Higher IgG Levels Research Articles

Chronic mucocutaneous candidiasis and immune dysregulation due to STAT1 Gain of Function

BackgroundGermline gain-of-function (GOF) mutations in the Signal Transducer and Activator of Transcription 1 (STAT1) gene have been associated with autosomal dominant chronic mucocutaneous candidiasis (CMCC), autoimmune and inflammatory manifestations. Although most patients with STAT1 GOF have CMCC, the disease has a broad phenotypic spectrum.Case Description: A 13-year-old male born to non-consanguineous parents with a past medical history of chronic mucocutaneous candidiasis, autoimmune hypothyroidism, and recurrent viral respiratory tract infections presented for immune evaluation. His medical history was also significant for chronic fatigue refractory to thyroid replacement therapy, chronic paronychia, oral thrush, pneumonia requiring hospitalization, recurrent chalazia status post excision, and prolonged tonsillitis. Laboratory results showed high total serum IgG levels with elevated IgG1 and IgG3 subclasses, elevated B cell counts with atypical lymphocytes, and chronic EBV-viremia. He had no clinical or laboratory evidence of active lymphoproliferative disease. He had normal lymphocyte proliferation to mitogens with impaired response to antigens. He had an adequate humoral response to protein and polysaccharide antigens. Targeted genetic testing for inborn errors of immunity showed a heterozygous variant in the STAT1 gene (c.1169T>C, p.MET390Thr), which had been previously reported in patients with STAT1 GOF. The patient was treated with oral fluconazole with interval improvement in CMCC and subsequently maintained on prophylactic fluconazole and TMP/SMX. He had an unremarkable family history, which suggests a de novo mutation in STAT1. ConclusionThe presence of CMCC and autoimmunity should raise concern for STAT1 GOF. Genetic testing for inborn errors of immunity can be a valuable tool in the diagnosis of patients with CMCC and can help guide therapy. Unfortunately, hematopoietic stem cell transplant has been associated with a high mortality rate in patients with STAT1 GOF. JAK inhibition therapy was recommended for this patient. However, there is currently no consensus regarding JAK inhibitor selection, dosing, treatment duration or biomarkers in STAT1 GOF.

Characterization of immune response towards modified Coxsackie B virus-like particle vaccine in a murine model

Abstract Coxsackievirus Bs (CVBs) are common human RNA viruses that belong to the enterovirus genus of Picornaviridae. Most commonly, infections with these viruses manifest with mild flu-like symptoms. However, CVBs are also known to cause severe diseases, including aseptic meningitis, myocarditis, and chronic dilated cardiomyopathy (DCM), encephalitis, pancreatitis, and hand-foot-and-mouth disease. In this study, we aimed for a versatile characterization of a modified CVB virus-like particle vaccine in a murine model. The modified CVB-VLP was produced using baculovirus-insect cell production platform. Purified and characterized vaccine was administered to mice via s.c. or i.m. routes, either with or without an adjuvant. Immunological characterization of vaccine response included both humoral and cellular characterization. Antigen-specific IgG levels and neutralizing antibodies in the sera were measured to determine the humoral immune response. To characterize the cellular immunity, activation markers of the lymphocytes were identified using flow cytometry. Additionally, the cytokine secretion of the stimulated splenocytes was determined with FluoroSpot assay. The modified CVB-VLP induced high levels of IgG and neutralizing antibodies in the sera of vaccinated mice. Further, the in vitro stimulation of splenocytes induced activation of mainly CD4+ T-cells, and adjuvanted vaccine induced a significant production level of IFN-γ and IL-2. These results indicate that the virus-like particle combined with an adjuvant is a promising vaccine candidate. In addition, our current challenge study with coxsackie B1 virus will shed us more insight on the protective role of this vaccine. Supported by grants from Finnish Foundations (Instrumentarium Science Foundation, Paulo Foundation and Ida Montini Foundation)

The quantity and quality of anti-SARS-CoV-2 antibodies show contrariwise association with COVID-19 severity: lessons learned from IgG avidity.

