Response to Vaccination in Infants Exposed to Antitumor Necrosis Factor Alpha In Utero.

In this retrospective cohort study, the response to routinely administered Haemophilus influenzae type B vaccine, pneumococcal and pertussis vaccinations in 27 children exposed to antitumor necrosis factor alpha (anti-TNFα) during pregnancy was measured. The overall vaccination response seems comparable for children exposed to anti-TNFα and healthy infants. After primary vaccination series, inadequate response was present in some patients and might be related to exposure to anti-TNFα.

A bacterial vaccine polypeptide protective against nontypable Haemophilus influenzae.

Nontypeable strains of Haemophilus influenzae (NTHi) are one of the most common cause of otitis media and the most frequent infection associated with exacerbations of chronic obstructive pulmonary disease; there is currently no vaccine in the U.S. to prevent NTHi. Using bioinformatics and structural vaccinology, we previously identified several NTHi species-conserved and sequence-conserved peptides that mediate passive protection in the rat model of infection. Using these, and similar peptides, we designed Hi Poly 1, a Bacterial Vaccine Polypeptide, comprising 9 unique peptides from 6 different surface proteins. Recombinant Hi Poly 1 was purified by affinity chromatography. Forty chinchillas were immunized three times with 200 µg of Hi Poly 1 with alum adjuvant; similarly, 41 controls were immunized with adjuvant alone. The average Log2 IgG titer among immunized animals was 17.04, and IgG antibodies against each component peptide were detected. In the infant rat model, antisera from immunized chinchillas provided significant passive protection compared to PBS (p = 0.01) and pre-immune sera (p = 0.03). In the established chinchilla model of NTHi otitis media, the vaccinated group cleared infection faster than the control group as indicated by significantly decreased positive findings on video-otoscopy (p < 0.0001) and tympanometry (p = 0.0002) on day 7, and for middle ear fluid obtained by aspiration (p = 0.0001) on day 10 post-infection. Using 12 representative NTHi strains in a Live-Cell ELISA, greater antibody binding to each strain was detected with post Hi Poly 1 than the pre-immune chinchilla antisera. The data from this proof-of-principle study demonstrate the effectiveness of Hi Poly 1 against the NTHi in two relevant preclinical models of bacteremia and otitis media as well as surface antibody binding across the species. The Bacterial Vaccine Polypeptide approach to a vaccine against NTHi also serves as a paradigm for development of similar vaccines to protect against other bacteria.

Cardiopulmonary Bypass and Infant Vaccination Titers.

BACKGROUND: Infants with congenital heart disease remain vulnerable to potentially preventable pathogens. Although immunization can significantly reduce this risk, it is unknown how immunization status can be affected by cardiac surgery with cardiopulmonary bypass (CPB). The objective was to evaluate the effect of CPB on infant vaccination status after cardiac surgery. METHODS: We conducted a prospective observational study of patients between 2 and 14 months of age who had received at least their first round of infant vaccinations and who required cardiac surgery with CPB. Antibody titers were measured before CPB and again the following morning. Demographic and surgical variables were assessed via regression methods for their effects on the change in titers. RESULTS: Among the 98 patients followed, there was no demonstrated difference between the pre- and postoperative values in regard to diphtheria, tetanus, polio 1, polio 3, or Haemophilus influenzae titers. Bordetella (1.03 vs 0.84, P < .001), and hepatitis B (log 2.10 vs 1.89, P = .001) titers did reduce after CPB but did not fall below the immunized threshold. Changes in antibody titers were not associated with time between immunization and surgery, age or weight at surgery, blood products administered, number of previous doses, time on CPB, or heterotaxy diagnosis for most of the vaccines. CONCLUSIONS: Infant vaccine antibody titers were minimally affected by CPB and not associated with any easily modifiable surgical variables. Although antibody titers are only 1 marker of immunity, deviation from the recommended vaccination schedule may be unnecessary for children requiring congenital heart surgery.

Antibody persistence in pre-school children after hexavalent vaccine infant primary and booster administration.

