment techniques is challenging. We employed a mineralizing elastin-like recombinamer (ELR) self-assembling platform to mediate mineralization on Zr-16Nb-xTi (x = 4,16 wt%) alloy surfaces, resulting in the modification of surface morphology and bioactivity while improving the biocompatibility of the material. We modulated the level of nanocrystal organization by adjusting the cross-linker ratio. Nanoindentation tests revealed that the mineralized configuration had nonuniformity with respect to Young's modulus and hardness, with the center areas having higher values (5.626 ± 0.109 GPa and 0.264 ± 0.022 GPa) compared to the edges (4.282 ± 0.327 GPa and 0.143 ± 0.023 GPa). The Scratch test results indicated high bonding strength (2.668 ± 0.117 N) between the mineralized coating and the substrate. Mineralized Zr-16Nb-xTi (x = 4,16 wt%) alloys had higher viability compared to untreated alloys, which exhibited high cell viability (>100 %) after 5 days and high alkaline phosphatase activity after 7 days. Cell proliferation assays indicated that MG 63 cells grew faster on mineralized surfaces than on untreated surfaces. Scanning electron microscopy imaging confirmed that the cells adhered and spread well on mineralized surfaces. Furthermore, hemocompatibility test results revealed that all mineralized samples were non-hemolytic. Our results demonstrate the viability of employing the ELR mineralizing platform to improve alloy biocompatibility.

Hierarchical Electrode Architecture Enabling Ultrahigh-Capacity LiFePO4 Cathodes with Low Tortuosity.

Thickening electrodes are expected to increase the energy density of batteries. Unfortunately, the manufacturing issues, sluggish electrolyte infiltration, and restrictions on electron/ion transport seriously hamper the development of thick electrodes. In this work, an ultrathick LiFePO4 (LFP) electrode with hierarchically vertical microchannels and porous structures (I-LFP) is rationally designed by combining the template method and the mechanical channel-making method. By using ultrasonic transmission mapping technology, it is proven that the open and vertical microchannels and interconnected pores can successfully overcome the electrolyte infiltration difficulty of conventional thick electrodes. Meanwhile, both the electrochemical and simulation characterizations reveal the fast ion transport kinetics and low tortuosity (1.44) in the I-LFP electrode. As a result, the I-LFP electrode delivers marked improvements in rate performance and cycling stability even under a high areal loading of 180 mg cm-2. Moreover, according to the results of operando optical fiber sensors, the stress accumulation in the I-LFP electrode is effectively alleviated, which further confirms the improvement of mechanical stability.

Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron BA.2: a population-based study in Hong Kong.

