Antibody response to capsular polysaccharide vaccine of Streptococcus pneumoniae in patients with nephrotic syndrome.

Twenty-three normal subjects and 19 patients with nephrotic syndrome were vaccinated with tridecavalent pneumococcal capsular polysaccharide vaccine of Streptococcus pneumoniae. The antibody response of the nephrotic patients to pneumococcal capsular antigens was equal to that of the control subjects. These findings indicate that patients with nephrotic syndrome, despite hypogammaglobulinemia, can mount an adequate antibody response to pneumococcal polysaccharides and that there is no evidence of suppressor thymus-derived (T) cells of dysfunctioning bone marrow-derived (B) cells in these patients.     

Attachment of capsular polysaccharide to the cell wall of Streptococcus pneumoniae type 2 is required for invasive disease

The capacity of Streptococcus pneumoniae to produce capsular polysaccharide (CPS) is essential for virulence. The CPS biosynthesis proteins CpsB, CpsC, and CpsD function to regulate CPS production via tyrosine phosphorylation of CpsD. This mechanism of regulating CPS production is important for enabling S. pneumoniae to cause invasive disease. Here, we identify mutations affecting the attachment of CPS to the cell wall. These mutations were located in cpsC, such that CpsC functioned independently from CpsD tyrosine phosphorylation. These mutants produced WT levels of CPS, but were unable to cause bacteremia in mice after intranasal challenge. This finding suggests that cell-wall attachment of CPS is essential for invasive pneumococcal disease; production of WT levels of CPS alone is not sufficient. We also show that cpsB mutants, which lack the phosphotyrosine-protein phosphatase, produced less CPS than the WT strain, but attached substantially more CPS to their cell wall. Thus, the phosphorylated form of CpsD promotes attachment of CPS to the cell wall.     

Clinical features of patients with recurrent invasive Streptococcus pneumoniae disease

IntroductionInvasive Streptococcus pneumoniae (pneumococcal) disease (IPD) carries a high risk of death, approximately 15% to 20% in pneumonia, 40% in meningitis and 10% to 15% in septicemia. The occurrence of 2 or more IPD (recurrent) in the same individual is uncommon. The authors investigated the clinical features of patients with recurrent IPD to assess whether they possessed risk factors that increased their likelihood of recurrent IPD.MethodsBetween 1983 and 2010, the authors identified 27 patients with recurrent IPD during inpatient surveillance of 889 patients with IPD in Huntington, WV, by recovery of pneumococci from otherwise sterile sites. Serotype/serogroup (ST/SG) was determined by capsular swelling and the penicillin MIC by E-strip. Clinical data were abstracted from hospital charts.ResultsSixteen (59%) of 27 patients were 65 years and older at first IPD, males predominated (67%), two-thirds had pneumonia and 21 (78%) had the same clinical diagnosis at both IPD. Four (80%) of 5 patients with the same ST experienced their second IPD 1 to 6 months apart, unlike most patients with discordant ST/SGs (P = 0.047). Eighty-four percent of ST/SGs were included in the 23-valent pneumococcal vaccine and occurred as often during the first and second IPD. Twenty (77%) of 26 adults suffered from comorbid diseases placing them at high risk of IPD, including multiple myeloma, HIV/AIDS, neoplasia of hematological origin and sickle cell disease.conclusionRecurrent IPD occurred uncommonly. Comorbid conditions including multiple myeloma and immunosuppressive/immunodeficient conditions, chronic alcoholism and splenectomy represented unique risk factors for recurrent IPD but did not predict recurrences.     

Streptococcus pneumoniae colonisation: the key to pneumococcal disease

Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.     

Experimental otitis media in chinchillas following nasal colonization with type 7F Streptococcus pneumoniae: prevention after vaccination with pneumococcal capsular polysaccharide.

Chinchillas were colonized intranasally with type 7F Streptococcus pneumoniae, and pneumococcal otitis media developed in greater than 50% of the animals during the first week after negative middle ear pressure (-25 mm Hg) was briefly applied. Twenty-three chinchillas were vaccinated subcutaneously with the capsular polysaccharde of type 7F S. pneumoniae to determine whether vaccination could prevent the development of experimental otitis media. Following vaccination, 14 animals seroconverted with at least a twofold rise in serum antibody concentration; nine animals that were vaccinated did not seroconvert. All of 23 vaccinated animals and 42 of 42 unvaccinated control animals became colonized after intranasal inoculation with pneumococci. Only one (7%) of the vaccinated seroconverting animals developed pneumococcal otitis media, whereas 26 (62%) of the control animals developed middle ear infection with type 7F pneumococci. Four (44%) of nine vaccinated nonseroconverting animals developed pneumococcal otitis media. Protection was associated with high levels of serum antibody prior to intranasal inoculation. Higher antibody levels were found in sterile middle ear effusions than in S. pneumoniae-infected effusions. Vaccination with type 7F pneumococcal capsular polysaccharide significantly reduced the incidence of pneumococcal otitis media following intranasal inoculation of type 7F S. pneumoniae in chinchillas.     

