Prophylactic HIV vaccine: vaccine regimens in clinical trials and potential challenges

Figures & data

Table 1. Summary of HIV vaccine trials in recent years (2009 – to date).

Year (start)	Study ID (citation)	Study Design	Vaccine Regimen	Trial Site	Target group	N	Safety	Efficacy	Immune response
2009	HVTN505 [9] (collaborators: NIAID, HVTN)	Randomized, Placebo-Controlled Test-of-Concept Phase 2b trial	Recombinant DNA plasmid vaccine injection at D 0, 28 and 56, followed by Recombinant adenoviral serotype 5 (rAD5) vaccine on Day 168	USA	18–50 yrs HIV-Uninfected, Circumcised Men and (MTF) Transgenders, MSM	2504	Vaccine recipients had a significantly higher rate of reactogenicity than did placebo recipients, but most reactions were mild or moderate.	Study haulted by DSMB recommendation for lack of efficacy. The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied	The vaccine induced a rate of IgG response of 100% to the vaccine strain envelopes (VRC clades A, B, and C) IgG response rates to V1-V2 Env were low. Response rates for neutralizing antibodies were low (2.5 to 27.5%). Vaccine induced HIV-specific CD4 + T cell response (61.5%) and CD8 + T cell response (64.1%) by intracellular cytokine staining
2010	IAVI B003 [12] (IAVI, HVTN, NIAID, BIDMC, Ragon Institute of MGH, MIT and Harvard)	Randomized, Double-blind, Placebo-controlled Phase 1	2 HIV-1 vaccines (Ad26.EnvA) (Ad35.Env), both administered at a dose of 5 × 10^10 viral particles) in homologous and heterologous combinations at months 0, 3 or 0, 6.	USA, East Africa, South Africa	18 – 50 Years low risk healthy adults	218	No vaccine-associated serious adverse events occurred	-	All regimens elicited humoral and cellular immune responses in nearly all participants. Baseline vector immunity did not significantly affect responses. The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States.
2012	RV305 [16] (collaborators: USAMRMC, NIH)	Randomized, double blinded, placebo-controlled phase II trial	RV144 regimen 6–8 years earlier Boosting with -ALVAC-HIV (vCP1521) + AIDSVAX B/E (gr 1) or -AIDSVAX B/E alone (gr 2) or -ALVAC-HIV alone (gr 3) At weeks 0, 24	Thailand	162 HIV-negative RV144 vaccine recipients 6–8 yrs earlier	162 (45 gr 1, 45 gr 2, 45 gr 3, 27 placebo)	Well tolerated	-	Memory to the RV144 vaccination regimen persisted although late boosts failed to increase durability of antibody responses. Regimens containing AIDSVAX B/E with or without ALVAC-HIV generated increased, but short-lived, humoral and CD4 + T-cell responses that did not rise further after subsequent boosting.
2012	[14] (collaborators: Sumagen)	Randomized, observer-blinded, and placebo-controlled phase I trial	Genetically modified and killed whole-HIV-1 vaccine, SAV001 (Clade B NL4-3) single dose IM	USA	chronic HIV infected 21–50 yrs on cART	33 (SAV001 25, Placebo 8)	Safe and well tolerated	-	Approximately 50% of subjects’ sera in SAV001 recipients showed an elevated neutralizing antibody level against HIV-1 clades B, D, and A
2013	RV306 (NCT01931358) (USAMRMC, NIAID)	Randomized, Double Blind, placebo-controlled phase II trial	The RV144 regimen plus ALVAC-HIV/AIDSVAX B/E or AIDSVAX B/E or ALVAC-HIV boost at week 48	Thailand	20–40 yrs HIV uninfected low risk Thai adult	360