Gaining more appreciation on the protective/damaging aspects of anti-SARS-CoV-2 immunity associated with disease severity is of great importance. This study aimed to evaluate the avidity of serum IgG antibodies against SARS-CoV-2 spike (S) and nucleocapsid (N) in hospitalized symptomatic COVID-19 patients and asymptomatic RT-PCR-confirmed SARS-CoV-2 carriers as well as to compare antibody avidities with respect to vaccination status, vaccination dose and reinfection status. Serum levels of anti-S and anti-N IgG were determined using specific ELISA kits. Antibody avidity was determined by urea dissociation assay and expressed as avidity index (AI) value. Despite higher IgG levels in the symptomatic group, AI values of both anti-S and anti-N IgG were significantly lower in this group compared to asymptomatic individuals. In both groups, anti-S AI values were elevated in one-dose and two-dose vaccinees versus unvaccinated subjects, although significant differences were only detected in the symptomatic group. However, anti-N avidity showed no significant difference between the vaccinated and unvaccinated subgroups. Almost all vaccinated patients of different subgroups (based on vaccine type) had higher anti-S IgG avidity, while the statistical significance was detected only between those receiving Sinopharm compared to the unvaccinated subgroup. Also, statistically significant differences in antibody AIs were only found between primarily infected individuals of the two groups. Our findings indicate a key role for anti-SARS-CoV-2 IgG avidity in protection from symptomatic COVID-19 and calls for the incorporation of antibody avidity measurement into the current diagnostic tests to predict effective immunity toward SARS-CoV-2 infection or even for prognostic purposes.

A novel multi-component protein vaccine ECP001 containing a protein polypeptide antigen nPstS1 riching in T-cell epitopes showed good immunogenicity and protection in mice.

Tuberculosis (TB) is an infectious disease that seriously affects human health. Until now, the only anti-TB vaccine approved for use is the live attenuated Mycobacterium bovis (M. bovis) vaccine - BCG vaccine, but its protective efficacy is relatively low and does not provide satisfactory protection against TB in adults. Therefore, there is an urgent need for more effective vaccines to reduce the global TB epidemic. In this study, ESAT-6, CFP-10, two antigens full-length and the T-cell epitope polypeptide antigen of PstS1, named nPstS1, were selected to form one multi-component protein antigens, named ECP001, which include two types, one is a mixed protein antigen named ECP001m, the other is a fusion expression protein antigen named ECP001f, as candidates for protein subunit vaccines. were prepared by constructing one novel subunit vaccine by mixing or fusing the three proteins and combining them with aluminum hydroxide adjuvant, and the immunogenicity and protective properties of the vaccine was evaluated in mice. The results showed that ECP001 stimulated mice to produce high titre levels of IgG, IgG1 and IgG2a antibodies; meanwhile, high levels of IFN-γ and a broad range of specific cytokines were secreted by mouse splenocytes; in addition, ECP001 inhibited the proliferation of Mycobacterium tuberculosis in vitro with a capacity comparable to that of BCG. It can be concluded that ECP001 is a novel effective multicomponent subunit vaccine candidate with potential as BCG Initial Immunisation-ECP001 Booster Immunisation or therapeutic vaccine for M. tuberculosis infection.

Fermented Bamboo Fiber Improves Productive Performance by Regulating Gut Microbiota and Inhibiting Chronic Inflammation of Sows and Piglets during Late Gestation and Lactation.

Sows exhibit metabolic syndrome and significant changes in intestinal microbiota during late gestation and lactation, affecting sow performance and piglet health. Dietary fiber (DF) is widely applied to improve sow performance by modulating gut microbiota and their by-products. Here, 60 sows were randomly allocated to groups, including CON (8% wheat bran), FBF-1 (1% fermented bamboo fiber), FBF-2 (2.5% fermented bamboo fiber), and FBF-3 (4% fermented bamboo fiber) from day 80 of gestation (G80d) to the end of lactation (L21d). Compared with CON, the FBF-3 diet decreased lactation backfat loss, increased average daily feed intake (ADFI) during lactation, and the weight gain of piglets, while supplementation of FBF increased fecal water content and reduced the rate of constipation in sows. Further, the yield and quality of milk of sows in FBF groups were improved. The FBF-3 diet significantly reduced markers of intestinal permeability (diamine oxidase and endotoxin) and systemic inflammation (interleukin-6 [IL-6] and tumor necrosis factor alpha) in sow serum during lactation, while it increased the anti-inflammatory marker (IL-10). Similarly, the piglets in the FBF-2 and FBF-3 groups had lower levels of IL-6 and higher levels of IgG, IgM, and insulin-like growth factor in serum. In addition, sows fed the 4% FBF diet had higher levels of acetate, propionate, butyrate, and total short-chain fatty acids (SCFAs) in feces than CON, and total SCFAs were promoted in piglets from the FBF-3 group. Spearman correlation analysis showed that immunity, inflammation, and intestinal microbiota are closely related to sow performance, which can affect piglet growth. The potential mechanism could be that FBF promoted the enrichment of beneficial genera such as Lachnospira, Lachnospiracea_XPB1014_Group, and Roseburia and the production of SCFAs in the sow's intestine, and reduced the relative abundance of harmful bacteria such as Fusobacterium, Sutterellaceae, and Sutterella. Meanwhile, the intake of FBF by sows affected the gut microbial composition of their offspring piglets, significantly increasing the relative abundance of beneficial bacteria Alistipes and Lachnoclostridium and decreasing the relative abundance of pathogenic bacteria Trueperella among colonic microorganisms. IMPORTANCE Dietary fiber is widely applied in the nutrition of sows due to its potential value in improving performance and intestinal health. Fermented bamboo fiber, rich in dietary fiber, has not been fully evaluated to be used in sow diets. Sows mobilize body reserves during gestation and lactation due to nutrients being prioritized for lactation purposes while feeding piglets, which generally leads to metabolism and immunity undergoing drastic changes. The main manifestations are increased inflammation and intestinal permeability and disturbed intestinal flora, which ultimately reduces the ADFI and milk quality, thus affecting the growth of piglets. The study described here is the first attempt to provide FBF for sows in late gestation and lactation can reverse this process. The 4% FBF was initially explored to have the most significantly beneficial effect. It provides a potentially effective method for dietary modification to control the gut microbiota and its metabolites to improve sow and piglet health. Moreover, the sow-piglet model offers a reference for investigating the impact of dietary fiber on the intestinal health of human mothers and infants.

A clinical case of multifocal chorioretinitis associated with Herpes zoster

The Varicella-Zoster virus (VZV) is the etiologic agent of one of the most common infectious diseases among children, chickenpox. In its recurrent form it may cause a far more devastating disease, Herpes zoster. The disease can be manifested as conjunctivitis, episcleritis, scleritis, keratitis, anterior uveitis. Chorioretinal lesions may occur in patients with immunosuppression.
 A 14-year-old male patient has been admitted to the Ophthalmologic center after S.V. Malayan with complaints of visual decrease, redness and pains. In the history of the patient the transferred chickenpox was marked a few months ago. By biomicroscopic and fundoscopic examination conjunctival hyperemia, corneal precipitates, severe inflammatory reaction in the anterior chamber, sectoral iris atrophy, posterior synechiae, yellow-white multifocal, peripheral lesions on the fundus of both eyes and pigmented macular scar in the right eye were found out. Laboratory tests showed high levels of anti-VZV IgG. Treatment was prescribed in the form of local instillations and subtenon injections, as well as antiviral tablets. As a result of treatment, remission of inflammatory process and improvement of visual acuity were registered. The specific characteristic of present case study is the description of single clinical manifestations of Herpes zoster, which are necessary to detect for correct and timely treatment.

Efficient mRNA Delivery with mRNA Lipoplexes Prepared Using a Modified Ethanol Injection Method.

Messenger RNA (mRNA)-based therapies are a novel class of therapeutics used in vaccination and protein replacement therapies for monogenic diseases. Previously, we developed a modified ethanol injection (MEI) method for small interfering RNA (siRNA) transfection, in which cationic liposome/siRNA complexes (siRNA lipoplexes) were prepared by mixing a lipid-ethanol solution with a siRNA solution. In this study, we applied the MEI method to prepare mRNA lipoplexes and evaluated the in vitro and in vivo protein expression efficiencies. We selected six cationic lipids and three neutral helper lipids to generate 18 mRNA lipoplexes. These were composed of cationic lipids, neutral helper lipids, and polyethylene glycol-cholesteryl ether (PEG-Chol). Among them, mRNA lipoplexes containing N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16) or 11-((1,3-bis(dodecanoyloxy)-2-((dodecanoyloxy)methyl) propan-2-yl) amino)-N,N,N-trimethyl-11-oxoundecan-1-aminium bromide (TC-1-12) with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and PEG-Chol exhibited high protein expression in cells. Furthermore, mRNA lipoplexes composed of DC-1-16, DOPE, and PEG-Chol exhibited high protein expression in the lungs and spleen of mice after systemic injection and induced high antigen-specific IgG1 levels upon immunization. These results suggest that the MEI method can potentially increase the efficiency of mRNA transfection, both in vitro and in vivo.