OBJECTIVE: Antibody persistence evaluation for all antigens of a fully liquid DTaP-IPV-HB-PRP~T vaccine at 3.5 and 4.5 y of age following different primary series and booster schedules in South Africa and Latin America. METHODS: Participants had completed one of two previous studies (Study 1-South Africa; Study 2-Latin America). In Study 1, participants who had not received HB vaccine at birth received a 6-10-14 week primary series of DTaP-IPV-HB-PRP~T or DTwP/PRP~T-Hib+HB+OPV and a third group who had received HB vaccine at birth received a 6-10-14 week primary series of DTaP-IPV-HB-PRP~T; all received a booster (15-18 months) of the primary series vaccine(s) except for HB in the DTwP/PRP~T-Hib group. In Study 2, participants received HB vaccine at birth, a 2-4-6 month primary series of DTaP-IPV-HB-PRP~T or DTaP-HB-IPV//PRP~T, and a DTaP-IPV-HB-PRP~T or DTaP-HB-IPV//PRP~T booster (12-24 months). Participants were followed up at 3.5 and 4.5 y of age for antibody persistence. RESULTS: Approximately 80% of eligible participants were assessed. In Study 1, a birth dose of HB increased anti-HBs persistence (≥10 mIU/mL) following DTaP-IPV-HB-PRP~T primary and booster vaccination from 76.3% to 96.1% at 3.5 y of age and from 73.3% to 96.1% at 4.5 y of age; in Study 2, anti-HBs persistence was high and similar in each group. For the other antigens, there were no differences between groups or studies at 3.5 or 4.5 y. CONCLUSION: Good persistence of antibodies to each antigen in the DTaP-IPV-HB-PRP~T vaccine up to pre-school age, irrespective of the vaccination schedule during the first 2 y of life.

Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

BACKGROUND: People affected with sickle cell disease (SCD) are at high risk of infection from Haemophilus influenzae type b (Hib). Before the implementation of Haemophilus influenzae type b conjugate vaccination in high-income countries, this was responsible for a high mortality rate in children under five years of age. In African countries, where coverage of this vaccination is still extremely low, Hib remains one of the most common causes of bacteraemias in children with SCD. The increased uptake of this conjugate vaccination may substantially improve the survival of children with SCD. This is an update of a previously published Cochrane Review. OBJECTIVES: The primary objective was to determine whether Hib conjugate vaccines reduce mortality and morbidity in children and adults with SCD.The secondary objectives were to assess the following in children and adults with SCD: the immunogenicity of Hib conjugate vaccines; the safety of these vaccines; and any variation in effect according to type of vaccine, mode of administration (separately or in combination with other vaccines), number of doses, and age at first dose. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched trial registries (04 July 2018) and contacted relevant pharmaceutical companies to identify unpublished trials.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinoapthies Trials Register: 18 December 2017. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs comparing Hib conjugate vaccines with placebo or no treatment, or comparing different types of Hib conjugate vaccines in people with SCD. DATA COLLECTION AND ANALYSIS: No trials of Hib conjugate vaccines in people with SCD were found. MAIN RESULTS: There is an absence of evidence from RCTs relating to the subject of this review. AUTHORS' CONCLUSIONS: There has been a dramatic decrease in the incidence of invasive Hib infections observed in the post-vaccination era in people with SCD living in high-income countries. Therefore, despite the absence of evidence from RCTs, it is expected that Hib conjugate vaccines may be useful in children affected with SCD, especially in African countries where there is a high prevalence of the disease. The implementation of childhood immunisation schedules, including universal Hib conjugate vaccination, may substantially improve the survival of children with SCD living in low-income countries. We currently lack data to evaluate the potential effect of Hib vaccination among unvaccinated adults with SCD. Further research should assess the optimal Hib immunisation schedule in children and adults with SCD.

Long-term regulation of local cytokine production following immunization in mice.

