Clinical findings in relation to mortality in non-tuberculous mycobacterial infections: patients with Mycobacterium avium complex have better survival than patients with other mycobacteria.

We compared the clinical findings and survival in patients with Mycobacterium avium complex (MAC) and other non-tuberculous mycobacteria (NTM). A total of 167 adult non-human immunodeficiency virus (HIV) patients with at least one positive culture for NTM were included. Medical records were reviewed. The patients were categorised according to the 2007 American Thoracic Society (ATS) criteria. MAC comprised 59 % of all NTM findings. MAC patients were more often female (70 % vs. 34 %, p < 0.001) and had less fatal underlying diseases (23 % vs. 47 %, p = 0.001) as compared to other NTM patients. Symptoms compatible with NTM infection had lasted for less than a year in 34 % of MAC patients but in 54 % of other NTM patients (p = 0.037). Pulmonary MAC patients had a significantly lower risk of death compared to pulmonary other NTM (hazard ratio [HR] 0.50, 95 % confidence interval [CI] 0.33-0.77, p = 0.002) or subgroup of other slowly growing NTM (HR 0.55, 95 % CI 0.31-0.99, p = 0.048) or as rapidly growing NTM (HR 0.47, 95 % CI 0.25-0.87, p = 0.02). The median survival time was 13.0 years (95 % CI 5.9-20.1) for pulmonary MAC but 4.6 years (95 % CI 3.4-5.9) for pulmonary other NTM. Serious underlying diseases (HR 3.21, 95 % CI 2.05-5.01, p < 0.001) and age (HR 1.07, 95 % CI 1.04-1.09, p < 0.001) were the significant predictors of mortality and female sex was a predictor of survival (HR 0.38, 95 % CI 0.24-0.59, p < 0.001) in the multivariate analysis. Pulmonary MAC patients had better prognosis than pulmonary other NTM patients. The symptom onset suggests a fairly rapid disease course.

Foresight in medicine: current challenges with Haemophilus influenzae type b conjugate vaccines.

An effective vaccine to prevent invasive infections caused by Haemophilus influenzae type b (Hib) bacteria has been available for more than 20 years. Hib conjugate vaccine is safe, efficacious and easy to use, and its cost-benefit ratio is high both in industrialized as well as in developing countries. In spite of this, WHO estimates that every year approximately 8 million children contract life-threatening Haemophilus infections, especially meningitis or severe pneumonia. If we want to take seriously the Millenium Development Goal of reducing the mortality of under 5-year-old children by two-thirds before the year 2015, an effective means to contribute to this would be more efficient use of Hib vaccines.

The second Geneva Consensus: Recommendations for novel live TB vaccines.

Infection with Mycobacterium tuberculosis continues to be a major public health burden in most developing parts of the world and efforts to develop effective strategies for containing the disease remain a priority. It has long been evident that effective mass vaccination programmes are a cost effective and efficient approach to controlling communicable diseases in a public health setting and tuberculosis (TB) continues to be a major target. One approach with increasing acceptance is based upon on live mycobacterial vaccines, either as recombinant BCG or rationally attenuated M. tuberculosis, thus generating a new live TB vaccine. The Geneva Consensus published in March 2005 set out the opinion on priorities and requirements for developing live mycobacterial vaccines for Phase I trials. In the intervening period much progress has been made in both preclinical and clinical development of new TB vaccines and has provided the impetus for organising the second Geneva Consensus (held at WHO headquarters, April 2009) to discuss issues, including: i. Explore the regulatory requirements for live TB vaccines to enter Phase I trials, in particular those based on attenuated M. tuberculosis. Particular attention was paid to the characterisation and safety package likely to be required, including issues of attenuation, the presence of antibiotic resistance markers in live vaccines and the nature of any attenuated vaccine phenotype. ii. To identify the general criteria for further clinical development from Phase I through to Phase III. iii. Obtain a perspective of the regulatory landscape of developing countries where Phase II and III trials are to be held. iv. Review manufacturing considerations for live TB vaccines and relevance of the WHO and European Pharmacopeia guidelines and requirements for BCG vaccine. v. Consider requirements and associated issues related to the use of these new vaccines within an existing BCG vaccination programme.

