High Antibody Levels Research Articles

Phase II Trial of HER-Vaxx, a B-cell Peptide-Based Vaccine, in HER2-Overexpressing Advanced Gastric Cancer Patients Under Platinum-Based Chemotherapy (HERIZON).

A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA). Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated. A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52-14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01-9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells. HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.

Increased levels of anti-Encephalitozoon intestinalis antibodies in patients with colorectal cancer.

The prevalence of microsporidiosis in the general population, or within specific groups of individuals/patients, is largely underestimated. The absence of specific seroprevalence tools limits knowledge of the epidemiology of these opportunistic pathogens, although known since the 1980s. Since microsporidia hijack the machinery of its host cell and certain species multiply within intestinal cells, a potential link between the parasite and colorectal cancer (CRC) has been suggested. To explore a potential epidemiological link between microsporidia and CRC, we evaluated the seroprevalence of Encephalitozoon intestinalis among CRC patients and healthy subjects using ELISA assays based on two recombinant proteins, namely rEiPTP1 and rEiSWP1, targeting polar tube and spore wall proteins. ELISA were performed in 141 CRC patients and 135 healthy controls. Patients with CRC had significantly higher anti-rEiPTP1 IgG levels than subjects in the control group. Anti-rEiPTP1 IgG, anti-rEiSWP1 IgG and anti-rEiPTP1 IgA levels were significantly increased among men with CRC compared to healthy men. Women with CRC who had died had higher rEiSWP1 IgG levels than those who were still alive. These higher antibody levels against microsporidia in patients with CRC suggest a relationship between microsporidia and pathophysiology of CRC.

Influenza A Vaccine Candidates Based on Virus-like Particles Formed by Coat Proteins of Single-Stranded RNA Phages Beihai32 and PQ465.

Efficient control of influenza A infection can potentially be achieved through the development of broad-spectrum recombinant vaccines based on conserved antigens. The extracellular domain of the transmembrane protein M2 of influenza A virus (M2e) is highly conserved but poorly immunogenic and needs to be fused to an adjuvant protein or carrier virus-like particles (VLPs) to increase immunogenicity and provide protection against infection. In this study, we obtained VLPs based on capsid proteins (CPs) of single-stranded RNA phages Beihai32 and PQ465 bearing the M2e peptides. Four copies of the M2e peptide were linked to the C-terminus of the CP of phage Beihai32 and to the N and C termini of the CP of phage PQ465. The hybrid proteins, being expressed in Escherichia coli, formed spherical VLPs of about 30 nm in size. Immunogold transmission electron microscopy showed that VLPs formed by the phage PQ465 CP with a C-terminal M2e fusion present the M2e peptide on the surface. Subcutaneous immunization of mice with VLPs formed by both CPs containing four copies of the M2e peptide at the C termini induced high levels of M2e-specific IgG antibodies in serum and provided mice with protection against lethal influenza A virus challenge. In the case of an N-terminal fusion of M2e with the phage PQ465 CP, the immune response against M2e was significantly lower. CPs of phages Beihai32 and PQ465, containing four copies of the M2e peptide at their C termini, can be used to develop recombinant influenza A vaccine.

Assessment of health impacts in retired antisera-producing horses: Blood biochemistry and serum amyloid A analysis.

