Immunogenicity and protective efficacy of mycobacterial DNA vaccines incorporating plasmid-encoded cytokines against Mycobacterium bovis.
DNA-based vaccines, alone or in combination with other sub-unit vaccination regimes, represent an alternative to live mycobacterial vaccines for protective immunization against tuberculosis. Here, we have used a murine immunization or Mycobacterium bovis aerosol challenge model to assess the immunogenicity and protective efficacy of mycobacterial DNA vaccines. Mice that received immunization with DNA constructs encoding M. bovis antigen 85A (Ag85-A) and arget(ESAT-6) produced measurable interferon-gamma (IFN-gamma) responses to CD4(+) T-cell epitope-peptide recall antigens in vitro. The magnitude of these responses was enhanced by co-delivery of a construct encoding murine cytokines (macrophage inhibitory protein (MIP)-1 alpha or interleukin(IL)-7), although they did not the match responses observed in mice that received Bacille Calmette-Guerin(BCG) immunisation. In contrast, DNA priming followed by boosting with modified vaccinia Ankara (MVA) vaccine (expressing M. tuberculosis Ag85-A) invoked higher IFN-gamma levels, with the most immunogenic regime of Ag85 or ESAT or IL-7 prime followed by MVA boost being of commensurate immunogenicity to BCG. Despite this, neither DNA alone nor DNA-prime or MVA boost regimes conferred measurable protection against aerosol challenge with virulent M. bovis. These data highlight both the promise and the shortcomings of new generation subunit tuberculosis vaccines, with particular emphasis on their potential as vaccines against M. bovis.
Young
Sarah L
SL
Department of Microbiology & Immunology, University of Otago, Dunedin, New Zealand. sarah.young@stonebow.otago.ac.nz
Slobbe
Lynn J
LJ
Peacey
Matthew
M
Gilbert
Sarah C
SC
Buddle
Bryce M
BM
de Lisle
Geoffrey W
GW
Buchan
Glenn S
GS
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis / Q000276:immunology* / Q000472:pathogenicity; D010957:Plasmids / Q000235:genetics; D032581:Tuberculosis Vaccines; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D019444:Vaccines, DNA; D014765:Viral Vaccines
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D018984:Epitopes, T-Lymphocyte; D015851:Interleukin-7; C549320:MVA 85A; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D014765:Viral Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis