Multi-omics analysis of mucosal and systemic immunity to SARS-CoV-2 after birth.

The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.

SREBP signaling is essential for effective B cell responses.

Our previous study using systems vaccinology identified an association between the sterol regulatory binding protein (SREBP) pathway and humoral immune response to vaccination in humans. To investigate the role of SREBP signaling in modulating immune responses, we generated mice with B cell- or CD11c+ antigen-presenting cell (APC)-specific deletion of SCAP, an essential regulator of SREBP signaling. Ablation of SCAP in CD11c+ APCs had no effect on immune responses. In contrast, SREBP signaling in B cells was critical for antibody responses, as well as the generation of germinal centers,memory B cells and bone marrow plasma cells. SREBP signaling was required for metabolic reprogramming in activated B cells. Upon mitogen stimulation, SCAP-deficient B cells could not proliferate and had decreased lipid rafts. Deletion of SCAP in germinal center B cells using AID-Cre decreased lipid raft content and cell cycle progression. These studies provide mechanistic insights coupling sterol metabolism with the quality and longevity of humoral immunity.

Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

Systems vaccinology of the BNT162b2 mRNA vaccine in humans.

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.

Cleaner tillage and irrigation options for food-water-energy-carbon synergism in wheat-maize cropping systems.

The conventional wheat-maize systems in the North China Plain are energy and water intensive with high carbon emissions. It is imperative to find cleaner production technologies for sustainable food-water-energy-carbon synergism. Here, a three-year field experiment was performed to explore the effects of two tillage modes and four irrigation regimes during wheat season on crop yield, economic profile, water use efficiency, energy utilization, and carbon footprint in typical wheat-maize cropping systems in the North China Plain. Pre-sowing irrigation resulted in the lowest crop yield and benefit profile. Pre-sowing + anthesis irrigation decreased economic benefit and water use efficiency with higher carbon footprint. Pre-sowing + jointing + anthesis irrigation led to the greatest energy consumption and greenhouse gas emissions. However, pre-sowing + jointing irrigation increased yield by 2.3-8.7%, economic benefit by 4.0-11.1%, water use efficiency by 7.4-10.9%, and net energy by 6.5-12.0% but reduced carbon footprint by 9.8-14.3% compared to pre-sowing + anthesis irrigation and pre-sowing + jointing + anthesis irrigation. The corresponding metrics in rotary tillage improved by 9.6%, 13.9%, 7.0%, and 14.2%, respectively, relative to subsoiling, whereas carbon footprint decreased by 12.4-17.2%. Besides, rotary tillage coupled with additional jointing irrigation obtained the highest value based on a Z-score method, which was recommended as a cleaner management practice to improve benefit return and water use efficiency with lower energy consumption and carbon footprint. This work provides valuable insights into food-water-energy-carbon nexus for ensuring food security and achieving environmental sustainability in the wheat-maize cropping systems.

Human Serum Albumin Nanoparticles as a Carrier of 20(S)-Protopanaxadiol via Intramuscular Injection to Alleviate Cyclophosphamide-Induced Myelosuppression.

Myelosuppression is a prevalent and potentially life-threatening side effect during chemotherapy. As the main active component of ginseng, 20(S)-protopanaxadiol (PPD) is capable of relieving myelosuppression by restoring hematopoiesis and immunity. In this study, PPD was encapsulated in human albumin nanoparticles (PPD-HSA NPs) by nanoparticle albumin-bound (Nab) technology for intramuscular injection to optimize its pharmacokinetic properties and promote recovery of myelosuppression. The prepared PPD-HSA NPs had a particle size of about 280 nm with a narrow size distribution. PPD dispersed as an amorphous state within the PPD-HSA NPs, and the NPs exhibited in vitro sustained release behavior. PPD-HSA NPs showed a favorable pharmacokinetic profile with high absolute bioavailability, probably due to the fact that NPs entered into the blood circulation via lymphatic circulation and were eliminated slowly. In vivo distribution experiments demonstrated that PPD-HSA NPs were mainly distributed in the liver and spleen, but a strong fluorescence signal was also found in the inguinal lymph node, indicating drug absorption via a lymph route. The myelosuppressive model was established using cyclophosphamide as the inducer. Pharmacodynamic studies confirmed that PPD-HSA NPs were effective in promoting the level of white blood cells. Moreover, the neutrophil and lymphocyte counts were significantly higher in the PPD-HSA NPs group compared with the control group. This preliminary investigation revealed that PPD-HSA NPs via intramuscular administration may be an effective intervention strategy to alleviate myelosuppression.