2013	X001 [13] (Imperial college London, Wellcome Trust, NIHR)	Phase 1 Open-Labeled Trial	CN54gp140 mixed with GLA-AF adjuvant At months 0, 1, 2 and 6 (gr A) Or Months 0, 1, 2 and 12 (gr B)	UK	18 Years to 45 Years healthy adults	12 (6 at each group)	Safe and well tolerated		In both groups, decrease in Ag-specific IgG1 and an increase in IgG4 levels were modulated by booster injections, supporting that prime-boost strategies are essential for the induction of diverse Ag-specific HIV-1 responses. No positive Ag-specific T cell responses were detected in either group.
2014	IAVI A003 [15] (collaborators: IAVI, NIAID, Children’s hospital of Philadelphia)	Double-blind, phase 1, randomized-within-cohort, placebo-controlled, dose-escalation trial	Single time injection for Adeno-associated virus (AAV)-mediated HIV antibodies (PG9) expression. PG9 is a human monoclonal IgG1 antibody that reacts with the V1V2 loop of the HIV-1 envelope gp120 protein (clade A).	UK	healthy males aged 18–45 years	21 (16 intervention, 5 placebo)	No probable or definiteAEs or SAEs related	-	PG9 detected by HIV neutralization in the four volunteers’ sera, and by RT-PCR in muscle biopsy samples from four volunteers. No PG9 detected by ELISA. Anti-vector and anti-antibody immune responses present
2014	CR100965 [24] (Crucell Holland BV, MHRP, NIAID, BIDMC)	Single center, randomized, double-blinded, placebo-controlled phase I trial	MVA-vectored HIV-1 bivalent mosaic immunogen vaccine (MVA.mos1 and MVA.mos2; MVA Mosaic) total dose of 1*10^8 pfu/mL at weeks 0 and 12 to groups 1 and 2 (group 1: vaccine naïve, group 2: previously vaccinated with [Ad26.ENVA.010] 4–6 years earlier)	USA	19–49 yrs healthy low risk for acquiring HIV	25 Group 1: 12 Group 2: 8 5 placebos (3 naïve, 2 previous vaccinees)	safe and generally well tolerated	-	MVA Mosaic vaccine induced HIV-1-specific cellular immune responses in groups 1 and 2 after 1^st or 2^nd immunization. CD8 + T-cell response to Env peptide pool was more predominant in group 2. Almost all in group 1, 2 had cross-clade Env-specific Ab responses. CI, HI response persisted until 1 year follow up period
2014 – ongoing	RV328 (NCT01933685) (USAMRMC, NIH)	Randomized, Double Blind placebo-controlled phase II	AIDSVAX B/E at Weeks 0, 4, 24 and 48 (300 mcg dose/antigen, a total of 600mcg/dose)	Thailand	20–40 yrs healthy low risk adult	40
2015	CR106152 (APPROACH) [25] (Crucell Holland BV, NIAID, MHRP BIDMC, IAVI)	Multicenter, randomized, double-blind, placebo-controlled phase I/IIa	Priming twice with adenovirus serotype 26 (Ad26) vaccine (Mosaic Env/Gag/Pol antigens) at Wks 0, 12 Boosting twice with -Ad26 (mosaic Env/Ga/Pol) or -Ad26+ gp140 HD (250mcg), or -Ad26+ gp140 LD (50mcg), or -MVA (same antigen expr) -MVA+gp140 HD, or -MVA+gp140 LD, or -gp140 HD At Wks 24, 48	East Africa, South Africa, Thailand, USA	18–50 yrs healthy low risk HIV uninfected	393 randomized (49–50 at each group) into 8 groups	Safe and tolerable. No grade 4 AEs or deaths reported. 5 Gr3 AEs considered related to vaccine: Abd pain & diarrhea, increased AST, postural dizziness, malaise, back pain	Ad26/Ad26 + gp140 boost induced 67% protection against SHIV-SF162P3 infection in rhesus monkeys when challenged 6 times by intrarectal route	The mosaic Ad26 prime/Ad26+ HD gp140 boost vaccine was the most immunogenic: elicited Env-specific binding Ab responses (in 100%), antibody-dependent cellular phagocytosis responses (ADCP) (in 80%), and T-cell responses (in 83% of of vaccine recipients)
