Novel recombinant Mycobacterium bovis BCG, ovine atadenovirus, and modified vaccinia virus Ankara vaccines combine to induce robust human immunodeficiency virus-specific CD4 and CD8 T-cell responses in rhesus macaques.
Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA(401) as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA(401) was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA(401) and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.
Rosario
Maximillian
M
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford OX3 9DS, United Kingdom.
Hopkins
Richard
R
Fulkerson
John
J
Borthwick
Nicola
N
Quigley
Máire F
MF
Joseph
Joan
J
Douek
Daniel C
DC
Greenaway
Hui Yee
HY
Venturi
Vanessa
V
Gostick
Emma
E
Price
David A
DA
Both
Gerald W
GW
Sadoff
Jerald C
JC
Hanke
Tomás
T
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
D016915:AIDS Vaccines; C505104:MVA-HIVA vaccine; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D014765:Viral Vaccines