Exploring wheat-based management strategies to balance agricultural production and environmental sustainability in a wheat-maize cropping system using the DNDC model.

Faced with the great challenge of food demand and environmental pollution, optimizing agricultural practices can potentially balance food security and environmental protection. In this study, the DeNitrification-DeComposition (DNDC) model was applied to explore the effect of wheat-based management strategies on crop productivity and greenhouse gas emissions in the wheat-maize system. The DNDC model was tested against crop yield, daily nitrous oxide (N2O) fluxes, and cumulative N2O emissions determined from field measurements in a typical winter wheat-summer maize cropping system. Model evaluations demonstrated a good agreement between the observations and simulated crop yield (4.4%≤NRMSE≤8.0%), daily N2O fluxes (0.68 ≤ d ≤ 0.88), and cumulative N2O emissions (4.9%≤NRMSE≤11.9%). By adopting sensitivity analysis, the DNDC model then assessed the impacts on crop yield and cumulative N2O emissions of multiple management practices from the winter wheat season. Delaying the sowing date from October 7 to November 4 reduced annual yield by 1.9%, while cumulative N2O emissions were increased by 10.4%. Furthermore, postponing the supplementary irrigation date from April 1 to May 20 decreased annual yield by 2.4% without affecting cumulative N2O emissions. An N fertilizer rate of 120-150 kg N ha-1 was able to reduce N usage and cumulative N2O emissions without sacrificing annual yield. Despite an improvement in the annual yield at the 0-30 cm tillage depth by 2.9%, cumulative N2O emissions increased by 11.6%. The results suggest that sowing in early October, applying supplementary irrigation in early April, an N fertilizer rate of 120-150 kg N ha-1, and no-tillage from the winter wheat season can improve crop yield and mitigate N2O emissions. This is conducive to the synergism of agricultural production and environmental sustainability.

MiR-26a inhibits prostate cancer progression by repression of Wnt5a.

MicroRNAs (miRNAs) are small noncoding RNAs that are involved in different biological processes by suppressing target gene expression. miRNA microarray analysis revealed a significant decrease of miR-26a in prostate cancer tissues versus their normal counterparts, but the role of miR-26a is needed to investigate. In the present study, we found that miR-26a expression was lower in prostate cancer tissues compared with their normal controls, so did the prostate cancer cells. Next, by lentivirus-mediated gain-of-function studies, it was showed that stable miR-26a inhibited cell proliferation, metastasis, and epithelial mesenchymal transition and induced G1 phase arrest in prostate cancer. It was predicted that Wnt5a was a potential target gene of miR-26a by bioinformatics analysis. Then, luciferase assay and Western blot analysis identified that Wnt5a was a new direct target gene of miR-26a and miR-26a inhibited prostate cancer progression via Wnt5a. Altogether, the findings suggested that miR-26a may function as a tumor suppressor in prostate cancer by targeting Wnt5a.

An intracellularly activatable, fluorogenic probe for cancer imaging.

A newly designed, dual-functional probe based on intracellular activation has been successfully developed for the detection of cancer cells. The probe is nearly non-fluorescent in buffer due to its highly efficient FRET quenching, but it can be specifically activated with dramatic fluorescence enhancement upon intracellular cathepsin B cleavage in target cancer cells after selective internalization via folate receptor-dependent endocytosis. Therefore, this probe enables "turn-on" visualization of cancer cells with desirable specificity and contrast enhancement. This targeted, intracellularly activatable probe exhibits low fluorescence-quenched background when compared with "always-on" probes and avoids non-specific activation by non-specifically expressed enzymes in normal tissue, which normally occurs when using common "turn on" probe design strategies. Therefore, this probe can be potentially applied in intraoperative inspection during clinical cancer surgery with higher contrast and sensitivity.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans.

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4+ T cell and memory B cell responses. Antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin.

Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma.

Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicit anti-cancer immune responses by modulating tumor microenvironment.

Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.

Enzyme/pH dual stimuli-responsive nanoplatform co-deliver disulfiram and doxorubicin for effective treatment of breast cancer lung metastasis.

OBJECTIVES: Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis. METHODS: DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs. RESULTS: The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs. CONCLUSION: DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.

The interplay between PEGylated nanoparticles and blood immune system.

