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

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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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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Pneumococcal Capsular Polysaccharide Immunity in the Elderly

Clinical and Vaccine Immunology ◽

10.1128/cvi.00004-17 ◽

2017 ◽

Vol 24 (6) ◽

Cited By ~ 14

Author(s):

Hugh Adler ◽

Daniela M. Ferreira ◽

Stephen B. Gordon ◽

Jamie Rylance

Keyword(s):

Older People ◽

Pneumococcal Disease ◽

Capsular Polysaccharide ◽

The Elderly ◽

Pneumococcal Infections ◽

Opsonic Activity ◽

Serotype Replacement ◽

Colonization Dynamics ◽

And Function ◽

Antibody Levels

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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When to use the new pneumococcal vaccine

Drug and Therapeutics Bulletin ◽

10.1136/dtb.28.8.31 ◽

1990 ◽

Vol 28 (8) ◽

pp. 31-32

Keyword(s):

United States ◽

Pneumococcal Vaccine ◽

Pneumococcal Disease ◽

Pneumococcal Pneumonia ◽

Pneumococcal Infection ◽

The Elderly ◽

The United States ◽

Cell Disease ◽

Large Groups ◽

Special Risk

Pneumococcal pneumonia probably affects about one in every thousand adults each year. Like other serious pneumococcal infection, it is more common and severe in the elderly, in those without a functional spleen (including patients with sickle-cell disease,1) and in patients with a variety of chronic diseases. In the United States a 23-valent pneumococcal vaccine was introduced in 1983, replacing a 14-valent vaccine; it is now recommended there for large groups of people.2 This newer 23-valent vaccine (Pneumovax-II - MSD) was licensed in Britain last May. Its use should be considered for those at special risk of pneumococcal disease.3–5

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Two DHH Subfamily 1 Proteins Contribute to Pneumococcal Virulence and Confer Protection against Pneumococcal Disease

Infection and Immunity ◽

10.1128/iai.01383-10 ◽

2011 ◽

Vol 79 (9) ◽

pp. 3697-3710 ◽

Cited By ~ 28

Author(s):

L. E. Cron ◽

K. Stol ◽

P. Burghout ◽

S. van Selm ◽

E. R. Simonetti ◽

...

Keyword(s):

Otitis Media ◽

Pneumococcal Disease ◽

Capsular Polysaccharide ◽

Pneumococcal Infection ◽

Bacterial Pathogen ◽

Protein Vaccine ◽

Double Knockout ◽

Content Type ◽

Knockout Mutants ◽

Different Strains

ABSTRACTStreptococcus pneumoniaeis an important human bacterial pathogen, causing such infections as pneumonia, meningitis, septicemia, and otitis media. Current capsular polysaccharide-based conjugate vaccines protect against a fraction of the over 90 serotypes known, whereas vaccines based on conserved pneumococcal proteins are considered promising broad-range alternatives. The pneumococcal genome encodes two conserved proteins of an as yet unknown function, SP1298 and SP2205, classified as DHH (Asp-His-His) subfamily 1 proteins. Here we examined their contribution to pneumococcal pathogenesis using single and double knockout mutants in three different strains: D39, TIGR4, and BHN100. Mutants lacking both SP1298 and SP2205 were severely impaired in adherence to human epithelial Detroit 562 cells. Importantly, the attenuated phenotypes were restored upon genetic complementation of the deleted genes. Single and mixed mouse models of colonization, otitis media, pneumonia, and bacteremia showed that bacterial loads in the nasopharynx, middle ears, lungs, and blood of mice infected with the mutants were significantly reduced from those of wild-type-infected mice, with an apparent additive effect upon deletion of both genes. Minor strain-specific phenotypes were observed, i.e., deletion of SP1298 affected host-cell adherence in BHN100 only, and deletion of SP2205 significantly attenuated virulence in lungs and blood in D39 and BHN100 but not TIGR4. Finally, subcutaneous vaccination with a combination of both DHH subfamily 1 proteins conferred protection to nasopharynx, lungs, and blood of mice infected with TIGR4. We conclude that SP1298 and SP2205 play a significant role at several stages of pneumococcal infection, and importantly, these proteins are potential candidates for a multicomponent protein vaccine.

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Extracellular adenosine signaling reverses the age-driven decline in the ability of neutrophils to kill S. pneumoniae

10.1101/2020.04.14.041418 ◽

2020 ◽

Cited By ~ 1

Author(s):

Manmeet Bhalla ◽

Shaunna R. Simmons ◽

Alexsandra Abamonte ◽

Sydney E. Herring ◽

Sara E. Roggensack ◽

...

Keyword(s):

Ex Vivo ◽

Pneumococcal Infection ◽

The Elderly ◽

Extracellular Adenosine ◽

Genetic Ablation ◽

Serious Infections ◽

Antimicrobial Function ◽

A1 Receptor ◽

Old Mice ◽

Young Mice

SummaryThe elderly are susceptible to serious infections by Streptococcus pneumoniae (pneumococcus), which calls for a better understanding of the pathways driving the decline in host defense in aging. We previously found that extracellular adenosine (EAD) shaped polymorphonuclear cell (PMN) responses, which are crucial for controlling infection. EAD is produced by CD39 and CD73, and signals via A1, A2A, A2B and A3 receptors. The objective of this study was to explore the age-driven changes in the EAD pathway and its impact on PMN function. We found in comparison to young mice, PMNs from old mice expressed significantly less CD73, but similar levels of CD39 and adenosine receptors. PMNs from old mice failed to efficiently kill pneumococci ex vivo; however, supplementation with adenosine rescued this defect. Importantly, transfer of PMNs expressing CD73 from young mice reversed the susceptibility of old mice to pneumococcal infection. To identify which adenosine receptor(s) is involved, we used specific agonists and inhibitors. We found that A1 receptor signaling was crucial for PMN function as inhibition or genetic ablation of A1 impaired the ability of PMNs from young mice to kill pneumococci. Importantly, activation of A1 receptors rescued the age-associated defect in PMN function. In exploring mechanisms, we found that PMNs from old mice failed to efficiently kill engulfed pneumococci and that A1 receptor controlled intracellular killing. In summary, targeting the EAD pathway reverses the age-driven decline in PMN antimicrobial function, which has serious implications in combating infections.

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Newcastle Disease Virus as a Vaccine Vector for SARS-CoV-2

Pathogens ◽

10.3390/pathogens9080619 ◽

2020 ◽

Vol 9 (8) ◽

pp. 619

Author(s):

Edris Shirvani ◽

Siba K. Samal

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Vaccine Vector ◽

Effective Vaccine ◽

Vaccine Strategy ◽

Vaccine Platform ◽

Vector Vaccine ◽

Advantages And Disadvantages ◽

Avian Virus

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 16 million infections and more than 600,000 deaths worldwide. There is an urgent need to develop a safe and effective vaccine against SARS-CoV-2. Currently, several strategies are being pursued to develop a safe and effective SARS-CoV-2 vaccine. However, each vaccine strategy has distinct advantages and disadvantages. Therefore, it is important to evaluate multiple vaccine platforms to select the most efficient vaccine platform for SARS-CoV-2. In this regard, Newcastle disease virus (NDV), an avian virus, has several well-suited properties for development of a vector vaccine against SARS-CoV-2. Here, we elaborate on the idea of considering NDV as a vaccine vector for SARS-CoV-2.

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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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Invasive pneumococcal infection in South and West England

Epidemiology and Infection ◽

10.1017/s0950268897008522 ◽

1998 ◽

Vol 120 (2) ◽

pp. 117-123 ◽

Cited By ~ 23

Author(s):

M. D. SMITH ◽

J. STUART ◽

N. J. ANDREWS ◽

W. A. TELFER BRUNTON ◽

K. A. V. CARTWRIGHT

Keyword(s):

Blood Culture ◽

Invasive Pneumococcal Disease ◽

Pneumococcal Disease ◽

Statistical Significance ◽

Pneumococcal Infection ◽

Vaccine Uptake ◽

Pneumococcal Infections ◽

Sex Structure ◽

Catchment Population ◽

Admission Rates

Variation in the incidence of invasive pneumococcal disease across South and West England, in 1995, was measured through a survey of microbiology laboratories. A 100% response rate was achieved. The incidence by laboratory varied between 5·2 and 20·4 per 100000 catchment population (P<0·001). Adjusting for pneumococcal vaccine uptake rate in over 65 year olds, hospital admission rates, blood culture system used and for the age and sex structure of the population, did not account for this variation. When blood culture sampling rates were included in a logistic regression model, the variation between laboratories was much less and of lower statistical significance (P=0·019). Higher rates of blood culture sampling were associated with a higher incidence of invasive pneumococcal disease. Consistently high sampling should be encouraged because a higher diagnostic rate should result in more selective prescribing of antibiotics, and secondly because improved ascertainment of severe pneumococcal infections is a prerequisite for the evaluation of new pneumococcal conjugate vaccines.

