Subharmonic Resonance of Van Der Pol Oscillator with Fractional-Order Derivative

The subharmonic resonance of van der Pol (VDP) oscillator with fractional-order derivative is studied by the averaging method. At first, the first-order approximate solutions are obtained by the averaging method. Then the definitions of equivalent linear damping coefficient (ELDC) and equivalent linear stiffness coefficient (ELSC) for subharmonic resonance are established, and the effects of the fractional-order parameters on the ELDC, the ELSC, and the dynamical characteristics of system are also analysed. Moreover, the amplitude-frequency equation and phase-frequency equation of steady-state solution for subharmonic resonance are established. The corresponding stability condition is presented based on Lyapunov theory, and the existence condition for subharmonic resonance (ECSR) is also obtained. At last, the comparisons of the fractional-order and the traditional integer-order VDP oscillator are fulfilled by the numerical simulation. The effects of the parameters in fractional-order derivative on the steady-state amplitude, the amplitude-frequency curves, and the system stability are also studied

Sex-biased immunogenicity of a mucosal subunit vaccine against SARS-CoV-2 in mice

IntroductionCurrent vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated.MethodsWe evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses.ResultsOur results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine.DiscussionOur findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice

Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants

IntroductionAdjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) induced effective mucosal and systemic immunity and conferred nearly sterile protection against SARS-CoV-2 viral replication in macaque models.MethodsIn this study, we used a hamster model, which mimics the human scenario and reliably exhibits severe SARS-CoV-2 disease similar to hospitalized patients, to investigate the protection efficacy of the vaccines against COVID-19 disease. We compared the weight loss, viral loads (VLs), and clinical observation scores of three different vaccine regimens. All three regimens consisted of priming/boosting with S1 subunit vaccines, but adjuvanted with alum and/or CP15 administrated by either intramuscular (IM) or intranasal (IN) routes: Group 1 was adjuvanted with alum/alum administrated IM/IM; Group 2 was alum-IM/CP15-IN; and Group 3 was CP15-IM/CP15-IN.ResultsAfter challenge with SARS-CoV-2 WA strain, we found that the alum/CP15 group showed best protection against weight loss, while the CP15 group demonstrated best reduction of oral SARS-CoV-2 VLs, suggesting that the protection profiles were different. Sex differences for VL and clinical scores were observed. Humoral immunity was induced but not correlated with protection. Moreover, S1-specific binding antibody titers against beta, omicron BA.1, and BA.2 variants showed 2.6-, 4.9- and 2.8- fold reduction, respectively, compared to the Wuhan strain.DiscussionOverall, the data suggested that adjuvants in subunit vaccines determine the protection profiles after SARS-CoV-2 infection and that nasal/oral mucosal immunization can protect against systemic COVID-19 disease

Innate protection against intrarectal SIV acquisition by a live SHIV vaccine.

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development

Large intestine–targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection

Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both mucosal sites in animal studies, can be achieved successfully by direct intra-colorectal (i.c.r.) administration, which is, however, clinically impractical. Oral delivery seems preferable, but risks vaccine destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal or vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible novel strategy for immune protection of rectal and vaginal mucosa

Myeloid Cell Crosstalk Regulates the Efficacy of the DNA/ALVAC/gp120 HIV Vaccine Candidate

Vaccination with DNA-SIV + ALVAC-SIV + gp120 alum results in inflammasome activation, high levels of IL-1β production, emergency myelopoiesis, and the egress of CXCR4+ CD14+ pre-monocytes from bone marrow. Previously we have shown that this vaccine-induced innate monocyte memory is associated with decreased risk of SIVmac251 acquisition. Because IL-1β also promotes the propagation of monocyte-derived suppressor (M-MDSC)-like cells, here we extended our analysis to this negative regulator subset, characterizing its levels and functions in macaques. Interestingly, we found that DNA prime engages M-MDSC-like cells and their levels are positively associated with the frequency of CD14+ classical monocytes, and negatively with the levels of CD16+ monocytes, correlates of decreased and increased risk of SIV acquisition, respectively. Accordingly, M-MDSC frequency, arginase activity, and NO were all associated with decrease of CD8 T cells responses and worse vaccination outcome. DNA vaccination thus induces innate immunity by engaging three subsets of myeloid cells, M-MDSCs, CD14+ innate monocyte memory, and CD16+ monocytes all playing different role in protection. The full characterization of the immunological space created by myeloid cell crosstalk will likely provide clues to improve the efficacy of HIV vaccine candidates

Low-dose versus standard-dose alteplase in acute ischemic stroke in Asian stroke registries: an individual patient data pooling study

10.1177/1747493019858777INTERNATIONAL JOURNAL OF STROKE147670-67

Potential SARS-CoV-2 Immune Correlates of Protection in Infection and Vaccine Immunization

Both SARS-CoV-2 infections and vaccines induce robust immune responses. Current data suggested that high neutralizing antibody titers with sustained Th1 responses might correlate with protection against viral transmission and disease development and severity. In addition, genetic and innate immune factors, including higher levels of type I interferons, as well as the induction of trained immunity and local mucosal immunity also contribute to lower risk of infection and amelioration of disease severity. The identification of immune correlates of protection will facilitate the development of effective vaccines and therapeutics strategies

Potential SARS-CoV-2 Immune Correlates of Protection in Infection and Vaccine Immunization

Both SARS-CoV-2 infections and vaccines induce robust immune responses. Current data suggested that high neutralizing antibody titers with sustained Th1 responses might correlate with protection against viral transmission and disease development and severity. In addition, genetic and innate immune factors, including higher levels of type I interferons, as well as the induction of trained immunity and local mucosal immunity also contribute to lower risk of infection and amelioration of disease severity. The identification of immune correlates of protection will facilitate the development of effective vaccines and therapeutics strategies