During the last two decades, an increasing number of reports have pointed out that the immunogenicity of polyethylene glycol (PEG) may trigger accelerated blood clearance (ABC) and hypersensitivity reaction (HSR) to PEGylated nanoparticles, which could make PEG modification counterproductive. These phenomena would be detrimental to the efficacy of the load and even life-threatening to patients. Consequently, further elucidation of the interplay between PEGylated nanoparticles and the blood immune system will be beneficial to developing and applying related formulations. Many groups have worked to unveil the relevance of structural factors, dosing schedule, and other factors to the ABC phenomenon and hypersensitivity reaction. Interestingly, the results of some reports seem to be difficult to interpret or contradict with other reports. In this review, we summarize the physiological mechanisms of PEG-specific immune response. Moreover, we speculate on the potential relationship between the induction phase and the effectuation phase to explain the divergent results in published reports. In addition, the role of nanoparticle-associated factors is discussed based on the classification of the action phase. This review may help researchers to develop PEGylated nanoparticles to avoid unfavorable immune responses based on the underlying mechanism.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Extremely potent pan-sarbecovirus neutralizing antibodies generated by immunization of macaques with an AS03-adjuvanted monovalent subunit vaccine against SARS-CoV-2.

The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination. 514 monoclonal antibodies (mAbs) were generated from antigen-specific memory B cells. Antibodies isolated at 5 to 12 months following vaccination displayed greater potency and breadth, relative to those identified at 1.4 months. Notably, 15 out of 338 (∼4.4%) antibodies isolated at 1.4∼6 months after the primary vaccination showed extraordinary neutralization potency against SARS-CoV-2 omicron BA.1, despite the absence of BA.1 neutralization in serum. Two of them, 25F9 and 20A7, neutralized authentic clade Ia sarbecoviruses (SARS-CoV, WIV-1, SHC014) and clade Ib sarbecoviruses (SARS-CoV-2 D614G, SARS-CoV-2 BA.1, Pangolin-GD) with half-maximal inhibition concentrations of (0.85 ng/ml, 3 ng/ml, 6 ng/ml, 6 ng/ml, 42 ng/ml, 6 ng/ml) and (13 ng/ml, 2 ng/ml, 18 ng/ml, 9 ng/ml, 6 ng/ml, 345 ng/ml), respectively. Furthermore, 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants of concern and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1 and XBB variants. X-ray crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved RBD sites. In vivo prophylactic protection of 25F9, 20A7 and 27A12 was confirmed in aged Balb/c mice. Notably, administration of 25F9 provided complete protection against SARS-CoV-2, SARS-CoV-2 BA.1, SARS-CoV, and SHC014 challenge, underscoring that these mAbs are promising pan-sarbecovirus therapeutic antibodies. One Sentence Summary: Extremely potent pan-sarbecovirus neutralizing antibodies.

Durability of immune responses to mRNA booster vaccination against COVID-19.

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster vaccination improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received a booster dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of the antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster vaccine, we measured serum antibody titers and memory B and T cell responses.ResultsThe booster (third immunization) dose at 6 to 10 months increased the half-life of the serum-neutralizing antibody (nAb) titers to 76 days from 56 to 66 days after the primary 2-dose vaccination. A second booster dose (fourth immunization) a year after the primary vaccination further increased the half-life to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss of neutralization capacity against the Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48-, 71-, and 66-fold drop in titers, respectively, relative to the WA.1 strain). Although only 45% to 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (third dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months.ConclusionThe durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.

Systems biological assessment of the temporal dynamics of immunity to a viral infection in the first weeks and months of life.

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memory B cell (MCB) responses were durable for 150 days but waned thereafter. Somatic hypermutation of V-genes in MCB accumulated progressively over 9 months. The innate response was characterized by upregulation of activation markers on blood innate cells, and a plasma cytokine profile distinct from that seen in adults, with no inflammatory cytokines, but an early and transient accumulation of chemokines (CXCL10, IL8, IL-18R1, CSF-1, CX3CL1), and type I IFN. The latter was strongly correlated with viral load, and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell transcriptomics. Consistent with this, single-cell ATAC-seq revealed enhanced accessibility of chromatic loci targeted by interferon regulatory factors (IRFs) and reduced accessibility of AP-1 targeted loci, as well as traces of epigenetic imprinting in monocytes, during convalescence. Together, these data provide the first snapshot of immunity to infection during the initial weeks and months of life.