Table 2.
Representative preclinical studies.
| Animals | Immunogen | Vectors, regimen and route of immunization | Immune responses generated | Outcomes | References |
|---|---|---|---|---|---|
| (I) HETEROLOGOUS PRIME-BOOST STUDIES | |||||
| Mice and rabbits | HIV Env/Gag-Pol-Nef DNA, MVA-C (HIV Env/Gag-Pol-Nef and CN54gp140 protein) | Intramuscular delivery of DNA/MVA/Protein with TLR4 (GLA-AF adjuvant) for protein boost | Antibody and T cell responses | – | McKay et al., 2014 |
| Rhesus macaques | SIVmac239 Env/Gag DNA, rmIL-12 DNA and SIVmac239 protein vaccines | DNA-prime (by electroporation)/i.m. or i.d. Protein-boost, or DNA and protein co-immunization | Persistent mucosal Envelope-specific antibody responses | Enhanced immunity by the co-immunization modality | Jalah et al., 2014 |
| Rhesus macaques | SIV-Gag mosaic | DNA-prime (x3, i.m.) Ad5-boost (i.m.) | -NAbs | Protection against SIVsmE660 challenge | Roederer et al., 2014 |
| SIV-Env mosaic | -ADCC | ||||
| SIVmac239 Env | -Cellular responses | ||||
| Rhesus monkeys | DNA expressing SIVmac239 antigens + rmIL-12 and inactivated SIVmac239 virus particles as protein | DNA prime (i.m. followed by in vivo electroporation) /protein-boost | -SIV-specific CTLs | -Protection from SIVSME660 acquisition | Patel et al., 2013 |
| -CD4+ and CD8+ memory T cells | |||||
| -Binding antibodies | -Reduced peak and chronic phase viremia | ||||
| Mice | pCCMp24 | DNA prime/Tiantan boost (i.m.) | Antibody and T cells | – | Excler et al., 2010; Liu et al., 2013 |
| rddVTT-CCMp24 | |||||
| Rhesus macaques | SIVSME543-Gag/Pol/Env | Prime-boost (i.m.) with: Ad26/MVA, Ad35/Ad26, DNA/MVA, MVA/Ad26 | -NAbs | Protection from SIVmac251 acquisition or disease progression | Barouch et al., 2012 |
| -Binding antibodies | |||||
| -Cellular responses | |||||
| Mice | Ad35-GRIN/ENV and MVA-C (Gag/Env/Pol) | Ad35-GRIN/ENV-prime (i.m.)/MVA-boost (i.m.) | Polyfunctional CD8+ T cells | – | Ratto-Kim et al., 2012 |
| Macaques | SIV DNA/GM-CSF (SIV239 Gag/PR/RT/Env/Tat/Rev) and MVA-SIVgpe | DNA/GM-CSF- prime (i.m.)/MVA-boost (i.m.) | -Neutralizing antibody responses | Sterile protection after SIVsmE660 challenge | Lai et al., 2011 |
| -ADCC | |||||
| Murine | DNA-Env and gp120 protein vaccines | DNA Env-prime/gp120 protein-boost (i.m. and i.n.) | -Persistent mucosal and systemic Abs | – | Cristillo et al., 2011 |
| (Advax-M and Advax-P adjuvants) | -T cell responses | ||||
| New-born and adult mice | BCG-HIVA, MVA-HIVA and HAdV5.HIVA | BCG-prime (i.p./i.d./s.c.) followed with i.m. MVA- or HAdV5- boost | -Strong, cytotoxic CD8+ T cell responses | – | Hopkins et al., 2011a; Saubi et al., 2011 |
| Rhesus macaques | VSV and SFV replicon expressing SIV-Gag/Env | VSV-prime (i.m. and i.n.)/SFVG-boost (i.m.) | -High titer NAbs to Env proteins and weak cellular responses | -Sterilizing immunity Control of SIVsmE660 breakthrough infections | Schell et al., 2011 |
| New-born macaques | VSV-SIVgpe (rVSV- Gag/Pol/Env) and MVA-SIVgpe | VSV-prime (oral)/MVA-boost (i.m.) | -Systemic Abs, both systemic and local cellular responses | – | Van Rompay et al., 2010 |
| Mice, rabbits and macaques | Consensus or Polyvalent mosaic DNA and protein (gp120) vaccines | DNA-prime (i.m.)/i.m. and i.d. rVaccinia-boost. | -Broadly neutralizing antibodies and CD8+ T cell responses | Enhanced immunogenicity | Wang et al., 2006b; Santra et al., 2010 |
| DNA-prime (gene gun)/ Protein-boost (i.d.) + IFA | |||||
| Rhesus macaques | VSV-SHIVGag/Pol/Env | VSV-prime (i.m.)/MVA-boost (i.m.) | -Persistent multi-functional | Durable (over 5 years) control of SHIV89.6P replication | Rose et al., 2001 Schell et al., 2009 |
| MVA-SHIVGag/Pol/Env | CD8+ T cells and NAbs | ||||
| Rabbits macaques | HIV-1 Env gp120 | DNA (electroporation)/gp120 protein boost | -Persistent Th1, CTL and Env responses | Neutralization of sensitive SHIV isolates | Cristillo et al., 2008 |
| Rhesus macaques | CMV-SHIVdEN and SeV-Gag | DNA prime (i.m.)/Sendai Virus boost (i.n.) | -CD8+ T cells | Durable control of SIVmac239 and SHIV89.6PD | Matano et al., 2001; Takeda et al., 2003; Kawada et al., 2007 |
