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Re-designing the hepatitis B vaccine: helping WHO achieve one of the 2030 elimination targets as Chronic hepatitis B (CHB) remains a global health problem.

According to WHO, as the epidemics of HIV, malaria, and tuberculosis retroceded, viral hepatitis became more evident as a leading killer worldwide. WHO estimates that in 2015, infections with hepatitis B and C virus caused 1.34 million deaths worldwide, compared with 1.1 million deaths from HIV in the same year. The major concern is not in European countries, however with the increasing migratory trend from Africa and Asia to European countries, it is expected that the number of cases will increase in Europe in the coming years.

Consequently, hepatitis returned to the agenda of World Health Assembly and in 2016 was adopted the first ‘global health sector strategy on viral hepatitis’. The objective is to reduce new viral hepatitis infections by 90% and to reduce deaths due to viral hepatitis by 65% by 2030. The elimination of hepatitis is an important goal of WHO for which scientific community can contribute. The hepatitis B epidemic affects parts of Africa and the Western Pacific most severely, where mother-to-child transmission is an important route of infection. It is important to note that infection acquired at birth is more likely to result in chronic infection and subsequent liver disease, such as cirrhosis and hepatocellular carcinoma (HCC).

Needle-free vaccines: the solution for two glitches

According with last WHO global hepatitis report (2017), the coverage with the initial birth dose hepatitis B vaccination is still low, about 39% in endemic countries. The health-care-related injections remained unsafe and the cool chain during the storage and handling of vaccines, which prevents the loss of vaccine stability, is often interrupted resulting in a loss of vaccine stability and so vaccine efficacy. Therefore, more stable and needle-free vaccines would help, not only to increase the vaccine coverage, but also to decrease the infections associated with bad clinical practices during the administration of injectables. The administration of vaccines by mucosal administration routes, such as oral or intranasal, entails enormous challenges, including the difficulty of protecting antigens from mucosal resident enzymes, from acidic environment in stomach and from the immunological tolerance mechanism (an active process by which the immune system does not respond to an orally administered antigen).1

The vaccine industry is setting aside projects aimed at developing mucosal-administered vaccines because the results obtained until now have not been promising. In addition to this, the financial return is not guaranteed as developing countries would be the main stakeholders. This research thinks about the specific needs of certain populations living in countries that cannot afford the costs of research to solve their specific problems, and that should be led by academic researchers from developed countries. The institutions of the European community must support these projects as a sign of their social responsibility on a global scale. At the same time, private institutions such as biotechnology companies will certainly be available to collaborate in these projects; helping to improve living conditions in these countries is the best strategy for preventing migratory flows.

Nanotechnology: the tool to design and produce artificial virus

The nanotechnology is the facilitating tool to obtain ‘pathogen-like’ adjuvants. Our research group assumed that combining on same nanoparticle several immunopotentiators, the resultant adjuvant would have predictable immunomodulatory properties for an intended vaccine. Therefore, the main objective has been to design and develop the methods for obtaining nanoparticles with pathogen-mimicking characteristics without having the toxic components of the virus. Chitosan has been the polymer chosen as the base of numerous blend adjuvants already tested by the group. One of them is the chitosan/aluminium nanoparticles (CH-Al NP) to deliver HBsAg and a plasmid that codifies the HBsAg (DNA vaccine).2,3

Concerning this new adjuvant, it was found that it is able to modulate cytokine secretion produced by murine bone-marrow derived dendritic cells (BMDCs). CH-Al NPs promoted NLRP3 inflammasome activation, enhancing the release of IL-1β without significantly inhibiting the T helper 1 (Th1) and Th17 cell- polarising cytokines, IL-12p70 or IL-23, and induced DC maturation, but they did not promote pro-inflammatory cytokine production on their own.2 In vivo experiments showed that intraperitoneal (i.p.) injection of mice with CH-Al NPs generated a local inflammatory response comparable to that elicited by the vaccine adjuvant alum, characterised by an increase in the recruitment of neutrophils and eosinophils. Importantly, after subcutaneous immunisation with CH-Al NPs combined with the hepatitis B surface antigen (HBsAg), mice developed high antigen-specific IgG titers in serum, nasal and vaginal washes comparable with titers obtained with the commercial formulation.2

Oral vaccines: are they a dream come true?

For the oral administration of the HBsAg, the challenge is to choose polymers that had immunostimulatory properties (chitosan) while protecting the antigen during its passage through the gastrointestinal tract (alginate). Therefore, a method to obtain alginate coated chitosan nanoparticles was developed and the HBsAg and the CpGODN were encapsulated into these NPs.4 The immunisation studies with this oral vaccine formulation revealed not only the production of the anti-HBsAg IgG in serum, but also anti-HBsAg IgA in the gut.5

In addition to this, due to the presence of the CpGODN in the same formulation, the immune response generated was a balanced Th1/Th2 with production of the typical IgG isotypes and the IFN-γ. However, this type of immune response was observed in less than 50% of mice.5 Later, a second vaccine formulation was evaluated during immunisation studies, the CpG ODN and the HBsAg were encapsulated into glucan shells.6 The oral vaccination schedule resulted in 60% of mice seroconversion, easily surpassed by a SC priming prior the oral boosts. The presence of the HBsAg-specific IgA on mucosal surfaces and IFN-γ in the liver were the major advantages found for these new formulation making it a very promising choice.6

