Pneumococcal Capsular Polysaccharide Immunity in the Elderly

ABSTRACT Immunity to pneumococcal infections is impaired in older people, and current vaccines are poorly protective against pneumococcal disease in this population. Naturally acquired immunity to pneumococcal capsular polysaccharides develops during childhood and is robust in young adults but deteriorates with advanced age. In particular, antibody levels and function are reduced in older people. Pneumococcal vaccines are recommended for people >65 years old. However, the benefits of polysaccharide and protein-conjugated vaccines in this population are small, because of both serotype replacement and incomplete protection against vaccine serotype pneumococcal disease. In this review, we overview the immune mechanisms by which naturally acquired and vaccine-induced pneumococcal capsular polysaccharide immunity declines with age, including altered colonization dynamics, reduced opsonic activity of antibodies (particularly IgM), and impaired mucosal immunity.

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Liposomal encapsulation of polysaccharides (LEPS) as an effective vaccine strategy to protect aged hosts against S. pneumoniae infection

10.1101/2021.10.18.464850 ◽

2021 ◽

Author(s):

Manmeet Bhalla ◽

Roozbeh Nayerhoda ◽

Essi Y. I Tchalla ◽

Alexsandra Abamonte ◽

Dongwon Park ◽

...

Keyword(s):

Pneumococcal Disease ◽

Complex Disease ◽

Capsular Polysaccharide ◽

Pneumococcal Infection ◽

The Elderly ◽

Effective Vaccine ◽

Pneumococcal Infections ◽

Vaccine Strategy ◽

Vaccine Platform ◽

Old Mice

Despite the availability of licensed vaccines, pneumococcal disease caused by the bacteria Streptococcus pneumoniae (pneumococcus), remains a serious infectious disease threat globally. Disease manifestations include pneumonia, bacteremia, and meningitis, resulting in over a million deaths annually. Pneumococcal disease disproportionally impacts elderly individuals ≥65 years old. Interventions are complicated through a combination of complex disease progression and 100 different bacterial capsular polysaccharide serotypes. This has made it challenging to develop a broad vaccine against S. pneumoniae, with current options utilizing capsular polysaccharides as the primary antigenic content. However, current vaccines are substantially less effective in protecting the elderly. We previously developed a Liposomal Encapsulation of Polysaccharides (LEPS) vaccine platform, designed around limitations of current pneumococcal vaccines, that allowed the non-covalent coupling of polysaccharide and protein antigen content and protected young hosts against pneumococcal infection in murine models. In this study, we modified the formulation to make it more economical and tested the novel LEPS vaccine in aged hosts. We found that in young mice (2-3 months), LEPS elicited comparable responses to the pneumococcal conjugate vaccine Prevnar-13. Further, LEPS immunization of old mice (20-22 months) induced comparable antibody levels and improved antibody function compared to Prevnar-13. Importantly, LEPS protected old mice against both invasive and lung localized pneumococcal infections. In summary, LEPS is an alternative and effective vaccine strategy that protects aged hosts against different manifestations of pneumococcal disease.

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Liposomal Encapsulation of Polysaccharides (LEPS) as an Effective Vaccine Strategy to Protect Aged Hosts Against S. pneumoniae Infection

Frontiers in Aging ◽

10.3389/fragi.2021.798868 ◽

2021 ◽

Vol 2 ◽

Author(s):

Manmeet Bhalla ◽

Roozbeh Nayerhoda ◽

Essi Y. I. Tchalla ◽

Alexsandra Abamonte ◽

Dongwon Park ◽

...

Keyword(s):

Pneumococcal Disease ◽

Complex Disease ◽

Capsular Polysaccharide ◽

Pneumococcal Infection ◽

The Elderly ◽

Effective Vaccine ◽

Pneumococcal Infections ◽

Vaccine Strategy ◽

Vaccine Platform ◽

Old Mice

Despite the availability of licensed vaccines, pneumococcal disease caused by the bacteria Streptococcus pneumoniae (pneumococcus), remains a serious infectious disease threat globally. Disease manifestations include pneumonia, bacteremia, and meningitis, resulting in over a million deaths annually. Pneumococcal disease disproportionally impacts older adults aged ≥65 years. Interventions are complicated through a combination of complex disease progression and 100 different bacterial capsular polysaccharide serotypes. This has made it challenging to develop a broad vaccine against S. pneumoniae, with current options utilizing capsular polysaccharides as the primary antigenic content. However, current vaccines are substantially less effective in protecting the elderly. We previously developed a Liposomal Encapsulation of Polysaccharides (LEPS) vaccine platform, designed around limitations of current pneumococcal vaccines, that allowed the non-covalent coupling of polysaccharide and protein antigen content and protected young hosts against pneumococcal infection in murine models. In this study, we modified the formulation to make it more economical and tested the novel LEPS vaccine in aged hosts. We found that in young mice (2–3 months), LEPS elicited comparable responses to the pneumococcal conjugate vaccine Prevnar-13. Further, LEPS immunization of old mice (18–22 months) induced comparable antibody levels and improved antibody function compared to Prevnar-13. Importantly, LEPS protected old mice against both invasive and lung localized pneumococcal infections. In summary, LEPS is an alternative and effective vaccine strategy that protects aged hosts against different manifestations of pneumococcal disease.

