Journal Summary: Therapeutic Vaccines for Chronic Hepatitis B—Hope or Hype

Ever since the first trail for assessing the therapeutic potential of hepatitis B vaccination by Pol et al[1] in 1994 using recombinant peptide vaccine (S and pre-S2 antigen), a fully functional therapeutic vaccine is yet to be translated from clinical trials to clinical practice. Wei et al[2] recently conducted a phase 2 clinical trial involving hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients who received a liposome-based nanoparticle vaccine (εPA-44). It had been shown previously by Wang et al[3] that nanoparticles as a delivery system target distinct receptors in T helper cells involved in the pathogenesis of CHB. Improving the delivery of peptide to designated receptor elicit greater immune response in CHB from SIGNR1⁺ of T follicular helper cells. Li et al[4] have shown that liposome as a vaccine adjuvant promote antigen presentation in dendritic cells via NLRP3 inflammasome pathway. In contrast to previous recombinant vaccines, Wei et al have used a novel liposome-based nanoparticle vaccine delivering a synthetic peptide which was derived from hepatitis B core antigen (HBcAg), tetanus toxoid, and hepatitis B surface antigen (HBsAg), thus combining immunogen, adjuvant, and a delivery system.

Study was done in two stages: stage 1 was a double-blinded placebo-controlled trial where 360 patients were randomized to six doses of placebo arm (900 µg empty liposome), 600 μg (600 µg εPA-44 with 300 µg empty liposome), or 900 μg of εPA-44 and followed for 72 weeks. Stage 2 was an open label study where patients with serological response (HBeAg seroconversion) and virological response (hepatitis B virus deoxyribonucleic acid [HBV-DNA] level < 2.93 × 10⁴ IU/mL) in stage 1 were followed until week 144 without any intervention (follow-up group) and nonresponders were given additional 15 doses of 900 µg εPA-44 and followed until week 144 (extended treatment group), primary endpoint of study being HBeAg seroconversion at end of 76 weeks. The results suggest that HBeAg seroconversion rate in the 900 μg group was significantly higher when compared with placebo (38.8% vs. 20.2%, p-value 0.002) and no significant difference between the 600 μg group and placebo (28.6% vs. 20.2%, p-value 0.13), seroconversion rate of 20.2% in the placebo group was attributed to liposomal activation of immunity. The combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization, and HBV DNA < 2,000 IU/m was 5% in placebo which was significantly lower when compared with 900 μg (18.1%, p-value 0.002) and 600 μg (14.3%, p-value 0.02). Analysis of the individual endpoints at week 76 showed no significant difference in number of patients with HBV DNA < 2000 IU/mL and undetectable HBV DNA among three groups. Study of change in serum HBsAg levels revealed significant reductions in HBsAg in the 600 µg group in comparison with placebo and 900 µg group at week 52, 64, and 76, although baseline levels were almost similar, which was not explained by authors. Stage 2 further showed 22.1% of patients in the extended treatment group additionally achieved seroconversion, although none achieved functional cure. However, these results cannot be generalized to other population groups as the individuals selected in the study were human leukocyte antigen-A2 positive whose frequency is greater in northern Asian groups as compared with Indian[5] (30.88%) or U.S.[6] (47.6%) population. The vaccine is now undergoing a phase 3 trial (ChiCTR number: ChiCTR2100043708).

Therapeutic vaccination has been gaining new frontiers in the era of precision medicine; it is based on the principle of stimulating the immune system with a target antigen (vaccine) and overcoming the immune tolerance to better recognize deleterious organisms or cells. Given its novel way of stimulating the immunity several phase 1 and 2 clinical trials are being performed in infectious diseases (human immunodeficiency virus, CHB, tuberculosis, urinary tract infections), deaddiction, autoimmune diseases (arthritis, diabetes, multiple sclerosis), degenerative diseases (Alzheimer's disease), malignancies, chronic conditions like hypertension, atherosclerosis, and allergies.[5]

Approximately 5 to 10% of acute HBV infection in adults becomes chronic due to defective functioning of HBV-specific T cells.[6] This is due to multiple mechanisms: induction of immune tolerance, expression of immune checkpoint inhibitors, and increased apoptosis. T cells play a major role in HBV clearance.[6] Concordantly, T cell responses are far more abundant and of higher quality in those who achieve clearance after acute HBV infection. Hence, basis of newer modalities for treating HBV infection is to boosting or introducing HBV-directed T cell responses on which therapeutic vaccination is based.

Ethical Statement

Not applicable.

Author Contributions

P.B.N. wrote the initial draft and performed literature search; S.T. did critical revisions; both authors approved the final version.

Data Availability Statement

There are no associated data.

Publication History

Received: 20 February 2022

Accepted: 25 March 2022

Article published online:
22 September 2023

• References

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