2015	HVTN 100 [21] (NIAID, HVTN, BMGF, MRC, Sanofi, GSK)	Phase 1–2 Randomized, Double-blind, Placebo-controlled	ALVAC-HIV vaccine [vCP2438] at 0, 1, 3, 6, 12 months + bivalent subtype C gp120/MF59 adjuvanted vaccine at 3, 6, 12 months ALVAC-HIV (vCP2438) was the same as that used for vCP1521 in the RV144 vaccine regimen, but the CRF01_AE gp120 insert (92TH023) was exchanged for a subtype C gp120 insert (96ZM651) * Bivalent: TV1.C gp120 Env and 1086.C gp120 Env proteins viral titer 10^7 CCID50 at each vaccination	South Africa	aged 18–40 years HIV negative at low risk of infection	252 (210 were randomly assigned to vaccine and 42 placebo)	No safety concerns identified yet		100% vaccine recipients developed IgG binding antibodies to all three vaccine-matched gp120 antigens with significantly higher titers (3.6–8.8 fold; all p < 0 · 0001) than the corresponding vaccine-matched responses of RV144. The rate and magnitude of CD4 T cell response to vaccine-matched env insert was higher in HVTN 100 than in RV 144. The response rate and the breadth of responses to subtype V1V2 were significantly higher in RV 144 than those in HVTN 100 vaccine recipients.
2016 – ongoing	HVTN 702 (NCT02968849) (NIAID Sanofi, GSK, BMGF)	Phase 2b/3 Multisite, Randomized, Double-blind, Placebo-controlled	ALVAC-HIV (vCP2438) at months 0, 1, 3, 6, 12 *Bivalent subtype C gp120/MF59 at months 3, 6, and 12 (same as HVTN 100) *Bivalent: TV1.C gp120 Env and 1086.C gp120 Env proteins	South Africa	18 to 35 years considered at risk for HIV infection	5400
2016	CR108152 (NCT02788045) (Janssen Vaccines & Prevention B.V.)	Randomized, Parallel-Group, Placebo-Controlled, Double-Blind Phase 1/2a Study	Priming with Trivalent Ad26.Mos.HIV vaccine (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol) At weeks 0, 12 Boosting with Trivalent Ad26.Mos.HIV + Clade C Gp140 (250mcg)/AlPO4 Adjuvant At weeks 24, 48 Priming with Tetravalent Ad26.Mos4.HIV vaccine (Ad26.Mos.1.Env + Ad26.Mos.2S.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol) At weeks 0, 12 Boosting with Tetravalent Ad26.Mos4.HIV + Clade C Gp140 (250 mcg)/AlPO4 adjuvant At weeks 24, 48	USA, Rwanda	Healthy low risk 18–50 Years	201
2016	CR108068 (NCT02685020) (Janssen Vaccines & Prevention B.V.)	Randomized, Parallel-group, Placebo-controlled, Double-blind Phase 1 Study	Ad26.Mos.HIV vaccine (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol) at Week 0 and 12 Boost by Ad26.Mos.HIV vaccine + Clade C gp 140 (250 mcg) with AlPO4 adjuvant at Week 24 and 48. Ad26.Mos.HIV vaccine (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol) + Clade C gp 140 (250 mcg protein) with AlPO4 adjuvant Week 0, 12 and 24.	USA	Healthy 18–50 years	36
2017 – ongoing	HVTN 705/HPX2008 (Imbokodo study) (NCT03060629) (collaborators: Janssen Vaccines & Prevention B.V.)	Multicenter, Randomized, Double-blind, Placebo-controlled Phase 2b Efficacy Study	Ad26.Mos4.HIV at Months 0, 3, 6, and 12 Clade C gp140 (250 mcg) with Aluminum phosphate adjuvant at Months 6 and 12	South Africa, Malawi, Mozambique, Zambia, Zimbabwe.	healthy, HIV-negative, between 18 and 35 years old	2600 women