Horses used for antisera production are repeatedly hyperimmunized to produce high levels of specific antibodies. This prolonged process can lead to various health issues, including amyloidosis, which involves the accumulation of amyloid proteins in organs and tissues, potentially causing organ dysfunction and failure. These horses are often retired when they no longer produce adequate antibody levels. This study aimed to evaluate the impact of prolonged antisera production on the health of retired horses by examining their blood biochemistry and serum amyloid A (SAA) levels, which are indicators of systemic inflammation and organ damage. Blood samples were collected from 12 horses for this study. Nine horses were retired antisera-producing horses that had been discontinued for 2 years, while three healthy non-antisera-producing horses were used as controls. These twelve horses were divided into four groups based on the duration of their active period as antisera producers (never been used, 2-3 years, 4-5 years, and 6-7 years). We measured key blood biochemistry parameters and SAA levels to evaluate the health status of the horses. Total protein, fibrinogen, and globulin levels were elevated, whereas other parameters remained normal. The findings indicate that despite normal SAA levels, the horses exhibited signs of ongoing health issues related to their previous use in antisera production, such as increased total plasma protein, fibrinogen, and globulin levels, as well as the presence of amyloid deposits in vital organs such as the liver and kidneys, as observed in post-mortem examinations. Despite normal SAA levels, retired antisera-producing horses showed elevated total protein, fibrinogen, and globulin levels, indicating ongoing health issues.

Immune response and protection efficacy of formalin-killed vaccines against Streptococcus iniae in four-finger threadfin Eleutheronema tetradactylum.

Four-finger threadfin, Eleutheronema tetradactylum farming in southern Taiwan has been facing disease problems caused by Streptococcus iniae since 2018. The development of a vaccine against infectious S. iniae in the cultured threadfin industry is necessary. Thus, this study aimed to examine the efficacy of threadfin immunized formalin-killed cells (FKC) from S. iniae GSI-111 for 42 days post-vaccination (dpv) using two doses of FKC alone (a booster at 14 dpv) as group A, and FKC mixed with ISA763A adjuvant using a single dose as group B or double doses as group C. Immunoglobulin (Ig)-M was purified from threadfin, and rabbit anti-threadfin IgM polyclonal antibodies were used to detect antibody level in immunized fish; the vaccinated group A displayed higher levels at 3 dpv and all vaccinated treatments demonstrated high antibody levels between 14 and 42 dpv. All vaccine groups showed significantly higher values of lysozyme activity at 42 dpv compared with the control group; the vaccinated A group peaked at 14 dpv. The expression profiles of pro-inflammatory and immune-related genes, TNF-α, IL-12A, and C2 were upregulated at 3 dpv, while CD8A and chemokine receptor CXCR4 were upregulated at 42 dpv. Finally, the threadfins were challenged with S. iniae at 42 dpv. The average relative percent survival was 96% for vaccination A and B treatments, and 100% for vaccination C treatment. In summary, this study demonstrated that FKC vaccines whether formulated with an adjuvant could stimulate immune response and effective protect threadfins against S. iniae infection.

Maternal-Fetal Transfer of Anti-SARS-CoV-2 Antibodies in Amniotic Fluid: Insights from Maternal Vaccination and COVID-19 Infection.

Objectives: As the COVID-19 pandemic wanes, understanding maternal-fetal antibody transfer remains crucial for optimizing vaccination strategies. This study evaluates anti-SARS-CoV-2 antibody levels in amniotic fluid following maternal BNT162b2 mRNA vaccination and/or COVID-19 infection during early pregnancy, focusing on the first and second trimesters. Methods: A retrospective cohort study was conducted at a tertiary university-affiliated hospital, involving 149 pregnant women who underwent amniocentesis. Anti-SARS-CoV-2 spike IgG levels were measured in amniotic fluid samples. Participants were categorized based on vaccination and infection status: vaccine-only, infection-only, vaccine + infection, and no vaccine/infection. Correlations between antibody levels and the time since vaccination or infection were analyzed. Results: The vaccine + infection group had a higher proportion of positive antibody levels compared to the vaccine-only group (63.6% vs. 35.9%, p = 0.029). Median SARS-CoV-2 IgG levels were significantly higher in the vaccine + infection group (283.0 AU/mL) than in the vaccine-only group (64.1 AU/mL, p = 0.006). Women who received three vaccine doses had higher antibody levels and more positive antibody rates compared to those with one or two doses. A significant negative correlation was found between antibody levels and the interval since the last vaccine dose or infection. Conclusions: Our results indicate the presence of anti-SARS-CoV-2 antibodies in the amniotic fluid, reflecting antibody transfer during early pregnancy. However, a noticeable decrease in immunity was observed, as indicated by declining amniotic fluid antibody levels over time. Further studies are needed to determine the optimal timing and number of boosters required to protect against new variants of SARS-CoV-2.