Immunogenicity of a spike protein subunit-based COVID-19 vaccine with broad protection against various SARS-CoV-2 variants in animal studies.

SARS-CoV-2 pandemic has profound impacts on human life and global economy since the outbreak in 2019. With the new variants continue to emerge with greater immune escaping capability, the protectivity of the available vaccines is compromised. Therefore, development a vaccine that is capable of inducing immunity against variants including omicron strains is in urgent need. In this study, we developed a protein-based vaccine BCVax that is consisted of antigen delta strain spike protein and QS21-based adjuvant AB801 in nanoparticle immune stimulation complex format (AB801-ISCOM). Results from animal studies showed that high level of anti-S protein IgG was induced after two doses of BCVax and the IgG was capable of neutralizing multiple variants of pseudovirus including omicron BA.1 or BA.2 strains. In addition, strong Th1 response was stimulated after BCVax immunization. Furthermore, BCvax with AB801-ISCOM as the adjuvant showed significant stronger immunity compared with the vaccine using aluminum hydroxide plus CpG 1018 as the adjuvant. BCVax was also evaluated as a booster after two prior vaccinations, the IgG titers and pseudovirus neutralization activities against BA.2 or BA.4/BA.5 were further enhanced suggesting BCVax is a promising candidate as booster. Taken together, the pre-clinical data warrant BCVax for further development in clinic.

Using an Aluminum Hydroxide-Chitosan Matrix Increased the Vaccine Potential and Immune Response of Mice against Multi-Drug-Resistant Acinetobacter baumannii.

Acinetobacter baumannii is a Gram-negative, immobile, aerobic nosocomial opportunistic coccobacillus that causes pneumonia, septicemia, and urinary tract infections in immunosuppressed patients. There are no commercially available alternative antimicrobials, and multi-drug resistance is an urgent concern that requires emergency measures and new therapeutic strategies. This study evaluated a multi-drug-resistant A. baumannii whole-cell vaccine, inactivated and adsorbed on an aluminum hydroxide-chitosan (mAhC) matrix, in an A. baumannii sepsis model in immunosuppressed mice by cyclophosphamide (CY). CY-treated mice were divided into immunized, non-immunized, and adjuvant-inoculated groups. Three vaccine doses were given at 0D, 14D, and 28D, followed by a lethal dose of 4.0 × 108 CFU/mL of A. baumannii. Immunized CY-treated mice underwent a significant humoral response, with the highest IgG levels and a higher survival rate (85%); this differed from the non-immunized CY-treated mice, none of whom survived (p < 0.001), and from the adjuvant group, with 45% survival (p < 0.05). Histological data revealed the evident expansion of white spleen pulp from immunized CY-treated mice, whereas, in non-immunized and adjuvanted CY-treated mice, there was more significant organ tissue damage. Our results confirmed the proof-of-concept of the immune response and vaccine protection in a sepsis model in CY-treated mice, contributing to the advancement of new alternatives for protection against A. baumannii infections.

Antibody response in children with multisystem inflammatory syndrome related to COVID-19 (MIS-C) compared to children with uncomplicated COVID-19.

To comprehensively analyze the quality of the antibody response between children with Multisystem inflammatory syndrome (MIS-C) and age-matched controls at one month after SARS-CoV-2 exposure, and infected in the same time-period. Serum from 20 MIS-C children at admission, and 14 control children were analyzed. Antigen specific antibody isotypes and subclasses directed against various antigens of SARS-CoV-2 as well as against human common coronavirus (HCoVs) and commensal or pathogenic microorganisms were assessed by a bead-based multiplexed serological assay and by ELISA. The functionality of these antibodies was also assessed using a plaque reduction neutralization test, a RBD-specific avidity assay, a complement deposition assay and an antibody-dependent neutrophil phagocytosis (ADNP) assay. Children with MIS-C developed a stronger IgA antibody response in comparison to children with uncomplicated COVID-19, while IgG and IgM responses are largely similar in both groups. We found a typical class-switched antibody profile with high level of IgG and IgA titers and a measurable low IgM due to relatively recent SARS-CoV-2 infection (one month). SARS-CoV-2-specific IgG antibodies of MIS-C children had higher functional properties (higher neutralization activity, avidity and complement binding) as compared to children with uncomplicated COVID-19. There was no difference in the response to common endemic coronaviruses between both groups. However, MIS-C children had a moderate increase against mucosal commensal and pathogenic strains, reflecting a potential association between a disruption of the mucosal barrier with the disease. Even if it is still unclear why some children develop a MIS-C, we show here that MIS-C children produce higher titers of IgA antibodies, and IgG antibodies with higher functionality, which could reflect the local gastro-intestinal mucosal inflammation potentially induced by a sustained SARS-CoV-2 gut infection leading to continuous release of SARS-CoV-2 antigens.