| Rhesus Macaques | replication-defective SHIV particles and MVA-SHIV (SIV Gag, SIV Pol and HIV Env) | Intrarectal DNA prime/MVA boost | -Antibodies in plasma | -Preserved CD4 T cells -Reduced disease progression after SHIV 89.6P challenge | Wang et al., 2004 |
| -Cellular responses | |||||
| Rhesus macaques | SHIV-DNA plus IL-2 and rMVA | DNA + IL-12-prime (i.n.)/MVA-boost (i.n.) | -Mucosal and systemic antibody and cellular responses | Protection from SHIV 89.6P challenge | Bertley et al., 2004 |
| Mice and monkeys | E1/E3-deleted AdHu5 and E1-deleted AdC7 or AdC6, expressing Gag37 | i.m. prime-boost with: AdC7/AdC6/AdHu5 or AdHu5/AdC6/AdC7 | -Robust CD8+ CD4+ T cells | – | Reyes-Sandoval et al., 2004 |
| -Antibody responses | |||||
| Cynomolgus macaques | DNA- HIV-1 IIIB Env/Gag/RT/Rev/Tat/Nef, MVA- HIV-1 IIIB Nef-Tat- Rev, SIVmacJ5 Gag/Pol and Vaccinia HIV-1 Env | DNA prime/MVA boost (i.m. or mucosally) | -Antibody and cellular responses | Protection from infection | Makitalo et al., 2004 |
| Mice | HIV-1 Env IIIB Ag (DNA-Env and MVA-Env) | DNA-Env-prime/MVA-Env-boost (i.n. with Cholera toxin adjuvant) | -Mucosal CD8+ T cells, mucosal and systemic antibodies | – | Gherardi et al., 2004 |
| -Beta-chemokines | |||||
| Rhesus monkeys | DNA, MVA and Ad5 vectors expressing SIVmac239 Gag | DNA Prime (i.m.)/MVA- or Ad5- boost (i.m.) | -Robust CD8+ T cells with cytotoxic activity | Pronounced attenuation of SHIV infection and mitigated disease progression | Shiver et al., 2002 |
| Macaques | DNA and NYVAC SIV-gpe (Gag/Pol/Env) | DNA-prime (i.m.)/NYVAC-boost (i.m.) | -Durable CD8+ T cell responses | – | Hel et al., 2001 |
| (II) HOMOLOGOUS PRIME-BOOST OR SINGLE DOSE STUDIES | |||||
| Mice and rabbits | Ad4Env160 | i.m., i.n., or s.c. delivery of rAd4 | -T cell and antibody responses | Neutralization of tier-1 and tier-2 pseudoviruses | Alexander et al., 2013 |
| Ad4Env140 | |||||
| Ad4Env120 | |||||
| Mice | Ad35-GRIN/ENV and MVA- Gag/Env/Pol | Ad35-prime (i.m.)/Ad35-boost i.m.): MVA-prime (i.m.)/MVA-boost (i.m.) | -Polyfunctional CD8+ T cells | – | Ratto-Kim et al., 2012 |
| Rhesus macaques | SIVSME543-Gag/Pol/Env | MVA-prime (i.m.)/MVA-boost (i.m.) | -Neutralizing Abs, binding antibodies and cellular responses | Protection from SIVmac251 acquisition or disease progression | Barouch et al., 2012 |
| Rhesus macaques | RhCMV-SIV/Gag, Rev/Nef/Tat, Pol, Env | RhCMV vectors delivered by s.c. injection | -Strong and persisting, polyfunctional effector memory CD8+ and CD4+ cells | Viral clearance and durable protection from SIVmac239 disease progression | Hansen et al., 2009, 2011 |
| Rhesus monkeys | SIV-Gag, SIV-Env and SIV Rev-Tat-Nef fusion protein | Intravenous delivery of recombinant Rhadinovirus | -Persistent effector memory CD8+ T cells | Control of SIVmac239 replication | Bilello et al., 2011 |
| Rhesus macaques | Rabies virus (RV) expressing SIVmac239 Gag/Pol or Env | Intramuscular delivery of rRV constructs | -Polyfunctional CD8+ T cells in the mucosa | Control of SIVmac251-CX challenge | Faul et al., 2009 |
| -NAbs | |||||
| Rhesus and Cynomolgus macaques | SIV-Gag DNA + rIL-12 DNA vaccines | Intramuscular DNA delivery | T cell and Antibody responses | Improved clinical outcome after SHIV[89.6P] challenge | Boyer et al., 2005; Chong et al., 2007 |
| Juvenile and Infant Rhesus macaques | ALVAC-SIV and MVA-SIV both expressing SIV-Gag/Pol/Env | Multiple immunizations with ALVAC-SIV (i.m.) or MVA-SIV (i.m.) | -High titres of binding antibodies, low-level T cell responses | Protection from oral SIVmac251 challenge, and reduced viremia in breakthrough infections | Van Rompay et al., 2005 |
| Mice | HIV-1 Env IIIB Ag (DNA-Env and MVA-Env) | MVA-Env/MVA-Env | -Mucosal CD8+ T cells, mucosal and systemic antibodies | – | Gherardi et al., 2004 |
| DNA-Env/DNA-Env (i.n. with Cholera toxin adjuvant) | -Beta-chemokines | ||||
| Mice | Influenza virus expressing HIV-1 ELDKWA epitope | i.n. prime/boost with chimeric influenza virus, followed with i.p. boost with live virus | -Neutralizing antibodies | Neutralization of distantly related HIV-1 isolates | Muster et al., 1994 |
i.m., intramuscular; i.n., intranasal; i.d., intradermal; s.c., subcutaneous; i.p., intraperitoneal; ADCC, antibody dependent cytotoxicity; NAbs, neutralizing antibodies; BNAbs, broadly neutralizing antibodies.