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Pneumococcal proteins that may constitute the next generation vaccine for pneumococcal disease
International Congress Series 1257 (2003) 27 – 31
www.ics-elsevier.com
Pneumococcal proteins that may constitute the next generation vaccine for pneumococcal disease David E. Briles a,b,*, Susan K. Hollingshead a, Marilyn J. Crain b, Bing Ren a, Shaper Mirza a, James Watt a, Jason Johnston a a
Department of Microbiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA b Department of Pediatrics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
Abstract. Cross-reactive ‘‘common’’ pneumococcal antigens offer an attractive alternative, or complement, to polysaccharides and polysaccharide-protein conjugate vaccines. These common antigens should be protective against strains of a wider range of capsular types than can be achieved with conjugate vaccines. Common protein antigens would be expected to be highly immunogenic in young children and should be able to be manufactured relatively inexpensively using recombinant techniques. It is hoped that these antigens will lead to a vaccine(s) that could have application worldwide, even in the poorest developing countries where the rates of fatal pneumococcal disease in children are the highest. D 2003 Elsevier B.V. All rights reserved. Keywords: Streptococcus pneumoniae; Common protein vaccine; PspA; Pneumolysin; PspC; PcpA; PsaA; Neuraminidase; Autolysin
1. Introduction Even before the acquisition of high-level antibiotic resistance by Streptococcus pneumoniae, it has been a major cause of morbidity and death. The pneumococcus causes bacterial pneumonia, meningitis and otitis media. The most pervasive antigen on the pneumococcal surface is the capsular polysaccharides. Each strain expresses one of over 90 different polysaccharides. When isolated, these polysaccharides are not immunogenic in children. An immunogenic seven-valent polysaccharide-protein conjugate vaccine has been developed that contains polysaccharides of the seven capsular types most common on strains infecting children in the US and Northern Europe. This vaccine has been found to be highly effective against invasive disease in children [1]. Adults are infected with strains of many more capsular types; the vaccine licensed for adults contains 23 capsular types in a non-conjugated form [2].
* Corresponding author. Postal address: BBRB 658, 1530 3rd Avenue South, Birmingham, AL 35294-2170, USA. Tel.: +1-205-934-6595; fax: +1-205-934-0605. E-mail address: [email protected] (D.E. Briles). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01157-9
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D.E. Briles et al. / International Congress Series 1257 (2003) 27–31
Unfortunately, the 23-valent vaccine for the elderly is of controversial efficacy, but in some populations is of clear benefit to patients [2]. The seven-valent vaccine for children does not cover all of the childhood capsular types, and is far too expensive for use in much of the developing world where most of the fatal infections with this pathogen occur. To make matters worse, the seven-valent vaccine covers as few as 50% or less of the strains causing infection in many of the developing countries [3]. Much effort has been expended to identify protein antigens of the pneumococcus that might be more cross-reactive and more immunogenic in children than pneumococcal polysaccharides. Since the protection-eliciting regions of these proteins can frequently be produced relatively inexpensively by recombinant technology, it is likely that a vaccine containing several of these proteins could be produced inexpensively enough to be affordable in most of the regions of the world where it is needed the most. 2. Potential protein vaccine antigens Summaries of the large number of pre-clinical studies of protein vaccines for the pneumococcus have been the subject of several recent reviews [4,5]. Of those pneumococcal proteins that have been proposed as vaccine candidates, those that have been studied most extensively are PspA, pneumolysin, autolysin, neuraminidase, PspC (also called CbpA) and PsaA. A number of other protection-eliciting proteins have been identified with various genetic screening methods, but the published data documenting the ability of these proteins to elicit protection is limited. 2.1. Pneumococcal proteins eliciting protection against colonization PsaA, PspC and PspA are each able to elicit immunity to nasal colonization in the mouse. Better protection was observed, however, if mice were immunized with both PsaA and PspA than with either antigen alone [6] (Table 2). PsaA and PspC, so far appear to be the best proteins for this purpose when immunized by themselves. PsaA is a component of a critical transporter for Mn2 + [7]. Although there is some controversy about whether this protein serves as an adhesin, it is likely that its effect on adherence is through its requirement for Mn2 + transport. Although the molecule is closely associated with the bacterial surface [8], it is assumed that in carriage (where most bacteria are in the transparent phase) that antibodies to the PsaA are able to reach and inactivate PsaA because of the relatively thin cell wall and capsule of transparent phase pneumococci. PspC and its allelic variant Hic are able to bind to factor H, and thus interfere with C3 activation at the pneumococcal surface [9,10]. However, this property may not explain why PspC is critical for nasal carriage or why immunity to PspC can prevent carriage. It has been proposed that PspC promotes carriage and invasion through its interaction with the polymeric-Ig receptor [11]. PspA is able to bind apolactoferrin and thereby reduce the ability of apolactoferrin to kill pneumococci (Mirza and Briles, manuscript in preparation). Apolactoferrin is present in milligrams per milliliter concentrations on the mucosal surface. PspA also inhibits C3 activation through an as yet unknown mechanism [12] and can even reduce the amount of C3 deposited by antibody to capsule (Ren and Briles, manuscript in preparation). We
D.E. Briles et al. / International Congress Series 1257 (2003) 27–31
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suspect that it is PspA’s ability to inhibit apolactoferrin-mediated killing that accounts for any role it may have in carriage. We have recently shown that even cell-free PspA can interfere with apolactoferrin-mediated killing of pneumococci (Mirza and Briles, manuscript in preparation). Antibody to PspA blocks the interaction of PspA with lactoferrin and thus indirectly enhances the killing of pneumococci by apolactoferrin. A recent carriage challenge study was conducted in humans using a challenge strain of pneumococci that secreted, rather than surface-expressed, its PspA. Volunteers who had pre-existing antibody to PspA were less likely to carry the challenge strain than those lacking antibody to PspA [13]. We feel that these antibodies may have mediated their effect by blocking the binding of PspA to lactoferrin (Mirza and Briles, unpublished). This would block PspA’s ability to block lactoferrin killing of the challenge strain. As a result, in those individuals with antibody to PspA, it would be expected that there would be more killing of the pneumococci by lactoferrin. 2.2. Penumococcal protein eliciting protection against bacteremia and sepsis PspA, pneumolysin, autolysin, neuraminidase and PspC have all been shown to be able to protect against systemic infection of mice with pneumococci [14 – 17]. Although all of these proteins elicit significant protection, the most complete protection against sepsis and death was provided by PspA, pneumolysin and PspC. PspA inhibits C3 activation [12,18,19] and pneumolysin depletes complement before it reaches the pneumococcal surface [20]. Pneumolysin also interferes with protective inflammation against pneumococci. Both proteins therefore, probably interfere with phagocytic killing of the pneumococci in vivo. Both PspA and pneumolysin have been able to provide protection against challenge at doses of 10 – 100 LD50 with a majority of challenge strains tested. In combination the two proteins can elicit protection against much larger challenge doses of pneumococci than either protein alone [21]. PspC (CbpA) preformed very well as a vaccine in recent studies [16,17,22]. Pneumococci lacking these virulent proteins are of reduced virulence and combinations of mutations in pneumolysin and either pspA or pspC (cbpA) resulted in decreases in virulence comparable to those of strains unable to make capsule [23]. 