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10. Kinetics of Post-Vaccination Seroprotection to S. Pneumonia for the Immune-Compromised and Vaccine-Naïve Populations

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.055 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S27-S28

Author(s):

Jeffrey Gruenglas ◽

James Mond ◽

Micaela Scobie ◽

Cynthia Tolman ◽

Joseph Martinez

Keyword(s):

Capsular Polysaccharide ◽

The Elderly ◽

Community Acquired Pneumonia ◽

Prior History ◽

Antibody Activity ◽

Vaccine Response ◽

Serum Samples ◽

Opsonic Activity ◽

And Control

Abstract Background S. pneumonia infection presents a significant challenge, accounting for 20–38% of hospital-acquired pneumonia, and the leading cause of community-acquired pneumonia despite availability of effective vaccines. Incidence is highest in children under 2 years, the immunocompromised, and elderly. CDC has reported the emergence of antibiotic resistance in ~30% of cases, adding to risk of morbidity and mortality. Fewer than half of the elderly are vaccinated and vulnerable to infection on admission. Passive immunotherapy as an adjunct to vaccines may improve outcomes in such populations. The objective of this study was to evaluate whether seroprotective response induced with a pneumococcal conjugate vaccine could rapidly yield protective opsonic levels of antibody within anticipated duration of hospitalization. Methods Healthy donors (n=30) were immunized with Prevnar. Blood was drawn on days 0, 3, 7, 10, 14, 21, and 28. Samples were pooled and tested for presence of functional opsonic antibodies recognizing capsular polysaccharides. Clearance mechanism of S. pneumonia was based on antibody recognition to pneumococcal capsular polysaccharide and opsonic titers used as an in vitro surrogate to evaluate the efficacy of vaccine. Results There was little to no opsonic activity against most serotypes on day 0, except for low antibody activity with serotypes 1, 3, 4, and 5. Titers increased, with protective levels achieved by day 10 for most serotypes (except 14 and 18C), peaking at day 14 or after across serotypes (Figures 1 and 2). Average titers rose from log2 titer 2 on day 0 to log2 titer 8 on days 21 and 28. Titers against most serotypes reached log2 10 (titer 1024) or higher. Patients remained susceptible to nosocomial infection for at least 10 days post admission until protective titers are reached. OPK titers (log2 scale) for serum samples on day 0 (pre), day 3, 7, 10, 14, 21, 28, and control for S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V. N=2. OPK titers (log2 scale) for serum samples on day 0 (pre), day 3, 7, 10, 14, 21, 28, and control for S. pneumoniae serotypes 14, 18C, 19A, 19F, and 23F. N=2. Conclusion Patients with no prior history of vaccination (or inability to mount response) with Prevnar or pneumovax remain vulnerable to S. pneumonia infection even if vaccinated on entry, due to delayed kinetics in reaching protective titers. These patients may require prophylactic intervention of hyperimmune Ig with high opsonic titers to S. pneumonia, providing protection until vaccine response elicits protective antibodies. Disclosures All Authors: No reported disclosures

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The Pneumococcal Polysaccharide-Tetanus Toxin Native C-Fragment Conjugate Vaccine: The Carrier Effect and Immunogenicity

Mediators of Inflammation ◽

10.1155/2020/9596129 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Rui Yu ◽

Junjie Xu ◽

Tao Hu ◽

Wei Chen

Keyword(s):

