Cellular and humoral immune responses to COVID-19 booster vaccination in Japanese dialysis patients.

BACKGROUND: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity. METHODS: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group. RESULTS: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1ß, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group. CONCLUSIONS: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients.

Different immunological responses following immunization with two mRNA vaccines.

INTRODUCTION: Immunological responses were investigated following immunization with two mRNA vaccines: BNT162b2 and mRNA-1273. METHODS: Neutralizing antibody (NAb) was assayed before, 2-4 weeks after, and 3 and 6 months after the primary immunization, and the same time-points after booster dose with 6- or 8-months interval. Whole-blood culture was stimulated with spike antigen, and cytokine production was assayed. RESULTS: NAb was detected after primary immunization, NAb titers began to decrease three months after primary immunization with BNT162b2, lower than those after mRNA-1273, and elevated after booster immunization. The NAb level was 1/2 lower against δ variant, and 1/16 lower against omicron variant in comparison with that against α variant. Cytokine production following immunization with mRNA-1273 was maintained within three months at higher levels of Th1 (TNF-α), Th2 (IL-4 and IL-5), and inflammatory cytokines (IL-6 and IL-17) than that following immunization with BNT162b2, reflecting prominent levels of NAb following immunization with mRNA-1273. Cytokine production decreased six months after primary immunization in both vaccine recipients and was enhanced following booster doses. During the omicron outbreak, medical staff members in the outpatient office experienced asymptomatic infection, with a greater than 4-fold increase in NAb titers against omicron variant even after booster immunization. Asymptomatic infection enhanced the production of Th2 and inflammatory cytokines. CONCLUSION: mRNA-1273 induced stronger NAb responses with wide-range cross-reactive antibodies against δ and omicron variants. mRNA-1273 induced higher levels of Th1, Th2, and inflammatory cytokines than BNT162b2 did, reflecting higher levels of NAb against variant strains.

Cytokine and Chemokine Production in Mice Inoculated with NVX-CoV2373 (Nuvaxovid®) in Comparison with Omicron BA.4/5 Bivalent BNT162b2 (Comirnaty®).

A recombinant SARS-CoV-2 spike protein vaccine (NVX-CoV2373) has been licensed and has a lesser incidence of adverse events. To know the immunological mechanisms of adverse events, the production of cytokines and chemokines was investigated in mice inoculated with NVX-CoV2373. Serum IL-6 was detected on Day 1 of the first and second doses and the IFN-γ, IL-4, IL-10, TNF-α, and IL-6 levels increased on Day 1 of the second dose at the inoculation site. The enhanced production of the inflammatory chemokines (CCL2), homeostatic chemokine (CXCL13), and Th2 chemokine (CCL17) was observed at the inoculation site on Day 1 of the second dose. These findings were compared with data obtained following inoculation with BNT162b2 bivalent vaccine containing omicron BA.4/5. Significantly lower levels of inflammatory chemokines were detected on Day 1 after the first dose of NVX-CoV2373 in sera and inoculation site than those following inoculation with bivalent BNT162b2 (p < 0.01), reflecting a lower incidence of adverse events after immunization with NVX-CoV2373 in humans. NVX-CoV2373 induced significantly higher concentrations of IFN-γ, TNF-α, and IL-10 at the inoculation site obtained on Day 1 of the second dose (p < 0.05). Significant higher levels of Th2 chemokines, CCL11 and CCL17, were induced at the inoculation site on Day 1 of the second dose (p < 0.01) and they explain the booster IgG EIA antibody response after the second dose of NVX-CoV2373.

DS-5670a, a novel mRNA-encapsulated lipid nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2: Results from a phase 2 clinical study.