Caprine Paratuberculosis Seroprevalence and Immune Response to Anti-Mycobacterium avium Subspecies paratuberculosis Vaccination on the Canary Islands, Spain.

Paratuberculosis (PTB), caused by Mycobacterium avium subspecies paratuberculosis (MAP), is a chronic disease with economic impact on ruminant farming worldwide. The Canary Islands count with the fourth largest goat population in Spain and are "officially free" of bovine tuberculosis. Twelve farms were included with 2774 serum samples tested by an enzyme-linked immunosorbent assay (ELISA) for detection of anti-MAP antibodies in two sessions. In the first session, an overall apparent prevalence of 18.4% (2.5% up to 61.1%) was obtained. Farms with prevalences (0-10%], (10-20%] and >20% were identified, with differences in seroconversion in the same prevalence group between farms and age ranges. Non-vaccinated (nV) and vaccinated (V) animals were included in the second sampling session. Higher levels of antibodies were detected in V animals older than 12 months, with considerable variations between age ranges and farms. Our results describe the current PTB status of the Canary Islands' goat farming. Furthermore, new insights on the effect of the farm prevalence on seroconversion in V animals are provided, although further studies are needed to evaluate the multiple factors affecting the immune response to anti-MAP vaccination.

Generating the Evidence Base for Convalescent Plasma Use for a New Infectious Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept across the world in the waning months of 2019 and emerged as the cause of the coronavirus disease 19 (COVID-19) pandemic in early 2020. The use of convalescent plasma (CP) for prior respiratory pandemics provided a strong biological rationale for the rapid deployment of COVID-19 convalescent plasma (CCP) in early 2020 when no validated treatments or prior immunity existed. CCP is an antiviral agent, with its activity against SARS-CoV-2 stemming from specific antibodies elicited by the virus. Early efforts to investigate the efficacy of CCP in randomized clinical trials (RCTs) that targeted hospitalized patients with COVID-19 did not demonstrate the overall efficacy of CCP despite signals of benefit in certain subgroups, such as those treated earlier in disease. In contrast, studies adhering to the principles of antibody therapy in their study design, choice of patient population, and product qualification, i.e., those that administered high levels of specific antibody during the viral phase of disease in immunocompromised or very early in immunocompetent individuals, demonstrated benefits. In this chapter, we leverage the knowledge gained from clinical studies of CCP for COVID-19 to propose a framework for future studies of CP for a new infectious disease. This framework includes obtaining high-quality CP and designing clinical studies that adhere to the principles of antibody therapy to generate a robust evidence base for using CP.

Pathogenicity of Duck Adenovirus Type 3 in Chickens.