Tetanus Toxin ◽

Capsular Polysaccharide ◽

Low Cost ◽

Culture Conditions ◽

Carrier Protein ◽

Pneumococcal Infections ◽

Conjugate Vaccines ◽

Carrier Effect ◽

Encapsulated Bacteria ◽

Antibody Levels

The encapsulated bacteria, as Streptococcus pneumonia, Haemophilus influenzae type b, and Neisseria meningitidis, cause serious morbidity and mortality worldwide. The capsular polysaccharide (PS), which could elicit a weak T cell-independent immune response, is a vital virulence determinant. One of the strategies to improve the PS-specific immunogenicity is to conjugate PS with a nontoxic carrier protein. Tetanus toxoid (TT) and CRM197 are the typical carrier proteins for the PS conjugate vaccines. TT is the inactivated tetanus toxin manipulated with formaldehyde, which suffers from the pollution from residual formaldehyde and the incomplete detoxification. CRM197 has the disadvantage of low-yield purification with the requirement of sophisticated culture conditions. Thus, a novel carrier protein without these disadvantages is highly required. The tetanus toxin native C-fragment (Hc) is safe, low-cost, and highly immunogenic with easy purification, which can act as a promising carrier protein. Pneumococcal serogroups 14 and 23F were major epidemic causes of pneumococcal infections. In the present study, the capsular PSs (PS14 and PS23F) were conjugated with Hc, TT, and CRM197, respectively. TT- and CRM197-based conjugates acted as controls for Hc-based conjugates (PS14-Hc and PS23F-Hc). The structural properties of Hc were not fundamentally changed after conjugated with PS. PS14-Hc and PS23F-Hc could potentiate sound PS-specific antibody levels comparable to the controls. Thus, Hc exhibited a practical carrier effect to help the pneumococcal conjugate vaccines perform good immunogenicities.

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Alterations in serum opsonic activity and complement levels in pneumococcal disease

Infection and Immunity ◽

10.1128/iai.29.3.1062-1066.1980 ◽

1980 ◽

Vol 29 (3) ◽

pp. 1062-1066

Author(s):

G S Giebink ◽

T H Dee ◽

Y Kim ◽

P G Quie

Keyword(s):

Host Defense ◽

Complement Activation ◽

Pneumococcal Disease ◽

Capsular Polysaccharide ◽

Defense Mechanism ◽

Polysaccharide Antigen ◽

Opsonic Activity ◽

Factor B ◽

Host Defense Mechanism ◽

Important Host

Pneumococcal opsonic activity and concentrations of pneumococcal capsular polysaccharide antigen, C3, C4 factor B, C3 and factor B breakdown products were measured in the serum obtained acutely from 12 patients with serious pneumococcal disease. One patient showed markedly reduced pneumococcal opsonic activity, borderline-low C3, and the presence of C3 and factor B breakdown products and died. Although eight additional patients showed depressed levels of C3 or C4 or the presence of C3 or factor B breakdown products, none had reduced pneumococcal opsonic activity. All of the three remaining patients had normal opsonic activity and C3 and C4 levels. Covalescent serum was obtained from eight patients; six had normal C3 and C4 levels, and two had persistent C4 depression. These data show that complement is activated during pneumococcal disease and suggest that extensive complement activation may impair pneumococcal opsonic activity in certain patients and thereby compromise an important host defense mechanism.

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Serum Opsonic Activity in Infants with Sickle-Cell Disease Immunized with Pneumococcal Polysaccharide Protein Conjugate Vaccine

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.7.5.788-793.2000 ◽

2000 ◽

Vol 7 (5) ◽

pp. 788-793 ◽

Cited By ~ 13

Author(s):

Anna Nowak-Wegrzyn ◽

Jerry A. Winkelstein ◽

Andrea J. Swift ◽

Howard M. Lederman

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Booster Dose ◽

Cell Disease ◽

Pneumococcal Infections ◽

Opsonic Activity ◽

Protein Conjugate ◽

Healthy Infants ◽

Antibody Levels ◽

Biologic Function

ABSTRACT Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4.8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.

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Animal Models of Pneumococcal pneumonia

International Journal of Molecular Sciences ◽

10.3390/ijms20174220 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4220 ◽

Cited By ~ 3

Author(s):

Borsa ◽

Pasquale ◽

Restrepo

Keyword(s):

Animal Models ◽

Pneumococcal Disease ◽

Pneumococcal Pneumonia ◽

Respiratory Tract Infections ◽

Bacterial Pathogen ◽

The Elderly ◽

Lower Respiratory Tract Infections ◽

Bacterial Inoculation ◽

Pneumococcal Infections ◽

Tract Infections

Streptococcus pneumoniae remains the most common bacterial pathogen causing lower respiratory tract infections and is a leading cause of morbidity and mortality worldwide, especially in children and the elderly. Another important aspect related to pneumococcal infections is the persistent rate of penicillin and macrolide resistance. Therefore, animal models have been developed to better understand the pathogenesis of pneumococcal disease and test new therapeutic agents and vaccines. This narrative review will focus on the characteristics of the different animal pneumococcal pneumonia models. The assessment of the different animal models will include considerations regarding pneumococcal strains, microbiology properties, procedures used for bacterial inoculation, pathogenesis, clinical characteristics, diagnosis, treatment, and preventive approaches.