2.3. Protection against lung infection Using a model of lung infection that results in focal pneumonia in a mouse, we have shown that both PspA and pneumolysin were able to elicit protection against pneumonia. The best protection, however, was obtained by immunizing with a mixture of these two proteins as it was able to reduce the number of pneumococci in the lung by more than 1000-fold [24]. 3. Application of pneumococcal proteins to vaccines One of the pneumococcal proteins, PspA, has been tested in humans and it was found to be safe and able to elicit antibodies in man that could protect mice from fatal systemic infection with S. pneumoniae [14]. PspA and the other pneumococcal proteins could be
30
D.E. Briles et al. / International Congress Series 1257 (2003) 27–31
used alone as vaccines, but would be expected to be more protective if used in combinations of two or more proteins [6,21,24]. For protection against nasal colonization, mouse data suggest that mucosal immunization may be necessary to provide the highest levels of protection [25]. There is also the possibility that the pneumococcal proteins might be used as carriers for some or all of the polysaccharides that make up the present vaccines for pneumococci. Pneumolysin and PspA have both been shown to be effective carriers [5,26]. 4. Phosphocholine as a vaccine candidate Another non-capsular pneumococcal antigen that has been examined as a potential vaccine candidate is the phosphocholine epitope of C-polysaccharide and lipoteichoic acid (F-antigen). Antibodies to this epitope can protect against infection in mice with virtually all mouse virulent strains of S. pneumoniae [27]. Even human antibodies to PC were shown to be able to protect mice from otherwise fatal challenge [28]. This antigen is expressed by all pneumococci and is serologically invariant. It has long been known that most human sera contain a significant level of IgM antibodies to PC and it would appear likely that these antibodies contribute to the general resistance of adults to pneumococcal infection. The rationale for using this antigen in man has been increased by a recent report that immune responses to phosphocholine can, in an atherosclerotic mouse model, protect against atherosclerosis by blocking inflammation [29]. Thus, a vaccine that elicited antibodies to phosphocholine in the elderly might protect against both heart disease and pneumococcal infection. References [1] H.R. Shinefield, S. Black, Efficacy of pneumococcal conjugate vaccines in large scale field trials, Pediatr. Infect. Dis. J. 19 (4) (2000) 394 – 397. [2] E.D. Shapiro, A.T. Berg, R. Austrian, et al., Protective efficacy of polyvalent pneumococcal polysaccharide vaccine, N. Engl. J. Med. 325 (21) (1991) 1453 – 1460. [3] J.L. Di Fabio, E. Castaneda, C.I. Agudelo, et al., Evolution of Streptococcus pneumoniae serotypes and penicillin susceptibility in Latin America, Sireva-Vigia Group, 1993 to 1999, PAHO Sireva-Vigia Study Group, Pan American Health Organization, Pediatr. Infect. Dis. J. 20 (10) (2001) 959 – 967. [4] J.C. Paton, D.E. Briles, Streptococcus pneumoniae vaccines, in: R.W. Ellis, B.R. Brodeur (Eds.), New Bacterial Vaccines, Landes Bioscience, Georgetown, TX, 2003, pp. 294 – 310. [5] D.E. Briles, J.C. Paton, S.K. Hollingshead, Pneumococcal common proteins and other vaccine strategies, in: M.M. Levine, J.B. Kaper, R. Rappuoli, M. Liu, M. Good (Eds.), New Generation Vaccines, Marcel Dekker, New York, NY, in press. [6] D.E. Briles, E. Ades, J.C. Paton, et al., Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA and PspA is highly protective against nasopharyngeal carriage of Streptococcus pneumoniae, Infect. Immun. 68 (2) (2000) 796 – 800. [7] J.-P. Claverys, C. Granadel, A.M. Berry, J.C. Paton, Penicillin tolerance in Streptococcus pneumoniae autolysis and the Psa ATP binding cassette (ABC) manganese permease, Mol. Microbiol. 32 (1999) 881 – 891 (letter to editor). [8] M.C. Lawrence, P.A. Pilling, V.C. Epa, A.M. Berry, A.D. Ogunniyi, J.C. Paton, The crystal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABCtype binding protein, Structure 6 (12) (1998) 1553 – 1561. [9] S. Dave, A. Brooks-Walter, M.K. Pangburn, L.S. McDaniel, PspC, a pneumococcal surface protein, binds human factor H, Infect. Immun. 69 (5) (2001) 3435 – 3437.