Duck adenovirus Type 3 (DAdV-3) severely affects the health of ducks; however, its pathogenicity in chickens remains unknown. The objectives of this study were to evaluate the pathogenicity and major pathological changes caused by DAdV-3 in chickens. Viral DNA was extracted from the liver of the Muscovy duck, and the fiber-2 and hexon fragments of DAdV-3 were amplified through polymerase chain reaction (PCR). The evolutionary tree revealed that the isolated virus belonged to DAdV-3, and it was named HE-AN-2022. The mortality rate of chicks that received inoculation with DAdV-3 subcutaneously via the neck was 100%, while the mortality rate for eye-nose drop inoculation was correlated with the numbers of infection, with 26.7% of chicks dying as a result of exposure to multiple infections. The main symptoms exhibited prior to death were hepatitis-hydropericardium syndrome (HHS), ulceration of the glandular stomach, and a swollen bursa with petechial hemorrhages. A histopathological examination revealed swelling, necrosis, lymphocyte infiltration, and basophilic inclusion bodies in multiple organs. Meanwhile, the results of quantitative real-time PCR (qPCR) demonstrated that DAdV-3 could affect most of the organs in chickens, with the gizzard, glandular stomach, bursa, spleen, and liver being the most susceptible to infection. The surviving chicks had extremely high antibody levels. After the chickens were infected with DAdV-3 derived from Muscovy ducks, no amino acid mutation was observed in the major mutation regions of the virus, which were ORF19B, ORF66, and ORF67. On the basis of our findings, we concluded that DAdV-3 infection is possible in chickens, and that it causes classic HHS with ulceration of the glandular stomach and a swollen bursa with petechial hemorrhages, leading to high mortality in chickens. The major variation domains did not change in Muscovy ducks or in chickens after infection. This is the first study to report DAdV-3 in chickens, providing a new basis for preventing and controlling this virus.

Evaluating Immunologic and Illness Outcomes of SARS-CoV-2 Infection in Vaccinated and Unvaccinated Children Aged ≥ 5 Years, in a Multisite Longitudinal Cohort.

A longitudinal cohort study of children aged ≥ 5 was conducted during August 2021-August 2022, at sites in Arizona, Texas, Utah, and Florida. Children submitted weekly nasal swabs for PCR testing and provided sera 14-59 days after PCR-confirmed SARS-CoV-2 infection. Antibodies were measured by ELISA against the receptor-binding domain (RBD) and S2 domain of ancestral Spike (WA1), in addition to Omicron (BA.2) RBD, following infection in children, with and without prior monovalent ancestral mRNA COVID-19 vaccination. Among the 257 participants aged 5 to 18 years, 166 (65%) had received at least two mRNA COVID-19 vaccine doses ≥ 14 days prior to infection. Of these, 53 occurred during Delta predominance, with 37 (70%) unvaccinated at the time of infection. The remaining 204 infections occurred during Omicron predominance, with 53 (26%) participants unvaccinated. After adjusting for weight, age, symptomatic infection, and gender, significantly higher mean RBD AUC values were observed among the vaccinated group compared to the unvaccinated group for both WA1 and Omicron (p < 0.0001). A smaller percentage of vaccinated children reported fever during illness, with 55 (33%) reporting fever compared to 44 (48%) unvaccinated children reporting fever (p = 0.021). Children with vaccine-induced immunity at the time of SARS-CoV-2 infection had higher antibody levels during convalescence and experienced less fever compared to unvaccinated children during infection.

Knowledge of the Serological Response to the Third BNT162b2 Vaccination May Influence Compliance of Healthcare Workers to Booster Dose.

Previous studies showed that the fourth SARS-CoV-2 vaccine dose has a protective effect against infection, as well as against severe disease and death. This study aimed to examine whether knowledge of a high-level antibody after the third dose may reduce compliance to the fourth booster dose among healthcare workers (HCWs). We conducted a prospective cohort study among HCWs vaccinated with the first three doses at Rambam Healthcare Campus, a tertiary hospital in northern Israel. Participants underwent a serological test before the fourth booster vaccine was offered to all of them, with results provided to participants. The population was divided into two groups, namely those with antibodies below 955 AU/mL and those with 955 AU/mL and higher, a cutoff found protective in a previous study. Multiple logistic regression was carried out to compare the compliance to the fourth booster between the two groups, adjusted for demographic and clinical variables. After adjusting for the confounding variables, the compliance was higher in those with antibody levels below 955 AU/mL (OR = 1.41, p = 0.05, 95% CI 1.10-1.96). In addition, male sex and age of 60 years and above were also associated with higher vaccination rates (OR = 2.28, p < 0.001, 95% CI 1.64-3.17), (OR = 1.14, p = 0.043, 95% CI 1.06-1.75), respectively. Knowledge of the antibody status may affect compliance with the booster dose. Considering waning immunity over time, reduced compliance may affect the protection of HCWs who declined the fourth dose.