Vaccines based on pathogen components require adjuvants to enhance the antigen-specific adaptive immune response. Intramuscular injection of adjuvanted-vaccines induces inflammatory cytokines and inflammatory nodules at the injection site within 48 hr after injection (Vaccine 2014; 32: 3393-401). In the present study, long-term regulation of cytokine production was investigated at 3, 6, 24, and 48 hr, 5 and 7 days, and 2 and 4 weeks after immunization with human papilloma virus (HPV), diphtheria and tetanus toxoids combined with acellular pertussis (DTaP), Haemophilus influenza type B (Hib), and pneumococcal conjugated (PCV) vaccines in mouse models. The second dose was given 4 weeks later, and cytokine profiles were investigated 2, 5, and 7 days after re-immunization. IL-1ß, IL-6, granulocyte-colony stimulating factor (G-CSF), and MCP-1 were produced from 3 hr and peaked at 48 hr after immunization with Cervarix in mice. IL-4, MCP-1, and TNF-α peaked at 5 or 7 days after immunization with Gardasil. These cytokines decreased 7 days after immunization with Cervarix and Gardasil. After the second dose, similar responses were observed. Both vaccines induced neutrophil extracellular traps (NET) in inflammatory nodules. The peak amount of IL-1ß, IL-6, G-CSF, and MCP-1 was observed on day 5 of immunization and that of IL-4 on days 5-7 of immunization with DTaP, but no increase in IL-6 and G-CSF was observed after re-immunization. A similar response was noted after immunization with PCV13. An inflammatory response is essential for the development of adaptive immunity through the production of inflammatory cytokines.

In silico design, cloning, expression and immunologic evaluation of ED fusion protein of NT H. influenzae.

Infections due to nontypeable Haemophilus influenzae (NTHi) are important causes of child mortality throughout the world. Given the lack of effective vaccines for these strains and the spread and prevalence of these infections in the world, it is necessary to design novel vaccine candidates against these strains. D and E proteins are conserved membrane-specific lipoproteins among encapsulated and non-encapsulated H. influenza strains, which, according to the exposure surface and conservation degree between both strains, can be considered as vaccine candidates suitable for studies. This research was conducted to design a recombinant truncated fusion protein ED. Vaccination of BALB/c mice with recombinant truncated fusion protein ED showed high level of protective responses against NTHi. There were also strong responses of IgG and its subclasses (especially IgG1) as well as high titer levels of IL-4. A mixture of responses was observed considering IgG2a and INF-γ antibody titers, but the dominant response was toward Th2. According to the obtained results and the importance of humoral immunity in the immune system and vaccines production, it could be concluded that the produced recombinant construct can be used as a suitable vaccine candidate against NTHi or together with other carrier proteins.

Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens.

Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable Haemophilus influenzae (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations.

Incompatibility of lyophilized inactivated polio vaccine with liquid pentavalent whole-cell-pertussis-containing vaccine.

A hexavalent vaccine containing diphtheria toxoid, tetanus toxoid, whole cell pertussis, Haemophilius influenza type B, hepatitis B and inactivated polio vaccine (IPV) may: (i) increase the efficiency of vaccination campaigns, (ii) reduce the number of injections thereby reducing needlestick injuries, and (iii) ensure better protection against pertussis as compared to vaccines containing acellular pertussis antigens. An approach to obtain a hexavalent vaccine might be reconstituting lyophilized polio vaccine (IPV-LYO) with liquid pentavalent vaccine just before intramuscular delivery. The potential limitations of this approach were investigated including thermostability of IPV as measured by D-antigen ELISA and rat potency, the compatibility of fluid and lyophilized IPV in combination with thimerosal and thimerosal containing hexavalent vaccine. The rat potency of polio type 3 in IPV-LYO was 2 to 3-fold lower than standardized on the D-antigen content, suggesting an alteration of the polio type 3 D-antigen particle by lyophilization. Type 1 and 2 had unaffected antigenicity/immunogenicity ratios. Alteration of type 3 D-antigen could be detected by showing reduced thermostability at 45°C compared to type 3 in non-lyophilized liquid controls. Reconstituting IPV-LYO in the presence of thimerosal (TM) resulted in a fast temperature dependent loss of polio type 1-3 D-antigen. The presence of 0.005% TM reduced the D-antigen content by ∼20% (polio type 2/3) and ∼60% (polio type 1) in 6h at 25°C, which are WHO open vial policy conditions. At 37°C, D-antigen was diminished even faster, suggesting that very fast, i.e., immediately after preparation, intramuscular delivery of the conceived hexavalent vaccine would not be a feasible option. Use of the TM-scavenger, l-cysteine, to bind TM (or mercury containing TM degradation products), resulted in a hexavalent vaccine mixture in which polio D-antigen was more stable.