A TL-based anthropomorphic benchmark for verifying 3-D dose distributions from external electron beams calculated by radiotherapy treatment planning systems.

Initial results are reported of a Polish-Finnish project to verify electron dose distributions calculated by treatment planning systems (TPSs), CadPlan v.6.3.2 and Theraplan v.3.5, which use different electron beam dose distribution algorithms. Treatment of gross tumour volumes representing lung and parotid cancer was simulated in an Alderson anthropomorphic phantom with thermoluminescent detectors (TLDs) (Li(2)B(4)O(7):Mn,Si) placed at selected measurement points inside its volume. The observed discrepancy between relative values of dose calculated and measured by TLDs at each of the measurement points and those calculated by the different TPSs at the same points is discussed.

Avidity and subclasses of IgG after immunization of infants with an 11-valent pneumococcal conjugate vaccine with or without aluminum adjuvant.

Finnish and Israeli infants received an 11-valent mixed-carrier pneumococcal conjugate vaccine with or without aluminum adjuvant at 2, 4, 6, and 12 months of age. The relative avidity of serotype 1-, 5-, 6B-, 14-, 19F-, and 23F-specific IgG antibodies in serum obtained at 7, 12, and 13 months of age was measured by EIA, using thiocyanate as a chaotropic agent. For all serotypes, except 14, avidity increased between the ages of 7 and 12 months. After boosting at 12 months, avidity further increased for all serotypes. The adjuvant improved antibody avidity against serotype 5. The IgG antibodies produced were mainly IgG1 subclass, although some infants also produced IgG2 after boosting. In conclusion, the immunization of infants with this 11-valent pneumococcal conjugate vaccine increased avidity of IgG, suggesting successful immunologic priming.

Booster response to the tetanus and diphtheria toxoid carriers of 11-valent pneumococcal conjugate vaccine in adults and toddlers.

We measured the tetanus and diphtheria antitoxin responses after administration of one dose of a mixed carrier (tetanus and diphtheria toxoids) 11-valent pneumococcal conjugate vaccine (PncDT) in 20 Finnish adults (mean age 26.1 years) and 20 Finnish (mean age 23.2 months) and 23 Israeli (mean age 18.5 months) toddlers. The vaccinees had previously been immunised with multiple doses of vaccines containing diphtheria and tetanus toxoids. A double-antigen ELISA was used to measure the antitoxin concentrations. PncDT induced significant booster responses in both adults and toddlers to the tetanus and the diphtheria carrier proteins. Thus, the effect on the tetanus and diphtheria immunity of multivalent conjugate vaccines containing tetanus and diphtheria toxoids as carriers needs to be evaluated before such vaccines are routinely implemented.

Serum and salivary anti-capsular antibodies in infants and children vaccinated with octavalent pneumococcal conjugate vaccines, PncD and PncT.

We studied the immunogenicity of two octavalent pneumococcal (Pnc) conjugate vaccines; Pnc polysaccharides (PS) of serotypes 3, 4, 6B, 9V, 14, 18C, 19F, and 23F were conjugated to diphtheria or tetanus toxoid (PncD and PncT, respectively). Fifty healthy Finnish infants were vaccinated at the ages of 2, 4, 6, and 15 months with either PncD or PncT. Serum IgG antibodies to the vaccine serotypes were analysed by enzyme-linked immunosorbent assay (EIA). All eight PSs induced a significant antibody response both after the primary series and after the booster. Response to PncD was higher for PSs 3, 9V, 14 and 18C and to PncT for serotype 4. Salivary IgA and IgG anti-Pnc antibodies were measured for serotypes 4, 6B, 9V, 14, 18C, and 19F. Mucosal antibodies were found rarely after the primary series but in a greater proportion after the booster. In conclusion, both vaccines were immunogenic.

Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae, evoked by pneumococcal conjugate vaccines, in infants.

Streptococcus pneumoniae serotypes 6B and 6A are important causes of infections, yet only 6B is included in current vaccines. It is, therefore, crucial to evaluate whether functional antibodies are produced against both types after vaccination. Concentration and opsonophagocytic activity (OPA) of antibodies to 6B and 6A polysaccharides were determined in serum samples from infants immunized with 3 different pneumococcal conjugate vaccines containing serotype 6B. In all vaccine groups, a significant correlation was found between the anti-6B and -6A antibody concentration and OPA. However, OPA to the vaccine serotype was detectable more commonly than OPA to the cross-reactive type. Furthermore, 5%-15% of the serum samples showed high OPA against the 6B but not the 6A strain. On average, 2-6 times more anti-6B antibodies were needed for 50% opsonophagocytic killing of the type 6A than the type 6B strain. Although pneumococcal type 6B conjugate vaccines elicit antibodies that cross-react with type 6A, not all anti-6B antibodies are functionally cross-reactive.

Tolerability and immunogenicity of an eleven-valent pneumococcal conjugate vaccine in healthy toddlers.

BACKGROUND: A need to increase the serotype coverage of pneumococcal conjugate vaccines exists. The use of a single carrier protein may cause overload of the carrier and decrease the immune response by not providing sufficient carrier-specific T helper cell support. A vaccine composed of a mixture of tetanus- and diphtheria-conjugated polysaccharides (PS) is a potential solution to this issue. OBJECTIVES: The aim of this study was to assess the tolerability and immunogenicity in healthy toddlers of an 11-valent pneumococcal conjugate vaccine that uses both tetanus and diphtheria toxoids as carriers. We explored the effect of an aluminum adjuvant on safety and immunogenicity by comparing the vaccine with and without adjuvant. METHODS: Twenty Finnish and 23 Israeli toddlers received the conjugate vaccine with or without aluminum adjuvant. Safety data were recorded for 5 days after vaccination. Sera were obtained before and 28 days after the immunization. IgG antibodies to the 11 vaccine-type PSs were determined by enzyme immunoassay. RESULTS: No serious adverse events occurred. The formulation with the adjuvant tended to induce fewer local but more systemic reactions than the non-adjuvant-containing formulation. Both vaccine formulations induced significant IgG increases for the vaccine-specific PSs. Types 3 and 7F were the most immunogenic; antibodies reached a concentration of 1 microg/ml in all individuals. Conjugates of types 6B, 14 and 23F were the weakest immunogens; antibodies reached the concentration of 1 microg/ml in 36, 27 and 32% of the individuals in the nonadjuvant group and in 53, 38 and 53% in the adjuvant group, respectively. CONCLUSIONS: An 11-valent mixed carrier pneumococcal conjugate vaccine is safe and immunogenic in toddlers. The use of an adjuvant do not seem to offer any significant benefit.

Activation of cell-mediated immunity following immunization with pneumococcal conjugate or polysaccharide vaccine.

The immunogenicity of pneumococcal polysaccharide (PS) vaccines can be improved by conjugating PS to a polypeptide carrier that alters the immune response from T-cell independent to T-cell dependent. In order to study the influence of PS or protein antigens as inducers of cell-mediated responses, 30 adults were immunized with a 23-valent pneumococcal PS vaccine (PS-group) or an 11-valent, tetanus and diphtheria mixed carrier conjugate vaccine with (adjuvant group) or without aluminium adjuvant (nonadjuvant group). Cell-mediated responses were analyzed on days 0, 14 and 28 after vaccination by measuring lymphocyte proliferation and production of interferon (IFN)-gamma (Th1 marker) or interleukin (IL)-4 and IL-5 (Th2 markers) cytokines after in vitro stimulation with the PS and protein components of the vaccines. Tetanus and diphtheria proteins were the main inducers of lymphocyte proliferative and cytokine responses. Conjugate vaccines induced increased proliferative responses to the tetanus or diphtheria protein, but not to the PS components. In the PS-group, a lymphocyte proliferative response to protein antigens was not observed. The number of antigen-specific and nonspecific IFN-gamma-secreting cells detected by ELISPOT tended to increase in all three groups in response to protein or to PS antigen. No major differences were detected in the number of IL-4-secreting cells measured 14 and 28 days after vaccination. The conjugate vaccine with adjuvant was associated with Th2 type of activation indicated by an enhanced IL-5 secretion in response to the tetanus and diphtheria protein antigens.