BACKGROUND: DS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2. METHODS: The study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part. A total of 80 Japanese participants were assigned to receive intramuscular DS-5670a, containing either 30 or 60 µg of mRNA, as two injections administered 4 weeks apart. Safety was assessed by characterization of treatment-emergent adverse events (TEAEs). Immunogenicity was assessed by neutralization titers against SARS-CoV-2, anti-RBD immunoglobulin (Ig)G levels, and SARS-CoV-2 spike-specific T cell responses. Plasma pharmacokinetic parameters of DS-5670a were also evaluated. RESULTS: Most solicited TEAEs were mild or moderate with both the 30 and 60 µg mRNA doses. Four participants (10 %) in the 60 µg mRNA group developed severe redness at the injection site, but all cases resolved without treatment. There were no serious TEAEs and no TEAEs leading to discontinuation. Humoral immune responses in both dose groups were greater than those observed in human convalescent serum; the 60 µg mRNA dose produced better responses. Neutralization titers were found to be correlated with anti-RBD IgG levels (specifically IgG1). DS-5670a elicited antigen-specific T helper 1-polarized cellular immune responses. CONCLUSIONS: The novel mRNA-based vaccine candidate DS-5670a provided favorable immune responses against SARS-CoV-2 with a clinically acceptable safety profile. Confirmatory trials are currently ongoing to evaluate the safety and immunogenicity of DS-5670a as the primary vaccine and to assess the immunogenicity when administered as a heterologous or homologous booster. TRIAL REGISTRY: https://jrct.niph.go.jp/latest-detail/jRCT2071210086.

Cellular and Humoral Immune Responses after Breakthrough Infection in Patients Undergoing Hemodialysis.

Coronavirus disease 2019 (COVID-19) following primary immunization (breakthrough infection) has been reported in hemodialysis patients; however, their post-infection immune status remains unclear. We evaluated the humoral and cellular immunity of hemodialysis patients after breakthrough infection. Hemodialysis patients who had received primary immunization against COVID-19 at least six months prior to the study but developed mild/moderate COVID-19 before a booster dose (breakthrough infection group) and hemodialysis patients who were not infected with COVID-19 but received a booster dose (booster immunization group) were recruited. In both groups, SARS-CoV-2 antigen-specific cytokines and IgG levels were measured three weeks after infection or three weeks after receiving a booster dose. Memory T and B cells were also counted in the breakthrough infection group using flow cytometry three weeks after infection. Significantly higher SARS-CoV-2 antigen-specific IgG, IFN-γ, IL-5, TNF-α, and IL-6 levels occurred in the breakthrough infection group compared to the booster immunization group (p = 0.013, 0.039, 0.024, 0.017, and 0.039, respectively). The SARS-CoV-2 antigen-specific IgG and cytokine levels were not significantly different between the two groups. The breakthrough infection group had significantly higher percentages of central and effector memory T cells and regulatory T cells than the comparison group (p = 0.008, 0.031, and 0.026, respectively). Breakthrough infections may induce stronger cellular and humoral immune responses than booster immunizations in hemodialysis patients.

A Marked Eosinophilic Infiltration in Mucosa Could Be a Better Predictive Factor for Intractable Non-Esophageal Eosinophilic Gastrointestinal Disorders.

INTRODUCTION: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are rare, but their prevalence has recently increased. Although it has been reported that one-half of patients with non-EoE EGIDs have intractable clinical courses, their clinical features are not fully understood. METHODS: This is a multicenter retrospective study in which 10 institutions in Japan participated. Clinical databases from January 1998 to December 2020 were reviewed to identify patients with non-EoE EGIDs. A total of 44 patients were identified; they were divided into two groups based on their clinical course: an intractable group and a non-intractable group. The clinical features were compared between the two groups by a logistic regression analysis. Remarkable eosinophilic infiltration (REI) was defined histologically when the maximal counts of mucosal eosinophils reached a threshold level in the respective area of biopsy. RESULTS: Prevalence of drug allergy and eosinophil counts more than 500/µL (EOS), vomiting symptoms, abnormalities of the stomach, duodenum, and jejunum on computed tomography (upper gastrointestinal abnormality on computed tomography [UACT]), and REI were significantly different between the two groups. Among the factors that were potentially associated with an intractable clinical course, logistic regression revealed that REI, EOS, and UACT were significant factors. Based on an analysis of the area under the receiver operator characteristic curve, a combination of REI and EOS had the lowest Akaike's information criterion, indicating the best model to predict an intractable clinical course. CONCLUSIONS: REI may predict an intractable course in patients with non-EoE EGIDs. In addition, the combination of REI and EOS was a better predictor than REI alone.

Comparison of cytokine production in mice inoculated with messenger RNA vaccines BNT162b2 and mRNA-1273.

