Pneumococcal bacteria cause a range of illness from common ear and sinus infections to potentially life-threatening diseases like meningitis, septicaemia and pneumonia.
Recently, a new 'conjugate' vaccine that provides some protection against these infections in young children has become available in America and is now licensed for use in Europe. However, pneumococcal bacteria exist in over 90 different varieties and, while this vaccine is highly effective against the most common types, it does not cover all those that cause illness. It is possible that bacteria not covered by this vaccine may emerge as more frequent causes of disease. Secondly, its current production costs probably rule out its use in developing countries where disease rates are highest.
In this project, scientists have used a strategy derived from classical vaccinology to develop an experimental vaccine to overcome these problems.
We know that animals and humans vaccinated with killed whole pneumococcal bacteria develop resistance to the disease. Using this approach, the researchers have taken a strain of pneumococcal bacteria that has no sugar coat, killed it and then applied it inside the nose of experimental animals. In preliminary studies, this whole-cell vaccine protected animals against death, meningitis, and ear infection, regardless of the infecting strain.
This project will show how the vaccine works and optimise its effectiveness, by adjusting vaccine formulation, dose and schedule of administration.
At the completion of this project, safety and immunogenicity studies in humans will be ready to begin.
Results from this study have been published in scientific journals as follows:
Malley R, Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, Thompson C, Briles D, Anderson P.
Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci.
Infect Immun 2001 Aug;69(8):4870-3.
Nigrovic LE, Kuppermann N, Malley R.
Development and validation of a multivariable predictive model to distinguish bacterial from aseptic meningitis in children in the post-Haemophilus influenzae era.
Pediatrics 2002 Oct;110(4):712-9.
Henneke P, Takeuchi O, Malley R, Lien E, Ingalls RR, Freeman MW, Mayadas T, Nizet V, Akira S, Kasper DL, Golenbock DT.
Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways.
J Immunol 2002 Oct 1;169(7):3970-7.
Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT.
Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection.
Proc Natl Acad Sci USA 2003 Feb 18;100(4):1966-71. Epub 2003 Feb 4.
Malley R, Morse SC, Leite LC, Areas AP, Ho PL, Kubrusly FS, Almeida IC, Anderson P.
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 Jul;72(7):4290-2.
Lipsitch M, Whitney CG, Zell E, Kaijalainen T, Dagan R, Malley R.
Are Anticapsular Antibodies the Primary Mechanism of Protection against Invasive Pneumococcal Disease?
PLoS Med 2005 Jan;2(1):e15. Epub 2005 Jan 25.
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 USA 2005 Mar 29;102(13):4848-53. Epub 2005 Mar 21. http://www.pnas.org/cgi/reprint/102/13/4848.pdf
Trzcinski K, Thompson C, Malley R, Lipsitch M.
Antibodies to conserved pneumococcal antigens correlate with, but are not required for, protection against pneumococcal colonization induced by prior exposure in a mouse model.
Infect Immun 2005 Oct;73(10):7043-6.
Srivastava A, Henneke P, Visintin A, Morse SC, Martin V, Watkins C, Paton JC, Wessels MR, Golenbock DT, Malley R.
The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease.
Infect Immun 2005 Oct;73(10):6479-87.