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.

BACKGROUND: Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. METHODS: We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0µg/mL, after the primary series. RESULTS: Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15µg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. CONCLUSION: The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns. CLINICAL TRIAL REGISTRY: Registered on ClinicalTrials.gov: NCT01379846.

Introduction of pentavalent vaccine in Indonesia: a policy analysis.

The introduction of pentavalent vaccine containing Haemophilus influenzae type b antigen in Indonesia's National Immunization Program occurred nearly three decades after the vaccine was first available in the United States and 16 years after Indonesia added hepatitis B vaccine into the program. In this study, we analyzed the process that led to the decision to introduce pentavalent vaccine in Indonesia. Using process tracing and case comparison, we used qualitative data gathered through interviews with key informants and data extracted from written sources to identify four distinct but interrelated processes that were involved in the decision making: (a) pentavalent vaccine use policy process, (b) financing process, (c) domestic vaccine development process and (d) political process. We hypothesized that each process is associated with four necessary conditions that are jointly sufficient for the successful introduction of pentavalent vaccine in Indonesia, namely (a) an evidence-based vaccine use recommendation, (b) sufficient domestic financing capacity, (c) sufficient domestic vaccine manufacturing capacity and (d) political support for introduction. This analysis of four processes that led to the decision to introduce a new vaccine in Indonesia may help policy makers and other stakeholders understand and manage activities that can accelerate vaccine introduction in the future.

Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

BACKGROUND: People affected with sickle cell disease are at high risk of infection from Haemophilus influenzae type b. Before the implementation of Haemophilus influenzae type b conjugate vaccination in high-income countries, this was responsible for a high mortality rate in children under five years of age. In African countries, where coverage of this vaccination is still extremely low, Haemophilus influenzae type b remains one of the most common cause of bacteraemias in children with sickle cell disease. The increased uptake of this conjugate vaccination may substantially improve the survival of children with sickle cell disease. OBJECTIVES: The primary objective was to determine whether Haemophilus influenzae type b conjugate vaccines reduce mortality and morbidity in children and adults with sickle cell disease.The secondary objectives were to assess the following in children and adults with sickle cell disease: the immunogenicity of Haemophilus influenzae type b conjugate vaccines; the safety of these vaccines; and any variation in effect according to type of vaccine, mode of administration (separately or in combination with other vaccines), number of doses, and age at first dose. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also contacted relevant pharmaceutical companies to identify unpublished trials.Date of last search: 23 November 2015. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing Haemophilus influenzae type b conjugate vaccines with placebo or no treatment, or comparing different types of Haemophilus influenzae type b conjugate vaccines in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: No trials of Haemophilus influenzae type b conjugate vaccines in people with sickle cell disease were found. MAIN RESULTS: There is an absence of evidence from randomised controlled trials relating to the subject of this review. AUTHORS' CONCLUSIONS: There has been a dramatic decrease in the incidence of invasive Haemophilus influenzae type b infections observed in the post-vaccination era in people with sickle cell disease living in high-income countries. Therefore, despite the absence of evidence from randomised controlled trials, it is expected that Haemophilus influenzae type b conjugate vaccines may be useful in children affected with sickle cell disease, especially in African countries where there is a high prevalence of the disease. The implementation of childhood immunisation schedules, including universal Haemophilus influenzae type b conjugate vaccination, may substantially improve the survival of children with sickle cell disease living in low-income countries. We currently lack data to evaluate the potential effect of Haemophilus influenzae type b vaccination among unvaccinated adults with sickle cell disease. Further research should assess the optimal Hib immunisation schedule in children and adults with sickle cell disease.

