Designing Vaccines against Human Papillomavirus and Hepatitis B Virus: Similarities and Differences for Preventable Viral Infections and role of AS04 Adjuvant System in Addressing Specific Challenges

Abstract

IntroductionSeveral intracellular pathogens can establish long-lasting chronic infections and may lead to clinical disease. Two examples of such pathogens are the Human papillomavirus (HPV) and the Hepatitis B virus (HBV). Immunological mechanisms are involved both in the establishment and maintenance of the tolerance to these infections. Chronic infections and diseases are the results of a delicate interplay between the pathogen's actions to survive in the host and the attempts of the immune system to eradicate it.HPV is one of the most common chronic viral infections in humans. The virus consists of circular, double stranded DNA and has no envelope. Approximately 130 different HPV types have been identified so far [1] and about 40 of these infect the human genital tract, including 15 of types considered as oncogenic [2]. It is estimated that up to 80% of women will acquire a HPV infection in their lifetime [3]. Cervical HPV infections are asymptomatic; although most of them clear spontaneously and only 5-10% will become persistent infection possibly leading to the development of clinical pre-cancerous lesions and cancer.Upon natural infection, HPV remains at the site of infection, evades the immune system, and does not reliably induce protective immunity as the virus does not kill infected cells and hence neither inflammation nor release of danger signals to be recognised by the immune system is triggered. As a result, new infections and re-infection can occur [4]. A prophylactic HPV vaccine should therefore induce a better immune response than natural infection by overcoming the challenges due to the pathogen (i.e. have the ability to block the virus at the site of entrance), hence induce higher level of antibodies, and provide longterm protection [4].HBV infects hepatocytes and consists of a double-stranded circular DNA genome, an outer envelope protein (HBsAg), an inner nucleocapsid protein, (HBcAg), and a soluble small molecular weight protein (HBeAg) produced by the core gene. The HBsAg envelope protein can be shed and is also found as a non-infectious self-assembling tubular or spherical particle in the bloodstream of infected patients [5]. Overall eight genotypes of HBV are known [6,7]. AbstractPathogen characteristics and the mechanism of host/pathogen interaction play a key role in design, formulation, and development of vaccines. Here we present the experience of GSK Bio in developing two vaccines with a novel Adjuvant System (AS04) against two viral infections, Human papillomavirus (HPV) and Hepatitis B virus (HBV), that have some similarities and many differences.Developing a vaccine against HPV is difficult because the virus remains local, evades the immune system, and does not induce a reliable long lasting protection upon natural infection. Vaccination of pre-haemodialysis and haemodialysis patients against hepatitis B represents a challenge as well, because these patients are immunocompromised and develop a reduced and short lasting immune response to administration of conventional HBV vaccine...

Immunogenicity of Antigen Adjuvanted with AS04 and Its Deposition in the Upper Respiratory Tract after Intranasal Administration

“…Nonetheless, it would be interesting to investigate in future studies whether the proportion of particulates in the nanometer range correlates with a greater or lesser immunogenicity. As a TLR4 agonist, MPL is capable of directly activating key innate immune mechanisms, including the activation of APCs and the induction of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-6, and IL-12, which in turn enhance the adaptive immune response, that is, induce Th cells and B cell responses. − Because of the addition of MPL, AS04 is more effective in enhancing the immunogenicity of antigens as compared with insoluble aluminum salts only. , This additive effect was also observed with other adjuvants. For example, Beck (2018) reported that combining the saponin liposome adjuvant with an insoluble aluminum salt resulted in an adjuvant with more potent adjuvant activity .…”