Table 3.

The 10 most advanced therapeutic vaccine candidates/approaches by 2024*

Product status [Developer]	Next targets	Action mechanism/Rationale Antigens in bold	Main results[References/CT-code]
HeberNasvac® [CIGB] • Phase IV in CHB HBsAg(+) patients. • Phase III follow-up. • Phase IIb IN-only developments. • Pilot study in NUC treatment cessation.	• Post marketing Phase IV completion. • Large-scale sanitary intervention (2025–2030). • Develop of the IN-only formulation. • Vaccination in the set of NUC discontinuation.	• The recHBsAg-HBcAg vaccine induces high frequency multi-functional CD4+ T-cells in liver, “only” after IN immunization. • HBcAg multi-TLR agonist effect stimulates type I and II, ISG, HLA class II Th1 cytokines via TRIF and MyD88 pathways. Mucoadhesive CVP enhance mucosal uptake.	Competitive in safety and efficacy vs PegIFN. Sustained and increased antiviral effect after 2, 3, and 5 years.6,15–18 Absence of cirrhosis progression or clinical complication vs PegIFN group at 5 years follow-up. Gen “C” patients with 12.7% functional cure using a nasal-only product and mucoadhesive (48 months follow-up) and HBeAg, HBcrAg reductions. Uniform antiviral response across genotypes.83
VTP-300 [Vaccitech, Oxford] • Phase IIb trial with results	• Assess efficacy, safety, and immunogenicity of ChAdOx1-HBV and MVA-HBV, combined with Nivolumab, in CHB under NUC. Primary outcome % patients >1 log HBsAg.	Two vectors ChAdOx1-HBV prime-boost with MVA-HBV approach (together VTP-300). Adenovirus prime and poxvirus boost further enhance the immunogenicity. Vectors deliver the gene encoding the HBV Ags into human cells. PD-1 inhibitor will further optimize the regimen.	Phase Ib/IIa trial met primary and secondary endpoints. Well-tolerated, no grade 3 incidents no serious adverse events. Reductions of HBsAg most prominent in patients with lower baseline HBsAg (≤200 IU/mL). 13 (23%) of patients reported a >0.5 log HBsAg reduction at day 113, and 5 (9%) reported a >1 log reduction.98 Next study: [NCT05343481]
BRII-179 (VBI-2601) [BRII Biosciences] • Phase II Study in Combination with PEG-IFNα completed	• Assess efficacy, safety, tolerability and immunogenicity in a Phase II study of BRII-179.	The combination of the antigen Pre-S1/Pre-S2/S and PegIFN increase the immune response against the HBV and contribute to reduce the HBsAg, and HBsAb seroconversion. Studying triple combination of PegIFN+ Vaccine+NUCs in phase II CT.	Only CHB patients with HBsAg levels (<100 UI/mL): at EOT, 26.3% (15 patients) treated with BRII-179/PEG-IFNα (G1) achieved HBsAg loss compared to 19.3% (11 patients) with placebo/PEG-IFNα (G2). At 12 weeks follow-up (W36), 24.6% (14 patients) G1 had HBsAg loss, compared with 14.0% (8 patients) with placebo/PEG-IFNα. 9 out of 15 patients in G1 HBsAb(+) at EOT vs 1 of 11 in G2.99
VVX001 [Viravaxx] • Phase II	• Immunogenicity assessment in 4 cohorts: (1) healthy subjects, (2) non-responders Hep B vaccine, (3) HBV inactive carriers and (4) the CHB patients on NUCs.	Researchers have found that the protein contained in the BM32 vaccine against allergy [comprising the PreS protein fused to allergen—against pollen] can also induce antibodies that prevent the HBV from docking onto liver cells used as CHB therapy.	PreS specific IgG Ab achieved in the four cohorts. Ab inhibit HBV virus spreading in HepG2-NTCP cells in cell culture [virus neutralization test]. HBV-neutralizing Ab induced in non-responders to conventional vaccination. >50% CHB patients had >50% reduction of HBsAg 8 months after EOT. NUCs safely stopped in most CHB patients after three VVX001 injections flares. [NCT03625934]
CVI-HBV-002 [Cha Vaccine] • Phase IIb	• Assess safety and efficacy in double-blinded, placebo-controlled, phase IIb of CVI-HBV-002 in CHB patients under NUCs (TDF).	L-HBsAg (including pre-S regions) and adjuvant L-pampo -an innovative system containing TLR2 and TLR3 agonists that recruits DCs into lymph nodes, where they prime Ag-specific T-cell.	Phase IIb results expected in 2024. Mean change in HBsAg (log10 IU/mL) at week 48 from baseline as primary outcome measure. [NCT04289987].