The Effect of Maternal Peripartum Anti-TNFα Use on Infant Immune Response.

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) cross the placenta in the third trimester and can be detectable in infants for up to 12 months. AIM: The aim of this study was to determine whether in utero IFX or ADA exposure results in an impaired immune response in infants, as measured by immunoglobulin levels and antibody responses to routine primary immunizations. METHODS: Infants who were exposed to in utero anti-TNFα agents were prospectively evaluated. Immunoglobulin levels (IgG, IgM, IgA) and antibodies to standard vaccinations, including tetanus toxoid (tetanus) and Haemophilus influenza type b (Hib), were measured in infants of at least 6 months of age. RESULTS: Twelve infants were prospectively studied: 10 exposed to in utero IFX and 2 exposed to ADA with at least one dose administered in the third trimester. Immunoglobulin levels were available on 10/12 patients, with all showing adequate immunoglobulin levels, except for low IgM levels in 5 (50 %) infants. Adequate responses to both the tetanus and Hib vaccines were seen in 11 of 12 (92 %) infants. CONCLUSIONS: Infants exposed to anti-TNFα agents in utero demonstrate appropriate response to two commonly administered neonatal vaccines and show adequate immunoglobulin levels, except for IgM. Newborns with a history of exposure to anti-TNFα agents should follow a standard vaccination schedule for inactive vaccines.

Neisseria meningitidis Group A IgG1 and IgG2 Subclass Immune Response in African Children Aged 12-23 Months Following Meningococcal Vaccination.

BACKGROUND: A group A meningococcal conjugate vaccine, PsA-TT, was licensed in 2010 and was previously studied in a phase 2 clinical trial to evaluate its safety and immunogenicity in African children 12-23 months of age. METHODS: Subjects received either PsA-TT; meningococcal group A, C, W, Y polysaccharide vaccine (PsACWY); or Haemophilus influenzae type b conjugate vaccine (Hib-TT). Forty weeks following primary vaccination, the 3 groups were further randomized to receive either PsA-TT, one-fifth dose of PsACWY, or Hib-TT. Group A-specific immunoglobulin G (IgG) subclass response was characterized using an enzyme-linked immunosorbent assay. RESULTS: The predominant IgG subclass response, regardless of vaccine, was IgG1. One month following primary vaccination, the geometric mean concentrations (GMCs) of IgG1 and IgG2 in the PsA-TT group were 21.73 µg/mL and 6.27 µg/mL, whereas in the PsACWY group the mean GMCs were 2.01 µg/mL and 0.97 µg/mL, respectively (P < .0001). Group A-specific IgG1 and IgG2 GMCs remained greater in the PsA-TT group than in the PsACWY group 40 weeks following primary vaccination (P < .0001). One week following revaccination, those given 2 doses of PsA-TT had the greatest IgG1 and IgG2 GMCs of 125.23 µg/mL and 36.12 µg/mL, respectively (P = .0008), and demonstrated a significant increase in IgG1:IgG2 mean ratio, indicative of the T-cell-dependent response associated with conjugate vaccines. CONCLUSIONS: Vaccination of African children aged 12-24 months with either PsA-TT or PsACWY elicited a predominantly IgG1 response. The IgG1:IgG2 mean ratio decreased following successive vaccination with PsACWY, indicating a shift toward IgG2, suggestive of the T-cell-independent immune response commonly associated with polysaccharide antigens. CLINICAL TRIALS REGISTRATION: SRCTN78147026.

Human Infant Memory B Cell and CD4+ T Cell Responses to HibMenCY-TT Glyco-Conjugate Vaccine.

