Elsevier

Vaccine

Volume 18, Issue 16, 25 February 2000, Pages 1707-1711
Vaccine

The potential to use PspA and other pneumococcal proteins to elicit protection against pneumococcal infection

https://doi.org/10.1016/S0264-410X(99)00511-3Get rights and content

Abstract

Pneumococcal proteins, alone, in combination with each other, or in combination with capsular polysaccharide–protein conjugates may be useful pneumococcal vaccine components. Four proteins with a potential for use in vaccines are PspA, pneumolysin, PsaA, and PspC. In a mouse model of carriage, PsaA and PspC were the most efficacious vaccine proteins. Of these, PsaA was the best at eliciting protection against carriage. However, a combination of PspA and pneumolysin may elicit stronger immunity to pulmonary infection and possibly sepsis than either protein alone. Recently, a phase one trial of a recombinant family 1 PspA was completed in man. PspA was observed to be safe and immunogenic. Injection of 0.1 ml of immune serum diluted to 1/400 was able to protect mice from fatal infection with S. pneumoniae. Under these conditions, pre-immune serum was not protective. The immune human serum protected mice from infections with pneumococci expressing either of the major PspA families (1 and 2) and both of the pneumococcal capsular types tested: 3 and 6.

Section snippets

Polysaccharide vaccines

It was demonstrated over 60 years ago that vaccines could be used to protect humans from pneumococcal infection [1]. The pneumococcal vaccine in widespread use at the present contains 23 different capsular polysaccharides and is efficacious in adults [2], [3]. Unfortunately, this vaccine was not able to elicit protective antibodies in infants, one of the major target groups of immunization. It was also no more than 60% efficacious in protecting the elderly from pneumococcal infection [4]. More

Pneumococcal protein candidates for vaccines

Because of these problems, several pneumococcal proteins that have been shown to elicit protection in mice (PspA, pneumolysin, PsaA, PspC and others [6], [7], [8] have been proposed as vaccine candidates. Recent studies at UAB, done in collaboration with James Paton [9] and Eddie Ades [10], have provided data on the comparative utility of these proteins in vaccines. Many of these results are still unpublished, but a summary of the general results is provided (Fig. 2). These studies have also

PspA

One of these proteins, PspA has recently undergone phase one clinical trials in man and has been found to be safe and highly immunogenic [11]. PspA is a protein that is found on all pneumococci [12]. PspA is able to interfere with fixation of complement component C3, thus potentially blocking downstream events leading to opsonization and phagocyte chemotaxis [13].

PspA has three major structural domains. The N-terminal, about 40% of the molecule, has a sequence consistent with a coiled-coil

Elicitation of protective antibody to PspA in man

While these studies have been encouraging regarding the potential development of a PspA vaccine, direct evidence that human antibodies to PspA could be protective has been lacking. There is some indirect evidence, however, that human antibody to PspA can be protective. Virolainen et al. showed that among children with invasive infections, those with the lowest titers of antibody to PspA are the ones who are infected most frequently with pneumococci [22]. These studies are correlative, however,

Potential application of pneumococcal proteins to human vaccines

PspA could be used in several different ways in the formulation of human vaccines. One possibility would be to formulate a vaccine containing a few PspAs of each of the two PspA families. If sufficiently efficacious, PspA could permit the development of a stand alone protein vaccine that would be much less costly to produce than conjugate vaccines. Another possibility would be to include one or more other pneumococcal proteins in the vaccine to maximize protection. A highly effective vaccine

Acknowledgements

Our studies have been supported by NIH, Grants AI21548 and HL58418, and support from Aventis Pasteur, Swiftwater, PA. Contributions to these studies from collaborators, J. S. Sampson and E. W Ades, at the Centers for Disease Control in Atlanta, and J. C. Paton A. G. Ogunniyi. at the Woman’s and Children’s Hospital in Adelaide, Australia, are greatly appreciated.

References (24)

  • J.C. Paton

    Novel pneumococcal surface proteins: role in virulence and vaccine potential

    Trends Microbiol

    (1998)
  • L.S. McDaniel et al.

    Localization of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260

    Microb. Pathog.

    (1994)
  • R. Heffron

    Pneumonia

    (1939)
  • R. Austrian

    The assessment of pnumococcal vaccine

    N. Engl. J. Med.

    (1980)
  • J.B. Robbins et al.

    Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups

    J. Infect. Dis.

    (1983)
  • E.D. Shapiro et al.

    Protective efficacy of polyvalent pneumococcal polysaccharide vaccine

    N. Engl. J. Med.

    (1991)
  • Black S, Shinefield H, Ray P, Edwi L, Fireman B, Group TKPVS et al. 1998. Efficacy of heptavalent conjugate...
  • D.E. Briles et al.

    Immunity to Streptococcus pneumoniae

  • Briles DE, Tart RC, Swiatlo E, Dillard JP, Smith P, Benton KA et al., Pneumococcal diversity: considerations for new...
  • Ogunniyi AD, Folland RL, Hollingshead SK, Briles DB, Paton JC. Immunization of mice with combinations of pneumococcal...
  • De BK, Sampson JS, Ades EW, Huebner RC, Jue DL, Johnson SE et al., Purification and characterization of Streptococcus...
  • Nabors GS, Braun PA, Herrmann DJ, Pyle DJ, Gravenstein S, Shilling M et al.. Immunization of healthy adults with a...
  • Cited by (122)

    • Rational selection of broadly cross-reactive family 2 PspA molecules for inclusion in chimeric pneumococcal vaccines

      2017, Microbial Pathogenesis
      Citation Excerpt :

      In order to improve the coverage of the existing polysaccharide-based vaccines, several conserved proteins have been investigated as alternative low cost strategies [3–6]. Pneumococcal Surface Protein A (PspA) is a largely studied virulence factor, able to induce protection in several animal models [7–12]. PspA is present in virtually all pneumococcal strains and is exposed at the bacterial surface, where it may interact with antibodies, complement molecules and other immune mediators [13].

    • Vaccine Potential of Pneumococcal Proteins

      2015, Streptococcus Pneumoniae: Molecular Mechanisms of Host-Pathogen Interactions
    • Genetic conjugation of components in two pneumococcal fusion protein vaccines enhances paediatric mucosal immune responses

      2015, Vaccine
      Citation Excerpt :

      However, these experiments do not directly demonstrate that the enhanced proliferative responses induced at higher concentrations of the fusion protein are directed against PsaA. Previously we and others have shown that PsaA is a good T-cell antigen and pneumococcal vaccine candidate [23–25,36], but we did not detect any proliferative responses to PsaA alone in the concentration range 0.04–1.28 μg/ml at which most of the cell cultures were stimulated. To test our antigen delivery hypothesis further, higher concentrations (8 μg/ml) of PsaA were tested and enhanced responses, presumably by increasing antigen uptake by APCs, thus circumventing any requirement for enhanced antigen-delivery by Ply/Δ6Ply (data not shown).

    View all citing articles on Scopus
    View full text