Intranasal hepatitis B vaccine: The advantages

Intranasal administration of vaccines, besides having the advantages of a needle-free vaccine, has also the advantage of inducing antibodies in the nasal and in the cervicovaginal mucosae, quite convenient in the prophylaxis of sexually transmitted infectious diseases.7 The HBsAg was  co-adsorbed with CpGODN onto CH NPs and administered by the intranasal route; a good humoral immune response, systemic and on mucosal surfaces was obtained.3

Another immunopotentiator association, a mast cell activator (C48/80) associated with chitosan, was likewise tested with the HBsAg by the intranasal route.8 The excellent results obtained showed that this association can also be very useful for mucosal pathways. In this case the results were confirmed with a second antigen, the protective antigen of anthrax.9 The presence of the CpGODN on vaccine formulations tested by nasal route readdressed the immune response for a more balanced Th1/Th2 immune response. This immune response is different from the immune response induced by the injectable prophylactic vaccine already on the market and would be more helpful for babies who have contact with the virus at birth (perinatal transmission) or for chronic hepatitis B patients (CHB).

Breaking the tolerance and improving immunotherapy to help CHB patients

The success of classical therapeutic intervention and the utility of the prophylactic vaccine on chronic hepatitis B are limited. There is a well-founded hope that similarly of what happened to hepatitis C, the discovery of a treatment for hepatitis B will consistently reduce the cases. Thus, new strategies are now seriously considered.

The projects currently taking place in the research group are intended to develop and test several nanoparticulate adjuvants. The association of beta-1,3-D-glucan with diverse immunopotentiators are being tested as adjuvants for either, the surface and core HBV antigens, and DNA vaccine. The antigen encapsulated into beta-1,3-D-glucan NPs aiming the selective delivery to phagocytic cells and stimulate the immune system not only to induce antigen-specific humoral but also cellular immune response and so, to revert the immune tolerance characterised by a lack of protective T cell memory maturation and exhausted HBV-specific CD8+ T cell responses. The first results obtained with the HBsAg and with a DNA vaccine are already encouraging, particularly using the glucan shells obtained from Saccharomyces cerevisiae to encapsulate the antigen.10-12

This work is being funded by the COMPETE 2020 – Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, I.P., under project POCI-01-0145-FEDER-030331 and strategic project POCI-01-0145-FEDER-007440 (UID/NEU/04539/2019).

 

References

 

1          O. Borges, F. Lebre, and D. Bento et al. 2010.Mucosal vaccines: recent progress in understanding the natural barriers. Pharm Res. 2010;27(2):211-23

2          F. Lebre, M.C Pedroso de Lima, and E.C Lavelle et al. 2018. Mechanistic study of the adjuvant effect of chitosan-aluminum nanoparticles. Int J Pharm. 2018;552(1-2):7-15

3          F. Lebre, G. Borchard, and H. Faneca et al. 2016. Intranasal Administration of Novel Chitosan Nanoparticle/DNA Complexes Induces Antibody Response to Hepatitis B Surface Antigen in Mice. Mol Pharm. 2016;13(2):472-82

4          O. Borges, G. Borchard, and J.C Verhoef et al. 2005. Preparation of coated nanoparticles for a new mucosal vaccine delivery system. Int J Pharm. 2005;299(1-2):155-66

5          O. Borges, J. Tavares, and A. de Sousa et al. 2007. valuation of the immune response following a short oral vaccination schedule with hepatitis B antigen encapsulated into alginate-coated chitosan nanoparticles. Eur J Pharm Sci. 2007;32(4-5):278-90

6          E. Soares, S. Jesus, and O. Borges. 2018. Oral hepatitis B vaccine: chitosan or glucan based delivery systems for efficient HBsAg immunization following subcutaneous priming. Int J Pharm. 2018;535(1-2):261-71

7          M.S Almeida, and O. Borges. 2015. Nasal Vaccines Against Hepatitis B: An Update. Curr Pharm Biotechnol. 2015;16(10):882-90

8          D. Bento, S. Jesus, and F. Lebre et al. 2019. Chitosan Plus Compound 48/80: Formulation and Preliminary Evaluation as a Hepatitis B Vaccine Adjuvant. Pharmaceutics. 2019;11(2)

9          D. Bento, H.F Staats, and O. Borges. 2015. Effect of particulate adjuvant on the anthrax protective antigen dose required for effective nasal vaccination. Vaccine. 2015;33(31):3609-13

10        E. Soares, Z.M.A Groothuismink, and A. Boonstra et al. 2019. Glucan Particles Are a Powerful Adjuvant for the HBsAg, Favoring Antiviral Immunity. Mol Pharm. 2019;16(5):1971-81

11        E. Soares, R. Cordeiro, and H. Franeca et al. 2018. Chitosan: beta-glucan particles as a new adjuvant for the hepatitis B antigen. Eur J Pharm Biopharm. 2018;131:33-43

12        E. Soares, R. Cordeiro, H. Faneca et al. 2019. Polymeric nanoengineered HBsAg DNA vaccine designed in combination with betaglucan. Int J Biol Macromol. 2019;122:930-9

 

Prof Olga Borges, PharmD, MSc, PhD

Assistant Professor

Centre for Neuroscience and Cell Biology

Faculty of Pharmacy – University of Coimbra

+351 239 820 190

[email protected]

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www.cnbc.pt/

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