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Cross-Protective Immunity of Mice Induced by Oral Immunization with Pneumococcal Surface Adhesin A Encapsulated in Microspheres

Infection and Immunity ◽

10.1128/iai.70.3.1143-1149.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1143-1149 ◽

Cited By ~ 44

Author(s):

Jun-Young Seo ◽

Seung Yong Seong ◽

Byung-Yoon Ahn ◽

Ick Chan Kwon ◽

Hesson Chung ◽

...

Keyword(s):

Immune System ◽

Oral Delivery ◽

Protective Immunity ◽

Capsular Polysaccharide ◽

Oral Vaccine ◽

Pneumococcal Infection ◽

The Elderly ◽

Oral Immunization ◽

Mucosal Antibody ◽

Lung Colonization

ABSTRACT The global use of a capsular polysaccharide-based pneumococcal vaccine has been limited because of serotype-specific protection and poor effectiveness in individuals with low immunocompetency. The mucosal immune system develops earlier in infants and lasts longer in the elderly than does the systemic immune system. Furthermore, mucosal immunization is beneficial for AIDS patients, because human immunodeficiency virus-infected subjects can develop normal mucosal antibody responses even in late clinical phases. For these reasons, we evaluated recombinant pneumococcal surface adhesin A (rPsaA) of Streptococcus pneumoniae in terms of cross-protective immune responses after oral delivery. Encapsulated rPsaA provided higher immunogenicity than naked rPsaA. Coencapsulation or codelivery of the cholera toxin (CT) B subunit (CTB) and CT also increased the immunogenicity of rPsaA. Cross-protective immunities against five strains of S. pneumoniae (types 4, 6B, 14, 19F, and 23F) were induced after oral immunization with microencapsulated rPsaA. Lung colonization and septicemia caused by the five serotypes were significantly inhibited by oral immunization with microencapsulated rPsaA. These results suggest that rPsaA coencapsulated with CTB can be used as an oral vaccine to induce cross-protective immunity for the prevention of pneumococcal infection.

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The epidemiology of pneumococcal infection in children in the developing world

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1999.0430 ◽

1999 ◽

Vol 354 (1384) ◽

pp. 777-785 ◽

Cited By ~ 113

Author(s):

Brian Greenwood

Keyword(s):

Young Children ◽

Invasive Pneumococcal Disease ◽

Pneumococcal Disease ◽

Developing World ◽

Pneumococcal Infection ◽

Field Trials ◽

Industrialized Countries ◽

Pneumococcal Infections ◽

Increased Risk ◽

Meningitis In Children

Pneumonia causes about three million deaths a year in young children, nearly all of which are in developing countries. Streptococcus pneumoniae (the pneumococcus) is the most important bacterial cause of pneumonia in young children and so is likely to be responsible for a high proportion of these deaths. The pneumococcus is also responsible for a substantial proportion of the 100 000–500 000 deaths that occur from meningitis in children each year. The incidence of invasive pneumococcal disease in children in the developing world is several times higher than in industrialized countries. This discrepancy may, in part, be due to socio–economic differences but genetic factors may also play a role. Children with sickle cell disease have a substantially increased risk of invasive pneumococcal infection and a search is being made for other possible genetic risk factors. Infection with human immunodeficiency virus (HIV) also predisposes to invasive pneumococcal disease and so the incidence of this disease in young children is expected to rise as increasing numbers of African and Asian children are born with a perinatally acquired HIV infection. Until recently, pneumococcal infections could be treated effectively with penicillin, a cheap and safe antibiotic. However, pneumococci that are resistant to penicillin are becoming prevalent in many countries, necessitating a change to more costly antibiotics which may be beyond the reach of the health services of poor, developing counties. The spread of antibiotic resistance has provided an added stimulus to the development of vaccines that might be able to prevent pneumococcal disease in infants. Recently developed polysaccharide–protein conjugate vaccines show promise and are now undergoing field trials. How deployment of these vaccines will influence the balance between invasive pneumococcal infections and asymptomatic nasopharyngeal carriage of pneumococci is uncertain.

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