Background: The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the model city of universal masking of the world, has resulted in a major public health crisis. Although the third vaccination resulted in strong boosting of neutralization antibody, vaccine efficacy and correlate of immune protection against the major circulating Omicron BA.2 remain to be investigated. Methods: We investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 470 public servants who had received different SARS-CoV-2 vaccine regimens including two-dose BNT162b2 (2 × BNT, n = 169), three-dose BNT162b2 (3 × BNT, n = 168), two-dose CoronaVac (2 × CorV, n = 34), three-dose CoronaVac (3 × CorV, n = 67) and third-dose BNT162b2 following 2 × CorV (2 × CorV+1BNT, n = 32). Humoral and cellular immune responses after three-dose vaccination were further characterized and correlated with clinical characteristics of BA.2 infection. Findings: During the BA.2 outbreak, 27.7% vaccinees were infected. The timely third-dose vaccination provided significant protection with lower incidence rates of breakthrough infections (2 × BNT 46.2% vs 3 × BNT 13.1%, p < 0.0001; 2 × CorV 44.1% vs 3 × CorV 19.4%, p = 0.003). Investigation of immune responses on blood samples derived from 90 subjects in three-dose vaccination cohorts collected before the BA.2 outbreak revealed that the third-dose vaccination activated spike (S)-specific memory B cells and Omicron cross-reactive T cell responses, which correlated with reduced frequencies of breakthrough infections and disease severity rather than with types of vaccines. Moreover, the frequency of S-specific activated memory B cells was significantly lower in infected vaccinees than uninfected vaccinees before vaccine-breakthrough infection whereas IFN-γ+ CD4 T cells were negatively associated with age and viral clearance time. Critically, BA.2 breakthrough infection boosted cross-reactive memory B cells with enhanced cross-neutralizing antibodies to Omicron sublineages, including BA.2.12.1 and BA.4/5, in all vaccinees tested. Interpretation: Our results imply that the timely third vaccination and immune responses are likely required for vaccine-mediated protection against Omicron BA.2 pandemic. Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested before the emergence of BA.2.12.1 and BA.4/5, the third dose vaccination-activated S-specific memory B cells and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Neutralizing antibody potency enhanced by BA.2 breakthrough infection in vaccinees with prior 3 doses of CoronaVac or BNT162b2 may reduce the risk of infection against ongoing BA.2.12.1 and BA.4/5. Funding: Hong Kong Research Grants Council Collaborative Research Fund, Health and Medical Research Fund, Wellcome Trust, Shenzhen Science and Technology Program, the Health@InnoHK, Innovation and Technology Commission of Hong Kong, China, National Program on Key Research Project, Emergency Key Program of Guangzhou Laboratory, donations from the Friends of Hope Education Fund and the Hong Kong Theme-Based Research Scheme.

A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Holin-assisted bacterial recombinant protein export.

A simple generic method for enhancing extracellular protein yields in engineered bacteria is still lacking. Here, we demonstrated that phage-encoded holin can be used to export proteins to the extracellular medium in both Gram-negative Escherichia coli and -positive Lactococcus lactis. When a putative holin gene LLNZ_RS10380 annotated in the genome of L. lactis NZ9000 (hol380) was recombinantly expressed in E. coli BL21(DE3), the Hol380 oligomerized up to hexamer in the cytoplasmic membrane, yielding membrane pore to allow the passage of cytosolic ß-galatosidase (116 kDa), whose extracellular production reached 54.59 U/µl, accounting for 76.37% of the total activity. However, the overexpressed Hol380 could not release cytosolic proteins across the membrane in L. lactis NZ9000, but increased the secretory production of staphylococcal nuclease to 2.55-fold and fimbrial adhesin FaeG to 2.40-fold compared with those guided by signal peptide Usp45 alone. By using a combination of proteomics and transcriptional level analysis, we found that overexpression of the Hol380 raised the accumulation of Ffh and YidC involved in the signal recognition particle pathway in L. lactis, suggesting an alternative road participating in protein secretion. This study proposed a new approach by expressing holin in bacterial cell factories to export target proteins of economic or medical interest.

Engineered Probiotic Lactococcus lactis for Lycopene Production against ROS Stress in Intestinal Epithelial Cells.

Lactococcus lactis is a food-grade chassis for delivery of bioactive molecules to the intestinal mucosa in situ, while its ability to produce lycopene for detoxification of reactive oxidative species (ROS) is not realized yet. Here, L. lactis NZ9000 was engineered to synthesize lycopene by heterologous expression of a gene cluster crtEBI in plasmids or chromosomes, yielding the recombinant strains NZ4 and NZ5 with 0.59 and 0.54 mg/L lycopene production, respectively. To reroute the pyruvate flux to lycopene, the main lactate dehydrogenase and α-acetolactate synthase pathways were sequentially disrupted. The resultant strains NZΔldh-1 and NZΔldhΔals-1 increased lycopene accumulation to 0.70 and 0.73 mg/L, respectively, while their biomasses were reduced by 12.42% and the intracellular NADH/NAD+ ratios increased by 3.05- and 2.10-fold. To increase the biomasses of these engineered strains, aerobic respiration was activated and tuned by the addition of exogenous heme and oxygen. As a result, the engineered L. lactis strains partly recovered the growth and redox balance, yielding the lycopene levels of 0.91-1.09 mg/L. The engineered L. lactis strain protected the intestinal epithelial cells NCM460 against H2O2 challenge, with a 30.09% increase of cell survival and a 29.2% decrease of the intracellular ROS level compared with strain NZ9000 treatment. In summary, this work established the use of the engineered probiotic L. lactis for lycopene production and prospected its potential in the prevention of intestinal oxidative damage.

HLA-E-restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities.

Human leukocyte antigen-E (HLA-E) normally presents an HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (SIV) vaccine generated Mamu-E (HLA-E homolog)-restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, HIV-1-specific, HLA-E-restricted T cells have not been observed in HIV-1-infected individuals. Here, HLA-E-restricted, HIV-1-specific CD8 + T cells were primed in vitro. These T cell clones and allogeneic CD8 + T cells transduced with their T cell receptors suppressed HIV-1 replication in CD4 + T cells in vitro. Vaccine induction of efficacious HLA-E-restricted HIV-1-specific T cells should therefore be possible.

A Successfully Treated Multiple Metastatic Choriocarcinoma Coexistent With Live Fetus: A Case Report and Literature Review.

Management of metastatic choriocarcinoma coexistent with live fetus is tricky for gynecologists. There is no consensus on treatment because of its rarity. We present a unique case of gestational choriocarcinoma with multiple metastases, who received EP chemotherapy in the third trimester. At 31 + 5 weeks, a healthy male baby was delivered by cesarean section. Then, she received six cycles of EMA/CO as postpartum chemotherapy. Her beta-human chorionic gonadotropin (ß-hCG) level decreased to the normal range, and the metastases vanished. The patient had no clinical symptoms 4 years after discharge, and the baby was also free from this disease. Short tandem repeat polymorphism (STR) analysis was performed to determine the genotype of the choriocarcinoma, placenta, and normal curettage tissue of the maternal uterine. Comparing the polymorphic genetic markers revealed that the tumor was gestational choriocarcinoma, but did not originate from the coexistent pregnancy. In spite of extensive metastases, antepartum chemotherapy is an effective and safe treatment for patients with gestational choriocarcinoma concurrent with pregnancy. STR analysis can be useful in distinguishing gestational choriocarcinoma from non-gestational, as well as the causative pregnancy, and serve as a helpful examination tool for guiding clinical management.

Viral and Antibody Kinetics of COVID-19 Patients with Different Disease Severities in Acute and Convalescent Phases: A 6-Month Follow-Up Study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly around the world, posing a major threat to human health and the economy. Currently, long-term data on viral shedding and the serum antibody responses in COVID-19 patients are still limited. Herein, we report the clinical features, viral RNA loads, and serum antibody levels in a cohort of 112 COVID-19 patients admitted to the Honghu People's Hospital, Hubei Province, China. Overall, 5.36% (6/112) of patients showed persistent viral RNA shedding (> 45 days). The peak viral load was higher in the severe disease group than in the mild group (median cycle threshold value, 36.4 versus 31.5; P = 0.002). For most patients the disappearance of IgM antibodies occurred approximately 4-6 weeks after symptoms onset, while IgG persisted for over 194 days after the onset of symptoms, although patients showed a 46% reduction in antibodies titres against SARS-CoV-2 nucleocapsid protein compared with the acute phase. We also studied 18 asymptomatic individuals with RT-qPCR confirmed SARS-CoV-2 infection together with 17 symptomatic patients, and the asymptomatic individuals were the close contacts of these symptomatic cases. Delayed IgG seroconversion and lower IgM seropositive rates were observed in asymptomatic individuals. These data indicate that higher viral loads and stronger antibody responses are related to more severe disease status in patients with SARS-CoV-2 infection, and the antibodies persisted in the recovered patient for more than 6 months so that the vaccine may provide protection against SARS-CoV-2 infection.

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly.

One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators.