Next generation pneumococcal vaccines

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Currently licensed pneumococcal vaccines are based on the generation of antibodies to the pneumococcal polysaccharide, of which there are more than 90 different types. While these vaccines are highly effective against the serotypes included, their high cost and limited serotype coverage limit their usefulness worldwide, particularly in low resource areas. Thus alternative or adjunctive options are being actively pursued. This review will present these various approaches, including variations of the polysaccharide–protein conjugate strategy, protein-based strategies, and whole cell pneumococcal vaccines. The immunological basis for these different approaches is discussed as well.

Highlights

► Currently licensed pneumococcal vaccines are effective but also have limitations for worldwide use. ► There is much interest in the development of novel, broad pneumococcal vaccines. ► Antibodies or effector T cells directed against conserved pneumococcal proteins are protective. ► Three novel vaccine approaches: modified conjugates, protein-based, or an inactivated whole cell vaccine.

Introduction

Streptococcus pneumoniae causes approximately 11% of mortality worldwide in children under five [1]. Pneumococcus causes invasive disease including sepsis, meningitis, and, most frequently, pneumonia; it is also a common cause of primarily mucosal diseases, such as acute otitis media (AOM) and sinusitis. Since the introduction of conjugated polysaccharide vaccines (PCVs) over 10 years ago, countries that have implemented universal vaccination programs have seen significant reductions in rates of pediatric invasive pneumococcal disease (IPD) due to strains covered by these vaccines [2]. While the success of PCVs has been substantial, their high manufacturing complexity and costs limit their use in developing nations where morbidity and mortality from pneumococcal disease are highest. Additionally, there are over 90 identified pneumococcal serotypes and the regional distribution of predominant serotypes varies. Therefore, an affordable vaccine that confers broad, preferably serotype-independent protection from pneumococcal disease remains a major global health priority.

Section snippets

Current vaccines

The longest standing pneumococcal vaccine currently available is Pneumovax®23 (Merck), composed of purified polysaccharides of 23 different serotypes. Pneumovax®23 is recommended for adults over the age of 65 and some high-risk patient populations, but its use in children is limited as polysaccharides are poorly immunogenic in infants and children under the age of two years. For the purposes of this review, further discussion of currently available vaccines will focus on PCVs.

A 7-valent PCV

Immunity to pneumococcal disease and colonization

Anticapsular antibodies are sufficient to prevent invasive disease such as meningitis and sepsis. Measurements of serotype-specific antibody titers and, more recently, opsonophagocytic activities (OPA) against various serotypes have been the mainstay of assessing immunogenicity of PCV preparations. What is less clear, however, is whether these antibodies are necessary for protection against invasive disease or whether these represent the natural mechanism whereby unimmunized children become

Mouse models of pneumococcal colonization and disease

It is important to remember that, with the exception of great apes, the only natural host of pneumococcus is the human. Thus, despite the wide use of mouse models in the scientific literature, some caution should be used when interpreting the results obtained from these studies, as they may not necessarily apply to the human. Mice are readily colonized by pneumococci of multiple types [10]; in some mice using specific pneumococcal strains, colonization can be shown to last several weeks, which

Novel vaccine approaches

For the purposes of this review, we will distinguish three vaccine approaches that are being considered.

Whole cell pneumococcal vaccines

Over a decade ago, our group began investigating the possibility of using a killed whole cell pneumococcal vaccine, where a large number of pneumococcal antigens would be presented at once. Such an approach is not novel, since published reports of numerous trials using this strategy date back as early as 1911. Accurately determining the efficacy of this approach in preventing pneumococcal infections or complications after influenza is difficult but a recent meta-analysis of this topic has

Conclusions

The advent and initial success of conjugate pneumococcal vaccines in 2000 brought about the hopes of reducing, if not virtually eliminating, pneumococcus as a major scourge of humanity. Since then, we have learned much about the ability of anticapsular antibodies to significantly reduce the burden of pneumococcal diseases both directly and indirectly, via the establishment of herd immunity. At the same time, we have also been reminded of the abilities of pneumococcus to adapt and overcome

Conflict of interest statement

RM is a member of the scientific advisory board of Genocea Biosciences, Cambridge MA and has served as a consultant for GSK Biologicals.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors gratefully acknowledge past and present support from PATH, the Meningitis Research Foundation, the Pamela and Jack Egan Fund and the U.S. Public Health Service (grants AI067737 and AI066013).

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