Immune Responses to Booster Vaccination With Meningococcal ABCWY Vaccine After Primary Vaccination With Either Investigational or Licensed Vaccines: A Phase 2 Randomized Study.

BACKGROUND: Current meningococcal prime-boost vaccination schedules include separate vaccines for serogroups ACWY and B. An investigational combined serogroups ABCWY vaccine (MenABCWY) was developed to protect against clinically important Neisseria meningitidis serogroups. METHODS: In this phase 2, randomized, observer-blind, extension study (NCT01272180), participants 10-25 years of age received 1 booster dose of MenABCWY vaccine at 24 months (M) postprimary series of MenABCWY (2 doses), 4CMenB (2 doses) or MenACWY-CRM vaccine (1 dose). Immune responses to booster dose (1M postbooster) and antibody persistence (24M, 36M postprimary series) were assessed using bactericidal assay with human complement (hSBA). Reactogenicity and safety were evaluated. RESULTS: One hundred ninety participants were vaccinated. At 1M after the MenABCWY booster dose, seroresponse rates against serogroups ACWY ranged between 85% and 96%, 73% and 100% and 83% and 95% for participants previously receiving MenABCWY, 4CMenB and MenACWY-CRM, respectively. At 12M postbooster dose, ≥67% of participants across all groups had hSBA titers ≥8 for serogroups ACWY, except in 4CMenB-primed individuals for serogroup Y (45%). Across MenABCWY and 4CMenB-primed groups, hSBA titers ≥5 across serogroup B test strains were observed in 82%-100% and 29%-100% of participants at 1M and 12M postbooster, respectively. Geometric mean titers against serogroups ACWY increased from pre- to 1M postboosting with MenABCWY and persisted at 12M. The reactogenicity and safety profile of MenABCWY was similar to that of 4CMenB. CONCLUSIONS: MenABCWY may be suitable for prime-boost schedules against meningococcal disease, including regimens involving a primary series of either 4CMenB or MenACWY-CRM licensed vaccines.

A randomized study of fever prophylaxis and the immunogenicity of routine pediatric vaccinations.

OBJECTIVE: Prophylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine. METHODS: Subjects received prophylactic paracetamol or ibuprofen at 0, 6-8, and 12-16 h after vaccination, or 6-8 and 12-16 h after vaccination at 2, 3, 4, and 12months of age. At 5 and 13months, immune responses were evaluated versus responses in controls who received no prophylaxis. RESULTS: After the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P<0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P<0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose. CONCLUSIONS: Prophylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration. ClinicalTrials.gov identifier: NCT01392378https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378&rank=1.

Antibody persistence and immunologic memory in children vaccinated with 4 doses of pneumococcal conjugate vaccines: Results from 2 long-term follow-up studies.

To investigate long-term antibody persistence following the administration of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV), we present results of 2 follow-up studies assessing antibody persistence following 2 3+1 schedules up to 4 (NCT00624819 - Study A) and 5 years (NCT00891176 - Study B) post-booster vaccination. In Study A, antibody persistence was measured one, 2 and 4 years post-booster in children previously primed and boosted with PHiD-CV, or primed with the 7-valent pneumococcal conjugate vaccine (7vCRM) and boosted with either PHiD-CV or 7vCRM. In Study B, PHiD-CV was co-administered with meningococcal vaccines, and pneumococcal antibody persistence was measured 2, 3 and 5 years post-booster. An age-matched control group, unvaccinated against Streptococcus pneumoniae, was enrolled in Study A, allowing assessment of immunologic memory by administration of one dose of PHiD-CV to both primed (4 years post-booster) and unprimed 6-year-old children. Four years post-booster (Study A), antibody concentrations and opsonophagocytic activity (OPA) titers remained higher compared to the pre-booster timepoint, with no major differences between the 3 primed groups. Antibody persistence was also observed in Study B, with minimal differences between groups. The additional PHiD-CV dose administered 4 years post-booster in Study A elicited more robust immune responses in primed children than in unprimed children. Long-term serotype-specific antibody persistence and robust immunologic memory responses observed in these 2 studies suggest induction of long-term protection against pneumococcal disease after PHiD-CV vaccination.

Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines.