Serotype distribution and penicillin-binding protein genes of Streptococcus pneumoniae in children with invasive pneumococcal infection

Between August 1998 and July 2005, we studied the serotypes and mutation of penicillin-binding protein (PBP) genes of 46 strains of Streptococcus pneumoniae isolated from children with invasive pneumococcal infection in Hokkaido. The clinical diagnosis was pneumonia in 16 cases, occult bacteremia in 15, meningitis in 8, upper respiratory infection in 6, and arthritis in 1. Patients ranged in age from 2 months to 9 years old. Prevalent serotypes were 6B (39.1%), 23F (17.4%) 6A (8.7%), and 19F (8.7%). The serotype coverage rate by the 7-valent pneumococcal vaccine was greater than 70% in children. Mutation of 3 genes (Penicillin-binding S. pneumoniae, PRSP) was detected in 18 isolates, mutation of 10 genes (pbp1a and pbp2x, or pbp2x and pbp2b) in 2, and of pbp2x alone in 15. PRSP was found in serotypes 6A, 6B, and 23F, and the rate of PRSP in 6A, 6B, and 23F was 75.0%, 62.5%, and 55.6%, respectively.     

Modification of otitis media following vaccination with the capsular polysaccharide of Streptococcus pneumoniae in chinchillas.

An animal model was used to determine whether vaccination with the capsular polysaccharide of Streptococcus pneumoniae could alter the development of experimental otitis media induced by the same type of S. pneumoniae as the vaccine. Following vaccination with the capsular polysaccharide of S. pneumoniae type 7, 36(63%) of 57 chinchillas seroconverted with at least a 100% increase in concentration of antibody in serum which remained elevated for at least six weeks. The middle ears of 23 chinchillas that were vaccinated and seroconverted, 13 that were vaccinated and did not seroconvert, and 47 that were not vaccinated were inoculated with S. pneumoniae type 7. Vaccinated animals that seroconverted developed otitis media as readily as nonseroconverting and unvaccinated animals but had fewer pneumococci in their middle ears, a lower incidence of bacteremia, and lower mortality rates during the first week after inoculation of bacteria. Animals that did not seroconvert showed no evidence of modification of their middle ear infections. These results indicate that type 7 pneumococcal capsular polysaccharide vaccine is antigenic for the chinchilla and modifies experimental otitis media due to type 7 S. pneumoniae.     

Immune response to pneumococcal conjugate and polysaccharide vaccines in otitis-prone and otitis-free children.

We compared responses to pneumococcal conjugate and polysaccharide vaccines in 48 otitis-free and 64 otitis-prone children. Pre- and postimmunization concentrations of antibodies to pneumococcal serotypes 6B, 14, 19F, and 23F were measured by enzyme-linked immunosorbent assay. Postimmunization mean concentrations of antibodies to all four serotypes were significantly higher for children receiving conjugate vaccine than for those receiving polysaccharide vaccine; the difference in responses was primarily due to a better response to conjugate vaccine in the otitis-prone group. Significantly higher postimmunization concentrations of antibodies to all four serotypes and to one of the four serotypes were found in otitis-prone children and otitis-free children who received conjugate vaccine, respectively. Pneumococcal conjugate vaccine has the potential to reduce the incidence of disease due to vaccine serotypes, even among children with recurrent otitis media.     

Antibody to capsular polysaccharide of Streptococcus pneumoniae at the time of hospital admission for Pneumococcal pneumonia

IgG to capsular polysaccharide (CPS) of Streptococcus pneumoniae is thought to provide the greatest degree of protection against pneumococcal disease. Serum obtained at hospital admission from 14 (27%) of 51 patients with bacteremic pneumococcal pneumonia and 11 (37%) of 30 with nonbacteremic pneumococcal pneumonia contained IgG to CPS of the infecting serotype; these percentages are similar to the prevalence of IgG to CPS in a control population. However, when compared with antibody from healthy adults, this IgG had far less capacity to opsonize the infecting pneumococcal serotype for phagocytosis in vitro by normal human polymorphonuclear leukocytes or to protect mice against experimental challenge. Failure to opsonize correlated closely with failure to protect mice, and each of these parameters correlated well with poor avidity for CPS. Future vaccine studies may need to examine the functional capacity of antibodies as a surrogate for infection, in addition to measuring their concentration in serum.     

