Recent approaches in whole cell pneumococcal vaccine development: a review study

  • Mona Mohammadzadeh Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Setareh Mamishi Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pediatric Infectious Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Babak Pourakbari Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Shima Mahmoudi Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
Keywords: Streptococcus pneumoniae, Vaccine, Protection


Despite the availability of relatively effective vaccines, Streptococcus pneumoniae still causes widespread morbidity and mortality. Current vaccines contain free polysaccharides or protein-polysaccharide conjugates, but do not induce protection against serotypes that are not included in the vaccines. Therefore, developing alternative vaccines is of high priority and importance. Several investigators have identified protective antigens common to pneumococci of many or all serotypes. Malley et al. in their study, have recommended unencapsulated whole cells, as an alternative vaccine, a number of such antigens unoccluded by capsule were presented in a native configuration in 2001. This review aimed at presenting this candidate of pneumococcal vaccine and results in an animal model.


Miyaji EN, Oliveira MLS, Carvalho E, Ho PL. Serotype-independent pneumococcal vaccines. Cell Mol Life Sci 2013;70:3303-3326.

O'Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374(9693):893-902.

Calix JJ, Porambo RJ, Brady AM, Larson TR, Yother J, Abeygunwardana C, et al. Biochemical, genetic, and serological characterization of two capsule subtypes among Streptococcus pneumoniae Serotype 20 strains: discovery of a new pneumococcal serotype. J Biol Chem 2012;287:27885-27894.

Calix JJ, Nahm MH. A new pneumococcal serotype, 11E, has a variably inactivated wcjE gene. J Infect Dis 2010;202:29-38.

Jin P, Kong F, Xiao M, Oftadeh S, Zhou F, Liu C, et al. First report of putative Streptococcus pneumoniae serotype 6D among nasopharyngeal isolates from Fijian children. J Infect Dis 2009;200:1375-1380.

Park IH, Park S, Hollingshead SK, Nahm MH. Genetic basis for the new pneumococcal serotype, 6C. Infect Immun 2007;75:4482-4489.

Wood WB, Jr., Smith MR. The inhibition of surface phagocytosis by the capsular slime layer of pneumococcus type III. J Exp Med 1949;90:85-96.

Schweinle JE. Pneumococcal intracellular killing is abolished by polysaccharide despite serum complement activity. Infect Immun 1986;54:876-881.

Frazao N, Brito-Avô A, Simas C, Saldanha J, Mato R, Nunes S, et al. Effect of the seven-valent conjugate pneumococcal vaccine on carriage and drug resistance of Streptococcus pneumoniae in healthy children attending day-care centers in Lisbon. Pediatr Infect Dis J 2005;24(3):243-252.

Huang SS, Platt R, Rifas-Shiman SL, Pelton SI, Goldmann D, Finkelstein JA. Post-PCV7 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004. Pediatrics 2005;116(3):e408-13.

Darrieux M, Goulart C, Briles D, Leite LCdC. Current status and perspectives on protein-based pneumococcal vaccines. Crit Rev Microbiol 2015:41:190-200.

Malley R, Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect Immun 2001;69:4870-4873.

Malley R, Anderson PW. Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity. Proc Natl Acad Sci U S A 2012;109:3623-3627.

Haneberg B, Herland Berstad AK, Holst J. Bacteria-derived particles as adjuvants for non-replicating nasal vaccines. Adv Drug Deliv Rev 2001;51(1-3):143-147.

Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 2006;440(7085):808-812.

Brodsky IE, Medzhitov R. Targeting of immune signalling networks by bacterial pathogens. Nat Cell Biol 2009;11:521-526.

Malley R, Morse SC, Leite LC, Areas APM, Ho PL, Kubrusly FS, et al. Multiserotype protection of mice against pneumococcal colonization of the nasopharynx and middle ear by killed nonencapsulated cells given intranasally with a nontoxic adjuvant. Infect Immun 2004;72:4290-4292.

