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The HIV Vaccines, Passive Immunization, and Antibody Gene Transfer Pipeline

July 2018
by Richard Jefferys

The most important news in preventive HIV vaccine research over the past year is the opening of a Phase IIb trial testing the efficacy of a prime-boost approach developed by Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson. The trial, known as Imbokodo or HPX2008/HVTN 705, plans to enroll 2,600 women in five southern African countries. The vaccine regimen comprises adenovirus serotype 26 (Ad26) vectors encoding mosaic HIV antigens, which are designed to induced immune responses capable of recognizing diverse viral variants, followed by a booster with a trimeric clade C gp140 Env protein in alum adjuvant. Results are anticipated in approximately four years.

The opening of the Imbokodo study means there are now two large HIV vaccine efficacy trials underway. The other, HVTN 702, began in South Africa in 2016 and is testing a prime-boost combination of an ALVAC vector and clade C Env protein.

In another potentially important recent development for vaccines, protein antigens engineered to coax the immune system down a pathway that might lead to the production of broadly neutralizing antibodies (bNAbs) are beginning to enter human trials. Examples include the eOD-GT8 60mer and EnvSeq-1 Env proteins. The induction of bNAbs—which are capable of neutralizing HIV variants from multiple different clades—remains the Holy Grail for vaccine researchers. It’s important to emphasize that these initial studies aren't expected to generate bNAbs, but rather induce B cell responses that represent the first step toward bNAb production. The idea is that additional protein antigens may be able to then push these B cells further along the desired pathway in future studies.  

The direct delivery of bNAbs into the body—passive immunization—is being explored in several trials. The largest are HVTN 704/HPTN 085 and HVTN 703/HPTN 081, also known as the antibody-mediated prevention (AMP) studies, which are testing the preventive efficacy of the bNAb VRC01 in different populations (men and transgender persons who have sex with men, and women). Several first-in-human trials of newer bNAbs (such as PGDM140, N6 and 10E8) are getting started, with some evaluating long-acting formulations and dual bNAb combinations.

Antibody gene transfer is an approach analogous to gene therapy, in which AAV vectors are used to try and deliver a long-lasting supply of bNAbs into the body. One ongoing trial is testing AAV-mediated delivery of the bNAb PG9, however preliminary results indicate that detectable levels of the bNAb have not been achieved. The problem appears to be that the participant’s immune systems produced anti-PG9 antibodies in response to the intervention. Researchers are now working to develop antibody gene transfer strategies that may avoid or ameliorate this problem.1


   1 Priddy F. A phase 1 trial of AAV1 vectored immunoprophylaxis for HIV. Paper presented at: Genetic Delivery of Monoclonal Antibodies for Prevention and Cure of HIV; 2018 June 14; Rockville, MD.

 

Table: HIV Vaccines, Passive Immunization, and Antibody Gene Transfer Pipeline 2018

 

Agent

Class/Type

Trial Registry Identifier(s)

Population(s)

Status

HIV VACCINES

ALVAC-HIV (vCP2438), bivalent clade C gp120/MF59

Canarypox vector encoding HIV-1 clade C gp120, clade B gp41, Gag, and protease + protein boost comprising two clade C Env proteins (TV1.Cgp120 and 1086.Cgp120)

NCT02968849
(HVTN 702)

NIAID/HVTN/Bill & Melinda Gates Foundation/South African Medical Research Council/

Sanofi Pasteur/

GlaxoSmithKline

Phase IIb/III

·       NIAID Press Release. First New HIV Vaccine Efficacy Study in Seven Years Has Begun. November 27, 2016

·       Bekker LG, Moodie Z, Grunenberg N, et al. Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial. Lancet HIV. 2018 Jun 8. pii: S2352-3018(18)30071-7. doi: 10.1016/S2352-3018(18)30071-7. [Epub ahead of print]

Ad26.Mos4.HIV, Clade C
gp140/alum

 

 

Ad26 vectors encoding four mosaic Env, Gag, and Pol antigens (Ad26.Mos1.Gag-Pol, Ad26.Mos2.Gag-Pol, Ad26.Mos1.Env, Ad26.Mos2S.Env)

Clade C gp140 protein

NCT03060629
(HPX2008/

HVTN 705)

Janssen Vaccines & Prevention B.V.

