What is Pneumococcal Disease?

Pneumococcal disease is caused by the bacterium Streptococcus pneumoniae. The infection commonly manifests as pneumonia, meningitis, sepsis, and middle ear infections. In the developing world, S. pneumoniae is a significant cause of death in infants while in the developed world the elderly and immunocompromised are at highest risk.

Global Burden

Pneumococcal Disease

Lower respiratory tract infections (LRTIs) are the leading cause of death in children under 5, representing 19% of all deaths worldwide. An estimated 33 million DALYs are also lost per year in children under 5 due to LRTIs.1 It is difficult to estimate the true proportion of LRTIs due specifically to pneumococcal disease as the prevalence of the organisms that can cause LRTIs varies geographically, but pneumococcal disease is found throughout the world. It is estimated that pneumococcal disease accounts for 50% of severe pneumonia worldwide and an even higher percentage of fatal cases.1

Causative Agent

example

Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium. Due to differences in composition of the polysaccharide capsule, there are at least 90 S. pneumoniae serotypes.

S. pneumoniae bacteria are transmitted from person to person through respiratory droplets, usually though coughing or sneezing. Although S. pneumoniae is widely found in the nose and throat of healthy asymptomatic individuals, variations in the virulence of the bacteria and the immune status of the host can allow the bacteria to invade other parts of the body and cause disease. The nasopharynx of young children is considered the largest reservoir for the pneumococcal disease.

Pathogenesis

The presentation of pneumococcal disease depends on where the bacteria invade the body.

Site of infection Disease Presentation Symptoms
Nasopharynx None None
Ear Otitis media Fever, ear ache
Lungs Pneumonia Fever, cough, difficulty breathing due to buildup of liquid in the lung alveoli
Blood Sepsis Fever, chills, rapid heartbeat, disorientation due to bloodstream infection
Brain/spinal cord Meningitis Fever, chills, stiff neck that may result in paralysis, neurological damage, or death due to infection of the outer layer of the brain or spinal cord

Once the bacteria invade the body, they replicate and eventually begin to lyse. Lysis of the bacteria leads to a large inflammatory immune response that is thought to cause the majority of symptoms associated with the disease.

Current Control Strategy

 The World Health Organization (WHO) has laid out an action plan for the prevention and control of pneumococcal disease that includes:2

  1. Improved case management
  2. Vaccination
  3. Prevention and management of HIV
  4. Improved nutrition and reduction in low birth weight
  5. Control of indoor air pollution

While the first two points are directly related to pneumococcal disease treatment and prevention, points three through five represent prevention strategies through control of risk factors for severe disease.

Existing Products

Drugs

Numerous antibiotics are effective against pneumococcal disease including penicillin, amoxicillin, cephalosporins, erythromycin, azithromycin, clarithromycin, and fluorquinolones. As noted above, treatment with azithromycin or co-trimoxazole is recommended by WHO/UNICEF for children with suspected pneumonia in the developing world.

Vaccines

There are currently three vaccines approved for the prevention of pneumococcal disease, each with different benefits and features.

Product Developer Approval Notes
Prevnar 13 (PCV13) Pfizer Approved in the U.S. February 2010 13-valent polysaccharides conjugated to diphtheria CRM197 protein

Recommended for children <5

Replaced Prevnar 7
Synflorix GlaxoSmithKline (GSK) Approved in Europe April 2009 10-valent polysaccharides conjugated to non-typable H. influenzae carrier

Includes 3 serotypes not available in Prevnar 13 

Also protects against Otitis media, meningitis, and sepsis from S. pneumoniae
Pneumovax 23 (PPSV) Merck Approved in U.S. June 1983 23-valent polysaccharide vaccine

Recommended for adults >65 or >2 at high risk

Although a significant market for pneumococcal vaccines exists in the developed world, the current vaccines have been cost prohibitive for use in the developing world. In order to incentivize access, a US $1.5 billion Advance Market Commitment (AMC) was established in 2009 to create a market for pneumococcal vaccines in the developing world.