An Adjuvanted Inactivated SARS-CoV-2 Microparticulate Vaccine Delivered Using Microneedles Induces a Robust Immune Response in Vaccinated Mice.

SARS-CoV-2, the causal agent of COVID-19, is a contagious respiratory virus that frequently mutates, giving rise to variant strains and leading to reduced vaccine efficacy against the variants. Frequent vaccination against the emerging variants may be necessary; thus, an efficient vaccination system is needed. A microneedle (MN) vaccine delivery system is non-invasive, patient-friendly, and can be self-administered. Here, we tested the immune response produced by an adjuvanted inactivated SARS-CoV-2 microparticulate vaccine administered via the transdermal route using a dissolving MN. The inactivated SARS-CoV-2 vaccine antigen and adjuvants (Alhydrogel® and AddaVax™) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer matrices. The resulting MP were approximately 910 nm in size, with a high percentage yield and percent encapsulation efficiency of 90.4%. In vitro, the vaccine MP was non-cytotoxic and increased the immunostimulatory activity measured as nitric oxide release from dendritic cells. The adjuvant MP potentiated the immune response of the vaccine MP in vitro. In vivo, the adjuvanted SARS-CoV-2 MP vaccine induced high levels of IgM, IgG, IgA, IgG1, and IgG2a antibodies and CD4+ and CD8+ T-cell responses in immunized mice. In conclusion, the adjuvanted inactivated SARS-CoV-2 MP vaccine delivered using MN induced a robust immune response in vaccinated mice.

Plasmodium vivax MSP1-42 kD Variant Proteins Detected Naturally Induced IgG Antibodies in Patients Regardless of the Infecting Parasite Phenotype in Mesoamerica

The serological tests using blood stage antigens might be helpful for detecting recent exposure to Plasmodium parasites, and seroepidemiological studies would aid in the elimination of malaria. This work produced recombinant proteins of PvMSP142 variants and evaluated their capacity to detect IgG antibodies in symptomatic patients from Mesoamerica. Three variant Pvmsp142 genes were cloned in the pHL-sec plasmid, expressed in the Expi293F™ eukaryotic system, and the recombinant proteins were purified by affinity chromatography. Using an ELISA, 174 plasma or eluted samples from patients infected with different P. vivax haplotypes were evaluated against PvMSP142 proteins and to a native blood stage antigen (NBSA). The antibody IgG OD values toward PvMSP142 variants (v88, v21, and v274) were heterogeneous (n = 178; median = 0.84 IQR 0.28-1.64). The correlation of IgG levels among all proteins was very high (spearman's rho = 0.96-0.98; p < 0.0001), but was lower between them and the NBSA (rho = 0.771; p < 0.0001). In only a few samples, higher reactivity to the homologous protein was evident. Patients with a past infection who were seropositive had higher IgG levels and lower parasitemia levels than those who did not (p < 0.0001). The PvMSP142 variants were similarly efficient in detecting specific IgG antibodies in P. vivax patients from Mesoamerica, regardless of the infecting parasite's haplotype, and might be good candidates for malaria surveillance and epidemiological studies in the region.

Short-Lived Antibody-Mediated Saliva Immunity against SARS-CoV-2 after Vaccination.