UNLABELLED: Carrier-specific T cell and polysaccharide-specific B cell memory responses are not well characterised in infants following glyco-conjugate vaccination. We aimed to determine if the number of Meningococcal (Men) C- and Y- specific memory B cells and; number and quality of Tetanus Toxoid (TT) carrier-specific memory CD4+ T cells are associated with polysaccharide-specific IgG post HibMenCY-TT vaccination. Healthy infants received HibMenCY-TT vaccine at 2, 4 and 6 months with a booster at 12 months. Peripheral blood mononuclear cells were isolated and polysaccharide-specific memory B cells enumerated using ELISpot. TT-specific memory CD4+ T cells were detected and phenotyped based on CD154 expression and intracellular TNF-α, IL-2 and IFN-γ expression following stimulation. Functional polysaccharide-specific IgG titres were measured using the serum bactericidal activity (SBA) assay. Polysaccharide-specific Men C- but not Men Y- specific memory B cell frequencies pre-boost (12 months) were significantly associated with post-boost (13 months) SBA titres. Regression analysis showed no association between memory B cell frequencies post-priming (at 6 or 7 months) and SBA at 12 months or 13 months. TT-specific CD4+ T cells were detected at frequencies between 0.001 and 0.112 as a percentage of CD3+ T cells, but their numbers were not associated with SBA titres. There were significant negative associations between SBA titres at M13 and cytokine expression at M7 and M12. CONCLUSION: Induction of persistent polysaccharide-specific memory B cells prior to boosting is an important determinant of secondary IgG responses in infants. However, polysaccharide-specific functional IgG responses appear to be independent of the number and quality of circulating carrier-specific CD4+ T cells after priming.

Identification of secreted proteins as novel antigenic vaccine candidates of Haemophilus parasuis serovar 5.

Haemophilus parasuis (H. parasuis) is a swine pathogen responsible for the Glässer's disease, which has received more attention in the past decade due to the increasing economic losses in the pig industry worldwide. As traditional inactive vaccine of H. parasuis has obvious disadvantage, to identify efficient immunoprotective antigens would undoubtedly contribute to the development of novel subunit vaccines. The putative secreted proteins of H. parasuis are potentially essential components of more potent vaccines. In the present study, six secreted proteins (PflA, Gcp, Ndk, HsdS, RnfC and HAPS_0017) were selected from the annotated H. parasuis serovar 5 genome as immunogenic protein with bioinformatic and experimental approaches. These proteins were successfully expressed in Escherichia coli and their immunogenicity was assessed in a mouse challenge model. The results showed that subcutaneous injection with the recombinant proteins resulted in the production of antibodies with high levels. Antigen-specific lymphoproliferative responses were detected in the splenocytes of the immunized animals. CD4(+) T-cell populations were higher in the vaccinated animals 3 weeks after the booster immunization than those of the control animals. A significant increase was observed in the cytokine levels of IL-2, IL-4 and IFN-γ in the culture supernatants of splenocytes. Furthermore, immunized mice conferred different levels of protection against challenge with a lethal dose of highly virulent serovar 5 strain (H46). Our results indicate that these six secreted proteins induced a good Th1 response and protection against H. parasuis infection, could be potential subunit vaccine candidates.

Internações sensíveis à atenção primária específicas de mulheres / Sensitive female-specific hospitalization in primary care

Objetivou-se analisar as internações por condições sensíveis à atenção primária (ICSAP) específicas em mulheres e os fatores que determinam ou influenciam a ocorrência dessas internações (fatores socioeconômicos, sociodemográficos e controle de saúde) por meio de um inquérito de morbidade hospitalar realizado com amostra de 429 mulheres internadas em hospitais conveniados ao Sistema Único de Saúde. O percentual de ICSAP foi 49,42% (n = 212), com destaque para as internações específicas do sexo feminino 19,35% (n = 83). Associaram ao risco de internar por CSAP: idade superior a 60 anos, baixa escolaridade, internação prévia, realização de controle regular de saúde, falta de vínculo com a Estratégia Saúde da Família (ESF) e ser gestante. As causas evidentes foram as condições relacionadas à gravidez, ao parto e ao puerpério e às inflamações nos órgãos pélvicos femininos. Os resultados sugerem falhas no atendimento ambulatorial que deveria ser oportuno e resolutivo no contexto da saúde da mulher.

