Determination of Antibody Responses of Elderly Adults to All 23 Capsular Polysaccharides after Pneumococcal Vaccination

The 23-valent pneumococcal polysaccharide vaccine was formulated to prevent invasive infection in the elderly and other high-risk populations from the most prevalent Streptococcus pneumoniae serotypes. However, the immunogenicity of all 23 vaccine polysaccharides has not been fully characterized in elderly adults. We previously reported that whereas the majority of elderly subjects had vigorous immune responses to selected pneumococcal vaccine polysaccharides, a subset of elderly individuals responded to fewer than two of seven vaccine serotypes after immunization. To determine whether these elderly low responders have a general inability to respond to pneumococcal vaccine and to determine whether elderly low responders might be identified by their responses to a few polysaccharides, we measured antibody responses of elderly adults to all 23 vaccine polysaccharides after pneumococcal immunization. As a group, elderly subjects showed a significant rise after immunization in geometric mean antibody levels to all 23 vaccine serotypes. However, when individual rather than group immune responses were assessed, the 23-valent vaccine did not appear to be uniformly immunogenic in these elderly subjects. Eleven elderly subjects (20%) had twofold increases in specific antibody after vaccination to only 5 or fewer of the 23 vaccine polysaccharides, and they did not respond to the most prevalent serotypes causing invasive disease. Antibody responses to serotype 9N were found to reliably distinguish low vaccine responders from other elderly subjects. However, no particular group of vaccine polysaccharides could be used as a marker for adequate immune responses if only postvaccination sera were analyzed.     

Racial Disparities in Adult Pneumococcal Vaccination Indications and Pneumococcal Hospitalizations in the U.S.

BackgroundRacial disparities in U.S. adult pneumococcal vaccination rates persist despite reduced barriers to access. Consequently, racial and ethnic minorities experience pneumococcal disease at higher rates than whites. This study examined prevalence of high-risk conditions and pneumococcal hospitalizations among U.S. black and non-black populations aged ≥50 years.MethodsNational Health Interview Survey, National Center for Health Statistics and National Inpatient Sample data were used to create black and non-black population cohorts, determine risk factors for pneumococcal disease (pneumococcal vaccine indications) and assess the impact of pneumococcal hospitalization. Each racial cohort was segmented into groups based on the presence of immunocompromising or other pneumococcal high-risk conditions. Persons without those conditions were separated into smokers (also a pneumococcal vaccine indication) and nonsmokers. Mortality was estimated from NCHS life table data. NIS data provided length of stay and costs (calculated from cost to charge ratios) for admissions related to pneumococcal disease including bacteremia, meningitis and nonbacteremic pneumonia.ResultsThere were similar proportions of immunocompromised (<5%) and smokers (14%) in both racial cohorts. Likelihood of non-immunocompromising pneumococcal high-risk conditions was higher for blacks than non-blacks at age 65, but higher for non-blacks than blacks at age 80 years (P < 0.001). Age-specific relative likelihood of mortality was 1.1%–12% higher in blacks than non-blacks (P < 0.001). Length of stay was significantly longer for blacks than non-blacks in all age and discharge status groups for non-bacteremic pneumonia and for blacks discharged alive with invasive pneumococcal disease. Costs were higher for blacks 65 years or older with invasive pneumococcal disease.ConclusionMarked differences exist between U.S. black and non-black populations in likelihood of conditions conferring a high-risk of pneumococcal disease, and for length of stay and costs of pneumococcal disease hospitalizations. Further research is recommended to identify cost-effective policies or interventions to increase vaccine uptake in higher risk populations.     

Outpatient-Based Pneumococcal Vaccine Campaign and Survey of Perceptions about Pneumococcal Vaccination in Patients and Doctors

Purpose

Despite the ready availability of pneumococcal vaccine, vaccination rates are quite low in South Korea. This study was designed to assess perceptions and awareness about pneumococcal vaccines among subjects at risk and find strategies to increases vaccine coverage rates.

Materials and Methods

A cross sectional, community-based survey was conducted to assess perceptions about the pneumococcal vaccine at a local public health center. In a tertiary hospital, an outpatient-based pneumococcal vaccine campaign was carried out for the elderly and individuals with chronic co-morbidities from May to July of 2007.