Characteristics of virus-specific immunological reactions following COVID-19 vaccination in heart transplant recipients

Heart transplant patients are at an increased risk of COVID-19 infection adverse outcomes because of underlying immunosuppression and concomitant comorbidities. To date, all large-scale randomized controlled trials for various COVID-19 vaccines have excluded solid organ transplant recipients. Therefore, the efficacy and safety of coronavirus infection prevention using COVID-19 vaccines in transplant heart patients has not been sufficiently studied. In this research, the evaluation of virus-specific immunological reactions after vaccination (double Vero Cell vaccination and Sputnik Light booster vaccination) in heart transplant patients has been carried out. In vaccinated heart transplant individuals who did not have a history of COVID-19, starting from 4–6 months after the 2nd dose of the vaccine, an increase in antibodies to S protein level of was observed, while maintaining statistically significant differences for 9–12 months after vaccination (regardless of whether with or without booster vaccination). However, the concentration of antibodies remained low, and 37% of patients detected no antibodies. In vaccinated heart transplant individuals following the previous COVID-19 infection, as compared to seronegative patients, post-vaccination immunity is accompanied by maintaining a high level of virus-specific IgG antibodies to the S protein of the SARS-CoV-2 virus in the dynamics of the post-vaccination period with a statistically significant increase of these antibodies by 9–12 months after booster vaccination. The specific cellular response (according to the assessment of CD3⁺154⁺ and CD3⁺IFNγ⁺ TNFα⁺ cells) to the S protein of the SARS-CoV-2 virus remained low throughout the entire follow-up period, was recorded in 5–40% of heart transplant patients and statistically significant changes in the number of spikereactive lymphocytes were observed in patients with a history of COVID-19 by 4–6 months after administration of the 2nd dose of the vaccine. This, together with the results of the assessment of the humoral response, indicates a more pronounced post-vaccination immunity in patients with a hybrid immunity. While developing a methodology for assessing the risk and benefit of a vaccination strategy for individual heart transplant patients, clinical efficacy, ongoing monitoring of rare serious adverse events, and data on vaccine immunogenicity should be taken into account.

Immunogenicity of an Inactivated Senecavirus A Vaccine with a Contemporary Brazilian Strain in Mice.

Senecavirus A (SVA) is a picornavirus that is endemic in swine, causing a vesicular disease clinically indistinguishable from other vesicular diseases, like foot-and-mouth disease. The widespread viral circulation, constant evolution, and economic losses caused to the swine industry emphasize the need for measures to control the agent. In this study, we evaluated the immunogenicity of a whole-virus-inactivated vaccine using a representative contemporary Brazilian SVA strain in Balb/ByJ mice. The animals were vaccinated with two doses by an intramuscular route. The humoral response induced by the vaccination was evaluated by an in-house ELISA assay for IgG detection. The cellular response was assessed by flow cytometry after in vitro SVA stimulation in splenocyte cultures from vaccinated and non-vaccinated groups. Protection against SVA was assessed in the experimental groups following an oral challenge with the homologous virus. The vaccination induced high levels of IgG antibodies and the proliferation of CD45R/B220+sIgM+, CD3e+CD69+, and CD3e+CD4+CD44+CD62L- cells. These results indicate the immunogenicity and safety of the vaccine formulation in a murine model and the induction of humoral and cellular response against SVA.

