TABLE 2.
Proposed CoPs in macaque SIV or SHIV challenge models
| Reference | Immunogen(s)a | Challenge virus, dose, routea | VEb (%) | Proposed CoP | NAb titer against challenge virus |
|---|---|---|---|---|---|
| Roederer et al. (43) | SIVmac239 Prime: DNA x 3 Boost: Ad5 x 1 IM | SIVsmE660 Dose: 30% infection per exposure in controls 12 iterations IR | 69% | NAb titers | 40-98% neutralization of variants; ID50 (half-maximal inhibitory dilution) against SIVsmE660 sensitive clone CP3C: 103 - 106 |
| Bradley et al. (13) | HIV-1 B/E Prime: ALVAC x 2 Boost: ALVAC + Env B/E or B/E/E/E/E protein x 4 IM | SHIV-1157(QNE)Y173H Dose: low 8 iterations IR | B/E =11% B/E/E/E/E = 56% after 8th challenge, NS | ADCC c MIP-1β | ND d |
| Ackerman et al. (36) | HIV-1 B/E Prime: ALVAC x 2 Boost: ALVAC + Env B/E or B/E/E/E/E protein x 4 IM | SHIV-1157(QNE)Y173H Dose: low 8 iterations IR | B/E B/E/E/E/E Pool 35% after 8th challenge, NS | IgG ADCP c | ND (as tested in (13)) |
| Ackerman et al. (36) | SIVmac239 Prime: DNA x 3 Boost: Ad5 x 1 IM | SIVsmE660 Dose: 30% infection per exposure in controls 12 iterations IR | 69% | IgG ADCP | ND (as tested in (45)) |
| Ackerman et al. (36) | SIVmac239 Prime: DNA x 3 Boost: Ad5 x 1 Aerosol | SIVsmE660 Dose: 30% infection per exposure in controls 12 iterations IR | 70% | IgA ADNP c | NAd |
| Barouch et al. (64) | SIVsmE543 Prime: MVA gag, pol and env Boost: Ad26 (or converse order) | SIVmac251 Dose: 930 TCID50 6 iterations IR | 80% | V2, Env binding Tier-1 NAbs | <50% extent of neutralization |
| Barouch et al. (168) | Mosaic HIV-1 gag, pol, env Prime: Ad26/35 x 1 Boost: MVA x 1 or Prime: Ad26/35 x 1 Boost: Ad26/35 x 1 IM | SHIVSF162P3 Dose: 1/100 dilution of stock 6 iterations IR | ∼90% | Env binding SF162 NAbs ADCP ADCD c trend | 70-110 |
| Barouch et al. (40) | Prime: Ad26 SIVsmE543 env, gag, pol Boost: SIVmac32H gp140 IM | SIVmac251 SHIVSF162P3 Dose: 500 TCID50 6 iterations IR | 90% | Env binding ADCP | ∼30% extent neutralization against SIVmac- 251.30 |
| Barouch et al. (4) | Prime: Ad26 Mosaic HIV-1 gag, pol, env x 2 Boost: Clade C gp140 IM | SHIVSF162P3 Dose: 500 TCID50 6 iterations IR | 94% | Clade C gp140 binding, ELISPOT | NA |
| Fouts et al. (171) | HIV-1 Ba-L Prime: gp120-CD4 chimera or gp120 x 2 IM or DNA gp120-CD4 gag, pol x 3 Boost: gp120-CD4 chimera or gp120 x 2 IM | SIVmac251 or SHIV162P3 Dose: 50 (or 50, 100, and 200) TCID50 14 iterations IR | ∼70% | ADCC when T-cell responses were low | ND |
| Bogers et al. (115) | HIV-1 89.6, SF162 Prime: Ad5hr env x 2 IN or IT Boost: SF162 gp140 protein or SF162 gp140ΔV2 alphavirus x 2 IM | SHIV-SF162p4 Dose: 1800 TCID50 IR | 50-75% based on final outcome | NAb titers on day of challenge ADCC | Protected >80 Unprotected <70 |
| Miller- Novak et al., Tuero et al. (79, 85) | SIV various Prime: Replicating Ad SIVsmH4 env/rev, SIV239 gag and SIV239nefΔ1–13 x 2 IN and OR then IT Boost: SIVmac239 monomeric gp120 or oligomeric gp140 x 2 IM | SIVmac251 Dose: 120 TCID50 9 iterations IR | NS overall delay in infection (current controls); significant delay for females only | Rectal IgA to Env overall Rectal Env-specific memory B and plasma cells in females Virion but not cell lysis by ADCML in males | ND: Only detected against a sensitive version of challenge virus; no sex difference |
| Xiao et al. (86) | SIV various Prime: Replicating Ad5 SIVsmH4 (env) SIVmac239 (gag) x 2 s.l. or IN then IT or IV or IR Boost: SIVmac251gp120 x 2 IM | SIVmac251 Dose: 130 TCID50 9 iterations IR | NS delay; one IR-immunized animal uninfected | Antibody avidity (chaotrope assay) ADCC Rectal sIgA | ND |
| Sui et al. (92) | Prime: MVA SIVmac239 gag, pol, env, tat, and nef x 2 OR Boost: HIV-1 gp120-CD4 chimera on NP x 2 OR (most successful of several regimens) | SHIV SF162.P4 Dose: high or low 8 iterations IR | 44% | Gut microbiome alteration; trained innate immunity; possibly virus-specific T cells | ND, no Env binding |
| Letvin et al. (65) | SIVmac239 Prime: DNA env and gag-pol x 3 IM Boost: Ad5 env and gag-pol x 1 IM | SIVmac251 or SIVsmE660 Dose: 1 AID50 12 iterations IR | ∼50% against SIVsm660; none against SIVmac251 | Neutralization (%) at 1/50 serum dilution CD4L+ T-cells | Extent of neutralization at 1/50 serum dilution (∼90% in uninfected, 20% in infected Mamu-A*- animals) |
| Helmold Hait et al. and Hunegnaw et al. (90, 91) | SIV various Prime: Replicating Ad5 SIVsmH4 env/rev SIVmac239 gag x 2 IN-or. then IT Boost: SIV M766 and later CGTV gp120 x 2 IM | SIVmac251 800 TCID50 12 iterations IV | NS delay | ADCC but not ADCP FcγRIII Expression in cervico-vaginal macropahges | NA |
| Musich et al. (89) | SIV various Prime: Ad5hr SIVmac239 gag SIVM766 gp120-TM x 2 OR-IN then IT Boost: ALVAC-SIVM766 env/gag/pro + SIVM766 & CG7V gp120 x 2 IM or DNA SIVM766 env SIVmac239 gag macaque IL-12 + SIVM766 & CG7V gp120 x 2 IM | SIVmac251 120 TCID50 15 iterations IR | NS delay | Env-specific rectal IgA/total rectal IgA in all vaccinated animals (r = 0.35) ADNP in male vaccinees Changes in gut microbiome, greatest in females | NA: Only tested against neutralization-sensitive viruses |
| Vaccari et al. (15) | SIVmac251 & SIVsmE660 Prime: ALVAC SIVmac251 gag-pro and gp120TM x 2 IM Boost: ALVAC SIVmac251 gag-pro and gp120TM + SIVmac251(M766) & SIVsmE660 (CG7V) gp120 in Alum or MF59 adjuvant x 2 IM | SIVmac251 low dose 10 iterations IR | Alum group: 44%; MF59 group: NS delay | Alum group: Env-stimulated IL-17 secretion from innate lymphoid cells, expression of 12 genes, 10 in the RAS pathway, rectal V2-specific IgG; MF59 group: rectal IgG to V2: higher risk | NA: Only tested against neutralization-sensitive variant of SIVmac251 |
| Vaccari et al. (172) | SIVmac251 & SIVsmE660 Prime: DNA x 2 or Ad26 x 1 IM Boost: ALVAC SIVmac251 gag-pro and gp120TM + gp120-SIVmac251(M766) and gp120 SIVsmE660(CG7V) x 2 IM | SIVmac251 Dose: low 10 iterations IR | DNA group: 52%; Ad26 group: NS delay | Hypoxia and inflammasome in CD14+ monocytes DNA group: Rectal IgG to cyclic V2 corr. but not higher levels than in Ad26 group; V1V2-binding IgG in serum and rectal secretions higher for Ad26 than DNA prime | NA: Only tested against neutralization-sensitive variant of SIVmac251 |
| Schifanella et al. (16) | HIV-1 B/C Prime: ALVAC SIVmac gag-pol + ALVAC-HIV gag-pro-env x 4 or 5 IM Boost: gp120 (Clade C TV1+1086) x 2 or 4 Low-dose Alum, High-dose Alum or MF59 adjuvant IM | SHIV-C (1157ipd3N4), neutralization-sensitive 12 or 17 iterations IV | Low-dose Alum: NS; high-dose Alum: NS MF59: 64% | Alum low dose: IgA to V2 Increased risk Alum high dose: IgG to V2 Decreased risk MF59: NAbs against SHIV-C (Tier-1) | ∼20-100 |
| Kwa et al. (173) | SIVmac239 Prime: DNA gag-pol-env-tat-rev +/- CD40L IM Boost: MVA gag-pol-env-tat-rev +/- CD40L IM | SIVmac251 low dose 8 iterations IR | + CD40L group: 50%; - CD40L group NS delay | Fewer linear epitopes recognized in V1 and gp41; stronger V2 response in +CD40L than -CD40L group | ND |
| Pegu et al. (14) | SIV mac251K6W Prime: ALVAC gag-pol (vCP172) env (vCP1420) x 4 IM Boost: gp120 x 2 IM | SIVmac251 120 TCID50 6 iterations IR | NS delay | High avidity of gp120-specific IgG; V1V2-specific Ab (not powered for CoP analysis) | NA: Only tested against neutralization-sensitive variant of SIVmac251 |
| Strbo et al. (174) | SIVmac251 Irradiated HEK293 cells transfected with gp96 SIVmac251 rev-tat-nef, gag, and env x 3 + SIV rgp120 x 2 IP | SIVmac251 120 TCID50 7 iterations IR | 73% | SIVmac251-specifc Abs and CTL | ND |