Results

Based on the survey, only 7.6% were ever informed about pneumococcal vaccination. The coverage rates of the pneumococcal vaccine before and after the hospital campaign showed an increased annual rate from 3.39% to 5.91%. The most common reason for vaccination was "doctor''s advice" (53.3%). As for the reasons for not receiving vaccination, about 75% of high risk patients were not aware of the pneumococcal vaccine, which was the most important barrier to vaccination. Negative clinician''s attitude was the second most common cause of non-vaccination.

Conclusion

Annual outpatient-based campaigns early in the influenza season may improve pneumococcal vaccine coverage rates. Doctor''s advice was the most important encouraging factor for vaccination.     

Response to Pneumococcal Vaccine in the Elderly: No Enhancement by Indomethacin

We investigated whether indomethacin administration would augment the antibody response to pneumococcal vaccine in a group of healthy elderly individuals. There was no significant difference in mean increases in antibody levels to 12 pneumococcal polysaccharide types between the 20 subjects who received indomethacin 25 mg q.i.d. for five days after immunization and the control subjects not receiving indomethacin. In addition, there was no correlation within this group of 40 individuals between three measures of immune function (absolute lymphocyte count, delayed hypersensitivity testing, and response to phytohemagglutinin) and the antibody response to the pneumococcal vaccine.     

Clinical Effectiveness of Conjugate Pneumococcal Vaccination in Hematopoietic Stem Cell Transplantation Recipients

Hematopoietic stem cell transplantation (HSCT) recipients are vulnerable to invasive pneumococcal disease (IPD), with reported IPD rates ranging from 3.81 to 22.5/1000 HSCT. This IPD risk could relate to immunodeficiency, low vaccination uptake, and poor immunogenicity of pneumococcal polysaccharide vaccine (PPV). Literature comparing the clinical effectiveness of pneumococcal conjugate vaccination (PCV) and PPV after HSCT is limited. In this retrospective analysis of HSCT recipients at our center from 2004 to 2015, we evaluated vaccination uptake and compared IPD rates in patients receiving PPV (pre-2010 group) and PCV (post-2010 group). IPD was determined from microbiological results for all HSCT recipients from January 2004 to June 30, 2019. Eight hundred patients had a total of 842 HSCT events, including autologous HSCT (auto-HSCT; n = 562) and allogeneic HSCT (allo-HSCT; n = 280). More than 90% of the HSCT recipients were enrolled, and >93% of surviving HSCT recipients completed the vaccination protocol. Fifteen IPD episodes occurred in 13 patients between 2004 and June 30, 2019. Thirteen episodes occurred in the pre-2010 group, even though 9 of 13 (69%) serotyped isolates were covered by PPV. Two episodes occurred in the post-2010 group; neither serotype was covered by PCV. Thus, with PCV introduction, IPD rate was significantly reduced from 38.5/1000 unique HSCTs pre-2010 to 4.0/1000 unique HSCTs post-2010 (P < .001). A significant reduction was seen in both auto-HSCTs (from 29.4 to 3.1 /1000 unique auto-HSCTs; P = .011) and allo-HSCTs (from 58.3 to 5.6/1000 unique allo-HSCTs; P = .011). PCV demonstrated superior clinical effectiveness over PPV, highlighting its importance in preventing infectious complications after HSCT. Robust vaccination programs at transplantation centers are needed to optimize vaccination uptake and completion.     

Impact of a Pneumococcal Conjugate Vaccination Program on Carriage among Children in Norway