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[10] H. Jarva, R. Janulczyk, J. Hellwage, P.F. Zipfel, L. Bjorck, S. Meri, Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded hic protein that binds to short consensus repeats 8 – 11 of factor H, J. Immunol. 168 (4) (2002) 1886 – 1894. [11] J.-R. Zhang, K.E. Mostov, M.E. Lamm, et al., The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells, Cell 102 (2000) 827 – 837. [12] B. Ren, A.J. Szalai, O. Thomas, S.K. Hollingshead, D.E. Briles, Both family 1 and family 2 PspAs can inhibit complement deposition and confer virulence to a capsular 3 serotype Streptococcus pneumoniae, Infect. Immun. 71 (2003) 75 – 85. [13] T.L. McCool, T.R. Cate, G. Moy, J.N. Weiser, The immune response to pneumococcal proteins during experimental human carriage, J. Exp. Med. 195 (3) (2002) 359 – 365. [14] D.E. Briles, S.K. Hollingshead, J. King, et al., Immunization of humans with rPspA elicits antibodies, which passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA, J. Infect. Dis. 182 (2000) 1694 – 1701. [15] R.A. Lock, D. Hansman, J.C. Paton, Comparative efficacy of autolysin and pneumolysin as immunogens protecting mice against infection by Streptococcus pneumoniae, Microb. Pathog. 12 (1992) 137 – 143. [16] A. Brooks-Walter, D.E. Briles, S.K. Hollingshead, The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia, Infect. Immun. 67 (1999) 6533 – 6542. [17] A.D. Ogunniyi, M.C. Woodrow, J.T. Poolman, J.C. Paton, Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA, Infect. Immun. 69 (10) (2001) 5997 – 6003. [18] C. Neeleman, P.M. Sibyl, S.P. Geelen, et al., Resistance to both complement activation and phagocytosis in type 3 pneumococci is mediated by binding of complement regulatory protein factor H, Infect. Immun. 67 (1999) 4517 – 4524. [19] A.-H.T. Tu, R.L. Fulgham, M.A. McCory, D.E. Briles, A.J. Szalai, Pneumococcal surface protein A (PspA) inhibits complement activation by Streptococcus pneumoniae, Infect. Immun. 67 (1999) 4720 – 4724. [20] J.C. Paton, B. Rowan-Kelly, A. Ferrante, Activation of human complement by the pneumococcal toxin pneumolysin, Infect. Immun. 43 (1984) 1085 – 1087. [21] A.D. Ogunniyi, R.L. Folland, D.B. Briles, S.K. Hollingshead, J.C. Paton, Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae, Infect. Immun. 68 (5) (2000) 3028 – 3033. [22] P. Balachandran, A. Brooks-Walter, A. Virolainen-Julkunen, S.K. Hollingshead, D.E. Briles, The role of pneumococcal surface protein C (PspC) in nasopharyngeal carriage and pneumonia and its ability to elicit protection against carriage of Streptococcus pneumoniae, Infect. Immun. 70 (2002) 2526 – 2534. [23] A.M. Berry, J.C. Paton, Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins, Infect. Immun. 68 (2000) 133 – 140. [24] D.E. Briles, S.K. Hollingshead, J.C. Paton, et al., Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae, J. Infect. Dis. 188 (3) (2003) 339 – 348. [25] H.-Y. Wu, M. Nahm, Y. Guo, M. Russell, D.E. Briles, Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage and infection with Streptococcus pneumoniae, J. Infect. Dis. 175 (1997) 839 – 846. [26] J.C. Paton, R.A. Lock, C.-J. Lee, et al., Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide, Infect. Immun. 59 (1991) 2297 – 2304. [27] D.E. Briles, J.C. Paton, M.H. Nahm, E. Swiatlo, Immunity to Streptococcus pneumoniae, in: M. Cunningham, R.S. Fujinami (Eds.), Effect of Microbes on the Immune System, Lippincott-Raven, Philadelphia, 2000, pp. 263 – 280. [28] D.E. Briles, C. Forman, J.C. Horowitz, et al., Antipneumococcal effects of C-reactive protein and monoclonal antibodies to pneumococcal cell wall and capsular antigens, Infect. Immun. 57 (1989) 1457 – 1464. [29] C.J. Binder, S. Horkko, A. Dewan, et al., Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL, Nat. Med. 9 (6) (2003) 736 – 743.