| Gonzales-Nieto et al. (47) | SIVmac239 and 316 Prime: DNA near-full-genome (E767 stop) x 4 IM Boost: 5 RRVs with SIVmac inserts) x 1 or x 2 IVE | SIVmac239 (clonal) 200 TCID50 6 iterations IR | 78% | None identified | Weak or ND |
| Martins et al. (48) | SIVmac239 and 316 Prime: 5 RRVs with SIVmac inserts) x 2 IVE then IVE-OR Boost: DNA near-full-genome (E767 stop) x 4 IM | SIVmac239 (clonal) 0.3-0.5 AID50 6 iterations IVE | 79% | None identified | ND |
| Martins et al. (49) | SIVmac239 entire proteome: DNA x 3 (IM-EP); MVA (IVE); VSV (IVE); Ad5 (IM); RRV (IVE); DNA x 4; (IM-EP): 11 immunizations over 74 weeks | SIVmac239 (clonal) 200 TCID50 6 iterations IR | NS | NA | ND except SIVmac239 NAb ID50 ∼30 in one monkey, infected upon first challenge |
| Arunachalam et al. (149) | HIV-1 BG505 SOSIP.664 trimers x 4; SC +/- HVV-gag x 3 IVE | SHIV- BG505.332N.375Y 10 iterations IV | After 10 challenges: 53% - HVV-gag 67%; +HVV-gag | NAbs in - HVV-gag group; NAbs and Gag-specific CD8+ in + HVV- gag group | Protective: >300 - HVV- gag; <300 + HVV- gag |
| Pauthner et al. (150) | HIV-1 BG505 SOSIP trimers x 3 SC | 1.4 x 107virions BG505.332N.375Y 12 iterations IR | 100% in highest NAb group | Autologous NAb ID50 >500 against pseudovirus | High and low autologous NAb-titer animals were selected |
| Bomsel et al. (175) | HIV-1 HxB2 gp41 peptides coupled to virosomes IM x 4 or IM x 2 then IN x 2 | SHIV-SF162P3 20-30 TCID50 13 iterations IV | After 13 challenges: IM group: 50% IM+IN group: 100% | Transcytosis-blocking mucosal IgA ADCC by mucosal IgG | No neutralization by serum; cervico-vaginal fluid neutralized HIV-1 JR-CSF |
| Zhang et al. (167) | mRNA VLP WITO N276 KO x 1 Different clades mRNA VLP or Env trimer protein x 9 IM | SHIV AD8 10 TCID50 13 iterations IR | 79% | bNAbs to CD4-binding site | 10-100 |
a
IM = intramuscular; IN = intranasal; IT = intratracheal; SL = sublingual; IP = intraperitoneal; IV = intravaginal; IVE = intravenous; OR = oral; EP = electroporation; SC = subcutaneous; NP = nanoparticle; ALVAC = Canarypox-viral vector; MVA = modified vaccinia Ankara; VV = vaccinia virus; VSV = vesicular stomatitis virus; Ad5 = Adenovirus 5; RRV = rhesus rhadinovirus; HVV = heterologous viral vectors: VV, VSV and Ad5. TCID50 = tissue culture infectious dose; AID50 = animal infectious dose; VLP = virus-like particle; KO = knock-out.
b
Some studies also evaluated effects on the viral loads (VL). Here, the focus is on protection against acquisition and on studies that have analyzed associations with the number of challenges needed for infection, even in the absence of net protection against acquisition. When calculated from Kaplan-Meier plots for decreasing uninfected status with increasing number of challenges, the term (incidence of infection among vaccinees)/(incidence of infection among controls) is the hazard ratio derived from a Cox regression model; the resulting VE is the efficacy per challenge. For some studies (13, 38, 115), which lack these analyses, VE was instead calculated on the basis of the final outcome as indicated; some research groups calculate both kinds of VE; i.e., per challenge and after a certain number of challenges (42, 170). NS = non-significant.
c
ADCC = antibody-dependent cellular cytotoxicity; ADCP = antibody-dependent cellular phagocytosis mediated by monocytes; ADNP = antibody-dependent neutrophil-mediated phagocytosis; ADCVI = antibody-dependent cell-mediated viral inhibition; ADCML = antibody-dependent complement-mediated lysis (of cells or virions); ADCD = antibody-dependent complement deposition. ASC = antibody-secreting cells; OD = optical density
d
ND = Not detectable; NA = not analyzed.