Serotypes of respiratory isolates of Streptococcus pneumoniae compared with the capsular types included in the current pneumococcal vaccine

The serotypes of 474 clinically significant Streptococcus pneumoniae respiratory isolates collected during a national surveillance study in 1987-1988 were compared to the capsular types included in the 23-valent pneumococcal polysaccharide vaccine licensed for use in the United States. Overall, 355 isolates (74.9%) belonged to types included in the current vaccine, while another 65 (13.7%) were types serologically related to vaccine types and likely to be protective by virtue of cross-reactivity. Relatively few isolates (9.1%) belonged to nonvaccine serotypes, and only 2.3% were nontypable. The mucoid serotype 3 was most frequent (13.1% of total), followed by 19F (9.3%), 23F (7.4%), 6B and 14 (5.7% each), and 4 and 6A (5.5% each). The most frequent type not included in the vaccine was type 16 (2.1% of all isolates). Thus, nearly 89% of respiratory isolates included in this study were encompassed within the antigenic spectrum of the currently marketed pneumococcal vaccine.     

Validation of urinary antigen test for Streptococcus pneumoniae in patients with pneumococcal pneumonia

The study was undertaken to prospectively evaluate a Streptococcus pneumoniae urinary antigen test for diagnosis of pneumococcal pneumonia among patient and control groups between 2004 and 2006. Microbiological analysis for these patients included Gram staining for sputum, sputum and blood culture. Nonconcentrated urine samples were tested using an immunochromatographic assay, the NOW S.pneumoniae antigen test. The urinary antigen test was positive in 9 (15.3%) of 59 patients enrolled in the study and in 8 (73%) of 11 patients with pneumococcal pneumonia confirmed by conventional methods. The test revealed a sensitivity of 72.7% and a specificity of 97.6% with conventional microbiological criteria used as the reference standard. The positive predictive value was 88.9% and the negative predictive value was 93%. We concluded that the urinary antigen test can supplement conventional microbiological tests in the diagnosis of pneumococcal pneumonia.     

Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine.

The Centers for Disease Control recommends that, because of a greatly increased susceptibility to pneumococcal infection, all persons infected with human immunodeficiency virus (HIV) receive pneumococcal vaccine. Using an ELISA specific for antibody to capsular polysaccharide, a postvaccination antibody was evaluated to five commonly infecting serotypes of Streptococcus pneumoniae. Thirty-nine HIV-infected persons with less than or equal to 500 CD4 cells exhibited significantly fewer responses than did healthy controls; overall, only 46 (24%) of 195 possible responses were positive compared with 45 (75%) of 60 in 12 HIV-infected subjects with greater than 500 CD4 cells and 92 (74%) of 125 in 25 healthy controls (P less than .001). Subjects with less than or equal to 500 CD4 cells responded to a mean of 1.1 antigens versus a mean of 3.8 and 3.7 in those with greater than 500 CD4 cells and controls, respectively (P less than .001). There were no differences between responses in those with less than 200 and those with 200-500 CD4 cells. Within groups stratified by CD4 cell counts, further stratification by clinical status did not reveal significant differences. Since asymptomatic HIV-infected persons with less than 500 CD4 cells show abnormal responses, pneumococcal vaccine should be given when HIV infection is first detected.     

Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab

Abstract

Objectives. To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy.

Methods. Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination.

Results. In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer < 40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed four-fold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients.

Conclusion. Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.     

Epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae associated with invasive pneumococcal disease in British Columbia - A call to strengthen public health pneumococcal immunization programs.