Phase IIb

·       NIH Press Release. NIH and partners launch HIV vaccine efficacy study. November 30, 2017

ALVAC-HIV vCP1521, AIDSVAX B/E

Canarypox vector encoding HIV-1 CRF01_AE Env, clade B Gag, the protease-encoding portion of the Pol protein, and a synthetic polypeptide encompassing several known CD8+ T-cell epitopes from the Nef and Pol proteins

AIDSVAX B/E recombinant protein vaccine containing gp120 from HIV-1 clades B and CRF01_AE

NCT01931358

NCT01435135

U.S. Army Medical Research and Materiel Command

Phase II

·       Akapirat S, Karnasuta C, Vasan S, et al. Characterization of HIV-1 gp120 antibody specificities induced in anogenital secretions of RV144 vaccine recipients after late boost immunizations. PLoS One. 2018 Apr 27;13(4):e0196397. doi: 10.1371/journal.pone.0196397.

·       Rerks-Ngarm S, Pitisuttithum P, Excler JL, et al. Randomized, Double-Blind Evaluation of Late Boost Strategies for HIV-Uninfected Vaccine Recipients in the RV144 HIV Vaccine Efficacy Trial. J Infect Dis. 2017 Apr 15;215(8):1255-1263. doi: 10.1093/infdis/jix099.

·       Easterhoff D, Moody MA, Fera D, et al. Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial. PLoS Pathog. 2017 Feb 24;13(2):e1006182. doi: 10.1371/journal.ppat.1006182.

Ad26.Mos.HIV MVA-Mosaic
gp140 protein

AD26 vectors encoding mosaic Env, Gag, and Pol MVA vectors encoding mosaic Env, Gag, and Pol gp140 protein boost

 

NCT02315703

Janssen Vaccines & Prevention B.V./NIAID/MHRP/

IAVI/Beth Israel Deaconess Medical Center

Phase I/IIa

·       Barouch DH, Tomaka FL, Wegmann F, et al. Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). The Lancet Online First DOI: https://doi.org/10.1016/S0140-6736(18)31364-3

ALVAC-HIV (vCP2438)

Bivalent clade C gp120/MF59

Bivalent clade C  gp120/alum

Bivalent clade C  gp120

Canarypox vector encoding HIV-1 clade C gp120, clade B gp41, Gag, and protease + protein boost comprising two clade C Env proteins (TV1.Cgp120 and 1086.Cgp120) with MF59 or alum adjuvant, or without adjuvant

NCT03284710

NIAID/HIV/Vaccine Trials
Network/ Sanofi
Pasteur/ Glaxo/SmithKline

Phase I/IIa

ALVAC-HIV (vCP2438)

Bivalent clade C gp120/MF59

Bivalent clade C gp120/ASO1B

Canarypox vector encoding HIV-1 clade C gp120, clade B gp41, Gag, and protease + protein boost comprising two clade C Env proteins (TV1.Cgp120 and 1086.Cgp120) with either MF59 or AS01B adjuvant

NCT03122223

NIAID/Glaxo/ SmithKline/Sanofi/ Pasteur

Phase I/IIa

MYM-V101

Virosome-based vaccine designed to induce mucosal IgA antibody responses to HIV-1 Env

NCT01084343

Mymetics

Phase I/II

·       Leroux-Roels G, Maes C, Clement F, et al. Randomized Phase I: Safety, Immunogenicity and Mucosal Antiviral Activity in Young Healthy Women Vaccinated with HIV-1 Gp41 P1 Peptide on Virosomes. PLoS One. 2013;8(2):e55438. doi: 10.1371/journal.pone.0055438. Epub 2013 Feb 20.

GEO-D03 DNA + MVA/HIV/62B

Prime: DNA vaccine with GM-CSF adjuvant

Boost: MVA vector

Both vaccines encode Gag, Pol, and Env proteins from HIV-1 clade B and produce VLPs

NCT01571960

GeoVax/NIAID

Phase I

·       Buchbinder SP, Grunenberg NA, Sanchez BJ, et al. Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults. PLoS One. 2017 Jul 20;12(7):e0179597. doi: 10.1371/journal.pone.0179597

MAG-pDNA, rVSVIN HIV-1 Gag

Multiantigen DNA vaccine encoding the Env, Gag, Pol, Nef, Tat, and Vif proteins of HIV-1 and GENEVAX, interleukin-12 (IL-12) pDNA adjuvant, attenuated replication-competent recombinant vesicular stomatitis virus (rVSV) vector encoding HIV-1 Ga

NCT01578889

Profectus
Biosciences/HVTN

Phase I

·       Li SS, Kochar NK, Elizaga M, et al. DNA Priming Increases Frequency of T-Cell Responses to a Vesicular Stomatitis Virus HIV Vaccine with Specific Enhancement of CD8+ T-Cell Responses by Interleukin-12 Plasmid DNA.Clin Vaccine Immunol. 2017 Nov 6;24(11). pii: e00263-17. doi: 10.1128/CVI.00263-17.

pSG2.HIVconsv DNA +
ChAdV63.HIVconsv, or MVA.HIVconsv

Prime: DNA vaccine pSG2

Boost: chimpanzee adenovirus vector ChAdV63 or MVA vector

All contain the HIVconsv immunogen,

designed to induce cross-clade T-cell responses by focusing on conserved parts of HIV-1

NCT01151319

University of Oxford

Phase I

·       Hayton EJ, Rose A, Ibrahimsa U, et al. Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial. PLoS One. 2014 Jul 9;9(7):e101591. doi: 10.1371/journal.pone.0101591.

