Heterologous prime-boost regimens using rAd35 and rMVA vectors elicit stronger cellular immune responses to HIV proteins than homologous regimens.
We characterized prime-boost vaccine regimens using heterologous and homologous vector and gene inserts. Heterologous regimens offer a promising approach that focuses the cell-mediated immune response on the insert and away from vector-dominated responses. Ad35-GRIN/ENV (Ad35-GE) vaccine is comprised of two vectors containing sequences from HIV-1 subtype A gag, rt, int, nef (Ad35-GRIN) and env (Ad35-ENV). MVA-CMDR (MVA-C), MVA-KEA (MVA-K) and MVA-TZC (MVA-T) vaccines contain gag, env and pol genes from HIV-1 subtypes CRF01_AE, A and C, respectively. Balb/c mice were immunized with different heterologous and homologous vector and insert prime-boost combinations. HIV and vector-specific immune responses were quantified post-boost vaccination. Gag-specific IFN-γ ELISPOT, intracellular cytokine staining (ICS) (CD107a, IFN-γ, TNF-α and IL-2), pentamer staining and T-cell phenotyping were used to differentiate responses to inserts and vectors. Ad35-GE prime followed by boost with any of the recombinant MVA constructs (rMVA) induced CD8+ Gag-specific responses superior to Ad35-GE-Ad35-GE or rMVA-rMVA prime-boost combinations. Notably, there was a shift toward insert-focus responses using heterologous vector prime-boost regimens. Gag-specific central and effector memory T cells were generated more rapidly and in greater numbers in the heterologous compared to the homologous prime-boost regimens. These results suggest that heterologous prime-boost vaccination regimens enhance immunity by increasing the magnitude, onset and multifunctionality of the insert-specific cell-mediated immune response compared to homologous vaccination regimens. This study supports the rationale for testing heterologous prime-boost regimens in humans.
United States Military HIV Research Program, Walter Reed Army Institute of Research, Rockville, Maryland, USA. sratto-kim@hivresearch.org
Silvia
S
Ratto-Kim
Jeffrey R
JR
Currier
Josephine H
JH
Cox
Jean-Louis
JL
Excler
Anais
A
Valencia-Micolta
Doris
D
Thelian
Vicky
V
Lo
Eddy
E
Sayeed
Victoria R
VR
Polonis
Patricia L
PL
Earl
Bernard
B
Moss
Merlin L
ML
Robb
Nelson L
NL
Michael
Jerome H
JH
Kim
Mary A
MA
Marovich
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006678:HIV / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007111:Immunity, Cellular; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D014764:Viral Proteins / Q000378:metabolism*
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D052118:Lysosomal-Associated Membrane Protein 1; D014764:Viral Proteins; D007371:Interferon-gamma