Two messenger RNA (mRNA) vaccines of BNT162b2 and mRNA-1273 were licensed. The most common adverse event is regional pain at the injection site in 80%. As systemic reactions, fatigue and headache were noted in 40%-60% and febrile illness in 10%-40% of the recipients. To investigate the mechanism of adverse events, cytokine profiles were investigated in mice. Muscle tissue and serum samples were obtained on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given 4 weeks after the first dose and samples were obtained. After inoculation with 0.1 mL of mRNA-1273, IFN-γ and IL-2 were detected in muscle tissues and serum samples on day 1 of the second doses, and similar profiles were observed for IL-4, IL-5, and IL-12 production. mRNA-1273 induced higher levels of Th1 and Th2 cytokines. TNF-α was induced in muscle tissues on day 1 of the first dose and enhanced on day 1 of the second dose after inoculation with BNT162b2 and mRNA-1273. IL-6 was also detected in muscle tissue on day 1 of the first dose, but it decreased after day 3, and enhanced production was demonstrated on day 1 of the second dose. Granulocyte colony-stimulating factor in muscle tissues showed a similar profile. The induction of inflammatory cytokines in the mouse model is related to the cause of adverse events in humans, with a higher incidence of adverse events after the second dose.

High prevalence of IgE sensitization to inactivated influenza vaccines, yet robust IgG4 responses, in a healthy pediatric population.

BACKGROUND: Anaphylaxis following influenza vaccination is a rare but serious problem. The underlying immune responses are not well understood. This study elucidated the IgE and IgG antibody responses in healthy children and adolescents following inactivated influenza vaccines (IIVs). METHODS: The efficacy and safety of quadrivalent IIV (QIV) and trivalent IIV (TIV) were compared in healthy subjects aged 0-18 years. Serum IIV-specific IgE, IgG, and IgG4 levels (sIgE, sIgG, and sIgG4) were measured with ImmunoCAP. Hemagglutination inhibition (HI) assay was performed for each influenza virus subtype. Sera from earlier patients who developed anaphylaxis to different IIVs were similarly tested. RESULTS: A total of 393 subjects were enrolled: 96 were 6 months-2 years old, 100 were 3-5 years old, 100 were 6-12 years old, and 97 were 13-18 years old. No anaphylaxis was observed. Generally, QIV and TIV induced similar antibody responses. IIV-sIgE levels rose significantly after vaccination in the 6 months-2 years old and 3-5 years old groups, did not change in the 6-12 years old group, and decreased in the 13-18 years old group. In contrast, the IIV-sIgG4/sIgE ratio increased significantly after vaccination in all age groups. Sensitized subjects had significantly higher HI titers and IIV-sIgG levels in the youngest age group and higher IIV-sIgG4 levels in all age groups compared with the non-sensitized. The IIV-sIgG4/sIgE ratio in five patients with anaphylaxis was significantly lower than in age-matched healthy subjects. CONCLUSION: IIVs induce IgE sensitization in healthy children but also robust IgG4 responses that may protect them from anaphylaxis.

Pertussis, diphtheria, and tetanus antibodies seroprevalence in pregnant women and neonates, as a preliminary data for introduction of preconception or prenatal DTaP vaccination among Japanese society.

An increasing number of countries have been introducing acellular pertussis vaccination during pregnancy for the prevention of neonatal pertussis. In response to the fact that infantile pertussis cases of 0-5 months age groups remained unchanged despite the universal vaccination program, prenatal pertussis vaccination has been a rising issue in Japan. Hence, we investigated the seroprevalence of pertussis, diphtheria, and tetanus antibodies in Japanese pregnant women and neonates, and evaluated the necessity of diphtheria-tetanus-acellular pertussis (DTaP) vaccination during the preconception or prenatal period. Maternal PT-IgG (EIA) and FHA-IgG (EIA) for the first trimester, within 1 week after delivery, and cord blood were collected, along with colostrum pertussis-IgA (ELISA), diphtheria-IgG (EIA), tetanus-IgG (EIA), and blood samples from the first trimester. The maternal seroprevalence of PT-IgG and FHA-IgG was 69 % and 75 %, respectively. All tested participants were positive for diphtheria-IgG and tetanus-IgG (100 %). First trimester PT-IgG/FHA-IgG antibody titers were significantly associated with cord blood PT-IgG/FHA-IgG titers (P < 0.001). We found that pertussis seroprevalence among pregnant Japanese women was approximately 70 %. The antibody seropositivity rate of pertussis was lower than that of diphtheria and tetanus. Fetal acquired passive immunity against pertussis is higher when the level of maternal antibody in the first trimester is sufficient. At least 30 % of study population did not reach to the threshold value to provide sufficient pertussis immunity for the neonates and themselves. The acellular pertussis vaccine (DTaP) approved in Japan lacks safety information for pregnancy, hence, a solution for prompt administration of prenatal acellular pertussis vaccination might be introducing DTaP in the preconception period.