www.ics-elsevier.com
Pneumococcal proteins that may constitute the next generation vaccine for pneumococcal disease David E. Briles a,b,*, Susan K. Hollingshead a, Marilyn J. Crain b, Bing Ren a, Shaper Mirza a, James Watt a, Jason Johnston a a
Department of Microbiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA b Department of Pediatrics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
Abstract. Cross-reactive ‘‘common’’ pneumococcal antigens offer an attractive alternative, or complement, to polysaccharides and polysaccharide-protein conjugate vaccines. These common antigens should be protective against strains of a wider range of capsular types than can be achieved with conjugate vaccines. Common protein antigens would be expected to be highly immunogenic in young children and should be able to be manufactured relatively inexpensively using recombinant techniques. It is hoped that these antigens will lead to a vaccine(s) that could have application worldwide, even in the poorest developing countries where the rates of fatal pneumococcal disease in children are the highest. D 2003 Elsevier B.V. All rights reserved. Keywords: Streptococcus pneumoniae; Common protein vaccine; PspA; Pneumolysin; PspC; PcpA; PsaA; Neuraminidase; Autolysin
1. Introduction Even before the acquisition of high-level antibiotic resistance by Streptococcus pneumoniae, it has been a major cause of morbidity and death. The pneumococcus causes bacterial pneumonia, meningitis and otitis media. The most pervasive antigen on the pneumococcal surface is the capsular polysaccharides. Each strain expresses one of over 90 different polysaccharides. When isolated, these polysaccharides are not immunogenic in children. An immunogenic seven-valent polysaccharide-protein conjugate vaccine has been developed that contains polysaccharides of the seven capsular types most common on strains infecting children in the US and Northern Europe. This vaccine has been found to be highly effective against invasive disease in children [1]. Adults are infected with strains of many more capsular types; the vaccine licensed for adults contains 23 capsular types in a non-conjugated form [2].
* Corresponding author. Postal address: BBRB 658, 1530 3rd Avenue South, Birmingham, AL 35294-2170, USA. Tel.: +1-205-934-6595; fax: +1-205-934-0605. E-mail address: [email protected] (D.E. Briles). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01157-9
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Unfortunately, the 23-valent vaccine for the elderly is of controversial efficacy, but in some populations is of clear benefit to patients [2]. The seven-valent vaccine for children does not cover all of the childhood capsular types, and is far too expensive for use in much of the developing world where most of the fatal infections with this pathogen occur. To make matters worse, the seven-valent vaccine covers as few as 50% or less of the strains causing infection in many of the developing countries [3]. Much effort has been expended to identify protein antigens of the pneumococcus that might be more cross-reactive and more immunogenic in children than pneumococcal polysaccharides. Since the protection-eliciting regions of these proteins can frequently be produced relatively inexpensively by recombinant technology, it is likely that a vaccine containing several of these proteins could be produced inexpensively enough to be affordable in most of the regions of the world where it is needed the most. 2. Potential protein vaccine antigens Summaries of the large number of pre-clinical studies of protein vaccines for the pneumococcus have been the subject of several recent reviews [4,5]. Of those pneumococcal proteins that have been proposed as vaccine candidates, those that have been studied most extensively are PspA, pneumolysin, autolysin, neuraminidase, PspC (also called CbpA) and PsaA. A number of other protection-eliciting proteins have been identified with various genetic screening methods, but the published data documenting the ability of these proteins to elicit protection is limited. 