We evaluated antibody persistence in children up to 5 years after administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine coadministered with a pneumococcal conjugate vaccine. This is the follow-up study of a randomized trial (ClinicalTrials.gov registration no. NCT00334334/00463437) in which healthy children were vaccinated (primary vaccinations at 2, 4, and 6 months of age and booster vaccination at 11 to 18 months of age) with Hib-MenC-TT or a control MenC conjugate vaccine, coadministered with diphtheria-tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent cross-reacting material 197 [CRM197] conjugate vaccine [7vCRM]). MenC antibody titers were measured with a serum bactericidal antibody (SBA) assay using rabbit complement (i.e., rabbit SBA [rSBA]), and antibodies against Hib polyribosylribitol phosphate (PRP) were measured with an enzyme-linked immunosorbent assay. Antibody persistence up to 5 years after booster vaccination is reported for 530 children ∼6 years of age. The percentages of children with seroprotective rSBA-MenC titers were between 24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-related serious adverse events and no events related to a lack of vaccine efficacy were reported. Approximately 5 years after booster vaccination, the majority of children retained seroprotective anti-PRP antibody concentrations. The percentage of children retaining seroprotective rSBA-MenC titers was low (≤40%), suggesting that a significant proportion of children may be unprotected against MenC disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT00891176.).

Predictors for diagnosis of tick-borne encephalitis infection in Poland, 2009-2010.

BACKGROUND: Tick-borne encephalitis (TBE) is a viral infection with no available treatment. Due to its non-specific symptoms, TBE tends to be under-diagnosed and under-reported. We aimed to identify factors predicting TBE diagnosis to develop a diagnostic algorithm for use by physicians. METHODS: We conducted a case-control study using data routinely collected in Poland during 2009-2010. We included patients admitted to hospitals, who were assigned an International Classification of Disease (ICD) code indicating aseptic meningo-encephalitis. Cases were confirmed by detection of specific IgG and IgM antibodies. Patients that tested negative for TBE were included as controls. We used logistic regression to determine associations and recursive partitioning to build a diagnostic algorithm based on 70% of the dataset, and validated the algorithm using the remaining 30%. RESULTS: Of 774 patients, 273 (35%) were TBE-positive. Cerebrospinal fluid protein levels and presence of a tick bite were key decision points in the algorithm, while living in a TBE endemic area was not important. Application of the algorithm to the validation dataset yielded a sensitivity of 89% and specificity of 37%. CONCLUSIONS: TBE should be included in routine diagnostic protocols for all cases admitted to hospitals with meningitis or encephalitis. However, in resource-limited settings and in regions with unknown TBE endemicity status, our algorithm could indicate which cases should be tested for TBE.

A randomized, controlled trial to assess the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, hib and meningococcal serogroup C combination vaccine administered at 2, 3, 4 and 12-18 months of age.

BACKGROUND: Combination vaccines offer protection against multiple diseases with fewer injections. This study evaluated the immunogenicity and safety of an investigational diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b (Hib) and meningococcal serogroup C (MenC) heptavalent combination vaccine (heptavalent vaccine) given as 4 doses at 2, 3, 4 and 12-18 months of age. METHODS: In this randomized, open, phase II study (NCT00970307/NCT01171989) conducted in Poland, 421 infants were enrolled to receive the heptavalent vaccine or licensed comparator vaccines. Immunogenicity against study vaccine antigens was measured prior to and 1 month after primary and booster vaccinations. Safety and reactogenicity of the vaccines were also evaluated. RESULTS: The primary noninferiority objectives of the MenC and Hib immune responses induced by the heptavalent vaccine versus comparator vaccines were reached after primary vaccination, but no statistical conclusion could be drawn after booster dose. One month after primary and booster vaccinations, ≥98.4% of the heptavalent vaccine recipients were seroprotected for MenC and Hib. Exploratory analyses indicated that the heptavalent vaccine induced higher postprimary vaccination antibody geometric mean concentrations against Hib, but lower postprimary and postbooster vaccinations geometric mean titers against MenC compared with the relevant comparator vaccines. The reactogenicity profiles of the vaccines were acceptable, although 1 infant vaccinated with the heptavalent vaccine experienced a serious adverse event (thrombocytopenia) considered possibly related to vaccination. CONCLUSIONS: The heptavalent vaccine was immunogenic and had a clinically acceptable safety profile when administered to infants and toddlers.