Chemokine/Interleukin Imbalance Aggravates the Pathology of Respiratory Syncytial Virus Infection.

(1) Background: Almost 100% of children are initially infected by respiratory syncytial virus (RSV) by the age of 2 years, with 30% to 40% of children developing lower respiratory tract infections, of which 1% to 3% become severe. The severity of RSV-induced disease correlates with the influx of leukocytes, which leads to damage of the airways. We hence performed an immunological study based on the assumption that a chemokine/interleukin imbalance affects respiratory disorders caused by bronchiolitis and severe pneumonia. (2) Methods: The subjects were 19 infants without any underlying diseases, who developed respiratory symptoms owing to RSV infection. The subjects were stratified by their symptom severity, and chemokine and interleukin levels in their serum and tracheal aspirate fluid (TAF) were measured. (3) Results: The data of TAF, which were only obtained from subjects with severe symptoms, indicated that levels of inflammatory interleukins were much lower than the levels of chemokines. Three out of 6 subjects with severe symptoms showed below detectable levels of IL-6. TNF-α and IFN-γ levels were also lower than those of chemokines. The main increased CCL chemokines were CCL21 and CCL25, and the main increased CXCL chemokines were CXCL5, 8, 10, 12, and CX3CL1 in the lower respiratory region. Multiple regression analysis demonstrated that serum CX3CL1 and IL-6 levels were most strongly associated with symptom severity. This is the first report to date demonstrating that serum CX3CL1 level is associated with the severity of RSV infection. (4) Conclusions: Our results demonstrated that specific chemokines and the imbalance of cytokines are suspected to be associated with aggravated symptoms of RSV infection.

Increased Production of Inflammatory Cytokines after Inoculation with Recombinant Zoster Vaccine in Mice.

Increasing numbers of patients with zoster were reported recently, and recombinant zoster vaccine (Shingrix®) was licensed using the AS01B adjuvant system. Although it induces highly effective protection, a high incidence of local adverse events (regional pain, erythema, and swelling) has been reported with systemic reactions of fever, fatigue, and headache. To investigate the mechanism of local adverse events, cytokine profiles were investigated in mice injected with 0.1 mL of Shingrix®. Muscle tissue and serum samples were obtained on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given 4 weeks after the first dose and samples were obtained on days 1, 3, 5, 7, and 14. IL-6 and G-CSF were detected in muscle tissues on day 1 of the first injection, decreased on day 3 and afterward, and enhanced production was demonstrated on day 1 of the second dose. In sera, the elevated levels of IL-6 were detected on day 1 of the first dose, and IL-10 was detected on day 1 with increased levels on day 3 of the first dose. IL-4 was detected in muscle tissue on day 1 of the second dose and IL-5 on day 1 of both the first and second doses. IFN-γ production was not enhanced in muscle tissue but increased in serum samples on day 1 of the first dose. These results in the mouse model indicate that the induction of inflammatory cytokines is related to the cause of adverse events in humans.

Appropriate Needle Length Determined by Ultrasonic Echography for Intramuscular Injection in Japanese Elderly over 50 Years.