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Isotypes and Opsonophagocytosis of Pneumococcus Type 6B Antibodies Elicited in Infants and Adults by an Experimental Pneumococcus Type 6B-Tetanus Toxoid Vaccine

Infection and Immunity ◽

10.1128/iai.66.6.2866-2870.1998 ◽

1998 ◽

Vol 66 (6) ◽

pp. 2866-2870 ◽

Cited By ~ 45

Author(s):

Gestur Vidarsson ◽

Sigurveig T. Sigurdardottir ◽

Thorolfur Gudnason ◽

Sveinn Kjartansson ◽

Karl G. Kristinsson ◽

...

Keyword(s):

Tetanus Toxoid ◽

The Elderly ◽

Immunoglobulin M ◽

Respiratory Pathogen ◽

Enzyme Linked Immunosorbent Assay ◽

Opsonic Activity ◽

Booster Injection ◽

Young Infants ◽

Antibody Levels ◽

Pneumococcus Type

ABSTRACT Streptococcus pneumoniae is a major respiratory pathogen of infants, children, and the elderly. Polysaccharide vaccines have been useful in adult populations but do not elicit protective immunity in infants and young children. To enhance their immunogenicity, vaccines of pneumococcal polysaccharides conjugated to proteins are being developed. In this study antibody levels and opsonic activities were compared in sera of infants and adults injected with pneumococcal polysaccharide type 6B (Pn6B) conjugated to tetanus toxoid (TT) (Pn6B-TT). Healthy infants were injected with Pn6B-TT; group A was injected at 3, 4, and 6 months of age, and group B was injected at 7 and 9 months of age. A booster injection was given at 18 months. Adults were injected once. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and their functional activities were measured by opsonophagocytosis of radiolabelled pneumococci. In adults, increases in immunoglobulin M (IgM), IgG, IgA, IgG1, and IgG2 to Pn6B were observed. Infants reached adult levels of IgG1 anti-Pn6B after the primary injections. After the booster injection the infant groups had total IgG- and IgM-Pn6B antibody levels similar to those of adults. After the booster injection, IgG1 was the dominant infant anti-Pn6B isotype and at a level higher than in vaccinated adults, but IgA and IgG2 antibodies remained at very low levels. Opsonic activity increased significantly after Pn6B-TT injections; the highest infant sera showed opsonic activity comparable to that of vaccinated adults. Overall, opsonic activity correlated best with total and IgG anti-Pn6B antibodies (r = 0.741,r = 0.653, respectively; n = 35) and was highest in sera with high levels of all Pn6B antibody isotypes. The results indicate the protective potential of a pneumococcal 6B polysaccharide protein conjugate vaccine for young infants.

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Pneumococcal Virulence Factors: Structure and Function

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.65.2.187-207.2001 ◽

2001 ◽

Vol 65 (2) ◽

pp. 187-207 ◽

Cited By ~ 289

Author(s):

Mark J. Jedrzejas

Keyword(s):

Virulence Factors ◽

Surface Antigen ◽

Pneumococcal Disease ◽

Protein A ◽

The Elderly ◽

Structure And Function ◽

Structural Level ◽

Hyaluronate Lyase ◽

Antigen A ◽

And Function

SUMMARY The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.

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Pneumococcal disease prevention from early infancy to the elderly

Orvosi Hetilap ◽

10.1556/oh.2014.29753 ◽

2014 ◽

Vol 155 (7) ◽

pp. 243-247 ◽

Cited By ~ 1

Author(s):

Zsófia Mészner

Keyword(s):

Pneumococcal Disease ◽

Age Groups ◽

Prevention Programs ◽

The Elderly ◽

Active Immunization ◽

Antimicrobial Treatment ◽

Medical Community ◽

Pneumococcal Infections ◽

Future Challenges ◽

Life Threatening

The real disease burden due to Streptococcus pneumoniae infections are underrecognised worldwide both by the lay public and by the medical community in general. In infants and children pneumococcal otitis media is the most common reason for antimicrobial treatment, while the far less frequent, though potentially life threatening pneumococcal pleuropneumonia, sepsis and pneumococcal meningitis are high risk conditions even if the causative pneumococcus is not multiresistant. Asplenic patients, patients with chronic underlying conditions, and/or those receiving immunosuppressive therapy are at risk of serious pneumococcal disease regardless of age. Morbidity and mortality due to pneumococcal pneumonia is most common in the elderly, and has not changed during the last decades in spite of all efforts in improving therapy and care. Presently the majority of the pneumococcal infections are preventable by active immunization. In this work the author briefly outlines the results of the pneumococcal prevention programs worldwide and in Hungary using presently available 10-valent, 13-valent protein conjugate and 23-valent polysaccharide pneumococcal vaccines. Also, the author describes the recently approved indications of the 13-valent pneumococcal conjugate vaccine such as its use in all age groups, discusses future challenges of these prevention programs. Orv. Hetil., 2014, 155(7), 243–247.

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