The scope of this paper was to analyze female-specific sensitive hospitalization occurring in primary care conditions and factors that determine or affect the occurrence of such hospitalizations (social, economic and demographic factors; health control). Analysis was performed by surveys on hospital morbidity with a sample of 429 females attended in Unified Health System (SUS) contracted hospitals. The sensitive hospitalizations percentage in primary care reached 49.42% (n = 212), highlighting female-specific hospitalization at 19.35% (n = 83). Hospitalization risks comprised elderly people over sixty, low schooling, previous hospitalizations, normal health control, lack of association with the Family Health Strategy and pregnancy. Evident causes were related to conditions of pregnancy, childbirth, post-partum and inflammations of the female pelvic organs. Results suggested flaws in outpatient attendance that should be adequate and provide solutions in women’s health.

Lower response to early T-cell-dependent vaccination after neurotrauma or neurosurgery in adults.

BACKGROUND: Recent international guidelines recommend vaccination with a 13-valent pneumococcal conjugate vaccine to reduce the risk of meningitis after neurotrauma with cerebrospinal fluid leak. The antibody response and optimal time point for vaccination have not been established and because the risk of meningitis is at the highest shortly after trauma, early vaccination is preferable. This study aimed to investigate the antibody response and to ensure that central nervous system injury-induced immunodepression did not affect the response to a T-cell-dependent conjugate vaccine when administered shortly after the injury. METHODS: So as not to interfere with routine pneumococcal vaccination, a conjugate vaccine against Haemophilus influenza type b (Hib) was chosen for the study. Thirty-three patients with basilar skull fracture and 23 patients undergoing transsphenoidal pituitary gland surgery were vaccinated within 10 days after trauma/surgery and 29 control patients at least three weeks after trauma/surgery. Sera were collected pre- and post-vaccination for analysis of anti-Hib concentration. RESULTS: Four patients with post-vaccination target antibody concentration before vaccination were excluded from analysis. In the neurotrauma and neurosurgery groups 10/32 (31%) and 5/20 (25%) patients, respectively, were non-responders compared with 3/29 (10%) in the control group. Log10 anti-Hib concentrations in the neurotrauma, neurosurgery and control groups were 1.52 ± 0.15, 1.38 ± 0.15 and 1.81 ± 0.12 µg/ml, respectively. CONCLUSIONS: The majority of the patients responded to vaccination. However, the number of responders was significantly decreased and antibody concentration significantly lower in patients vaccinated early after the trauma/surgery. Investigation of the pneumococcal conjugate vaccine response in neurotrauma patients is therefore urgent.

[Preparation and characterization of mouse monoclonal antibody against outer membrane protein P6 of Haemophilus influenzae].

OBJECTIVE: To prepare and identify monoclonal antibody against Haemophilus influenzae(Hi) outer membrane protein P6. METHODS: Recombinant protein P6 as an immunogen was administered intraperitoneally to BALB/c mice. The splenocytes of the mouse were isolated from spleen and hybridized with Sp2/0 myeloma cells. Indirect ELISA was used for screening hybridoma and the number of chromosomes in hybridoma cells was determined by karyotype analysis. The titers and specificity of monoclonal antibodies in their culture supernatant were detected by indirect ELISA. The immunoglobulin class, subclasses and type of the monoclonal antibody were identified with colloidal gold labeled IsoQuick(TM) strips. RESULTS: Two hybridoma cell lines designated α2G3 and γ2C4 were obtained. Karyotype analysis showed that the chromosome numbers of α2G3 and γ2C4 were 103 and 95, respectively. The highest titers of antibodies in their culture supernatant were 1:256 and 1:512, respectively. Both monoclonal antibodies only reacted with standard or clinical isolated strains of Hi, and they both did not react with other bacteria. A2G3 was IgG2b, and γ2C4 was IgM, both of which were kappa light chains. They could recognize different antigen epitope of protein P6. CONCLUSION: Two hybridoma cell lines producing the monoclonal antibodies against protein P6 of Hi outer membrane are obtained.