Adjuvanted vaccines are administered through intramuscular injection. To perform appropriate injection using an appropriate needle in different age groups or different daily living activities, we investigated the depth from the skin surface to muscle fascia and bone in the deltoid muscle area in 156 elderly aged ≥ 50 years by ultrasonic echography. Subjects consisted of 50 healthy elderly aged 50−64 years, 50 subjects aged 65−74 years, and 56 subjects aged ≥ 75 years (20 outpatients, 18 who needed nursing care, and 18 bedridden in a nursing home). The mean depth ± 1.0 SD from the skin surface to muscle fascia was 7.52 ± 2.13 mm for subjects aged ≥ 75 years, being shorter than 9.16 ± 3.02 mm in those aged 50−64years (p < 0.01). The depth from the skin surface to bone was 22.54 ± 3.85 mm for subjects aged ≥ 75 years and 25.41 ± 4.24 mm for those aged 65−74 years, significantly shorter than those aged 50−64 years (p < 0.01), depending on the reduced muscle volume. The subcutaneous volume length was greater in females (8.29 ± 2.63 mm) than in males (5.62 ± 2.80 mm) aged 50−64 years (p < 0.01). A similar result was obtained in those aged 65−74 years, but there was no difference in the muscle volume length. Our study found that a five-eighths of an inch (16 mm) needle was an appropriate length for average-sized elderly aged ≥ 50 years, but it should be longer for those with large body sizes.

Clinical chorioamnionitis criteria are not sufficient for predicting intra-amniotic infection.

AIM: To evaluate the diagnostic performance of three conventional clinical chorioamnionitis criteria; including Gibbs, Lencki, and suspected triple I; for the prediction of intra-amniotic infection. METHODS: A retrospective cohort study was conducted using data from three perinatal centers from 2014 to 2018. Patients with preterm labor or premature prelabor rupture of membranes between 22 and 33 weeks of gestation and those who underwent transabdominal amniocentesis to detect intra-amniotic infection were selected. Intra-amniotic infection was defined as a positive amniotic fluid culture for microorganisms, including genital mycoplasmas, plus low glucose level or leukocytosis in amniotic fluid. Sensitivity, specificity, and positive and negative likelihood ratios were calculated to determine the diagnostic performance of each criterion in predicting intra-amniotic infection. RESULTS: Of 99 pregnant women who met the study inclusion criteria, 13 (13.1%) had intra-amniotic infection confirmed by amniocentesis and 86 (86.9%) had no intra-amniotic infection. Maternal characteristics were not significantly different between groups, except for the higher incidence of preterm, prelabor rupture of membranes in pregnant women with intra-amniotic infection (53.8 versus 14%, p < .01). The incidences of clinical chorioamnionitis in the non-IAI and IAI groups were 1 of 86 (1.2%), 1 of 86 (1.2%), 0 of 86 (0%) and 2 of 13 (15.4%), 2 of 13 (15.4%), 2 of 13 (15.4%) according to Gibbs, Lenki, and suspected triple I criteria, respectively. The specificity of the three criteria ranged from 98.8 to 100%; however, the sensitivity was low (15.4%). The positive likelihood ratio was significant for three criteria from 13.2 (95% confidence interval [CI], 1.29-135) to infinite. However, the negative likelihood ratio was not low enough and not significant for the three criteria (0.85 [95% CI, 0.67-1.07] to 0.86 [95% CI, 0.68-1.08]). CONCLUSION: The conventional clinical chorioamnionitis criteria are not sensitive for the prediction of intra-amniotic infection in pregnant women with preterm labor and/or preterm prelabor rupture of membranes.

Chimeric Measles Virus (MV/RSV), Having Ectodomains of Respiratory Syncytial Virus (RSV) F and G Proteins Instead of Measles Envelope Proteins, Induced Protective Antibodies against RSV.

In our previous study, fusion (F) or glyco (G) protein coding sequence of respiratory syncytial virus (RSV) was inserted at the P/M junction of the measles AIK-C vector (MVAIK), and the recombinant measles virus induced protective immune responses. In the present study, the ectodomains of measles fusion (F) and hemagglutinin (HA) proteins were replaced with those of RSV F and G proteins, and a chimeric MV/RSV vaccine was developed. It expressed F and G proteins of RSV and induced cytopathic effect (CPE) in epithelial cell lines (Vero, A549, and HEp-2 cells), but not in lymphoid cell lines (B95a, Jurkat, and U937 cells). A chimeric MV/RSV grew similarly to AIK-C with no virus growth at 39 °C. It induced NT antibodies against RSV in cotton rats three weeks after immunization through intramuscular route and enhanced response was observed after the second dose at eight weeks. After the RSV challenge with 106 PFU, significantly lower virus (101.4±0.1 PFU of RSV) was recovered from lung tissue in the chimeric MV/RSV vaccine group than in the MVAIK control group with 104.6±0.2 PFU (p < 0.001) and no obvious inflammatory pathological finding was noted. The strategy of ectodomain replacement in the measles virus vector is expected to lead to the development of safe and effective vaccines for other enveloped viruses.