2.1. Pneumococcal proteins eliciting protection against colonization PsaA, PspC and PspA are each able to elicit immunity to nasal colonization in the mouse. Better protection was observed, however, if mice were immunized with both PsaA and PspA than with either antigen alone [6] (Table 2). PsaA and PspC, so far appear to be the best proteins for this purpose when immunized by themselves. PsaA is a component of a critical transporter for Mn2 + [7]. Although there is some controversy about whether this protein serves as an adhesin, it is likely that its effect on adherence is through its requirement for Mn2 + transport. Although the molecule is closely associated with the bacterial surface [8], it is assumed that in carriage (where most bacteria are in the transparent phase) that antibodies to the PsaA are able to reach and inactivate PsaA because of the relatively thin cell wall and capsule of transparent phase pneumococci. PspC and its allelic variant Hic are able to bind to factor H, and thus interfere with C3 activation at the pneumococcal surface [9,10]. However, this property may not explain why PspC is critical for nasal carriage or why immunity to PspC can prevent carriage. It has been proposed that PspC promotes carriage and invasion through its interaction with the polymeric-Ig receptor [11]. PspA is able to bind apolactoferrin and thereby reduce the ability of apolactoferrin to kill pneumococci (Mirza and Briles, manuscript in preparation). Apolactoferrin is present in milligrams per milliliter concentrations on the mucosal surface. PspA also inhibits C3 activation through an as yet unknown mechanism [12] and can even reduce the amount of C3 deposited by antibody to capsule (Ren and Briles, manuscript in preparation). We
D.E. Briles et al. / International Congress Series 1257 (2003) 27–31
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suspect that it is PspA’s ability to inhibit apolactoferrin-mediated killing that accounts for any role it may have in carriage. We have recently shown that even cell-free PspA can interfere with apolactoferrin-mediated killing of pneumococci (Mirza and Briles, manuscript in preparation). Antibody to PspA blocks the interaction of PspA with lactoferrin and thus indirectly enhances the killing of pneumococci by apolactoferrin. A recent carriage challenge study was conducted in humans using a challenge strain of pneumococci that secreted, rather than surface-expressed, its PspA. Volunteers who had pre-existing antibody to PspA were less likely to carry the challenge strain than those lacking antibody to PspA [13]. We feel that these antibodies may have mediated their effect by blocking the binding of PspA to lactoferrin (Mirza and Briles, unpublished). This would block PspA’s ability to block lactoferrin killing of the challenge strain. As a result, in those individuals with antibody to PspA, it would be expected that there would be more killing of the pneumococci by lactoferrin. 2.2. Penumococcal protein eliciting protection against bacteremia and sepsis PspA, pneumolysin, autolysin, neuraminidase and PspC have all been shown to be able to protect against systemic infection of mice with pneumococci [14 – 17]. Although all of these proteins elicit significant protection, the most complete protection against sepsis and death was provided by PspA, pneumolysin and PspC. PspA inhibits C3 activation [12,18,19] and pneumolysin depletes complement before it reaches the pneumococcal surface [20]. Pneumolysin also interferes with protective inflammation against pneumococci. Both proteins therefore, probably interfere with phagocytic killing of the pneumococci in vivo. Both PspA and pneumolysin have been able to provide protection against challenge at doses of 10 – 100 LD50 with a majority of challenge strains tested. In combination the two proteins can elicit protection against much larger challenge doses of pneumococci than either protein alone [21]. PspC (CbpA) preformed very well as a vaccine in recent studies [16,17,22]. Pneumococci lacking these virulent proteins are of reduced virulence and combinations of mutations in pneumolysin and either pspA or pspC (cbpA) resulted in decreases in virulence comparable to those of strains unable to make capsule [23]. 