Fusion expression and immunogenicity of receptor-binding domains of porcine deltacoronavirus and porcine epidemic diarrhea virus

This study aims to develop an effective bivalent subunit vaccine that is promising to prevent both porcine deltacoronavirus (PDCoV) and porcine epidemic diarrhea virus (PEDV). The receptor-binding domains (RBDs) of PDCoV and PEDV were fused and cloned into the eukaryotic expression vector pCDNA3.1(+). The fusion protein PDCoV-RBD-PEDV-RBD (pdRBD-peRBD) was expressed by the ExpiCHOTM expression system and purified. Mice were immunized with the fusion protein at three different doses (10, 20, and 30 μg). The humoral immune response and cellular immune response induced by the fusion protein were evaluated by ELISA and flow cytometry. The neutralization titers of the serum of immunized mice against PDCoV and PEDV were determined by the microneutralization test. The results showed that high levels of IgG antibodies were induced in the three different dose groups after booster immunization, and there was no significant difference in the antibody level between different dose groups, indicating that the immunization dose of 10 μg could achieve the fine immune effect. The results of flow cytometry showed that the immunization groups demonstrated increased proportion of CD3+CD4+ T cells and decreased proportion of CD3+CD8+ T cells, which was consistent with the expectation about the humoral immune response induced by the subunit vaccine. At the same time, the levels of interleukin (IL)-2, IL-4, and interferon (IFN)-γ in the serum were determined. The results showed that the fusion protein induced both humoral immune effect and cellular immune response. The results of the neutralization test showed that the antibody induced by 10 μg fusion protein neutralized both PDCoV and PEDV in vitro, with the titers of 1:179.25 and 1:141.21, respectively. The above results suggested that the pdRBD-peRBD could induce a high level of humoral immune response at a dose of 10 μg, and the induced antibody could neutralize both PDCoV and PEDV. Therefore, the fusion protein pdRBD-peRBD is expected to be an effective subunit vaccine that can simultaneously prevent PDCoV and PEDV.

Predictors of Therapy Success in Weekly Adalimumab for Refractory Uveitis: A Retrospective Cohort Study

PurposeTo determine predictors of treatment success after dose escalation of adalimumab, including measurement of anti-adalimumab antibodies as a predictor of success DesignRetrospective clinical cohort study SettingSingle-center academic institution Study PopulationPatients with noninfectious uveitis who were inadequately controlled or developed recurrent disease on biweekly adalimumab and required dose escalation or therapy modification Observation ProceduresPatients who had anti-adalimumab antibodies checked with resultant low to intermediate levels were compared to patients who had no testing performed prior to adalimumab dose escalation. Of note, patients with testing and resultant high levels of anti-adalimumab antibodies were not escalated. Predictors of escalation success and utility of antibody testing prior to escalation were analyzed using Kaplan Meier survival analysis and Cox proportional hazard models. Main Outcome MeasuresTreatment success defined as anterior chamber grade ≤0.5+ cell, topical corticosteroids ≤1 drop/day, oral prednisone ≤5 mg/day, resolution of macular edema, and resolution of angiographic signs of inflammation without any addition or escalation of therapy. Results24 patients had antibodies tested with low to intermediate levels (average: 32.3 ng/mL, range: 0 – 154), while 41 did not have antibody testing. A greater treatment success rate post escalation was observed among the “low antibody” group compared to the “no testing” group (HR: 2.63, standard error: 1.19, p=0.031, 95% CI 1.09 – 6.37). Among the entire cohort, patients with panuveitis (n = 14) had a lower treatment success rate compared to the reference of anterior uveitis (n = 26) (HR: 0.09, standard error: 0.11, p = 0.05, 95% CI 0.01 – 0.99). ConclusionsPatients with low anti-adalimumab antibodies had a greater treatment success compared to patients in whom antibodies were not checked. This suggests a utility to checking antibodies prior to dose escalation and that low levels of antibodies may confer a success advantage. Overall, patients with panuveitis had a lower rate of success after escalation while patients with anterior uveitis patients had a very high rate of success suggesting that certain disease characteristics may guide clinicians when determining who to escalate versus changing therapy.

Virus-Mimetic Extracellular-Vesicle Vaccine Boosts Systemic and Mucosal Immunity via Immune Recruitment.