SeV-G(NP),
Ad35-GRIN

Sendai virus vector encoding HIV-1 Gag protein delivered intramuscularly or intranasally, Ad35 vector encoding HIV-1 clade A Gag, reverse transcriptase, integrase, and Nef

NCT01705990

IAVI/DNAVEC

Phase I

·       Nyomabayire J, Anzala O, Gazzard B, et al. First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens. J Infect Dis. 2017 Jan 1;215(1):95-104. doi: 10.1093/infdis/jiw500. Epub 2016 Oct 17.

LIPO-5, MVA HIV-B, GTU-MultiHIV

Five lipopeptides comprising CTL epitopes from Gag, Pol, and Nef proteins

MVA vector encoding Env, Gag, Pol, and Nef proteins from HIV clade B

DNA vector encoding fusion protein comprising elements from six different HIV proteins

Given in four different prime-boost combinations

NCT02038842

INSERM-ANRS

Phase I
Phase II

·       Lelièvre J-D, Lacabaratz C, Wiedemann A, et al. Immunogenicity and safety of 4 prime-boost combinations of HIV vaccine candidates (MVA HIV-B; LIPO-5; GTU-MultiHIV B) in healthy volunteers: ANRS/INSERM VRI01 phase I/II randomized trial. Paper presented at: 9th IAS Conference on HIV Science (IAS 2017); 2017 July 23–26; Paris, France

GTU-MULTIHIV

DNA vector encoding fusion protein comprising elements from six different HIV proteins, administered by intramuscular, intradermal, or transcutaneous routes

NCT02038842

Imperial College London/European Commission- Cut’HIVAC Consortium

Phase I

·       Haidari G, Cope A, Miller A, et al. Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial. Sci Rep. 2017 Oct 12;7(1):13011. doi: 10.1038/s41598-017-13331-1.

DNA Nat-B Env
DNA CON-S Env
DNA mosaic Env
MVA-CMDR

Prime: DNA vector encoding Nat-B, CON-S, or mosaic Env proteins

Boost: MVA vector encoding Env (E), Gag (A), and Pol (E) proteins

NCT02296541

NIAID/CHAVI/ IPPOX/MHRP/HVTN

Phase I

MVA Mosaic

MVA vectors encoding HIV-1 mosaic proteins

NCT02218125

Crucell/MHRP/ NIAID/Beth Israel Deaconess Medical Center

Phase I

·       Baden LR, Walsh SR, Seaman MS, et al. First-in-Human Randomized Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector. J Infect Dis. 2018 Apr 13. doi: 10.1093/infdis/jiy212. [Epub ahead of print]

DNA-HIV-PT123 AIDSVAX/E

DNA vectors encoding HIV-1 clade C Gag, gp140, and Pol-Nef

AIDSVAX B/E recombinant protein vaccine containing gp120 from HIV-1 clades B and CRF01_AE

NCT03391375

EuroVacc/IAVI/Uganda Medical Research Council/UVRI Uganda Research Unit on AIDS/Centre Hospitalier Universitaire Vaudois

Phase I

Oral Ad26

Orally administered replicating Ad26 vector encoding mosaic Env protein

NCT02366013

IAVI/University of Rochester/ Beth Israel Deaconess Medical Center

Phase I

PENVAX- GP HIV-1 DNA vaccine
IL-12 DNA adjuvant

DNA vector encoding Gag, Pol, and Env proteins + DNA vector encoding IL-12 adjuvant, delivered via intradermal or intramuscular electroporation

NCT02431767

NIAID

Phase I

IHV01 (FLSC-001)

Full-length single-chain gp 120-CD4 complex vaccine

NCT02756208

University of Maryland/Bill & Melinda Gates Foundation/Profectus BioSciences, Inc.

Phase I

HIV DNA-C CN54ENV + recombinant HIV CN54gp140

DNA vector encoding HIV-1 clade C Env delivered intramuscularly and intradermally

Clade C Env protein boost

NCT02589795

Imperial College London

Phase I

HIV-1
Nef/Tat/VIf, Env pDNA + HIV-1 rVSV envC

DNA vector encoding HIV-1 Nef/Tat/Vif and Env

Attenuated replication-competent rVSV vector encoding HIV-1 clade C Env

NCT02654080

NIAID

Phase I

Ad4-mgag, Ad4-EnvC150

Live, replication-competent recombinant Ad4 vectors encoding HIV-1 clade C Env and HIV-1 mosaic Gag proteins, formulated either as enteric-coated capsules for oral administration or as an aqueous solution for tonsillar administration

NCT01989533

NIAID/PaxVax

Phase I

Ad4-mgag, Ad4-EnvC150 + AIDSVAX B/E

Orally administered replication-competent Ad4 HIV vaccine in combination with AIDSVAX B/E recombinant protein vaccine containing gp120 from HIV-1 clades B and CRF01_AE

NCT02771730

PaxVax, Inc./NIAID

Phase I

AD4-EnvCN54,
MVA-CN54, CN54gp140/MPL A

Orally administered replication-competent Ad4 vector and MVA vector encoding clade C Env protein, clade C Env protein in MPLA adjuvant

NCT03408262

Imperial College London

Phase I

·       Alexander J, Mendy J, Vang L, et al. Pre-clinical development of a recombinant, replication-competent adenovirus serotype 4 vector vaccine expressing HIV-1 envelope 1086 clade C. PLoS One. 2013 Dec 3;8(12):e82380. doi: 10.1371/journal.pone.0082380.

Tetravalent Ad26.Mos4.HIV + clade C gp140 ± mosaic gp140

Ad26 vectors encoding two mosaic HIV-1 Envs and mosaic Gag and Pol + clade C HIV Env protein boost ± mosaic HIV Env protein boost

NCT02935686

Janssen Vaccines & Precvcention B.V.

Phase I

MVA/HIV62B + AIDSVAX B/E

MVA vector encoding Gag, Pol, and Env proteins from HIV-1 clade B to produce VLPs + AIDSVAX B/E recombinant protein vaccine containing gp120 from HIV-1 clades B and CRF01_AE

NCT02852005

NIAID

Phase I

DNA-HIV-PT123

Bivalent clade C gp120/MF59

Bivalent clade C gp120/ASO1B

DNA vaccine encoding HIV-1 clade C Gag, gp140, and Pol-Nef + protein boost comprising two clade C Env proteins (TV1.Cgp120 and 1086.Cgp120) with either MF59 or AS01B adjuvant

NCT02915016

NIAID

Phase I

DNA-HIV-PT123 + clade C gp120/MF59

DNA vaccine encoding HIV-1 clade C Gag, gp140, and Pol-Nef + protein boost comprising two clade C Env proteins (TV1.Cgp120 and 1086.Cgp120) in MF59 adjuvant

NCT02997969

NIAID/HVTN/IPPOX Foundation/Novartis Vaccines

Phase I

EnvSeq-1 Envs adjuvanted with GLA-SE

DNA Mosaic-Tre env

Four individual EnvSeq-1 Env proteins (CH505TF, CH505w53,CH505w78, CH505w100), DNA vaccine encoding mosaic Env antigen

NCT03220724

NIAID

Phase I

gp145 C.6980 + aluminum hydroxide adjuvant

Oligomeric gp145 Clade C Env protein vaccine + aluminum hydroxide adjuvant

NCT03382418

NIAID

Phase I

p24CE1/2 DNA Vaccine

p55^gag DNA Vaccine

IL-12 DNA adjuvant

DNA vaccines encoding Gag p24 conserved elements and/or Gag p55 + DNA vector encoding IL-12 adjuvant, delivered via intramuscular electroporation

NCT03181789

NIAID

Phase I

Env (A,B,C,A/E)/gag (C) DNA vaccine gp120 (A,B,C,A/E) protein vaccine GLA-SE adjuvant

Polyvalent DNA vaccine encoding Envs from HIV-1 clades A,B,C,A/E and clade C Gag + polyvalent gp120 protein vaccine + GLA-SE advjuvant

NCT03409276

NIAID

Phase I

DNA COS-S Env + IHV01

DNA vaccine encoding CON-S Env protein

Full-length single-chain gp120-CD4 complex vaccine

NCT03505060

NIAID

Phase I

eOD-GT8 60 mer + AS01B/DPBS sucrose

Engineered priming immunogen designed to activate B cell precursors as a step toward induction of bNAbs + AS01B adjuvant

NCT03547245

IAVI

Phase I

·       Jardine JG, Ota T, Sok D, et al. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science. 2015 Jul 10;349(6244):156-61. doi: 10.1126/science.aac5894. Epub 2015 Jun 18.