In March 2010, GSK and Pfizer signed a 10 year deal with the Global Alliance for Vaccines and Immunizations (GAVI) to supply 60 million doses per year of their approved vaccines for US$3.50-7.00 per dose.3 This represents the first supply agreement signed under the AMC. GAVI launched the first program to introduce the new vaccines in Nicaragua through this program in December 2010.4

Diagnostics

The gold standard for diagnosis of pneumococcal disease is bacterial culture from sputum or blood. Blood cultures are less sensitive than sputum cultures but are often used in young children who are unable to produce sputum samples.

A rapid test for pneumococcal disease is also available that detects bacterial antigens in the urine. The test is highly sensitive when compared to bacterial culture for adults, but false positives often result in children who are asymptomatic nasopharyngeal carriers of the bacteria.
 

References

  1. UNICEF (2006) Pneumonia: the forgotten killer of children.
  2. WHO and UNICEF (2009) Global action plan for the prevention and control of pneumonia (GAPP).
  3. GAVI press release.
  4. GAVI press release.

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Drugs

Although drug resistance is a concern, numerous antibiotics are available for the treatment of pneumonia. Vaccines and tools for improved diagnosis rather than treatment are the focus of new product development for pneumococcal disease.

Vaccines

Analysis

The primary focus of the pneumococcal vaccine community is promoting access to existing vaccines, so it is unclear how much focus will be placed on new vaccine development in the near term.

There are currently three additional pneumococcal vaccines in clinical stage development. Details on these vaccines are not widely available, however two of the vaccines appear to be polysaccharide-based. Additional vaccines in discovery and pre-clinical development include recombinant/purified protein vaccines. As there are over 90 serotypes that vary based on the polysaccharide capsule, recombinant protein-based vaccines may offer the advantage of wider protection. However, recombinant protein-based vaccines are likely to elicit weaker immune responses.

 StrengthsWeaknessesOpportunitiesRisks
Polysaccharide Protein Conjugate Vaccines
Most advanced program:  Prevnar 13 and Synflorix, On Market; GSK2189242A and V114, Phase II Already on market and in use prevention of pneumonia Only protect against 10-15 of the over 90 serotypes of bacteria Vaccines that cover different combinations of polysaccharides targeted specifically for the developing worldIt is not clear if newer polysaccharide conjugate vaccines will have significant advantages over approved vaccines

Diagnostics

Analysis

There is a need for new point-of-care diagnostics for pneumonia in the developing world that:

  1. Can distinguish between S. pneumoniae carriers (especially children) and people who are sick from infection
  2. Do not require sputum which is difficult to obtain from children
  3. Profile antibiotic susceptibility
  4. Can differentially diagnose bacterial pneumonia from viral respiratory infections and other major causes of fever

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for pneumococcal disease. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for pneumococcal disease are generally well developed.  

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: Sequenced, studies of diversity ongoing 

Key databases:Genomic Sequencing Center for Infectious Diseases 

In vitro culture: Yes

Gene knock-outs: Yes 

Conditional gene knock-outs: Yes

Transposon mutagenesis: Yes 

RNAi: Host cell only 

Other antisense technology: Host cell only  

Viability assays: Yes  

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures: Yes

 

Whole-cell screening assays: Yes

Enzymatic screening assays: Yes

Animal models: Yes 

Pneumonia – Mouse, intranasal inoculation 

Meningitis - Mouse, intracerebral inoculation 

Sepsis – Mouse, intraperitoneal or intravenous inoculation

Otitis Media – Chinchilla, mouse and rat also possible

Monitoring treatment efficacy: Yes

Availability of endpoints: Yes, reduction in bacteremia in sputum 

Availability of surrogate endpoints: Yes, clearance of bacteremia 

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes, most commonly mouse

Detection of endogenous antigen specific response in clinical samples: Yes 

Natural immunity well characterized: Yes

Surrogate markers of protection: No 

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes

Access to clinical samples: Yes 

Possible sample types: Sputum, blood, urine

Access to clinical trial patients/sites: Yes 

Treatment available if diagnosed: Yes

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.