Oral Abstract Session 01 - Global HIV Vaccine Enterprise

ORAL ABSTRACT SESSIONS
90
Oral Abstract Sessions
Oral Abstract Session 12: Vaccine Concepts – Vectors and Inserts
OA12.03
Adenovirus Serotype 26 Utilizes CD46 as Primary
Cellular Receptor and Only Transiently Activates
T Lymphocytes Following Vaccination of Rhesus
Monkeys
H. Li 1 , E.G. Rhee 1 , K. Masek-Hammerman 2 , J.E. Teigler 1 ,
P. Abbink 1 , D.H. Barouch 1
1 Beth Israel Deaconess Medical Center, Boston, MA, USA;
2 New England Primate Research Center, Southborough, MA, USA
Background: Adenovirus serotype 5 (Ad5) utilizes coxsackievirus
and adenovirus receptor (CAR) as its primary cellular receptor.
However, the cellular receptor utilized by Ad26 and the
inflammatory responses elicited following Ad26 vaccination
remain unclear.
Methods: Receptor usage was assessed using CD46 transgenic
mouse cells, as well as by CAR- and CD46-specific mAb blocking
studies using human PBMC. Twelve adult rhesus monkeys
were inoculated with of 1011 viral particles (vp) of replicationcompetent
Ad5 and Ad26 (N=6) or saline (N=6) at weeks -8 and -4,
and were vaccinated intramuscularly with 3×1010 vp replicationincompetent
Ad26-Gag/Pol/Env vectors. At week 2, monkeys
were sacrificed to assess immunologic and inflammatory
responses at mucosal surfaces.
Results: Transduction by Ad26 and Ad35 vectors was markedly
enhanced in CD46 transgenic mouse cells compared with wild
type mouse cells. Moreover, transduction of human PBMC by
Ad26 and Ad35 vectors was efficiently blocked by the anti-CD46
mAbs 13/42, M177 and MEM-258, but not by the anti-CAR
mAbs RmcB and E1-1. Monkeys with and without baseline Ad5/
Ad26 immunity exhibited similar magnitude and only transient
activation (1-2 weeks) of vector-specific CD4 + T cell responses
in both PBMC and colorectal biopsies. Inflammatory cell
infiltrates in colorectal and foreskin mucosa were comparable
in baseline and vaccinated animals regardless of baseline Ad5/
Ad26 immunity.
Conclusion: Ad26 utilizes CD46 and not CAR as a primary cellular
receptor for infection. We also observed no increased mucosal
cellular activation or vector-specific CD4 + T lymphocytes in
baseline Ad5/Ad26-seropositive monkeys as compared with
baseline seronegative monkeys following Ad26 vaccination.
These data contribute to our understanding of the biology of
Ad26 as a candidate vaccine vector.
AIDS Vaccine 2012
OA12.04
Full-Length HIV-1 Immunogens Induce Greater
T Lymphocyte Responses to Conserved Epitopes
Than Conserved-Region-Only HIV-1 Immunogens in
Monkeys
K.E. Stephenson 1 , A. SanMiguel 1 , N.L. Simmons 1 , K. Smith 1 ,
J.J. Szinger 2 , B.T. Korber 2 , D.H. Barouch 1
1 Beth Israel Deaconess Medical Center and Harvard University,
Boston, MA, USA; 2 Los Alamos National Laboratory, Los
Alamos, NM, USA
Background: A global HIV-1 vaccine will need to induce broadly
reactive immune responses against conserved HIV-1 regions.
It is currently unclear how best to elicit these responses by
vaccination. We therefore compared the immunogenicity of a
bivalent full-length HIV-1 Gag/Pol/Env mosaic vaccine, a trivalent
full-length HIV-1 Gag/Pol/Env mosaic vaccine, and a bivalent
mosaic vaccine containing only conserved HIV-1 Gag/Pol/Env
epitopes in rhesus monkeys.
Methods: We immunized 18 rhesus monkeys with rAd35 (prime)
and rAd26 (boost) vectors expressing bivalent full-length (N=6),
trivalent full-length (N=6), or bivalent conserved-region-only
(N=6) HIV-1 Gag/Pol/Env mosaic immunogens. We assessed
HIV-1-specific and conserved-region-specific cellular immune
responses by ELISPOT using global PTE and vaccine-matched
peptides. Responses were mapped to individual epitopes and
were identified as CD4+ or CD8+ through cell-depletion assays.
Comparisons were performed by Wilcoxon rank-sum tests.
Results: There was no difference in the breadth of HIV-1-specific
T lymphocyte responses elicited by the bivalent and trivalent
full-length mosaic vaccines (P=.686). However, the bivalent fulllength
vaccine generated a greater breadth of HIV-1-specific
CD8+ T lymphocyte responses than the conserved-region-only
vaccine (P=.007). The bivalent full-length vaccine also generated
equivalent breadth of CD8+ T lymphocyte responses to conserved
HIV-1 epitopes compared to the conserved-region-only vaccine
(P=1.000), and surprisingly, the responses generated by the
full-length vaccine to conserved HIV-1 epitopes were greater in
magnitude than those generated by the conserved-region-only
vaccine (P=.008).
Conclusion: These data demonstrate that an HIV-1 mosaic
vaccine expressing full-length antigens elicited greater responses
to conserved epitopes than a mosaic vaccine expressing only
concatenated conserved HIV-1 regions. In addition, the bivalent
and trivalent full-length mosaic vaccines generated comparable
breadth of HIV-1-specific CD8+ T lymphocyte responses. These
results support the clinical development of the bivalent fulllength
HIV-1 mosaic vaccine.