PASSIVE IMMUNIZATION

VRC01

Monoclonal BNAb administered intranvenously

NCT02716675
(HVTN 704/HPTN 085)


NCT02568215
(HVTN 703/HPTN 081)

NIAID/HVTN/HPTN

Phase IIb

·       NIAID Press Release. NIH Launches Large Clinical Trials of Antibody-Based HIV Prevention. April 7, 2016

10-1074

Monoclonal BNAb administered intranvenously

 

NCT02511990

Rockefeller University

Phase I

·       Caskey M, Schoofs T, Gruell H, et al. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med. 2017 Feb;23(2):185-191. doi: 10.1038/nm.4268. Epub 2017 Jan 16.

3fBNC117 + 10-1074

Monoclonal BNAbs administered intranvenously

NCT02824536

Rockefeller University

Phase I

·       Cohen YZ, Butler A, Levin R, et al. A phase 1 trial of the combination of 3BNC117 and 10-1074 in HIV-uninfected adults (Abstract 1062). Paper presented at: 2018 Conference on Retroviruses and Opportunistic Infections; 2018 March 4–7; Boston, MA.

P2G12

Monoclonal neutralizing antibody administered intravenously

NCT02923999

St. George’s, University of London

Phase I

PGT121

Monoclonal bNAb administered intravenously

NCT02960581

IAVI

Phase I

VRC01

Monoclonal bNAb administered subcutaneously or intravenously

NCT01993706
NCT02165267
NCT02256631
NCT02797171

NIAID

Phase I (adults and HIV-exposed infants)

·       Mayer KH, Seaton KE, Huang Y, et al. Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial. PLoS Med. 2017 Nov 14;14(11):e1002435. doi: 10.1371/journal.pmed.1002435.

·       Ledgerwood JE, Coates EE, Yamshchikov G, et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol. 2015 Dec;182(3):289-301. doi: 10.1111/cei.12692. Epub 2015 Sep 24.

VRC01LS

LA monoclonal bNAb administered subcutaneously or intravenously

NCT02256631
NCT02599896

NCT02797171

NIAID

Phase I

VRC07-523LS

LA monoclonal bNAb administered intravenously

NCT03015181
NCT03387150

NIAID

Phase I

3BNC117-LS

A monoclonal bNAb administered intravenously

NCT03254277

Rockefeller University

Phase I

10-1074-LS + 3BNC117-LS

LA monoclonal bNAbs administered subcutaneously or intravenously

NCT03554408

Rockefeller University

Phase I

VRC07-523LS + 10E8VLS

LA monoclonal bNAbs administered subcutaneously

NCT03565315

NIAID

Phase I

PGDM1400 + PGT121

Monoclonal bNAbs administered intravenously

NCT03205917

IAVI

Phase I

N6LS

LA monoclonal bNAb administered subcutaneously or intravenously

NCT03538626

NIAID

Phase I

·       Huang J, Kang BH, Ishida E, et al. Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth. Immunity. 2016 Nov 15;45(5):1108-1121. doi: 10.1016/j.immuni.2016.10.027.

ANTIBODY GENE TRANSFER

rAAV1-PG9DP

Recombinant AAV vector encoding the PG9 broadly neutralizing antibody

NCT01937455

IAVI/NIAID/CHOP

Phase I

Shaded entries represent additions since the 2017 Pipeline Report.

ABBREVIATIONS

AAV: adeno-associated virus

Ad4: adenovirus serotype 4

Ad26: adenovirus serotype 26

Ad35: adenovirus serotype 35

BNAb: broadly neutralizing antibody

CAVD: Collaboration for AIDS Vaccine Discovery

CHAVI: Center for HIV/AIDS Vaccine Immunology

CHOP: Children's Hospital of Philadelphia

CMDR: Chiang Mai double recombinant

CTL: cytotoxic T lymphocyte

GLA-AF: glucopyranosyl lipid adjuvant (aqueous formulation)

GM-CSF: granulocyte-macrophage colony–stimulating factor
Hsp70: heat shock protein 70

HVTN: HIV Vaccine Trials Network

IAVI: International AIDS Vaccine Initiative

IL: interleukin

INSERM-ANRS: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis

LA: long-acting

MHRP: U.S. Military HIV Research Program

MVA: modified vaccinia Ankara strain

NIAID: U.S. National Institute of Allergy and Infectious Diseases

rVSV: recombinant vesicular stomatitis virus

UVRI: Uganda Virus Research Institute

VLP: virus-like particle