New endemic foci of tick-borne encephalitis (TBE) identified in districts where testing for TBE was not available before 2009 in Poland.

BACKGROUND: Tick-borne encephalitis (TBE) is found in limited endemic foci in Poland. Lack of diagnosis limits disease detection in non-endemic provinces. METHODS: In 2009, we enhanced TBE surveillance to confirm the location of endemic foci and inform vaccination policy. In 105 hospitals located in 11/16 provinces, we identified suspected TBE cases through admission ICD-10 codes indicating aseptic meningo-encephalitis or from specimens tested for TBE. The National Reference Laboratory confirmed cases at no cost, by testing serum and/or cerebrospinal fluid using ELISA method. We calculated TBE reported rates as the number of confirmed TBE cases per 100,000 inhabitants. Adjusting to neighbouring districts, we classified districts as non-endemic (<0.1 cases per 100,000 inhabitants), low endemic (> = 0.1 to <1), moderately endemic (> = 1 to <5) and highly endemic (> = 5). We compared surveillance data obtained in 2009 with 2004-2008 baseline data. RESULTS: Among 166,099 admissions, we identified 1,585 suspected TBE cases of which 256 were confirmed. Physicians reported more suspected cases among patients <40 years old (12 cases per 1,000 admissions) than among older patients (8 cases per 1,000 admissions). However, patients <40 years of age were confirmed less frequently (16%), than older patients (35%). Physicians reported more suspected cases in districts classed as endemic during 2004-2008 (12 cases per 1,000 admissions, 77% tested for TBE) than in districts classed as non-endemic (7 cases per 1,000 admissions, 59% tested). Of the 38 newly identified endemic districts, 31 were adjacent to 2004-2008 endemic districts and 7 were isolated. CONCLUSIONS: Enhanced surveillance detected 38 new endemic districts to be considered for TBE vaccination. However, lack of consistent testing in districts believed to be TBE-free remained an obstacle for mapping TBE risk. Although the disease affects mostly older adults and the elderly, more attention is given to the diagnosis of TBE in young patients. Solutions need to be identified to sustain sensitive, acceptable and affordable TBE surveillance in all districts of Poland. Also, higher attention should be given to the diagnosis of TBE in the elderly.

Phase 3 trial evaluating the immunogenicity, safety, and tolerability of manufacturing scale 13-valent pneumococcal conjugate vaccine.

13-valent pneumococcal conjugate vaccine (PCV13) includes polysaccharide conjugates from six pneumococcal serotypes in addition to those in the licensed 7-valent vaccine, thereby offering expanded protection against pneumococcal disease. The phase 3 trial reported here was conducted per a regulatory requirement to evaluate the immunogenicity, safety, and tolerability of two lots of the final PCV13 formulation that differed with respect to production scale but not the manufacturing process. The anti-pneumococcal polysaccharide immunogenicity and safety/tolerability were found to be similar between the two PCV13 vaccine lots.

Seropersistence of tick-borne encephalitis antibodies, safety and booster response to FSME-IMMUN 0.5 ml in adults aged 18-67 years.

A clinical study was carried out to evaluate the persistence of tick-borne encephalitis (TBE) antibodies 2 and 3 years after a primary vaccination series (three-dose regimen), and to assess the antibody response to a booster vaccination with FSME-IMMUN. Volunteers (N = 347, 18-67 years) who had received two doses of either FSME-IMMUN or Encepur adults and a third vaccination with FSME-IMMUN were enrolled. Seropositivity rates were assessed by ELISA and neutralization test (NT). After the primary series, seropositivity rates were 99.1% as determined by ELISA and 100% by NT, decreasing to 85% and 96.8% in the first two years and to 88.7% and 95.4% after 3 years. Following booster vaccination, 100% of subjects were seropositive. Age was the only variable with a significant influence on the probability of remaining TBE seropositive 2 or 3 years after the third vaccination. In subjects aged 18-50 years, the pre-booster seropositivity rate was higher (88.7% and 92.3% after 2 and 3 years, respectively) than in those aged 51-67 years (65.5% and 70.9% after 2 and 3 years, respectively). Adverse events after booster vaccination occurred with a low frequency and were predominantly mild. An annual TBE antibody decline rate of 0.58 (based on NT) was estimated to lead to antibody titer decrease from e.g., 260 to 45.6 after 3 years. To conclude, a booster vaccination with FSME-IMMUN, administered 3 years after primary vaccination, is well tolerated and induces a

Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with different neisseria meningitidis serogroup C conjugate vaccines.

