Human immunodeficiency virus vaccines: Advances, challenges and future perspectives

Table 1 Some landmark human immunodeficiency virus-1 vaccine trials and lessons learnt

Ref.	Trial (years)	Vaccine or strategy	Population	Lessons learnt
[7]	AIDSVAX B/E (1999-2003)	AIDSVAX B/E (gp120 protein, clade B/E)	2545 people who inject drugs in Bangkok, Thailand	The gp120 protein alone is insufficient, better immunogen design and/or vectors are needed
[5]	VAX004 (1998-2002)	AIDSVAX B/B (gp120 protein, clade B)	About 5400 MSM (men who have sex with men) and high-risk women in N. America/Europe	Protein-only approaches didn’t protect; highlighted the limits of the then available Env designs
[9]	STEP (2004-2007)	Modified adenovirus type 5 vector to deliver genes for gag/pol/nef (T-cell vaccine)	About 3000 MSM and high-risk women in the Americas/Australia	Vector pre-immunity and target biology matter. Avoid rAd5 strategies in at-risk subgroups
[10]	Phambili/HVTN 503 (2007)	Same rAd5 construct	Adults in South Africa (mostly heterosexual, clade C region)	Stopped early after STEP futility; no efficacy
[8]	RV144 (2003-2009)	Prime-boost: ALVAC-HIV (canarypox vector coding for HIV-1 Env, Gag, Pol) + AIDSVAX B/E (gp120 subunit)	16402 general-population adults in Thailand	Correlates: V1/V2-specific IgG linked to lower risk; high Env-IgA linked to higher risk
[11]	HVTN 702 (2016-2020)	RV144-like pox-protein regimen adapted for clade C	Men and women in South Africa	Vaccine components such as adjuvants, dosing schedules, and immune correlates of protection may need to be tailored to different viral subtypes and regional epidemic settings
[12]	HVTN 705 (Imbokodo) (2017-2021)	Ad26 mosaic prime + gp140 boost	2600+ young women in sub-Saharan Africa	No sufficient protection; trial ended. Elicit broadly neutralising activity and/or stronger functional antibody profiles
[13]	HVTN 706 (Mosaico) (2019-2023)	Ad26 mosaic prime + gp140 boost (modified)	About 3900 MSM and TG in America/Europe	No efficacy and trial discontinued. Results consistent with Imbokodo. The same vaccine platform cannot protect different populations

MSM: Men who have sex with men; rAd5: Recombinant adenovirus serotype 5; HIV: Human immunodeficiency virus; V1/V2: Variable loop 1/2; Ad26: Adenovirus serotype 26; gp: Glycoprotein; TG: Transgender.

Table 2 Post-2022 human immunodeficiency virus-1 vaccine trials

Ref.	Clinical trial	Vaccine concept	Platform	Vaccine description	Status
[127]	NCT03547245 (IAVIG001)	Germline targeting (CD4bs)	Protein nanoparticle + adjuvant (Phase 1)	eOD-GT8 60mer nanoparticle + AS01B (liposome-based adjuvant containing MPLA + QS-21)	Completed
[50]	NCT05001373 (IAVI G002)	Sequential germline targeting	mRNA-LNP (Phase 1)	eOD-GT8 60mer mRNA + core-g28 version 2 60mer mRNA nanoparticle	Active, not recruiting
[49]	NCT05414786 (IAVI G003)	Germline targeting (CD4bs)	mRNA-LNP (Phase 1)	eOD-GT8 60mer mRNA alone	Recruiting
[71]	HVTN 302 NCT05217641	Stabilized BG505 MD39.3 Env trimers	mRNA-LNP (Phase 1)	BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO mRNA (3 groups)	Active, not recruiting
[46]	NCT04864072 (HVTN 300)	B-cell lineage (CD4bs)	Protein + adjuvant (Phase 1)	CH505 transmitted/founder chimeric trimer + 3M-052 aqueous formulation with aluminum hydroxide	Active, not recruiting
[59]	NCT03961438 (ACTHIVE-001)	Native-like trimer	Protein + adjuvant (Phase 1)	Consensus M SOSIP version 7 gp140 + MPLA liposomes(as adjuvant)	Completed
[129]	HVTN 137A (NCT04177355)	Native-like trimer	Protein + adjuvant (Phase 1)	BG505 SOSIP.664 + 3M-052 aqueous formulation with aluminium hydroxide	Completed
[52]	NCT05182125 (HVTN 139)	B-cell lineage priming	Adenoviral vector + protein (Phase 1)	Adenovirus chimpanzee serotype 6/7 expressing HIV gp140 envelope glycoprotein+ CH505 transmitted/founder gp120 glycoprotein adjuvanted with glucopyranosyl lipid A stable emulsion	Recruiting
[131]	NCT03783130 (Trimer 4571)	Prefusion-stabilized trimer	Protein + adjuvant (Phase 1)	BG505 DS-SOSIP.664 (Trimer 4571) + alum	Completed
[132]	IAVI C114 (NCT06617091)	T -cell-inducing preventive/therapeutic HIV vaccine	Non-replicating Gorilla Adenovirus (Phase 1)	Gorilla adenovirus vectored HIV networked epitopes 1 encode highly networked, mutationally constrained HIV epitopes from stable structural regions (less prone to mutate)	Not yet recruiting

HIV: Human immunodeficiency virus; CD4bs: CD4 binding site; eOD-GT8: Engineered outer domain gp120 germline-targeting version 8; QS-21: Quillaja saponaria saponin-21; mRNA-LNP: Messenger RNA-lipid nanoparticle; MD39.3: Membrane distal variant 39.3; CD4KO: Cluster of differentiation 4 knockout; MPLA: Monophosphoryl lipid A.