Unencapsulated killed whole cells as an intranasal vaccine to prevent pneumococcal meningitis and invasive disease

Research archive

Newly-licensed heptavalent capsular conjugate pneumococcal vaccines have been shown to be effective in the prevention of bacteremia (and thus likely meningitis) in young children. While universal immunisation with these vaccines would be likely to reduce the incidence of pneumococcal meningitis, several problems remain. First, although they cover serotypes that cause the most disease in young children, these vaccines do not cover all invasive capsular serotypes. Secondly, the theoretical concern of serotype replacement, whereby pneumococcal serotypes not included in the current vaccine formulation may emerge as more important pathogens, has already been confirmed in several clinical studies. Should this phenomenon occur following the widespread use of the vaccine, the effectiveness of conjugate pneumococcal vaccines would be potentially compromised. Finally, at current costs, it is unlikely that this vaccine will be used in developing countries where, arguably, it is needed most.

We have developed a vaccine to circumvent these problems. A killed unencapsulated pneumococcal mutant is used to raise antibodies to pneumococcal surface antigens; antibodies to these so-called "species antigens" react with all or many serotypes of pneumococci and have been shown to be protective. In preliminary studies, we have shown that intranasal administration of this vaccine with an adjuvant protected animals (of three different species) against death, bacteremia, meningitis, and otitis media. An extremely exciting finding was that this vaccine was completely protective against nasopharyngeal colonisation with a capsulated pneumococcus in mice; should this finding be confirmed, our approach could lead to herd immunity against pneumococci of all serotypes, which current conjugate vaccines would not.

This proposal is to investigate the mechanisms and optimise the efficacy of this approach. We hypothesise that our whole-cell pneumococcal vaccine administered intranasally will protect against invasive pneumococcal disease (including meningitis), regardless of the capsular serotype. The mechanisms underlying the protection observed in our animal models will be studied extensively, via a combination of immunological and statistical techniques. From these investigations, studies to optimise the killed vaccine, dose and schedule of administration, and adjuvant used, will be performed. At the completion of this proposed project, we will plan safety and immunogenicity studies in humans.

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.
http://iai.asm.org/cgi/reprint/69/8/4870.pdf

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.
http://pediatrics.aappublications.org/cgi/reprint/110/4/712.pdf

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.
http://www.jimmunol.org/cgi/reprint/169/7/3970.pdf

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.
http://www.pnas.org/cgi/reprint/100/4/1966.pdf

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.
http://iai.asm.org/cgi/reprint/72/7/4290.pdf

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.
http://medicine.plosjournals.org/archive/1549-1676/2/1/pdf/10.1371_journal.pmed.0020015-L.pdf

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.
http://iai.asm.org/cgi/reprint/73/10/7043

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.
http://iai.asm.org/cgi/reprint/73/10/6479.pdf