BACKGROUND: This study examined the epidemiology, antibiotic susceptibility and serotype distribution of Streptococcus pneumoniae associated with invasive pneumococcal disease (IPD) in British Columbia. METHODS: Six hospitals and one private laboratory network participated in a prospective, sentinel laboratory based surveillance study of IPD, between October 1999 and October 2000. At each site, S pneumoniae isolates were collected and epidemiological data were gathered using a structured questionnaire, for all cases of IPD meeting the study case definition. Isolates were serotyped and tested for antimicrobial susceptibility. Bivariate associations were analyzed and multivariate logistic regression was used to identify independent risk factors associated with hospitalization or death. RESULTS: One hundred three reports and isolates were collected. Seventy-nine per cent of cases were community-acquired, 64% required hospitalization and 5% died. Cases with one or more assessed risk factor for IPD and of female sex were independent variables associated with hospitalization or death. One-third of isolates had reduced penicillin susceptibility and 96% of these represented serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV-23). Overall, 89% of serotypes identified are included in the PPV-23 vaccine and 88% of isolates from children under five years of age are found in the 7-valent pneumococcal conjugate vaccine (PCV-7). Forty-one per cent of cases qualified for publicly funded pneumococcal vaccine and 34% of eligible persons were vaccinated. CONCLUSIONS: Overall, pneumococcal serotypes associated with IPD in this study closely matched serotypes included in PPV-23 products currently licensed in Canada. Most serotypes associated with IPD in children under five years of age are included in a recently licenced PCV-7. One third of isolates demonstrated reduced penicillin susceptibility, most involving serotypes included in PPV-23. Effective delivery of current public health immunization programs using PPV-23 and extending protection to infants and young children using the PCV-7 will prevent many cases of IPD.     

A prospective study on antibody response to repeated vaccinations with pneumococcal capsular polysaccharide in splenectomized individuals with special reference to Hodgkin's lymphoma

BACKGROUND: Splenectomy is accompanied by a life-long risk of overwhelming postsplenectomy infection (OPSI), mainly caused by polysaccharide (PS) encapsulated bacteria such as Streptococcus pneumoniae. Despite extensive prophylactic efforts the mortality and morbidity rates remain high. The present study was based on a strategy with a predefined vaccination algorithm including repeated 23-valent pneumococcal vaccinations and monitoring of pneumococcal antibody levels. The antibody levels of splenectomized Hodgkin's lymphoma (HL) patients were compared with those patients splenectomized due to immune-mediated cytopenias [autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP)] and also individuals who were splenectomized because of trauma (TRAUMA). METHODS: A total of 311 splenectomized individuals were included in this prospective study (208 HL; 15 AIHA; 60 ITP; 28 TRAUMA). Depending on their individual anti-PS antibody levels measured by enzyme-linked immunosorbent assay technique the patients were revaccinated with 23-valent pneumococcal PS vaccine up to four times in accordance with the predefined algorithm. For each vaccination occasion, serum was collected at vaccination, after 1 month +/- 2 weeks (peak), and after 1 year +/- 6 months (follow-up). Patient files, a national population-based database, and microbiological databases were checked for 124 HL patients to identify OPSI. RESULTS: A significant response was recorded on primary vaccination as well as on two revaccination occasions for HL, AIHA/ITP, as well as TRAUMA patients. None of the variables age, gender, or time elapsed between splenectomy and first pneumococcal vaccination was found to be associated with mean PS antibody levels at prevaccination, peak or follow-up. No severe adverse events were reported. Amongst 124 clinically monitored HL patients, 10 OPSI were recorded in seven patients during the study period. One of these patients, a middle-aged female, died as a result of fulminant pneumococcal bacteraemia, which was her third OPSI during a 7-year period. CONCLUSIONS: A significant response to pneumococcal PS vaccination was found in all three groups (HL, AIHA/ITP and TRAUMA) of splenectomized patients. Importantly, both primary and repeated vaccinations were safe. Until further knowledge is gained regarding the protective concentration of serotype-specific antibody concentrations we believe that the value of vaccination and frequent revaccination (every 1-5 years) in combination with education of patients and health care professionals and clinical monitoring is beneficial for these patients at risk for OPSI.     

Capsular polysaccharide antibodies after pneumococcal polysaccharide vaccination in patients with chronic respiratory disease]

We investigated the antibody response to a 23-valent pneumococcal polysaccharide vaccine (23PSV), in 151 patients (average age: 70 years old) with chronic respiratory disease. Serotype-specific IgG antibodies to 4 pneumococcal capsular polysaccharides (6B, 14, 19F, and 23F) were analyzed by ELISA before, and one month after, 23PSV vaccination in all patients. Patients showed a significant increase in specific IgG levels to Streptococcus pneumoniae after 23PSV vaccination (5.5 times-20.9 times). Even patients aged over 80, patients with respiratory failure, and patients receiving corticosteroid therapy developed a significant immunologic response to 23PSV. Local pain or induration occurred in 9.1-14.3% and fatigue or chills occurred in 0.7-6.5% of patients. All adverse reactions disappeared in 2 or 3 days and there was no severe adverse events. Further studies are needed to confirm the exact protective antibody level and to examine the decline of antibody level after vaccination.     

Administration of protein-conjugate pneumococcal vaccine to patients who have invasive disease after splenectomy despite their having received 23-valent pneumococcal polysaccharide vaccine

Patients who undergo splenectomy are at greatly increased risk for overwhelming pneumococcal bacteremia and death. Twenty-three-valent pneumococcal polysaccharide vaccine (PPV-23), which contains capsular polysaccharides (PSs) from 23 common serotypes of Streptococcus pneumoniae, is strongly recommended for such patients. The capacity to respond to PPV-23 by producing immunoglobulin (Ig) G is genetically regulated. Some proportion of adults do not respond and, despite postsplenectomy administration of PPV-23, may remain susceptible to recurrent pneumococcal sepsis. Here, we describe 2 patients who had recurring pneumococcal bacteremia after undergoing splenectomy despite having received numerous doses of PPV-23. Heptavalent protein-conjugate pneumococcal vaccine (PCPV-7) was then administered, and it induced high levels of IgG to all 7 PSs; in one of the patients, functional activity against 5 of the 7 PSs was demonstrable, both in vitro and in vivo. Recurrent pneumococcal bacteremia in patients who have undergone splenectomy may indicate a genetically regulated failure to respond to PPV-23; PCPV-7 may stimulate production of IgG to PSs in such patients.     

Prevention of pneumococcal bacteremia by immunization with type 6 pneumococcal capsular polysaccharide vaccine in splenectomized rats

Postsplenectomy sepsis is well recognized and prophylactic vaccination with pneumococcal polysaccharide is recommended. However, the efficacy of vaccination with the polysaccharide in splenectomized individuals is not clear. The effect of type 6 pneumococcal polysaccharide vaccine on the clearance of pneumococci from the bloodstream and lung was studied in splenectomized rats as was survival after intravenous challenge with Streptococcus pneumoniae, serum opsonic activity, and specific antibody titer by ELISA. Rats immunized with type 6 pneumococcal polysaccharide vaccine had significantly increased survival (P less than .05) and clearance of pneumococci from the bloodstream and lung (P less than .05) after intravenous challenge with S. pneumoniae, significantly higher serum opsonic activity (P less than .02), and increased specific IgG and IgM antibody titer to the type 6 polysaccharide compared with controls treated with saline. There was close correlation between IgG antibody titer to type 6 polysaccharide and opsonic activity (r = .95). These results suggest that pneumococcal polysaccharide vaccine is effective for preventing pneumococcal bacteremia in splenectomized hosts.     

Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease

BACKGROUND: Use of heptavalent protein-polysaccharide pneumococcal conjugate vaccine (PCV7) has been associated with decreases in PCV7-type invasive pneumococcal disease and nasopharyngeal (NP) carriage in children. Vaccine use has also indirectly decreased the rate of invasive disease in adults, presumably through decreased transmission of pneumococci from vaccinated children to adults. METHODS: We conducted NP carriage surveys in 8 villages in Alaska in 1998-2004. Streptococcus pneumoniae isolates were characterized by serotype and antimicrobial susceptibility. We analyzed trends in serotype distribution, antibiotic resistance, and factors associated with adult carriage of PCV7-serotype pneumococci before and after the introduction of PCV7 in 2001. RESULTS: We collected 15,598 NP swabs; overall, 52% of adults living in the villages surveyed participated in the colonization study. The proportion of adult carriers with PCV7-type pneumococcal carriage decreased from 28% of carriers in 1998-2000 to 4.5% of carriers in 2004 (P<.0001). Among adults, the proportion of colonizing isolates that were resistant to penicillin decreased from 13% in 1998-2000 to 6% in 2004 (P=.05), whereas the percentage of isolates with intermediate susceptibility to penicillin increased from 12% in 1998-2000 to 19% in 2004 (P<.01). Adults were more likely to carry PCV7-type pneumococci if they lived with a child <5 years old or if they lived with a child who had not been age-appropriately vaccinated with PCV7. CONCLUSIONS: Pediatric vaccination with PCV7 has resulted in decreased PCV7-type pneumococcal carriage among adults and helps to explain recent decreases in the rate of PCV7-type invasive pneumococcal disease among adults.