Shoemaker NB, Guild WR. Destruction of low efficiency markers is a slow process occurring at a heteroduplex stage of transformation. Mol Gen Genet 1974;128:283-290.

Berry AM, Lock RA, Hansman D, Paton JC. Contribution of autolysin to virulence of Streptococcus pneumoniae. Infect Immun 1989;57(8):2324-2330.

Malley R. Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development. J Mol Med (Berl) 2010;88:135-142.

Malley R, Trzcinski K, Srivastava A, Thompson CM, Anderson PW, Lipsitch M. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc Natl Acad Sci U S A 2005;102(13):4848-4853.

Lu Y-J, Leite L, Gonçalves VM, Dias WdO, Liberman C, Fratelli F, et al. GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine 2010;28:7468-7475.

Lu Y-J, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 2008;4(9):e1000159.

Malley R, Srivastava A, Lipsitch M, Thompson CM, Watkins C, Tzianabos A, et al. Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect Immun 2006;74:2187-2195.

Lu Y-J, Yadav P, Clements JD, Forte S, Srivastava A, Thompson CM, et al. Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine. Clin Vaccine Immunol 2010;17(6):1005-1012.

Cernuschi T, Furrer E, Schwalbe N, Jones A, Berndt ER, McAdams S. Advance market commitment for pneumococcal vaccines: putting theory into practice. Bull W.H.O 2011;89:913-918.

Moffitt KL, Yadav P, Weinberger DM, Anderson PW, Malley R. Broad antibody and T cell reactivity induced by a pneumococcal whole-cell vaccine. Vaccine 2012;30:4316-22.

Rharbaoui F, Drabner B, Borsutzky S, Winckler U, Morr M, Ensoli B, et al. The Mycoplasma-derived lipopeptide MALP-2 is a potent mucosal adjuvant. Eur J Immunol 2002;32:2857-2865.

Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, et al. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J Immunol 2000;164:554-557.

Cianciarullo AM, Leme E, Beçak W, Raw I, Kubrusly FS. Ultrastructural chemical reaction to detect saturated phospholipids of a natural surfactant from pig lungs. Biotechnol Lett 2001;23:1293-1296.

Vernacchio L, Bernstein H, Pelton S, Allen C, MacDonald K, Dunn J, et al. Effect of monophosphoryl lipid A (MPL) on T-helper cells when administered as an adjuvant with pneumocococcal-CRM197 conjugate vaccine in healthy toddlers. Vaccine 2002;20(31-32):3658-3667.

Kozlowski PA, Williams SB, Lynch RM, Flanigan TP, Patterson RR, Cu-Uvin S, et al. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J Immunol 2002;169:566-574.

Basset A, Thompson CM, Hollingshead SK, Briles DE, Ades EW, Lipsitch M, et al. Antibody-independent, CD4+ T-cell-dependent protection against pneumococcal colonization elicited by intranasal immunization with purified pneumococcal proteins. Infect Immun 2007;75:5460-5464.

Bogaert D, Weinberger D, Thompson C, Lipsitch M, Malley R. Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model. Infect Immun 2009;77:1613-1622.

Moffitt KL, Malley R, Lu YJ. Identification of protective pneumococcal T(H)17 antigens from the soluble fraction of a killed whole cell vaccine. PLoS One 2012;7(8):e43445.

Gonçalves VM, Dias WO, Campos IB, Liberman C, Sbrogio-Almeida ME, Silva EP, et al. Development of a whole cell pneumococcal vaccine: BPL inactivation, cGMP production, and stability. Vaccine 2014;32:1113-1120.

Malley R, Morse S, Leite L, Areas A, Ho P, Kubrusly F, et al. Evaluation of adjuvants given intranasally with killed noncapsulated pneumococci in multi-serotype protection of mice against colonization and middle ear infection. Infect Immun 2004;72:4290-4292.

How to Cite
Mohammadzadeh M, Mamishi S, Pourakbari B, Mahmoudi S. Recent approaches in whole cell pneumococcal vaccine development: a review study. IJM. 9(6):381-8.
Review Article(s)