Age- and dose-interval-dependent antibody responses to inactivated poliovirus vaccine.

Antibody responses were studied in five groups of children immunized with different three-dose schedules of inactivated poliovirus vaccine (IPV). The age of the child at the first dose (1-4 months) and the interval between the first and second doses (2-4 months) influenced the initial responses in a serotype-dependent manner. All the groups attained sufficient antibody level after three doses but the third dose given at 18 months resulted in higher persisting antibody levels than that given at 12 months. The highest persisting antibody titers against PV1 and PV2 (but not against PV3) at the age of 3 years were measured in the control group immunized with the current schedule (P < 0.001) in which the first dose is given at 6 months. The level of maternal antibodies present at the time of the first dose correlated negatively with the antibody titers as late as at 3 years of age. It is concluded that three doses of IPV given in widely variable schedules may result in satisfactory immune responses in children but, for optimal results, very early onset of the program and short dosage intervals should be avoided.

Tetravalent meningococcal polysaccharide vaccine is immunogenic in adult allogeneic BMT recipients.

Forty-four adult BMT recipients transplanted from an HLA-identical sibling donor were randomized to receive meningococcal polysaccharide (Men PS) vaccine either 8 (early group; 22 patients) or 20 (late group; 22 patients) months after BMT. The geometric mean concentrations (GMC) of antibodies to serogroup A Neisseria meningitidis (Men A) and serogroup C Neisseria meningitidis (Men C), determined by an EIA method, decreased during the first 6 months after BMT but remained at a stable level thereafter. Before vaccination the GMCs of anti-Men A were 1.53 microg/ml and 1.61 microg/ml, but 1 month after vaccination they were significantly higher, 3.46 microg/ml and 6.39 microg/ml, in the early and late groups. The GMCs of anti-Men C increased from 0.37 microg/ml and 0.44 microg/ml before vaccination to 3.31 microg/ml and 4.62 microg/ml at 1 month after vaccination in the early and late groups, respectively. By 6 months after vaccination the GMCs of Men antibodies had decreased to levels of about 50% of those measured at 1 month after vaccination. Two-fold responses to Men A PS were seen in 52% and 74% and to Men C PS in 76% and 89% of the BMT recipients in the early and late groups, respectively. Chronic GVHD had no influence on the vaccination response. In the present study, Men PS vaccine induced good and equal antibody responses to Men A and Men C PSs in allogeneic BMT recipients regardless of timing after BMT. Vaccination against Neisseria meningitidis should be considered, especially in the event of travelling or military service > or = 8 months after BMT.

Tolerability and immunogenicity of an 11-valent pneumococcal conjugate vaccine in adults.

We studied the safety and immunogenicity in healthy adults of an 11-valent pneumococcal conjugate vaccine. Capsular polysaccharides (PS) of serotypes 1, 4, 5, 7F, 9V, 19F and 23F were conjugated to tetanus toxoid, and of serotypes 3, 6B, 14 and 18C to diphtheria toxoid. Ten subjects received the conjugate vaccine with and the other ten subjects without aluminium hydroxide adjuvant. The reference vaccine was a marketed 23-valent PS vaccine. Safety data were recorded over 5 days after the immunisation. IgG antibody concentrations, avidity and subclass distribution were measured by EIA. The conjugate without aluminium induced more local adverse effects than the conjugate with aluminium or PS vaccine. All vaccines evoked significant antibody increases to all vaccine specific antigens. Both conjugate vaccines induced antibodies mainly of IgG(2) subclass, and adjuvanted conjugate vaccine induced IgG antibodies with increased avidity. This first administration, to man, of a mixed protein carrier 11-valent pneumococcal conjugate vaccine demonstrated its ability to induce an immune response without significant adverse effects, enabling further study on its use in paediatric populations.