In July 2006, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in Norway with a reduced (2 doses + 1 boost) dose schedule. Post-PCV7 shifts in pneumococcal reservoirs were assessed by two point prevalence studies of nasopharyngeal colonization among children in day care centers, before (2006) and after (2008) widespread use of PCV7. Nasopharyngeal swabs were obtained from 1,213 children, 611 in 2006 and 602 in 2008. A total of 1,102 pneumococcal isolates were recovered. Serotyping, multilocus sequence typing, and antimicrobial drug susceptibility testing were performed on all isolates. Although carriage of PCV7 serotypes decreased among both vaccinated and unvaccinated children, the overall prevalence of pneumococcal carriage remained high (80.4%) after vaccine introduction. The pneumococcal populations were diverse, and in the shift toward non-PCV7 serotypes, expansion of a limited number of established clonal complexes was observed. While non-antimicrobial-susceptible clones persisted among PCV7 serotypes, antimicrobial resistance did not increase among non-PCV7 serotypes. Direct and indirect protection of PCV7 against nasopharyngeal colonization was inferred from an overall decrease in carriage of PCV7 serotypes. No preference was found for nonsusceptible clones among the replacing non-PCV7 serotypes.Streptococcus pneumoniae is a leading cause of otitis media, sinusitis, pneumonia, and meningitis worldwide (35). S. pneumoniae colonizes the nasopharynx and is considered a part of the normal flora in early childhood (1). Following the implementation of childhood vaccination with the seven-valent conjugated pneumococcal vaccine (PCV7), reports from several locations have described declines in carriage of the seven serotypes included in the vaccine, i.e., serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (4, 6, 13, 19, 24). Due to reduced transmission of PCV7 serotypes, the incidence of invasive pneumococcal disease (IPD) declines also among the unvaccinated, which is an indirect effect of conjugate pneumococcal vaccination. However, the effect of PCV7 may in part be eroded over time as non-PCV7 serotypes emerge as a more frequent cause of IPD (11). In the United States, non-antimicrobial-susceptible clones seem to have an advantage among the emerging and expanding non-PCV7 serotypes, both in asymptomatic colonization and IPD (10, 20). This is primarily demonstrated by increasing incidence rates of drug-resistant clones of serotype 19A (23).PCV7 was introduced into the Norwegian childhood vaccination program in a dose schedule of two doses and one boost (2 + 1 dose schedule) in July 2006 and has been offered free of charge to all children born in 2006 and since. A high level of effectiveness of the vaccination program among children was demonstrated quickly after vaccine introduction, and the effect included a decline in IPD caused by erythromycin-resistant S. pneumoniae (34).As part of the Norwegian surveillance of PCV7 introduction, a cross-sectional study of nasopharyngeal carriage of Streptococcus pneumoniae among children attending day care centers (DCC) was performed in the early autumn of 2006. Data from this study, with exception of data regarding 38 vaccinated participants, have been reported previously (33). To assess the impact of the 2 + 1 dose schedule PCV7 vaccination program on carriage of S. pneumoniae, a follow-up was performed in 2008. Serotyping, antimicrobial susceptibility testing, and genotyping of the isolates from 2008 were performed, and the results were compared to those from analyses of the previous collection. Shifts in clonal compositions of the pneumococcal populations were analyzed and are reported here.Limited outpatient use of antimicrobial agents is recommended in Norway, and the levels of nonsusceptibility to antimicrobials among S. pneumoniae isolates from both local infections and IPD are low (25). Hence, emphasis has been put on post-PCV7 changes in nonsusceptibility to antimicrobials and nonsusceptible clones in a setting with limited antimicrobial use and resistance.     

Waldenstr?m's Macroglobulinemia: Report of a Case With Pulmonary Involvement and Recurrent Pneumococcal Sepsis After Pneumococcal Vaccination

A patient with Waldenström''s macroglobulinemia who presented with pleuropulmonary manifestations is described. The course was complicated by recurrent Streptococcus pneumoniae infections despite pneumococcal immunization.     

Acute Disseminated Encephalomyelitis following Seasonal Influenza Vaccination in an Elderly Patient

Although such occurrences are rare, it should be recognized that certain vaccines might trigger serious neurological immune phenomena such as Guillain-Barre syndrome, seizures, cranial neuropathy, and acute disseminated encephalomyelitis (ADEM). Here we report on an elderly woman with ADEM following seasonal influenza vaccination who recovered after plasma exchange.     