Mucosal vaccines can prevent viruses from infecting the respiratory mucosa, rather than only curtailing infection and protecting against the development of disease symptoms. The SARS-CoV-2 spike receptor-binding domain (RBD) is a compelling vaccine target but is undermined by suboptimal mucosal immunogenicity. Here, we report a SARS-CoV-2-mimetic extracellular-vesicle vaccine developed using genetic engineering and dendritic cell membrane budding. After mucosal immunization, the vaccine recruits antigen-presenting cells rapidly initiating a strong innate immune response. Notably, it obviates the need for adjuvants and can induce germinal center formation through both intramuscular and intratracheal vaccination. It not only elicits high levels of RBD-specific antibodies but also stimulates extensive cellular immunity in the respiratory mucosa. A sequential immunization strategy, starting with an intramuscular injection followed by an intratracheal booster, significantly bolsters mucosal immunity with high levels of IgA and tissue-resident memory T cell responses, thereby establishing a formidable defense against pseudovirus infection.

Application prospects of the 2BS cell-adapted China fixed rabies virus vaccine strain 2aG4-B40

BackgroundRabies is a fatal zoonotic disease whose pathogenesis has not been fully elucidated, and vaccination is the only effective method for protecting against rabies virus infection. Most inactivated vaccines are produced using Vero cells, which are African green monkey kidney cells, to achieve large-scale production. However, there is a potential carcinogenic risk due to nonhuman DNA contamination. Thus, replacing Vero cells with human diploid cells may be a safer strategy. In this study, we developed a novel 2BS cell-adapted rabies virus strain and analysed its sequence, virulence and immunogenicity to determine its application potential as a human diploid cell inactivated vaccine.Methods and resultsThe 2BS cell-adapted rabies virus strain 2aG4-B40 was established by passage for 40 generations and selection of plaques in 2BS cells. RNA sequence analysis revealed that mutations in 2BS cell-adapted strains were not located at key sites that regulate the production of neutralizing antibodies or virulence in the aG strain (GQ412744.1). The gradual increase in virulence (remaining above 7.0 logLD50/ml from the 40th to 55th generation) and antigen further indicated that these mutations may increase the affinity of the adapted strains for human diploid cells. Identification tests revealed that the 2BS cell-adapted virus strain was neutralized by anti-rabies serum, with a neutralization index of 19,952. PrEP and PEP vaccination and the NIH test further indicated that the vaccine prepared with the 2aG4-B40 strain had high neutralizing antibody levels (2.24 to 46.67 IU/ml), immunogenicity (protection index 270) and potency (average 11.6 IU/ml).ConclusionsIn this study, a 2BS cell-adapted strain of the 2aG4 rabies virus was obtained by passage for 40 generations. The results of sequencing analysis and titre determination of the adapted strain showed that the mutations in the adaptive process are not located at key sequence regions of the virus, and these mutations may enhance the affinity of the adapted strain for human diploid cells. Moreover, vaccines made from the adapted strain 2aG4-B40 had high potency and immunogenicity and could be an ideal candidate rabies virus strain for inactivated vaccine preparation.

Autoimmune hepatitis – an increasingly common cause of hypertransaminasaemia among children. Case report and literature review