Knowledge about the effect of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on immunity reflected in the saliva is sparse. We examined the antibody response in saliva compared to that in serum 2 and 6 months after the first vaccination with the BNT162b2 vaccine. Four hundred fifty-nine health care professionals were included in a prospective observational study measuring antibody levels in saliva and corresponding serum samples at 2 and 6 months after BNT162b2 vaccination. Vaccinated, previously SARS-CoV-2-infected individuals (hybrid immunity) had higher IgG levels in saliva at 2 months than vaccinated, infection-naive individuals (P < 0.001). After 6 months, saliva IgG levels declined in both groups (P < 0.001), with no difference between groups (P = 0.37). Furthermore, serum IgG levels declined from 2 to 6 months in both groups (P < 0.001). IgG antibodies in saliva and serum correlated in individuals with hybrid immunity at 2 and 6 months (ρ = 0.58, P = 0.001, and ρ = 0.53, P = 0.052, respectively). In vaccinated, infection-naive individuals, a correlation was observed at 2 months (ρ = 0.42, P < 0.001) but not after 6 months (ρ = 0.14, P = 0.055). IgA and IgM antibodies were hardly detectable in saliva at any time point, regardless of previous infection. In serum, IgA was detected at 2 months in previously infected individuals. BNT162b2 vaccination induced a detectable IgG anti-SARS-CoV-2 RBD response in saliva at both 2 and 6 months after vaccination, being more prominent in previously infected than infection-naive individuals. However, a significant decrease in salivary IgG was observed after 6 months, suggesting a rapid decline in antibody-mediated saliva immunity against SARS-CoV-2, after both infection and systemic vaccination. IMPORTANCE Knowledge about the persistence of salivary immunity after SARS-CoV-2 vaccination is limited, and information on this topic could prove important for vaccine strategy and development. We hypothesized that salivary immunity would wane rapidly after vaccination. We measured anti-SARS-CoV-2 IgG, IgA, and IgM concentrations in saliva and serum in both previously infected and infection-naive individuals, 2 and 6 months after first vaccination with BNT162b2, in 459 hospital employees from Copenhagen University Hospital. We observed that IgG was the primary salivary antibody 2 months after vaccination in both previously infected and infection-naive individuals, but dropped significantly after 6 months. Neither IgA nor IgM was detectable in saliva at either time point. Findings indicate that salivary immunity against SARS-CoV-2 rapidly declines following vaccination in both previously infected and infection-naive individuals. We believe this study shines a light on the workings of salivary immunity after SARS-CoV-2 infection, which could prove relevant for vaccine development.

Immunogenicity of an inactivated vaccine for intravaginal application against bovine alphaherpesvirus type 5 (BoHV-5).

The present study was carried out to evaluate the intravaginal vaccine potential against bovine alphaherpesvirus type 5 (BoHV-5). Sixty three cows were divided into seven groups (n: 9) and inoculated intravaginally (VA) or intramuscularly (IM) with inactivated BoHV-5, associated with the recombinant B subunit of the heat-labile enterotoxin of E. coli (rLTB), 2-hydroxyethylcellulose (Drug Delivery System A - DDS-A) or Poloxamer 407 (Drug Delivery System B - DDS-B) as follows: G1 (DDS-A + BoHV-5+ rLTB), G2 (DDS-A + BoHV-5), G3 (DDS-B + BoHV-5+ rLTB), G4 (DDS-B + BoHV-5), G5 (BoHV-5+ rLTB), G6 (Negative control) e G7 (Positive control). The local and systemic humoral responses were measured by indirect ELISA (IgA and IgG) and serum neutralization tests, and the cellular response was measured by a quantitative direct ELISA (IL-2 and IFN-Gamma). The results showed the group inoculated by the IM route, G5, demonstrated the highest levels of IgG in the vaginal mucosa among the experimental groups (p<0.05). In the groups tested with polymers (G1 and G3) in the vaginal mucosa, even higher levels of IgG were seen in comparison to the positive control (G7; p<0.01). Higher levels of IgA were also noted in relation to the other groups (p<0.05) on days 30, 60 and 90 post-inoculations. The groups G1 and G3 also provided higher titers of neutralizing antibodies (Log2) in relation to other treatments (p<0.01) 90 days after inoculation. In the nasal mucosa, there was an increase in the levels of IgA and IgG with the use of vaccines from groups G1 and G3, in relation to the positive control, G7 (p<0.05) at 60 and 90 days after the first inoculation. Moreover, neutralizing antibodies titers were detected at 60 and 90 days by serum neutralization. The inclusion of the evaluated polymers resulted in a superior response (p<0.05) of immunoglobulins and IL-2 and IFN-Gamma in relation to the treatment using only rLTB (G5). This data demonstrates the capabilities of a vaccine with an intravaginal application in cattle to stimulate a local and systemic immune response.