BACKGROUND: Immunogenicity of the candidate 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed when coadministered with other routine pediatric vaccines including different Neisseria meningitidis serogroup C conjugate vaccines. METHODS: One thousand five hundred forty-eight healthy infants received, according to a balanced (1:1:1:1) randomization, either PHiD-CV coadministered with (1) DTPa-HBV-IPV/Hib (Infanrix hexa) and MenC-CRM (Meningitec), (2) DTPa-HBV-IPV/Hib and MenC-TT (NeisVac-C), or (3) DTPa-HBV-IPV (Infanrix penta/Pediarix) and Hib-MenC-TT (Menitorix); or 7vCRM (Prevenar/Prevnar) coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2-4-6 months of age with a booster dose at 11-18 months. Serotype-specific pneumococcal responses were measured by 22F-inhibition ELISA and opsonophagocytic (OPA) assay. RESULTS: In all 3 coadministration groups, PHiD-CV was immunogenic for each of the 10 pneumococcal vaccine serotypes as assessed by post-primary and post-booster antibody ELISA and OPA responses. When coadministered with DTPa-HBV-IPV, Hib, and MenC antigens, PHiD-CV responses after the third primary dose were within the same range as 7vCRM responses in terms of the percentage of subjects achieving an ELISA antibody concentration >or=0.2 microg/mL for all common vaccine serotypes (over 92% of subjects) except for serotype 6B (at least 87% of subjects). ELISA and OPA immune responses were also evident after the second primary doses of PHiD-CV or 7vCRM vaccine, although antibody levels were below that achieved after 3 primary doses, particularly for serotypes 6B and 23F. The kinetics of the immune responses from after the second dose to after the booster dose were similar for most of the serotypes in both PHiD-CV and 7vCRM groups. CONCLUSIONS: PHiD-CV was immunogenic when coadministered with other routine pediatric vaccines including MenC conjugate vaccines.

[Invasive pneumococcal disease in the Malopolska region of Poland, in the year 2002-2008. Is introduction of mass vaccination with conjugated pneumococcal vaccine justified?]. / Inwazyjna choroba pneumokokowa w malopolsce w latach 2000-2008. Czy wprowadzenie powszechnych szczepien z zastosowaniem skoniugowanej szczepionki pneumokokowej jest zasadne?

UNLABELLED: According to the WHO pneumococcal infections are the most common cause of morbidity and mortality in children. OBJECTIVES: The aim of the study was to establish the prevalence of pneumococcal isolates belonging to serotypes covered by 7-valent conjugated pneumococcal vaccine (7vPCV) isolated from invasive pneumococcal disease (IPD) in the Malopolska region of Poland in the years 2000-2008. MATERIAL AND METHODS: Retrospective clinical and microbiological analysis was performed on invasive, laboratory confirmed pneumococcal cases in the Malopolska region, between 2000-2008. RESULTS: During the study period there were 28 cases of IPD in children under 15 years of age in the Malopolska region. Most of the cases were diagnosed as meningitis, there were also cases of bacteraemic pneumonia and sepsis. The most common serotypes found during the study were: 14, 19F, 6B and 23F. Pneumococcal 7vPCV vaccine coverage among all cases was 78.0% and among children under 5 it was 94.0%. Nine isolates (32.1%) showed decreased susceptibility to penicillin. There were three fatal cases (CFR=10.7%) due to isolates of serotypes 19F, 23 F and 6B. In the six cases of meningitis, serious and lasting sequels were observed. All complicated and fatal cases as well as the cases caused by isolates with decreased susceptibility to penicillin were caused by serotypes covered by 7vPCV. CONCLUSIONS: The most serious cases of invasive pneumococcal infections in Malopolska region were caused by isolates of serotypes covered by 7-valent conjugated pneumococcal vaccine. The results of this study prove the advantages of wide usage of the pneumococcal vaccine in the Polish population children.