Autoimmune hepatitis is a chronic inflammatory process of unknown ethology, characterised by high levels of transaminases and IgG antibodies, the presence of tissue autoantibodies, and a typical histological picture. In the population of children, the paediatric form of autoimmune hepatitis and autoimmune sclerosing cholangitis are collectively classified as juvenile autoimmune liver disease. The condition often coexists with other autoimmune disorders. This paper aims to present the clinical profile of a paediatric patient with full-blown autoimmune hepatitis and describe the available therapies. The patient, a 13-year-old boy, was referred to a specialised hospital because of increasing hypertransaminasaemia. The patient was hospitalised for the first time at a district hospital for abdominal pain, and during his stay, elevated transaminases were found with a tendency to increase in follow-up tests. The picture suggested an inflammatory process of the liver and biliary tract. Upper gastrointestinal endoscopy revealed lesions consistent with chronic gastritis and portal gastropathy. Treatment included thiazolidinedioic acid, vitamin K, ursodeoxycholic acid, rifaximin, ciprofloxacin, and proton pump inhibitors. Therapy is aimed at maintaining immunosuppression and inhibiting the inflammatory response that leads to cirrhosis, and most commonly uses steroids alongside proton pump inhibitors for added protection or, alternatively, mycophenolate mofetil, cyclosporine A, tacrolimus, and biologic therapy. Ursodeoxycholic acid also exhibits immunomodulatory properties and makes it possible to reduce steroid doses and thus decrease the likelihood of adverse effects of therapy.

P-450 Maternal-fetal SARS-CoV-2 antibody transfer in relation to the trimester of infection

Abstract Study question What does the maternal-fetal SARS-CoV-2 antibody transfer look like depending on the trimester of infection? Summary answer There is a statistically significant tendency for newborns of SARS-CoV-2 positive mothers to have a higher IgG antibody level compared to their mother’s at delivery. What is known already Passive maternal-fetal transfer of SARS-CoV-2 antibodies has been demonstrated, whilst the degree of transfer depending on the trimester of infection is lacking, and so far, there is no stratification on all three trimesters of SARS-CoV-2 infection in relation to maternal antibody levels in SARS-CoV-2 positive women, and the degree of transfer of SARS-CoV-2 antibodies to the newborn. It is known that for perinatal infections such as Rubella and Toxoplasmosis the timing of infection related to gestational age is crucial for the severity of fetal/obstetric outcomes, hence the trimester of SARS-CoV-2 infection could potentially be crucial. Study design, size, duration This is a large prospective cohort study with full medical record of all 3,026 participating women and 3,073 of their newborns, as well as antibody measurements on all women who participated between April 4’th 2020 until April 30’st 2021. Of the 3,026 participating women 459 were SARS-CoV-2 positive. Participants/materials, setting, methods The positive cohort consisted of women who had a positive SARS-CoV-2 PCR test, antigen test or antibody test and participated with a maternal blood sample and an umbilicalcord blood sample at delivery. The negative cohort was established at Hvidovre Hospital (CHH), where all women with a first trimester double marker blood test taken at CHH could participate, all woman attending their second trimester ultrasound or giving birth were invited to participate with a blood sample. Main results and the role of chance This prospective cohort study found a strong and statistically significant tendency for newborns of SARS-CoV-2 positive mothers to have a higher IgG antibody level compared to their mother’s IgG antibody level at delivery. In total, 87.5%, 95.3% and 60.3% of newborns of women who tested positive in their first, second and third trimester respectively, had higher IgG antibody levels than their mother’s at delivery. The higher level of antibodies in the newborns’ cord blood compared to their mother’s demonstrated in this study, correlates with findings of for instance pertussis toxin antibodies during pregnancy and aligns with general findings on maternofetal transport of immunoglobins. Our findings indicates that the fetus is either able to concentrate antibody levels or maintain the level of IgG antibodies transferred. Limitations, reasons for caution With only 40 women being SARS-CoV-2 positive in their first trimester, analysis in this group should be taken with caution. Other limitations are the 56 newborns of positive women who did not have an umbilical cord blood sample taken due to PPH, acute cesarean section or blood sample coagulated. Wider implications of the findings This knowledge of the maternal-fetal antibody transmission pattern is valuable for the basic understanding of SARS-CoV-2 in pregnancy and for future investigation on expected degree of early life protection against SARS-CoV-2 but could also be of interest if investigating the paradoxically concept of blunting when considering vaccination of neonates. Trial registration number H-20022647

Three SARS-CoV-2 spike protein variants delivered intranasally by measles and mumps vaccines are broadly protective

As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1−/− mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate.