Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Oral Abstract Session 06: V1/V2 Antibody Responses
OA06.03
Design of an HIV Env Antigen That Binds with High
Affinity to Antibodies Against Linear, Conformational
and Broadly Neutralizing Epitopes Within V1/V2
L. Liao 1 , M. Bonsignori 1 , K. Hwang 1 , A.M. Moody 1 , R. Park 1 ,
S. Crawford 1 , H. Chen 1 , T.L. Jeffries 1 , M. Cooper 1 , X. Lu 1 ,
R. De 1 , N. Karasavvas 2 , S. Rerks-Ngarm 3 , S. Nitayaphan 4 ,
J. Kaewkungwal 5 , S. Tovanabutra 2 , P. Pitisuttithum 6 ,
J. Tartaglia 7 , F. Sinangil 8 , J. Kim 2 , N.L. Michael 2 , G.D. Tomaras 1 ,
Z. Yang 9 , K. Dai 9 , M. Pancera 9 , G.J. Nabel 9 , J.R. Mascola 9 ,
P.D. Kwong 9 , A. Pinter 10 , S. Zolla-Pazner9 11 , M.S. Alam 1 ,
B.F. Haynes 1
1 Duke University Medical Center, Durham, NC, USA; 2 U.S.
MHRP, Walter Reed Army Institute of Research, Silver Spring,
MD, USA; 3 Department of Disease Control, Ministry of Public
Health, Nonthaburi, Thailand; 4 Department of Retrovirology,
US Army Medical Component, AFRIMS, Bangkok, Thailand;
5 BIOPHICS, Faculty of Tropical Medicine, Mahidol University,
bangkok, Thailand; 6 Faculty of Tropical Medicine, Mahidol
University, Bangkok, Thailand; 7 Department of Research and
Development, Sanofi Pasteur, Swiftwater, PA, USA; 8 Global
Solutions for Infectious Diseases, South San Francisco, CA,
USA; 9 Vaccine Research Center/NIH, Bethesda, MD, USA;
10 Public Health Research Institute Center, New Jersey Medical
School, Newark, NJ, USA; 11 Veterans Affairs New York Harbor
Healthcare System, Manhattan Campus, New York, NY, USA
Background: The RV144 HIV-1 vaccine trial showed protection
from HIV-1 acquisition with vaccine efficacy of 31.2%. Study of
the immune correlates demonstrated an inverse association of
V1/V2 antibodies with infection risk. A key task for HIV-1 vaccine
development is to improve the level of efficacy seen in the RV144
trial with subsequent vaccine designs.
Methods: E.A244 V1/V2 Env tags contains an N-terminal Ig
leader sequence and C-terminal Avi- and His6-tags linked to
the V1/V2 domain, was expressed in 293F cells and purified by
nickel column. Binding of Tier 1 neutralizing mAb CH58 from
RV144 vaccinees, V2 conformational mAb 697D and broadly
neutralizing antibodies (bnAb) CH01 and PG9/PG16 to 33 HIV-1
gp140/gp120s and 12 HIV-1 V1/V2 scaffold Envs was tested by
ELISA and surface plasmon resonance.
Results: Among 45 HIV-1/SIV Envs tested, E.A244 V1/V2 tags and
E.A244 gp120Δ11 Env were the only Env antigens recognized by
all three types of mAbs: CH58, 697D, and bnAbs CH01, and PG9/
PG16. E.A244 V1/V2 tag bound CH58 with a Kd of 0.33 nM and
697D with a Kd of 117 nM. Although PG9 preferentially recognizes
trimers, PG9 bound well to both E.A244 gp120Δ11 (Kd = 47.3) and
E.A244 V1/V2 tags (Kd = 83.3 nM). BnAb CH01 bound V1/V2 tags
as well (Kd = 334 nM). E.A244 V1/V2 Env tags was also recognized
by the unmutated ancestor antibodies (UAs) of CH58 with ELISA
EC50 = 4.9 nM and CH01 with EC50 = ~1μM. E.A244 V1/V2 tags
and AE.gp70 V1/V2 scaffold were the best recombinant Envs for
detection of plasma V1/V2 antibodies in RV144 vaccinees.
Conclusion: Recombinant E.A244 V1/V2 Env tags Env expresses
linear as well as conformational determinants recognized by
V1/V2 mAbs and some of their UAs. This V1/V2 construct is a
candidate immunogen to target RUAs and intermediate ancestors
of V1/V2 antibodies to drive their induction.
Oral Abstract Sessions
OA06.04
Evidence for Env-V2 Sieve Effect in Breakthrough SIV
Infections in Rhesus Monkeys Vaccinated with
MAC251
Ad26/MVA and MVA/Ad26 Constructs
S. Sina 2 , S. Tovanabutra 2 , E. Sanders-Buell 2 , A. Bates 2 , M. Bose 2 ,
S. Howell 2 , G. Ibitamuno 2 , M. Lazzaro 2 , A. O’Sullivan 2 , J. Lee 2 ,
T. Cervenka 2 , J. Kuroiwa 2 , K. Baldwin 2 , D.H. Barouch 1 , M. Robb 2 ,
R. O’Connell 2 , N.L. Michael 2 , J.H. Kim 2 , M. Rolland 2
1 BIDMC, Harvard Medical School, and Ragon Institute, Boston,
MA, USA; 2 U.S. Military HIV Research Program/Henry M.
Jackson Foundation, Bethesda, MD, USA
Background: We had previously shown that rhesus monkeys
receiving Ad26/MVA and MVA/Ad26 vaccines expressing
SIV were protected against SIV challenge
SME543 MAC251
(doi:10.1038/nature10766). Protection was associated with
Env-specific binding ELISA antibody responses, including V2specific
antibodies.
Methods: We amplified 66 sequences from the SIV challenge
MAC251
stock, and 409 near-full length genomes from 13 vaccine and
13 control monkeys. A series of pre-specified phylogenetic and
statistical tests for sieve effects was performed.
Results: The mean pairwise AA diversity among the 66 SIVMAC251 Env sequences was 0.38%, and they differed from the vaccine
strain SIV (Env) by 21.94%. The repeated low-dose challenge
SME543
resulted in infections with an average of 1.7 founder variants
- with no evidence that the vaccine restricted the number of
variants (p = 0.813). We explored whether the vaccine induced a
sieve effect, i.e. whether breakthrough viruses differed between
the vaccine and control groups. There was no difference for fulllength
Env sequences. Focusing on Env segments preferentially
recognized by vaccinated monkeys in antibody arrays, we
identified a sieve effect in the Env-V2 segment AA163-193:
sequences from vaccinated animals were more divergent from
the vaccine SIV or from the challenge stock SIV than
SME543 MAC251
sequences in control animals (p ≤ 0.002).
Conclusion: The sieve effect in Env-V2, combined with Env-V2specific
binding antibodies identified as a correlate of protection
against SIV acquisition in the study, provide evidence
MAC251
supporting the importance of protective responses directed
against the Env-V2 region.
AIDS Vaccine 2012
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ORAL ABSTRACT SESSIONS