Comparison of IgG Against COVID-19 Between Postmenopausal and Nonmenopausal Women Vaccinated With Sinopharm Vaccine.

Since December 2019, the coronavirus disease has spread among the people of the world. Past studies have shown that viral diseases are more common and the immune response is stronger among menopausal women than nonmenopausal women. Therefore, in this study, we aimed to compare the amount of immunoglobulin (Ig)G against COVID-19 between postmenopausal and nonmenopausal women vaccinated with Sinopharm vaccine. In this case-control study, 90 females vaccinated with the Sinopharm vaccine were randomly selected from February to April 2022: 45 menopausal participants as the case group and 45 nonmenopausal controls. Demographic characteristics were obtained and blood samples were taken from all subjects. Acomplete blood count was carried out and the levels of IgG against COVID-19 were measured by using the enzyme-linked immunosorbent assay method. The mean age was 33.3 ± 7.3 yearsand 60.2 ± 7.02 yearsfor control and menopausal women, respectively. Asignificant difference was found between the2 groups for the levels of IgG antibodies against COVID-19 (P = .002, 17.2 ± 9.83 relative unit for case group and 10.2 ± 9.80 relative unit for control subjects). After adjusting, IgG against COVID-19 was significantly correlated to the menopausal state (odds ratio [confidence interval] = 1. 08 [1.03-1.15]; P = .003). The results of this study showed that menopausal women had higher levels of IgG against COVID-19 in comparison with nonmenopausal females. However, more complementary studies are needed in this regard.

VLPs containing stalk domain and ectodomain of matrix protein 2 of influenza induce protection in mice

BackgroundAs a result of antigenic drift, current influenza vaccines provide limited protection against circulating influenza viruses, and vaccines with broad cross protection are urgently needed. Hemagglutinin stalk domain and ectodomain of matrix protein 2 are highly conserved among influenza viruses and have great potential for use as a universal vaccine.MethodsIn this study, we co-expressed the stalk domain and M2e on the surface of cell membranes and generated chimeric and standard virus-like particles of influenza to improve antigen immunogenicity. We subsequently immunized BALB/c mice through intranasal and intramuscular routes.ResultsData obtained demonstrated that vaccination with VLPs elicited high levels of serum-specific IgG (approximately 30-fold higher than that obtained with soluble protein), induced increased ADCC activity to the influenza virus, and enhanced T cell as well as mucosal immune responses. Furthermore, mice immunized by VLP had elevated level of mucosal HA and 4M2e specific IgA titers and cytokine production as compared to mice immunized with soluble protein. Additionally, the VLP-immunized group exhibited long-lasting humoral antibody responses and effectively reduced lung viral titers after the challenge. Compared to the 4M2e-VLP and mHA-VLP groups, the chimeric VLP group experienced cross-protection against the lethal challenge with homologous and heterologous viruses. The stalk domain specific antibody conferred better protection than the 4M2e specific antibody.ConclusionOur findings demonstrated that the chimeric VLPs anchored with the stalk domain and M2e showed efficacy in reducing viral loads after the influenza virus challenge in the mice model. This antibody can be used in humans to broadly protect against a variety of influenza virus subtypes. The chimeric VLPs represent a novel approach to increase antigen immunogenicity and are promising candidates for a universal influenza vaccine.

Dysregulated biomarkers of innate and adaptive immunity predict infections and disease progression in cirrhosis

Cirrhosis-associated immune dysfunction (CAID) affects both innate and adaptive immunity. This study investigated the complement system, immunoglobulins, and acute-phase proteins and their prognostic relevance in patients with advanced chronic liver disease (ACLD). Patients with ACLD (hepatic venous pressure gradient [HVPG] ≥6mmHg) but without acute decompensation/infections were characterised by HVPG and by clinical EASL stages: compensated (cACLD; S0-2) vs. decompensated ACLD (dACLD) with previous variceal bleeding (S3), non-bleeding decompensation (S4), or further decompensation (S5). Complement factors (C3c, C4, CH50), immunoglobulins (IgA, IgM, IgG, IgG1-4), acute-phase proteins and systemic inflammation biomarkers (white blood cells, C-reactive protein, IL-6, procalcitonin) were measured. A total of 245 patients (median model for end-stage liver disease score: 11 [9-15], median HVPG: 17 [12-21] mmHg) were included with 150 (61%) presenting dACLD. Complement levels and activity significantly decreased in dACLD substages S4 and S5 (p <0.001). Total IgA/IgM/IgG and IgG1-4 subtype levels increased in patients with dACLD (all p <0.05). Complement and immunoglobulin levels correlated negatively and positively, respectively, with systemic inflammation (all p <0.05). High IgG-1 (adjusted hazard ratio per 100mg/dl: 1.12, 1.04-1.19, p= 0.002) and IL-6 (adjusted hazard ratio: 1.03, 1.00-1.05, p= 0.023) levels predicted the development of infections during follow-up. High IgA (stratified by median; log-rank p <0.001), high IgG1 (log-rank p= 0.043) and low C3c (log-rank p= 0.003) indicated a higher risk of first/further decompensation or liver-related death (composite endpoint). Next to HVPG and IL-6, low C3c (adjusted hazard ratio per mg/dl: 0.99, 0.97-0.99, p= 0.040) remained independently associated with the composite endpoint on multivariate Cox regression analysis. Complement levels and immunoglobulins may serve as surrogates of cirrhosis-associated immune dysfunction and associate with cirrhosis severity and systemic inflammation. Low complement C3c predicted decompensation and liver-related death, whereas high IgG-1 indicated an increased risk for infections. Patients with cirrhosis are at increased risk for infections, which worsen their prognosis. We found a significant dysregulation of several essential components of the immune system that was linked to disease severity and indicated a risk for infections and other complications. Simple blood tests identify patients at particularly high risk, who may be candidates for preventive measures. This study is registered at ClinicalTrials.gov (NCT03267615).

An oral NoV-rAd5 vaccine with built-in dsRNA adjuvant elicits systemic immune responses in mice

Norovirus (NoV) is an enteric pathogen notorious for causing epidemics of acute gastroenteritis. An effective vaccine against NoV is therefore urgently needed. A short double-stranded RNA (dsRNA) has been described that acts as a retinoic-acid-inducible gene-I agonist to induce the production of type I interferon; it also exhibits adjuvant activity. Using built-in dsRNA of different lengths (DS1 and DS2), we developed a recombinant adenovirus 5 (rAd5) expressing NoV VP1, and evaluated its immunogenicity following oral administration in a mouse model. An in vitro study demonstrated that the dsRNA adjuvants significantly enhanced VP1 protein expression in infected cells. The oral administration of both rAd5-VP1-DS vaccines elicited high serum levels of VP1-specific IgG and blocking antibodies, as well as strong and long-lasting mucosal immunity. There was no apparent difference in immunostimulatory effects in immunised mice between the two dsRNA adjuvants. This study indicates that an oral NoV-rAd5 vaccine with a built-in dsRNA adjuvant may be developed to prevent NoV infection in humans.

How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans.

Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.

Local and systemic immune responses induced by intranasal immunization with biomineralized foot-and-mouth disease virus-like particles.

Foot-and-mouth disease virus (FMDV) infects the host by invading mucosal epithelial cells of the respiratory or digestive tract. Therefore, establishing a specific antiviral mucosal immune barrier can effectively block viral invasion. We evaluated local mucosal and systemic immune responses elicited by intranasal immunization of mice with foot-and-mouth disease (FMD) calcium phosphate mineralized virus-like particles (CaP-VLPs) and tested whether three commercial mucosal adjuvants enhanced the immunogenicity of the antigen. The biosafety of the vaccine was verified through gross observation and pathological analysis of the lungs. CaP-VLPs effectively induced secretion of IgA (sIgA) from multiple sites in mouse mucosa and produced anti-FMD-specific IgG in the serum. Splenic lymphocytes specifically proliferated and secreted IFN-γ following antigen stimulation, indicating the vaccine can induce a certain level of cellular immune response. Finally, the pathological examination confirmed that CaP-VLPs did not cause substantial damage to the lungs of animals after immunization via mucosal administration. Notably, the vaccine mixed with S adjuvant increased the content of sIgA and serum IgG, and the high level of IgG in serum was maintained at least 7 weeks. Overall, this study reveals that FMD CaP-VLPs can induce good local mucosal immune and systemic immune response through intranasal immunization, and the immune response was specifically enhanced by S adjuvant. These data support that CaP-VLPs-S as a candidate mucosal vaccine for the prevention of FMD vaccine infection.