[Incidence of Haemophilus influenzae type b meningitis in children under 5 years from Malopolska region in the years 2003-2004--prospective study]. / Zapadalnosc na bakteryjne zapalenie opon mózgowo-rdzeniowych wywolane przez Haemophilus influenzae typu b, u dzieci w wieku do 5 lat, na terenie województwa malopolskiego w latach 2003-2004--badanie prospektywne.

AIM: the aim of the study was to establish the incidence of Haemophilus influenzae type b, Hib meningitis in the Malopolska province and to draw attention to the potential need for changing the rules of prophylaxis. MATERIAL AND METHODS: a prospective study was carried out among children from the Malopolska province under 5 years with meningitis who were hospitalized between 1 January 2003 and 31 December 2004. All paediatric and infectious diseases wards in 24 hospitals participated in the study. Diagnosis of Hib meningitis was based on symptoms of central nervous system inflammation together with (1) positive culture of Hib from cerebrospinal fluid and/or blood and/or (2) positive latex test identifying Hib in cerebrospinal fluid and/or blood and/or (3) detection of nucleic acid of Hib in cerebrospinal fluid and/or blood. RESULTS: in the studied period 27 cases of H. influenzae meningitis were observed (26 of type b and one case of type f). The incidence of Hib meningitis was as follows: 6.4/100000 children under 5 years, 7.4/100000 children under 4 years and 13.2/100000 children under 2 years. One 3.5-year-old girl died. CONCLUSIONS: the study shows a high incidence of Hib meningitis, similar to that in the neighboring EU countries before implementation of wide preventive measures. Cases of suspected vaccination failure should be carefully verified, with specific methods since the number of failures has been shown to be overrated.

[Paediatric Expert Group on the Immunization Programme. Activities focusing on effective immunization in Poland]. / Pediatryczny Zespól Ekspertów ds. Programu Szczepien Ochronnych. Dzialania na rzecz poprawy efektywnosci szczepien w Polsce.

INTRODUCTION: The Paediatric Expert Group on the Immunization Programme was established in January 2007. It is an independent advisory body to the Minister of Health. The Expert Group consists of paediatricians from various sub-specialities. Most of them are members of the Polish Society of Vaccinology (Table I). The Group started their activities informally in 2005. The first project concerned changes in immunization against tuberculosis and prophylaxis of measles, mumps and rubella. The project was fully implemented in 2006. The changes initiated three years ago, gradually implemented in the Immunization Programme are a result of wide cooperation with the Ministry of Health, Department of Health Policy Chief Sanitory Inspector, as well as the Institute of Tuberculosis and Pulmonary Diseases. The aim of the Paediatric Expert Group on the Immunization Programme is to present a unified policy in matters related to vaccination, leading to rapid changes in the prophylaxis of infective diseases which are still a threat to the life and health of children.

[Fever without a source. Diagnostic difficulties in invasive bacterial diseases in children observed on bacterial meningitis model]. / Goraczka nieznanego pochodzenia. Trudnosci w rozpoznawaniu inwazyjnego zakazenia bakteryjnego u dzieci na modelu zapalenia opon mózgowo-rdzeniowych.

Acute infection of the central nervous system is the most common cause of fever associated with signs and symptoms of CNS disease in children. Unfortunately most of these symptoms are non-specific. Specific signs appear very often late in the course of illness. 761 cases of bacterial meningitis in children above 1 month of life were investigated. Only 46.1% of cases were correctly diagnosed during the first doctor's exam. We found that correct diagnosis depends on time between the first symptoms of illness and the first physician visit. If this period of time is below 16 hours the risk of wrong diagnosis is very high due to lack of specific signs of CNS infection. In many cases only fever is present then.

Nitric oxide as a prognostic marker for neurological diseases.

The potential value of the nitric oxide (NO) level as a prognostic marker in human brain diseases is investigated. Cerebrospinal fluid (CSF) collected from neurological patients was examined for NO content using electron paramagnetic resonance (EPR) spectroscopy. In adult patients with meningitis, the level of NO was higher than that in other groups of brain disorders, such as brain traumas and brain tumors. Very high levels of NO in the CSF appeared to be correlated with a high incidence of fatal outcomes. In children with meningitis, it was possible to differentiate between viral and bacterial origin of the disease as evidenced by the EPR analysis of the CSF. The results indicated that NO levels in the CSF can be a useful prognostic marker in neurological diseases.