2.3. Protection against lung infection Using a model of lung infection that results in focal pneumonia in a mouse, we have shown that both PspA and pneumolysin were able to elicit protection against pneumonia. The best protection, however, was obtained by immunizing with a mixture of these two proteins as it was able to reduce the number of pneumococci in the lung by more than 1000-fold [24]. 3. Application of pneumococcal proteins to vaccines One of the pneumococcal proteins, PspA, has been tested in humans and it was found to be safe and able to elicit antibodies in man that could protect mice from fatal systemic infection with S. pneumoniae [14]. PspA and the other pneumococcal proteins could be
30
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used alone as vaccines, but would be expected to be more protective if used in combinations of two or more proteins [6,21,24]. For protection against nasal colonization, mouse data suggest that mucosal immunization may be necessary to provide the highest levels of protection [25]. There is also the possibility that the pneumococcal proteins might be used as carriers for some or all of the polysaccharides that make up the present vaccines for pneumococci. Pneumolysin and PspA have both been shown to be effective carriers [5,26]. 4. Phosphocholine as a vaccine candidate Another non-capsular pneumococcal antigen that has been examined as a potential vaccine candidate is the phosphocholine epitope of C-polysaccharide and lipoteichoic acid (F-antigen). Antibodies to this epitope can protect against infection in mice with virtually all mouse virulent strains of S. pneumoniae [27]. Even human antibodies to PC were shown to be able to protect mice from otherwise fatal challenge [28]. This antigen is expressed by all pneumococci and is serologically invariant. It has long been known that most human sera contain a significant level of IgM antibodies to PC and it would appear likely that these antibodies contribute to the general resistance of adults to pneumococcal infection. The rationale for using this antigen in man has been increased by a recent report that immune responses to phosphocholine can, in an atherosclerotic mouse model, protect against atherosclerosis by blocking inflammation [29]. Thus, a vaccine that elicited antibodies to phosphocholine in the elderly might protect against both heart disease and pneumococcal infection. References [1] H.R. Shinefield, S. Black, Efficacy of pneumococcal conjugate vaccines in large scale field trials, Pediatr. Infect. Dis. J. 19 (4) (2000) 394 – 397. [2] E.D. Shapiro, A.T. Berg, R. Austrian, et al., Protective efficacy of polyvalent pneumococcal polysaccharide vaccine, N. Engl. J. Med. 325 (21) (1991) 1453 – 1460. [3] J.L. Di Fabio, E. Castaneda, C.I. Agudelo, et al., Evolution of Streptococcus pneumoniae serotypes and penicillin susceptibility in Latin America, Sireva-Vigia Group, 1993 to 1999, PAHO Sireva-Vigia Study Group, Pan American Health Organization, Pediatr. Infect. Dis. J. 20 (10) (2001) 959 – 967. [4] J.C. Paton, D.E. Briles, Streptococcus pneumoniae vaccines, in: R.W. Ellis, B.R. Brodeur (Eds.), New Bacterial Vaccines, Landes Bioscience, Georgetown, TX, 2003, pp. 294 – 310. [5] D.E. Briles, J.C. Paton, S.K. Hollingshead, Pneumococcal common proteins and other vaccine strategies, in: M.M. Levine, J.B. Kaper, R. Rappuoli, M. Liu, M. Good (Eds.), New Generation Vaccines, Marcel Dekker, New York, NY, in press. [6] D.E. Briles, E. Ades, J.C. Paton, et al., Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA and PspA is highly protective against nasopharyngeal carriage of Streptococcus pneumoniae, Infect. Immun. 68 (2) (2000) 796 – 800. [7] J.-P. Claverys, C. Granadel, A.M. Berry, J.C. Paton, Penicillin tolerance in Streptococcus pneumoniae autolysis and the Psa ATP binding cassette (ABC) manganese permease, Mol. Microbiol. 32 (1999) 881 – 891 (letter to editor). [8] M.C. Lawrence, P.A. Pilling, V.C. Epa, A.M. Berry, A.D. Ogunniyi, J.C. Paton, The crystal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABCtype binding protein, Structure 6 (12) (1998) 1553 – 1561. [9] S. Dave, A. Brooks-Walter, M.K. Pangburn, L.S. McDaniel, PspC, a pneumococcal surface protein, binds human factor H, Infect. Immun. 69 (5) (2001) 3435 – 3437.
