Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection
Abstract
:1. Introduction
2. Limitation of Commercially Available Antiviral Drugs
3. Why Immune Therapy Became an Option for Treatment of CHB
4. The Advent of Vaccine Therapy for Treating CHB Patients
5. Different Modes of Vaccine Therapies for CHB Patients (from 1994 to 2022)
5.1. HBsAg-Based Vaccine Therapy
5.2. Different Forms of HBsAg-Based Vaccine Therapy for Treating CHB Patients and Their Limitations
5.3. Other Forms of Vaccine Therapy in Addition to HBsAg-Based Vaccine
5.4. A Bird’s Eye View of the “Vaccine Therapy” in CHB Patients
6. Limitations of “Vaccine Therapy” in CHB Patients
- HBsAg-based vaccine therapy is not an evidence-based immune therapy for CHB patients. Immunity to HBsAg, such as anti-HBs, is an essential factor for controlling circulating HBV. Thus, the HBsAg-based vaccine is critical in the context of preventing HBV infection. However, treatment of CHB patients is related to the control of intracellular HBV DNA, especially cccDNA. This cannot be accomplished by the anti-HB response initiated by the HBsAg-based vaccine.
- Almost all investigators have used their own protocol for accomplishing vaccine therapy. Thus, the dose and duration of immunization have varied among protocols. This makes it difficult to assess the real implication of the optimum dose or duration of HBsAg that should be used in vaccine therapy.
- Almost all studies about vaccine therapy in CHB patients have been accomplished as pilot studies or observational studies, or as clinical trials of a limited spectrum. Thus, phase I/II/III clinical trials along with a follow-up study of several years with vaccine therapy remain to be accomplished.
- In almost all cases of vaccine therapy for CHB, there has been no publication regarding the short- or long-term follow-up information of this therapy.
- In most cases of vaccine therapy in CHB patients, the mechanism of action has been elucidated. The query remains regarding the presence of HBsAg in all CHB patients. Further, what specific functions can be achieved by administering HBsAg? Thus, there is a need to show differences in the immune modulation of circulating HBsAg and administered HBsAg-based vaccines. This has not been properly dissected.
7. Role of HBcAg as a Component of Vaccine Therapy
8. Positive Sides of Vaccine Therapy for the Treatment of CHB Patients
- Almost all protocols of vaccine therapy against CHB have shown their excellent safety profiles.
- Most of the projects of vaccine therapy have been endowed with antiviral potentials in CHB patients.
- Some protocols of vaccine therapy have shown the capacity of therapy to induce HBeAg negativity or anti-HBeAg seroconversion.
- Normalization of ALT has been reported by most of the designs of vaccine therapy.
9. Future Projections of Vaccine Therapy for CHB Patients
- Nature of the antigen: various pieces of evidence indicate that only HBsAg-based vaccine therapy may not be an optimum type of vaccine therapy as HBsAg-based immunity is unlikely to have an impact on intracellular HBV DNA and cccDNA.
- In spite of using HBsAg-based vaccine therapy, more attention should be directed to the use of HBcAg or other HBV-related antigens as candidate antigens for vaccine therapy.
- Studies about vaccine therapy should be properly designed regarding the dose and duration of therapy.
- Studies should be formulated to provide safety and efficacy information for the end of treatment (EOT) and after the EOT for a prolonged duration (data from over one to five years).
- When antiviral and liver protection is recorded by vaccine therapy, the underlying mechanisms should be explored.
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Limitation of IFNs and NUCs | Possible Causes |
---|---|
IFNs and NUCs are unable to eradicate or substantially control cccDNA that acts as a template for HBV replication. | Interferons and nucleoside analogs are repurposed antiviral drugs developed for other viral infections. Thus, these drugs are not evidence-based drugs for CHB. |
The liver-protecting capacities and potency to block progression to LC and HCC are nominal for IFNs and NUCs. | The immune modulatory capacity and the nature of immune modulation of IFNs and NUCs are not purpose-oriented. |
NUCs is an infinite mode of therapy, and there is a need to continue NUC intake for years or even for life. | The half-life of NUCs is, at best, 60 h. Thus, the effect of NUCs would be of limited duration. Cessation of NUCs will favor a milieu of HBV replication. |
NUCs are not patient-friendly for developing and resource-constrained countries. | The infinite usage of NUCs along with periodic check-ups is unfriendly to developing countries that harbor 80% of CHB patients. |
Use of NUCs confuses patients in developing countries. | NUCs induce HBV DNA negativity after usage for a short duration. Many CHB patients consider this as a remedy from the disease and give up taking medication. However, the drug must be taken for a prolonged duration. |
Parameters | Explanations |
---|---|
Availability | The HBsAg-based vaccine has been used as a preventive vaccine for HBV infection since the 1980s and is available commercially around the world. |
Safety | The safety of the HBsAg-based vaccine has been validated in millions of individuals. |
Scientific rationality | Loss of HBsAg and development of antibodies to HBsAg (anti-HBs) have been regarded as a complete cure for HBV infection. It was assumed that the HBsAg-based vaccine will be able to accomplish immune modulation in favor of anti-HBs. |
Different Candidates of HBsAg-Based Vaccine Therapy | References |
---|---|
1. HBsAg-based protein vaccine | [46,47,48] |
2. HBsAg/anti-HB-based antigen/antibody complex vaccine | [49,50,51] |
3. HBsAg-based DNA vaccine | [53,54] |
4. HBsAg-based cellular vaccine | [55,56,57] |
5. HBsAg-based vaccine as part of combination therapy with antiviral drugs | [58,59,60] |
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Akbar, S.M.F.; Mahtab, M.A.; Khan, S.; Yoshida, O.; Hiasa, Y. Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection. Vaccines 2022, 10, 1644. https://doi.org/10.3390/vaccines10101644
Akbar SMF, Mahtab MA, Khan S, Yoshida O, Hiasa Y. Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection. Vaccines. 2022; 10(10):1644. https://doi.org/10.3390/vaccines10101644
Chicago/Turabian StyleAkbar, Sheikh Mohammad Fazle, Mamun Al Mahtab, Sakirul Khan, Osamu Yoshida, and Yoichi Hiasa. 2022. "Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection" Vaccines 10, no. 10: 1644. https://doi.org/10.3390/vaccines10101644
APA StyleAkbar, S. M. F., Mahtab, M. A., Khan, S., Yoshida, O., & Hiasa, Y. (2022). Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection. Vaccines, 10(10), 1644. https://doi.org/10.3390/vaccines10101644