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Infect Immun, April 1998, p. 1513-1520, Vol. 66, No. 4
Departments of Medicine1 and
Pathology6 and
Biomedical
Instrumentation Center,5 Uniformed Services
University of the Health Sciences, Bethesda, Maryland 20814-4799;
Laboratory of Parasitic Diseases, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland 208922;
Department of Microbiology, University of Alabama at
Birmingham, Birmingham, Alabama 35294-21703;
and
Departments of Surgery and Microbiology, University of
Mississippi Medical Center, Jackson, Mississippi
392164
Received 27 May 1997/Returned for modification 7 July 1997/Accepted 2 December 1997
Antibody to pneumococcal surface protein A (PspA) has been shown to
be protective for Streptococcus pneumoniae infections in mice. In an attempt to define a model for inducing protective antibody to PspA in the absence of adjuvant, we designed two genetic fusions, PspA-interleukin-2 [IL-2]) and
PspA-granulocyte-macrophage colony-stimulating factor (GM-CSF).
These constructs maintained high cytokine function in vitro, as tested
by their activity on IL-2 or GM-CSF-dependent cell lines. While
intranasal immunization with PspA induced no detectable anti-PspA
response, both PspA-IL-2 and PspA-GM-CSF stimulated high
immunoglobulin G1 (IgG1) antibody responses. Interestingly, only the
PspA-IL-2, not the PspA-GM-CSF, construct stimulated IgG2a antibody
responses, suggesting that this construct directed the response along a
TH1-dependent pathway. Comparable enhancement of the
anti-PspA response with similar isotype profiles was observed
after subcutaneous immunization as well. The enhancement observed with
PspA-IL-2 was dependent on IL-2 activity in that it was not seen in
IL-2 receptor knockout mice, while PspA in alum induced high-titer
antibody in these mice. The antibody was tested for its protective
activity in a mouse lethality model using S. pneumoniae WU-R2. Passive transfer of 1:90 dilutions of sera from
mice immunized with PspA-IL-2 and PspA-GM-CSF elicited protection of
CBA/N mice against intravenous challenge with over 170 50% lethal
doses of capsular type 3 strain WU2. Only 0.17 µg or less of IgG
antibody to PspA was able to provide passive protection
against otherwise fatal challenge with S. pneumoniae. The
data demonstrate that designing protein-cytokine fusions may be a
useful approach for mucosal immunization and can induce high-titer
systemic protective antibody responses.
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Enhanced Protective Antibody Responses to PspA after
Intranasal or Subcutaneous Injections of PspA Genetically Fused
to Granulocyte-Macrophage Colony-Stimulating Factor or
Interleukin-2
*
Corresponding author. Mailing address: Department of
Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799. Phone: (301) 295-3620. Fax:
(301) 295-3557. E-mail: usuhs{at}netvision.net.il.
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