HepTcell [Altimmune] • Phase II Enrollment completed.	• Assess safety and immunogenicity of the Phase II, double-blind, randomized, placebo-controlled study.	9 synthetic peptides of conserved regions, formulated with adjuvant IC31®, a TLR9-based adjuvant. Vaccine designed to drive T cell responses against all genotypes with the target in naive patients with inactive CHB and low HBsAg.	Phase II results expected in 2024. The primary outcome measure is the proportion of patients achieving virologic responses. Secondary outcome measures include the proportion of patients achieving serologic clearance of Hepatitis B surface antigen (HBsAg) and Hepatitis B virus (HBV) DNA. [NCT04684914]
YS-HBV-002 [YS Biopharma] • Phase I approved by Philippine FDA to start in June 2024.	• Assess immunogenicity, and efficacy in adult patients in a double blind, randomized, placebo-controlled, escalation study.	Recombinant HBV proteins HBsAg/HBcAg and proprietary PIKA adjuvant -synthetic analogue of double-stranded RNA (dsRNA) TLR3 agonist- will enhance innate and adaptive immune responses.	Successful Phase I clinical trial of PIKA YS-HBV-001 in Singapore demonstrated good tolerability/immunogenicity in healthy volunteers. PIKA adjuvant effect described and in use for other vaccine candidates. The new study will be in CHB patients [NCT06162299]
CLB-3000 [ClearB Therapeutics] • Phase Ib ongoing. Report expected in 2024.	Assess safety, tolerability, and anti-viral activity of a two ascending dose cohorts. 5 IM doses, monthly, combined with NUCs. The highest dose will be 500 µg.	CLB-405 and CLB-505 [two modified HBsAg, in Pichia pastoris] designed to display clearance profile-associated epitopes on HBsAg; these were identified from anti-HBs from patients with functional cure. The vaccine is adjuvanted with Alhydrogel.	Completion of GLP toxicology studies and presentation at ILC 2023. 15-week intramuscular toxicity study in rabbits with a 4-week recovery. Announcement of the start of the study with the immunization of the first patient. [ACTRN:1263000841673]
HBV003 [Vaxine Pty Ltd.] • Completed Phase I and Phase I clinical trial planned.	• Assess safety and efficacy of a novel adjuvanted vaccine against chronic HBV infection.	Pre-S HBsAg containing Advax-2 adjuvant based on Delta-inulin (Advax) bind monocytes and macro-phages via DC-SIGN. Confirmed higher HBsAb induction in poor responder subjects vs the standard alum-vaccine create hope for patients.	Adjuvant activity enhancing humoral, cellular, and long-lasting responses against antigens from influenza, hepatitis B, and allergy vaccines. Safe and well tolerated by SC and IM injections. GMP manufacture and defined action mechanism.100,101 Positive results in clinical trials in poor responding volunteers. [NCT03038802]
TherVacB [Technical Univ. of Munich/Univ. Medical Center Hamburg Eppendorf/Horizon Project] • Phase Ia, ongoing.	• Assess safety, immunogenicity in healthy subjects and start a multinational Phase 1b/2a dose escalating, open trial, in CHB patients.	Prime with CpG-HBsAg (Heplisav) + HBcAg to develop a strong CD4+ T cell response and booster with MVA to expand CD8+ T and B cell responses. Innate and adaptive stimulation of the immune responses in the setting of a strong prime-boost.	CD4 T-cell activation is a key determinant of HBV-specific antibody and CD8 T-cell responses.102 HBV-specific antibodies with loss of HBsAg and mild liver damage in HBe(+) and HBe(–) HBV carrier mice.103 A thermostable formulation was able to break immune tolerance in a mouse model of chronic hepatitis B.104 [NCT05727267]

*The list is consistent with the list of therapeutic vaccines presented at the EASL 2024 meeting