Changes in epidemiological characteristics and sero-prevalence against the varicella zoster virus in school-age children after the introduction of a national immunization program in Japan.

A national immunization program using two doses of live attenuated varicella vaccine was introduced for children aged one to two years in Japan in October 2014. Varicella cases declined after 2014, and immunological status against varicella among vaccinated children changed in post-vaccination era. A retrospective observational study of anti-varicella antibody seroprevalence, varicella vaccination status, and history of varicella among 528 students in the first grade of elementary school was conducted. The percentage of students who received at least a single dose of varicella vaccination increased from 67% (187 of 279 students) in 2007-2008 to 91% (226 of 249 students) in 2017. Students with a history of varicella decreased from 114 of 279 (41%) in 2007-2008 to 48 of 249 (19%, P < .01) in 2017. Among them, the rate of breakthrough varicella after a single dose of vaccine in students with a history of varicella significantly increased from 38% (43 of 114 students) in 2007-2008 to 58% (28 of 48 students) in 2017 (P < .05). The antibody-positive rate significantly decreased from 50% among subjects without varicella zoster who received a single dose (95%CI: 41-58%) in 2007-2008 to 29% (95%CI: 21-38%) in 2017 (P < .01). The antibody-positive rate among students without varicella history who received two doses of vaccine was only 43% (95%CI: 32-55%) in 2017. The number of varicella infections and antibody-positive rate among students without history of varicella who received varicella vaccination decreased after the introduction of a national immunization program.

Negative effect on immune response of repeated influenza vaccination and waning effectiveness in interseason for elderly people.

BACKGROUND: Through test negative designs for visiting a doctor because of influenza-like illness, many studies have found decreasing efficacy of repeated vaccination. Furthermore, waning effectiveness during interseason periods has been reported. This study was conducted to confirm negative effects of repeated vaccination in individuals with the same vaccine strain and to measure waning effects. METHODS: Our cohort includes 66 participants older than 65 years old recruited from an outpatient department of one hospital. All were vaccinated, with hemagglutination inhibition (HI) antibody titers measured from 2001/02 season through the 2003/04 season. HI antibody titers were measured three times in one season: pre-vaccination, post-vaccination, and post-epidemic. To test negative effects of immune response to the repeated vaccination, differences between protection rates and differences between response rates were analyzed for individuals in the two consecutive seasons. For the test of waning effectiveness, we measured the difference in geometric mean titers of HI antibody between post-epidemic results and pre-vaccination results obtained in the following season. RESULTS: Protection rates were 40-55% in A/New Caledonia/20/99 and ≥75% in A/Panama/2007/99 by repeated vaccination. In A/New Caledonia/20/99 and A/Panama/2007/99 in the 2003/04 season, significant decreases were found in protection rates from the earlier seasons, although the rate for A/Panama/2007/99 in the 2002/03 season increased significantly from that of the prior season. The respective response rates in the 2003/04 season in A/New Caledonia/20/99, and in the 2002/03 and 2003/04 seasons in A/Panama/2007/99 decreased significantly from those of earlier seasons. Regarding waning effectiveness, antibody titers for A/New Caledonia/20/99 in 2003/04 season, and A/Panama/2007/99 in 2002/03 and 2003/04 seasons decreased significantly to 37.0-66.7%. CONCLUSION: Results show significant negative effects of immune response by repeated vaccination and show significant waning effectiveness during the interseason for individuals with the same strain of influenza type A. The proportion of elderly people with HI antibody titers of ≥1:40 might be maintained by repeated influenza vaccination.

Recombinant Measles AIK-C Vaccine Strain Expressing Influenza HA Protein.

Recombinant measles AIK-C vaccine expressing the hemagglutinin (HA) protein of influenza A/Sapporo/107/2013(H1N1pdm) (MVAIK/PdmHA) was constructed. Measles particle agglutination (PA) and influenza hemagglutinin inhibition (HI) antibodies were induced in cotton rats immunized with MVAIK/PdmHA. Cotton rats immunized with two doses of the HA split vaccine were used as positive controls, and higher HI antibodies were detected 3 weeks after the first dose. Following the challenge of A/California/07/2009(H1N1pdm), higher viral loads (107 TCID50/g) were detected in the lung homogenates of cotton rats immunized with the empty vector (MVAIK) or control groups than those immunized with MVAIK/Pdm HA (103 TCID50/g) or the group immunized with HA split vaccine (105 TCID50/g). Histopathologically, destruction of the alveolar structure, swelling of broncho-epithelial cells, and thickening of the alveolar wall with infiltration of inflammatory cells and HA antigens were detected in lung tissues obtained from non-immunized rats and those immunized with the empty vector after the challenge, but not in those immunized with the HA spilt or MVAIK/PdmHA vaccine. Lower levels of IFN-α, IL-1ß, and TNF-α mRNA, and higher levels of IFN-γ mRNA were found in the lung homogenates of the MVAIK/PdmHA group. Higher levels of IFN-γ mRNA were detected in spleen cell culture from the MVAIK/PdmHA group stimulated with UV-inactivated A/California/07/2009(H1N1pdm). In conclusion, the recombinant MVAIK vaccine expressing influenza HA protein induced protective immune responses in cotton rats.

Immunogenicity and safety of a DTaP-IPV/Hib pentavalent vaccine given as primary and booster vaccinations in healthy infants and toddlers in Japan.

BACKGROUND: Globally, the use of single DTaP-IPV/Hib vaccines that combine DTaP-IPV and Hib is widespread, but in Japan vaccination is usually concomitant at separate sites. The immunogenicity and safety of a primary vaccination series and booster of a combined pentavalent DTaP-IPV/Hib vaccine were evaluated and compared to separate administration of DTaP-IPV and Hib in Japanese infants. METHODS: Healthy Japanese infants were administered DTaP-IPV/Hib (Group A: N = 207) or DTaP-IPV + Hib (Group B: N = 207) by the subcutaneous (SC) or DTaP-IPV/Hib by the intramuscular (IM) route (Group C: N = 10). All subjects received a 3-dose primary vaccination series and a booster. Non-inferiority (Group A versus Group B) was tested post-primary series and subsequent post hoc analyses were performed for anti-Hib. Safety was assessed by parental reports. RESULTS: Non-inferiority for SC administration of Group A versus Group B for the primary series was demonstrated for antibody responses to all antigens except Hib using the threshold of 1.0 µg/mL. Post hoc analyses for anti-Hib demonstrated non-inferiority for the primary series response using 0.15 µg/mL, and for pre-booster antibody persistence and the booster response using 0.15 µg/mL and 1.0 µg/mL. The immune response was similar for each antigen following SC or IM administration. There were no safety concerns in any group, and a lower incidence of injection sites for the IM route was observed as expected. CONCLUSIONS: These data show the good immunogenicity and safety profile of the DTaP-IPV/Hib vaccine as a 3-dose infant primary series followed by a booster in the second year of life in Japan.

Cervical lymph node metastasis of ovarian dysgerminoma: A case report with fine needle aspiration cytology.

Dysgerminoma is a rare germ cell tumor, accounting for 1% to 2% of all malignant ovarian tumors. Here, we report a case of dysgerminoma diagnosed by aspiration cytology of a cervical lymph node. A 20-year-old woman presented with an abdominal mass and left cervical swelling. CT revealed a large pelvic tumor, along with a nodular lesion on the left side of neck. Fine needle aspiration (FNA) cytology of a cervical lymph node showed large atypical cells and small lymphocytes. Immunocytochemical staining on cell block material revealed that these large tumor cells were positive for placental alkaline phosphatase, D2-40, and c-kit. Dysgerminoma was suggested by FNA cytology. Furthermore, bilateral oophorectomy was performed, and histology confirmed the diagnosis of ovarian dysgerminoma. FNA cytology of metastatic lymph nodes along with immunocytochemistry is a useful tool for diagnosis of dysgerminoma.