Kinetics of IgM and IgA Antibody Response to 23-Valent Pneumococcal Polysaccharide Vaccination in Healthy Subjects

Purpose

A poor antibody response of IgM and IgA antibodies upon vaccination with pneumococcal polysaccharides (PnPS) is discussed as independent risk factors for bronchiectasis in patients with antibody deficiency syndrome (ADS) receiving immunoglobulin replacement therapy. However, the kinetics of the specific IgM and IgA response to vaccination with multivalent pneumococcal polysaccharides requires a more detailed knowledge. In this study we aimed i) to develop a standardised multivalent PnPS-IgM and IgA-ELISA, and ii) to compare the sensitivity of the multivalent to the serotype specific antibody response, and iii) to determine the kinetics of the anti-PnPS IgM and IgA antibodies in healthy subjects.

Methods

We immunised n?=?20 healthy adults with a 23-valent PnPS vaccine (Pneumovax®). The kinetics of the 23-valent antibody response was assessed for 1 year with newly developed ELISAs for IgM and IgA isotypes, along with serotype specific responses.

Results

The IgA and IgM antibody response peaked at 2 and 3 weeks, respectively. IgM antibody levels remained at a plateau (above 80 % of peak response) for 3 months. After one year, specific antibody levels were still at about 30 % of the peak response. The 23-valent antibody response yielded significantly higher responder rates than assessment of single serotypes.

Conclusion

Testing the IgM and IgA immune response to polysaccharide vaccination with a multivalent PnPS ELISA may be a feasible tool for assessment of the immune function in patient groups who receive IgG replacement therapy.     

Adherence to Guidelines for Hepatitis B,Pneumococcal, and Influenza Vaccination in Patients With Diabetes

IN BRIEF This single-center, cross-sectional study was designed to assess adherence to national guidelines for the immunization of patients with diabetes and to evaluate predictors of vaccination with the hepatitis B, influenza, and 23-valent pneumococcal polysaccharide vaccines. In patients considered to be at increased risk for infection and infectious disease complications because of their history of diabetes, extensive nonadherence to immunization recommendations for all three vaccines was found. Nonadherence to the 2011 Advisory Committee on Immunization Practices’ recommendation for hepatitis B vaccination was ubiquitous. Allocation of health care resources to increase vaccine coverage should remain a priority, with a focus on spreading awareness of the hepatitis B vaccine recommendation for people with diabetes.Diabetes has long been perceived to be associated with an increased risk of infection and worse health outcomes. The rate of infection arising from many common viral and bacterial etiologies has been shown to occur more frequently in patients with diabetes (1–4). The odds of developing acute hepatitis B are estimated to be more than double in patients with diabetes compared with those without (4). The incidence of hospitalization and odds of death are consistently elevated in people with diabetes compared with those without, during both influenza epidemic and nonepidemic years (5,6). Studies have suggested that patients with diabetes who develop pneumococcal pneumonia are more likely than those without diabetes to progress to systemic bacteremia (7–9).This apparent susceptibility to infection has been attributed to abnormalities in host defense mechanisms, including deficiencies in antibody response, cell-mediated immunity, leukocyte function, and colonization rates (9–11). The higher risk of infection may also be explained by the large burden of chronic disease in this population and associated organ dysfunction. Despite the potential for impaired immune function, most people with diabetes are capable of generating an adequate humoral response and sufficient antibody titers from vaccination (12–14).Morbidity and mortality associated with influenza and pneumonia are reduced in people who have received appropriate vaccination for each of these infectious diseases (9,15–17). The Advisory Committee on Immunization Practices (ACIP) and the American Diabetes Association both recommend annual vaccination with the influenza vaccine and at least one lifetime vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) for individuals with diabetes or other conditions that increase the risk of complications from infection (18–22). As part of the Healthy People 2020 initiative, the U.S. Department of Health and Human Services has designated goal vaccination coverage rates for high-risk adults aged 18–64 years of 90% annually for the influenza vaccine and 60% for PPSV23 (22). Data from the 2011 National Health Interview Survey indicated that only 16.6% of these high-risk individuals had ever received the PPSV23 (23). Coverage with the influenza vaccine for the 2012–2013 season was estimated to be 47% for high-risk individuals (24). Substantial improvement will be required to meet coverage goals for these vaccines.

TABLE 1.

Adherence to ACIP Recommendations for Vaccination of People With Diabetes and Healthy People 2020 Coverage Goals for Each Vaccine

Changes in Molecular Epidemiology of Streptococcus pneumoniae Causing Meningitis following Introduction of Pneumococcal Conjugate Vaccination in England and Wales

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in September 2006 has markedly reduced the burden of invasive pneumococcal disease (IPD) including meningitis in England and Wales. This study examined changes in the molecular epidemiology of pneumococcal isolates causing meningitis from July 2004 to June 2009. The Health Protection Agency conducts enhanced pneumococcal surveillance in England and Wales. In addition to serotyping, pneumococcal isolates causing meningitis were genotyped by multilocus sequence typing (MLST). A total of 1,030 isolates were both serotyped and genotyped over the 5-year period. Fifty-two serotypes, 238 sequence types (STs), and 87 clonal complexes were identified, with no significant difference in the yearly Simpson''s diversity index values (range, 0.974 to 0.984). STs commonly associated with PCV7 serotypes declined following PCV implementation, with a proportionally greater decline in ST124 (commonly associated with serotype 14). No other ST showed significant changes in distribution, even within individual serotypes. Replacement disease following PCV7 introduction was mainly due to serotypes 1, 3, 7F, 19A, 22F, and 33F through clonal expansion. A single instance of possible capsule switching was identified where one ST4327 clone expressed a serotype 14 capsule in 2005 and a serotype 28A capsule in 2009. In 2008 to 2009, ST191 (7F) became the most prevalent clone causing meningitis (10.3%). Case fatality (145 fatalities/1,030 cases; 14.1%) was high across all age groups and serotype groups. Thus, the introduction of PCV7 resulted in an increase in non-PCV7 serotypes, including some not covered by the 13-valent vaccine, such as serotypes 22F and 33F, emphasizing the importance of long-term epidemiological and molecular surveillance.     

A Flow Cytometric Opsonophagocytic Assay for Measurement of Functional Antibodies Elicited after Vaccination with the 23-Valent Pneumococcal Polysaccharide Vaccine

Opsonophagocytosis is the primary mechanism for clearance of pneumococci from the host, and the measurement of opsonophagocytic antibodies appears to correlate with vaccine-induced protection. We developed a semiautomated flow cytometric opsonophagocytosis assay using HL-60 granulocytes as effector cells and nonviable 5,6-carboxyfluorescein, succinimidyl ester-labeled Streptococcus pneumoniae (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) as bacterial targets. The flow cytometric opsonophagocytosis assay was highly reproducible (for 87% of repetitive assays the titers were within 1 dilution of the median titer) and serotype specific, with ≥97% inhibition of opsonophagocytic titer by addition of homologous serotype-specific polysaccharide. In general, opsonophagocytic titers were not significantly inhibited by the presence of either heterologous pneumococcal polysaccharide or penicillin in the serum. The flow cytometric assay could reproducibly measure functional antibody activity in prevaccination (n = 28) and postvaccination (n = 36) serum specimens from healthy adult volunteers vaccinated with the 23-valent pneumococcal polysaccharide vaccine. When compared with a standardized manual viable opsonophagocytic assay, a high correlation (r = 0.89; P ≤ 0.01) was found between the two assays for the seven serotypes tested. The flow cytometric assay is rapid (~4 h) with high throughput (~50 serum samples per day per technician) and provides a reproducible measurement of serotype-specific functional antibodies, making it a highly suitable assay for the evaluation of the immune responses elicited by pneumococcal vaccines.     

Pneumococcal Vaccines

Streptococcus pneumoniae continues to take a heavy toll on childhood mortality and morbidity across the developing world. An estimated 10.6 million invasive pneumococcal diseases (IPDs) occur every year, with nearly 1 million deaths in children under 5 years of age. Introduction of vaccines in the childhood immunisation programme in developed world has brought down the incidence of the disease considerably. However, childhood immunocompromising illnesses including HIV have increased the risk of IPD several folds. There is also a growing concern on the increasing antibiotic resistance among these invasive strains to penicillin, other beta-lactams and macrolides, making treatment difficult and expensive. It is estimated that about 62% of IPD worldwide is caused by the 10 most common serotypes. Although the ranking of individual pneumococcal serotypes causing serious disease varies among nations, the 7–13 serotypes included in pneumococcal conjugate vaccines (PCVs) may prevent 50%–80% of all paediatric pneumococcal diseases globally. The World Health Organization has recommended the use of PCV-10/13 in the national immunisation programmes (NIPs) of developing countries. Four doses of PCV-13 have been recommended by the US Association of Pediatrics and Centers for Disease Control and Prevention, at intervals of each 2 months for the first 6 months and by the 12^th to 15^th months after birth. This is expected to reduce the morbidity and mortality associated with IPD and simultaneously decrease colonisation with circulating antibiotic-resistant strains in immunized communities. Nevertheless, continued surveillance of antimicrobial resistance in non-vaccine serotypes is necessary to prevent the resurgence of resistance. Other virulence factors which are not serotype specific also need to be studied to overcome the drawbacks of serotype-specific pneumococcal vaccines. PCV-13 was launched during May 2017 under the NIP of five Indian states with the highest pneumococcal diseases in the country and is expected to be rolled out in the other parts of the country in the coming days.     

Lactate Dehydrogenase Is the Key Enzyme for Pneumococcal Pyruvate Metabolism and Pneumococcal Survival in Blood

Streptococcus pneumoniae is a fermentative microorganism and causes serious diseases in humans, including otitis media, bacteremia, meningitis, and pneumonia. However, the mechanisms enabling pneumococcal survival in the host and causing disease in different tissues are incompletely understood. The available evidence indicates a strong link between the central metabolism and pneumococcal virulence. To further our knowledge on pneumococcal virulence, we investigated the role of lactate dehydrogenase (LDH), which converts pyruvate to lactate and is an essential enzyme for redox balance, in the pneumococcal central metabolism and virulence using an isogenic ldh mutant. Loss of LDH led to a dramatic reduction of the growth rate, pinpointing the key role of this enzyme in fermentative metabolism. The pattern of end products was altered, and lactate production was totally blocked. The fermentation profile was confirmed by in vivo nuclear magnetic resonance (NMR) measurements of glucose metabolism in nongrowing cell suspensions of the ldh mutant. In this strain, a bottleneck in the fermentative steps is evident from the accumulation of pyruvate, revealing LDH as the most efficient enzyme in pyruvate conversion. An increase in ethanol production was also observed, indicating that in the absence of LDH the redox balance is maintained through alcohol dehydrogenase activity. We also found that the absence of LDH renders the pneumococci avirulent after intravenous infection and leads to a significant reduction in virulence in a model of pneumonia that develops after intranasal infection, likely due to a decrease in energy generation and virulence gene expression.     

Differences within Mono- and Dizygotic Twin-Pairs in Spectrotypes and Clones of IgG2 Antibodies to Pneumococcal Polysaccharide Type 1 and C-Polysaccharide After Vaccination

Spectrotypes and clones of antibodies against pneumococcal capsular polysaccharide (Ps) type 1 and C-polysaccharide (C-Ps) were determined before and after immunization with a polyvalent pneumococcal Ps vaccine in 84 mono- or dizygotic twins. The method used was a micromodification of a rapid isoelectric focusing-amnity (lEF-affinity) immunoblot technique in agarose permitting characterization of isotype, light chain and Gm type. After vaccination the anti-type 1 Ps + anti-C-Ps clones were different in 75% of the monozygotic and 79% of the dizygotic twins. The anti-type 1 Ps clones differed among 72% of the monozygotic and 85% of the dizygotic twins (P > 0.05). Each twin had from zero to three clones producing IgG2 antibodies against type 1 Ps, A total of six different clones could be distinguished among all the twins. Vaccination enhanced the already actively secreting B-cell clones in 56 twins and newly recruited clones in 11 of the 84 twins; six among the 48 mono- and five among the 36 dizygotic twins. These new clones differed among the twins. Spectrotypes varied between all twins within the pairs. The fact that all twins differed in spectrotype is due to post-translational microheterogenity of the antibodies, events which are thus not genetically determined. The observation that even mono zygotic twins possessed and responded with different clones within the pairs indicates that the V-region genes, which determine the final specificity of B cells, either differ from the original germ-line V region genes, e. g. owing to hypermutations or junctional diversity, or the rearranged germ-line genes occur accidentally although highly restricted.