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[10] H. Jarva, R. Janulczyk, J. Hellwage, P.F. Zipfel, L. Bjorck, S. Meri, Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded hic protein that binds to short consensus repeats 8 – 11 of factor H, J. Immunol. 168 (4) (2002) 1886 – 1894. [11] J.-R. Zhang, K.E. Mostov, M.E. Lamm, et al., The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells, Cell 102 (2000) 827 – 837. [12] B. Ren, A.J. Szalai, O. Thomas, S.K. Hollingshead, D.E. Briles, Both family 1 and family 2 PspAs can inhibit complement deposition and confer virulence to a capsular 3 serotype Streptococcus pneumoniae, Infect. Immun. 71 (2003) 75 – 85. [13] T.L. McCool, T.R. Cate, G. Moy, J.N. Weiser, The immune response to pneumococcal proteins during experimental human carriage, J. Exp. Med. 195 (3) (2002) 359 – 365. [14] D.E. Briles, S.K. Hollingshead, J. King, et al., Immunization of humans with rPspA elicits antibodies, which passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA, J. Infect. Dis. 182 (2000) 1694 – 1701. [15] R.A. Lock, D. Hansman, J.C. Paton, Comparative efficacy of autolysin and pneumolysin as immunogens protecting mice against infection by Streptococcus pneumoniae, Microb. Pathog. 12 (1992) 137 – 143. [16] A. Brooks-Walter, D.E. Briles, S.K. Hollingshead, The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia, Infect. Immun. 67 (1999) 6533 – 6542. [17] A.D. Ogunniyi, M.C. Woodrow, J.T. Poolman, J.C. Paton, Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA, Infect. Immun. 69 (10) (2001) 5997 – 6003. [18] C. Neeleman, P.M. Sibyl, S.P. Geelen, et al., Resistance to both complement activation and phagocytosis in type 3 pneumococci is mediated by binding of complement regulatory protein factor H, Infect. Immun. 67 (1999) 4517 – 4524. [19] A.-H.T. Tu, R.L. Fulgham, M.A. McCory, D.E. Briles, A.J. Szalai, Pneumococcal surface protein A (PspA) inhibits complement activation by Streptococcus pneumoniae, Infect. Immun. 67 (1999) 4720 – 4724. [20] J.C. Paton, B. Rowan-Kelly, A. Ferrante, Activation of human complement by the pneumococcal toxin pneumolysin, Infect. Immun. 43 (1984) 1085 – 1087. [21] A.D. Ogunniyi, R.L. Folland, D.B. Briles, S.K. Hollingshead, J.C. Paton, Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae, Infect. Immun. 68 (5) (2000) 3028 – 3033. [22] P. Balachandran, A. Brooks-Walter, A. Virolainen-Julkunen, S.K. Hollingshead, D.E. Briles, The role of pneumococcal surface protein C (PspC) in nasopharyngeal carriage and pneumonia and its ability to elicit protection against carriage of Streptococcus pneumoniae, Infect. Immun. 70 (2002) 2526 – 2534. [23] A.M. Berry, J.C. Paton, Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins, Infect. Immun. 68 (2000) 133 – 140. [24] D.E. Briles, S.K. Hollingshead, J.C. Paton, et al., Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae, J. Infect. Dis. 188 (3) (2003) 339 – 348. [25] H.-Y. Wu, M. Nahm, Y. Guo, M. Russell, D.E. Briles, Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage and infection with Streptococcus pneumoniae, J. Infect. Dis. 175 (1997) 839 – 846. [26] J.C. Paton, R.A. Lock, C.-J. Lee, et al., Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide, Infect. Immun. 59 (1991) 2297 – 2304. [27] D.E. Briles, J.C. Paton, M.H. Nahm, E. Swiatlo, Immunity to Streptococcus pneumoniae, in: M. Cunningham, R.S. Fujinami (Eds.), Effect of Microbes on the Immune System, Lippincott-Raven, Philadelphia, 2000, pp. 263 – 280. [28] D.E. Briles, C. Forman, J.C. Horowitz, et al., Antipneumococcal effects of C-reactive protein and monoclonal antibodies to pneumococcal cell wall and capsular antigens, Infect. Immun. 57 (1989) 1457 – 1464. [29] C.J. Binder, S. Horkko, A. Dewan, et al., Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL, Nat. Med. 9 (6) (2003) 736 – 743.