Pneumococcal

Pneumococcal disease is recognized as a significant global health threat. The bacterium responsible for pneumococcal disease, Streptococcus pneumoniae, is subsequently also the most common cause of community-acquired pneumonia, bacterial meningitis, bacteremia, and otitis media. This is due to the progressive nature of S. pneumoniae infection, characterized by an initial colonization of a host (as a biofilm in the nasopharynx) prior to a virulence transition step that results in biofilm release, anatomical dispersion, and disease symptoms (Figure 1).

Figure 1. Overview of Pneumococcal Pathogenesis.                                                 

Source: Jones et al. Comprehensive vaccine design for commensal disease progression. Science Advances 18 Oct 2017: Vol. 3, no. 10, e1701797, DOI: 10.1126/sciadv.170179

Despite the success that routine use of polysacchride conjugate vacines (PCVs) have achieved in countries like the United States, where the incidence rate of invasive pneumococcal disease is less than 100 per 100,000 and the mortality rate is below 2% for children under 5, S. pneumoniae still remains a major global healthcare challenge. Furthermore, pneumococcal disease devastates resource-poor countries, causing an estimated 476,000 deaths annually, which represents ~32% of vaccine-preventable deaths in children age five and below. 

Polysaccharide conjugate vaccines (PCVs / glycoconjugates) represent the most potent currently available method of addressing pneumococcal disease and feature a chemical attachment of select S. pneumoniae serotype capsular polysaccharides to an immunogenic carrier protein. Of available commercial vaccine formulations, glycoconjugates are preferred over free polysaccharides, as conjugation to a protein carrier facilitates antibody class shifting from immunoglobulin M (IgM) to immunoglobulin G (IgG) in the background of strengthened immunological memory. This is especially critical in young children, in which polysaccharide-only vaccines are incapable of generating an adequate immune response.

However, glycoconjugate vaccines have three significant drawbacks that limit current and projected health impact:

  • First, commercial PCVs do not account for pneumococcal disease progression and instead only focus upon limiting initial bacterial colonization of a host (see Figure 1). This is a result of featuring the capsular polysaccharide as the primary vaccine component (linked to a carrier protein).
  • This design, in turn, leads to a second complication: complete vaccine protection requires the theoretical inclusion of all 95+ serotypes of S. pneumoniae. Such a demanding requirement leads to a third drawback, related to production and distribution. Specifically, manufacturing of this class of vaccine involves the separate production, purification, and processing of polysaccharide from each incorporated serotype within a specific vaccine formulation (for example, current commercial glycoconjugate vaccines options only cover up to 13 serotypes).
  • Further complicating economical production is the need to activate and chemically conjugate each polysaccharide to a separately generated immunogenic carrier protein (e.g., CRM197) using reductive amination, followed by additional purification and eventual co-formulation with other polysaccharide-conjugates.

Recognizing the need to develop a new generation of pneumococcal vaccines, and glycoconjugate vaccines more broadly, Abcombi Biosciences Inc. has developed an alternative protein-polysaccharide coupling strategy that circumvents the chemical conjugation required of current glycoconjugate vaccines while maintaining polysaccharide-specific antibody class shifting from IgM-to-IgG in a generalizable and scalable process. Specifically, our vaccine strategy utilizes our LEPS (liposomal encapsulation of polysaccharides) platform capable of displaying either traditional immunogenic carrier proteins (such as CRM197) or virulence-associated pneumococcal proteins through a non-covalent mechanism. 

Figure 2: LEPS Vaccine Mechanism of Protection 

Source: Jones et al. Comprehensive vaccine design for commensal disease progression. Science Advances 18 Oct 2017: Vol. 3, no. 10, e1701797, DOI: 10.1126/sciadv.1701797

Utilizing this formulation strategy, our vaccine product has the additional unique potential to offer a two-pronged protection strategy against pneumococcal disease through the combined vaccination pneumococcal capsular polysaccharides (CPS), which serve to prevent colonization by the most invasive pneumococcal serotypes, and a highly conserved protein (PncO) that prevent breakthrough disease (Figure 2). 

Through the development of our LEPS vaccine, we demonstrated that physical co-localization of the pneumococcal capusular polysacccharides (CPS) within a protein-decorated liposome, we are able to generate an glycoconjugate-like immune response without requring conjugation to a carrier protein. In our studies to date, we have demonstrated protection against 24 serotypes of S. pneumoniae via CPS. Furthermore, vaccination with our highly conserved pneumococcal protein has demonstrated immunogenicity against >70 serotypes through an opsonophagocytosis activity (OPA) assay. We subsequently provide glycoconjugate-like efficacy against the broadest array of serotypes available relative to current commercial pneumococcal conjugate vaccines (i.e., Prevnar 13®), Merck’s V114 vaccine currently in phase III clinical trials (a 15-valent vaccine) and even Pfizer’s 20-valent vaccine that is currently in development.

Abcombi has been recently awarded a Phase II SBIR to provided funding over the next three years to complete the CMC and toxicity studies to bring out technology to IND-readiness.

Main research publications:

1. Li Y, Hill A, Beitelshees M, Shao S, Lovell JF, Davidson BA, Knight PR, Hakansson AP, Pfeifer BA, Jones CH. Directed vaccination against pneumococcal disease. Proceedings of the National Academy of Sciences. 2016;113(25):6898-903.

2. Jones CH, Zhang G, Nayerhoda R, Beitelshees M, Hill A, Rostami P, Li Y, Davidson BA, Knight P, Pfeifer BA. Comprehensive vaccine design for commensal disease progression. Science Advances. 2017;3(10). doi: 10.1126/sciadv.1701797.

3.  Hill AB, Beitelshees M, Nayerhoda R, Pfeifer BA, Jones CH. Engineering a next-generation glycoconjugate-like Streptococcus pneumoniae Vaccine. ACS Infectious Diseases. 2018. doi: 10.1021/acsinfecdis.8b00100.