Efficacy of a pneumococcal conjugate vaccine against acute otitis media.

BACKGROUND: Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. METHODS: We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. RESULTS: Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously. There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age. The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent (95 percent confidence interval, -4 to 16 percent [the negative number indicates a possible increase in the number of episodes]), culture-confirmed pneumococcal episodes by 34 percent (95 percent confidence interval, 21 to 45 percent), and the number of episodes due to the serotypes contained in the vaccine by 57 percent (95 percent confidence interval, 44 to 67 percent). The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent, whereas the number of episodes due to all other serotypes increased by 33 percent. CONCLUSIONS: The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine.

Serum and salivary anti-capsular antibodies in infants and children immunized with the heptavalent pneumococcal conjugate vaccine.

AIM: To study the ability of seven-valent experimental pneumococcal polysaccharide CRM197 protein conjugate vaccine (PncCRM) to induce antibodies in serum and saliva of infants. METHODS: Sixty Finnish infants received Pnc-CRM vaccine at 2, 4 and 6 months of age and were boosted with PncCRM (n = 30) or pneumococcal polysaccharide (PncPS) (n = 29) vaccine at the age of 15 months. Serum IgG antibody concentrations to vaccine serotypes 4, 6B, 9V, 14, 18C, 19F and 23F were measured by enzyme immunoassay at 2, 4, 6, 7, 15, 16 and 24 months of age. Salivary IgA, IgG and secretory Ig antibody titers at 7 and 16 months of ages were analyzed by enzyme immunoassay against the same serotypes, except 23F. RESULTS: PncCRM induced systemic immune responses and immunologic memory. At 7 months of age 69 to 100% of children, depending on the serotype, had serum IgG antibody concentrations exceeding the value of 1.0 microg/ml. At 15 months the titers were still higher than before the vaccinations. Booster doses of either PncPS or PncCRM induced an increase in antibody concentrations. The titers were still elevated at 24 months of age. Salivary IgA and IgG antibodies were found rarely at 7 months of age, but in up to 80% of samples taken at 16 months of age, depending on the serotype and nature of the booster vaccine. Salivary IgG correlated with IgG in serum, supporting the theory that salivary IgG is derived from serum. Salivary IgA and secretory Ig correlated positively, which indicates that IgA was locally produced. CONCLUSIONS: PncCRM induces both systemic and mucosal immune responses in infants.

Influence of codon usage on the immunogenicity of a DNA vaccine against tetanus.

Two related DNA vaccine vector plasmids, harbouring either wild-type (pcDNA3/ntetC) or synthetic codon optimised (pcDNA3/stetC) DNA encoding fragment C (TetC) of tetanus toxin were constructed. COS-7 cells transformed with pcDNA3/stetC reproducibly expressed higher levels of TetC than similar cells transformed with pcDNA3/ntetC. BALB/c mice immunised intramuscularly with pcDNA3/stetC produced significantly higher levels of anti-TetC antibodies in their serum in the weeks following vaccination compared to mice immunised with pcDNA3/ntetC, even when differences in the CpG content between the two sequences were controlled for using non-expressing DNA.

Clara-cell secretory protein in preterm infants' tracheal aspirates correlates with maturity and increases in infection.

