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 |
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
|
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 HVTN 705) |
Janssen Vaccines & Prevention B.V. |
Phase IIb |
|
· NIH Press Release. NIH and partners launch HIV vaccine efficacy study. November 30, 2017 |
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|
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 |
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 |
AD26 vectors encoding mosaic Env, Gag, and Pol MVA vectors encoding mosaic Env, Gag, and Pol gp140 protein boost
|
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 |
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|
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 |
NIAID/HIV/Vaccine Trials |
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 |
NIAID/Glaxo/ SmithKline/Sanofi/ Pasteur |
Phase I/IIa |
|
|
MYM-V101 |
Virosome-based vaccine designed to induce mucosal IgA antibody responses to HIV-1 Env |
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 |
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 |
Profectus |
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. |
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|
pSG2.HIVconsv DNA + |
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 |
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), |
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 |
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. |
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|
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 |
INSERM-ANRS |
Phase I |
|
|
· 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 |
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 |
Prime: DNA vector encoding Nat-B, CON-S, or mosaic Env proteins Boost: MVA vector encoding Env (E), Gag (A), and Pol (E) proteins |
NIAID/CHAVI/ IPPOX/MHRP/HVTN |
Phase I |
|
|
MVA Mosaic |
MVA vectors encoding HIV-1 mosaic proteins |
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 |
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 |
IAVI/University of Rochester/ Beth Israel Deaconess Medical Center |
Phase I |
|
|
PENVAX- GP HIV-1 DNA vaccine |
DNA vector encoding Gag, Pol, and Env proteins + DNA vector encoding IL-12 adjuvant, delivered via intradermal or intramuscular electroporation |
NIAID |
Phase I |
|
|
IHV01 (FLSC-001) |
Full-length single-chain gp 120-CD4 complex vaccine |
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 |
Imperial College London |
Phase I |
|
|
HIV-1 |
DNA vector encoding HIV-1 Nef/Tat/Vif and Env Attenuated replication-competent rVSV vector encoding HIV-1 clade C Env |
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 |
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 |
PaxVax, Inc./NIAID |
Phase I |
|
|
AD4-EnvCN54, |
Orally administered replication-competent Ad4 vector and MVA vector encoding clade C Env protein, clade C Env protein in MPLA adjuvant |
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 |
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 |
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 |
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 |
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 |
NIAID |
Phase I |
|
|
gp145 C.6980 + aluminum hydroxide adjuvant |
Oligomeric gp145 Clade C Env protein vaccine + aluminum hydroxide adjuvant |
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 |
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 |
NIAID |
Phase I |
|
|
DNA COS-S Env + IHV01 |
DNA vaccine encoding CON-S Env protein Full-length single-chain gp120-CD4 complex vaccine |
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 |
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. |
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|
PASSIVE IMMUNIZATION |
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|
VRC01 |
Monoclonal BNAb administered intranvenously |
NCT02716675 NCT02568215 |
NIAID/HVTN/HPTN |
Phase IIb |
|
· NIAID Press Release. NIH Launches Large Clinical Trials of Antibody-Based HIV Prevention. April 7, 2016 |
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|
10-1074 |
Monoclonal BNAb administered intranvenously |
|
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. |
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|
3fBNC117 + 10-1074 |
Monoclonal BNAbs administered intranvenously |
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. |
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|
P2G12 |
Monoclonal neutralizing antibody administered intravenously |
St. George’s, University of London |
Phase I |
|
|
PGT121 |
Monoclonal bNAb administered intravenously |
IAVI |
Phase I |
|
|
VRC01 |
Monoclonal bNAb administered subcutaneously or intravenously |
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. |
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|
VRC01LS |
LA monoclonal bNAb administered subcutaneously or intravenously |
NIAID |
Phase I |
|
|
VRC07-523LS |
LA monoclonal bNAb administered intravenously |
NIAID |
Phase I |
|
|
3BNC117-LS |
A monoclonal bNAb administered intravenously |
Rockefeller University |
Phase I |
|
|
10-1074-LS + 3BNC117-LS |
LA monoclonal bNAbs administered subcutaneously or intravenously |
Rockefeller University |
Phase I |
|
|
VRC07-523LS + 10E8VLS |
LA monoclonal bNAbs administered subcutaneously |
NIAID |
Phase I |
|
|
PGDM1400 + PGT121 |
Monoclonal bNAbs administered intravenously |
IAVI |
Phase I |
|
|
N6LS |
LA monoclonal bNAb administered subcutaneously or intravenously |
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. |
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|
ANTIBODY GENE TRANSFER |
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|
rAAV1-PG9DP |
Recombinant AAV vector encoding the PG9 broadly neutralizing antibody |
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