Table 2. Vaccine-induced Sero-Reactivity (VISR) in HIV vaccine clinical trials with various HIV assays.

Study ID	Vaccine regimen	HIV diagnostic assay	Percentage of VISR at the end of the study	Duration of VISR
RV144 [35]	ALVAC-HIV (vCP1521)/AIDSVAX B/E	BioMerieux Vironostika HIV Ag/Ab	0.4%	NA
IVAI B001 [36]	Ad35-GRIN/Env 2 × 10^9 viral particles (vp)	HIV 1/2 Plus O ELISA	25%	NA
		Abbott Architect HIV Ag/Ab Combo EIA	50%
	Ad35-GRIN/Env 2 × 10^10 vp	HIV 1/2 Plus O ELISA	38%	NA
		Abbott Architect HIV Ag/Ab Combo EIA	100%
	Ad35-GRIN/Env 2 × 10^11 vp	HIV 1/2 Plus O ELISA	78%	NA
		Abbott Architect HIV Ag/Ab Combo EIA	56%
IAVI B003 [33]	Ad26-EnvA/Ad35-EnvA	Bio-Rad Multispot HIV-1/HIV-2 Rapid Test	12.5%	NA
		BioMerieux Vironostika HIV Ag/Ab	96.8%	NA
HVTN204 [33]	VRC-HIV DNA env A, env B, env C, gag B, pol B, nef B/Ad5 env A, env B, env C, gag B, pol B	Bio-Rad Genetic Systems HIV-1/HIV-2 plus O EIA	6%	0% after 5 years
		Abbot HIV AB HIV-1/HIV-2 (rDNA) EIA	85.8%	NA
		Abbot AxSYM HIV Ag/Ab Combo	NA	84.3% after 5 years
RV305 [16]	Previous RV144 vaccine + [ALVAC-HIV (vCP1521) + AIDSVAX B/E]	Bio-Rad Genetic Systems HIV-1/HIV-2 plus O EIA	8.9%	NA
	Previous RV144 vaccine + AIDSVAX B/E	Bio-Rad Genetic Systems HIV-1/HIV-2 plus O EIA	0%	NA
	Previous RV144 vaccine + ALVAC-HIV (vCP1521)	Bio-Rad Genetic Systems HIV-1/HIV-2 plus O EIA	6.8%	NA
RV306 [18]	RV144 regimen + ALVAC-HIV/AIDSVAX B/E or AIDSVAX B/E or ALVAC-HIV at week 48	ImmunoComb II HIV 1/2 (RDT)	3.1% (at week 96)	NA
		Determine HIV-1/2 (RDT)	0.8% (at week 96)	NA
		HIV Combi PT	0.4% (at week 96)	NA
APPROACH study (CR106152) [34]	Ad26/Ad26.Mos.HIV+gp140 High Dose (250 mcg)	Fourth-generation HIV Ag/Ab combo test *	97.5% (at week 96)	90.3% (at week 144)
	Ad26/Ad26.Mos.HIV+gp140 Low Dose (50 mcg)	Fourth-generation HIV Ag/Ab combo test *	94.4% (at week 96)	96.0% (at week 144)
	Ad26/gp140 High Dose (250mcg)	Fourth-generation HIV Ag/Ab combo test *	100% (at week 96)	NA

Abbreviation: RDT: rapid diagnostic test, EIA: enzyme immunoassay, ELISA: Enzyme-linked immunosorbent assay, VRC: Vaccine Research Center, vCP: viral Canarypox vector, Ad26: adenovirus 26, Ad35: Adenovirus 35, Ad35-GRIN/Env: adenovirus 35 containing gag, reverse transcriptase, integrase, nef/env genes, NA: Data not available.

* Fourth-generation HIV Ag/Ab combo test included either ARCHITECT HIV Ag/Ab Combo Assay, Bioelisa (Biokit), GS Biorad HIV Combo Ag/Ab EIA, Genscreen ULTRA HIV Ag-Ab, Vironostika HIV Uni-Form II Ag/Ab, Elecsys HIV combi PT, Determine HIV-1/2 Ag/Ab Combo.

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