Clara-cell secretory protein (CCSP), produced primarily by Clara cells in the conducting airways, is the most abundant soluble protein in pulmonary lavage fluid. CCSP is thought to be an immunosuppressive or anti-inflammatory protein with protective functions in the respiratory tract against exaggerated inflammatory reactions. CCSP was measured in 98 tracheoalveolar fluid (TAF) samples from 24 preterm infants (gestational age, 27.9 +/- 2.3 weeks, birth weight 1,020 +/- 305 g) with respiratory distress syndrome during the first 2 postnatal weeks. The ratio of urea-N in serum and in TAF was used to correct for dilution of TAF samples. Concentration of CCSP in TAF when corrected for dilution increased from 3.6 +/- 11 microg/mL on day 1 to 29.6 +/- 6.9 microg/mL on day 14. CCSP correlated with gestational age. A negative correlation was found between CCSP and inspiratory oxygen concentration, and a positive correlation between CCSP and both arterial pH and base excess during the first 2 postnatal weeks. Infants with clinical and laboratory signs of infection had higher CCSP than noninfected infants, and a negative correlation was found between CCSP and leukocyte count during the first 2 postnatal weeks (all P < 0.05). We suggest that pulmonary CCSP correlates with both gestational and postnatal age, and increases in response to infection in infants with respiratory distress during the early postnatal period.

Human immune response to streptococcal inhibitor of complement, a serotype M1 group A Streptococcus extracellular protein involved in epidemics.

Streptococcal inhibitor of complement (Sic) is a highly polymorphic extracellular protein made by serotype M1 group A Streptococcus strains that contributes to bacterial persistence in the mammalian upper respiratory tract. New variants of the Sic protein arise very rapidly by positive selection in human populations during M1 epidemics. The human antibody response to Sic was analyzed. Of 636 persons living in diverse localities, 43% had anti-Sic serum antibodies, but only 16.4% had anti-M1 protein serum antibody. Anti-Sic antibody was also present in nasal wash specimens in high frequency. Linear B cell epitope mapping showed that serum antibodies recognized epitopes located in structurally variable regions of Sic and the amino terminal hypervariable region of the M1 protein. Phage display analyses confirmed that the polymorphic regions of Sic are primary targets of host antibodies. These results support the hypothesis that selection of Sic variants occurs on mucosal surfaces by a mechanism that involves acquired host antibody.

Bacteremic urinary tract infection in children.

OBJECTIVE: To assess the clinical characteristics of bacteremic urinary tract infection (UTI) in children. DESIGN: Clinical data of Finnish children with bacteremic UTI (n = 134) from 1985 to 1994 were analyzed. Their symptoms, laboratory and imaging findings were compared with those of age- and sex-matched patients hospitalized for blood culture negative UTI. RESULTS: Generally, no major differences were seen in clinical findings between bacteremic and nonbacteremic patients. Bacteremic children had more frequent feeding problems (P = 0.02), and children > or =12 months of age tended more often to have abdominal pain and vomiting than did nonbacteremic patients. Fever was the major initial symptom in both study groups, but no significant difference occurred in the mean highest temperature or in the mean of duration of fever before admission to the hospital. The mean concentration of serum C-reactive protein on admission was significantly higher in bacteremic patients (116 vs. 76 mg/l; P < 0.01). After onset of antimicrobial treatment fever lasted significantly longer in bacteremic patients than in control patients (means, 2.3 vs. 1.1 days; P < 0.01). Anatomic or functional abnormalities in the urinary tract were detected in 51% vs. 46%, respectively. Obstruction of the urinary tract (9% vs. 1%, P < 0.01) and Grade 3 to 5 vesicoureteral reflux (30% vs. 16%, P = 0.02) were significantly more frequent in bacteremic patients with UTI. Obstruction or vesicoureteral reflux was found in 46% of children with bacteremic UTI caused by Escherichia coli vs. 89% of children with non-E. coli infection (P < 0.01). CONCLUSIONS: Clinical symptoms do not significantly distinguish bacteremic from nonbacteremic children with UTI. Outcome of bacteremic UTI was comparable with that of nonbacteremic UTI. Bacteremic children, especially those with non-E. coli UTI, more often had anatomical or functional abnormalities in the urinary tract.