Alberta Di Pasquale

Vaccine Adjuvants: from 1920 to 2015 and Beyond

The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines.

Adjuvant system AS01: helping to overcome the challenges of modern vaccines.

ABSTRACT Introduction: Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines. Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4ʹ-monophosphoryl lipid A (MPL) and the saponin QS-21. Here we describe studies investigating the mode of action of AS01, and consider the role of AS01 in enhancing specific immune responses to the antigen for selected candidate vaccines targeting malaria and herpes zoster. The effects of AS01 are rapid and transient, being localized to the injected muscle and draining lymph node. AS01 is efficient at promoting CD4+ T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting viruses or intracellular pathogens. Expert commentary: AS01 activity to enhance adaptive responses depends on synergistic activities of QS-21 and MPL. AS01 adjuvantation shows good prospects for use in new vaccines targeted to populations with challenging immune statuses and against diseases caused by complex pathogens.

Anamnestic response to administration of purified non-adsorbed hepatitis B surface antigen in healthy responders to hepatitis B vaccine with long-term non-protective antibody titres

A clinical trial with four groups receiving either 0.6, 3.5, 10 or 20 micro g of purified non-adsorbed hepatitis B surface antigen (HBsAg) was performed to study the kinetics as well as the capacity of the immune memory to respond following exposure to HBsAg in responders to a complete course of hepatitis B vaccine, in whom anti-HBs titres had declined below the seroprotective level. The study population included 64 healthy individuals. All response parameters seropositivity, seroprotection rates, booster response rates and geometric mean titres (GMTs), consistently showed that the immune response was highly satisfactory and dose-dependent. A remarkable immune response was obtained even with a trace amount of HBsAg. This study further supports recent indication that booster hepatitis B vaccine doses may be unnecessary in healthy adult responders to a full course of hepatitis B vaccination.

From discovery to licensure, the Adjuvant System story

ABSTRACT Adjuvants are substances added to vaccines to improve their immunogenicity. Used for more than 80 years, aluminum, the first adjuvant in human vaccines, proved insufficient to develop vaccines that could protect against new challenging pathogens such as HIV and malaria. New adjuvants and new combinations of adjuvants (Adjuvant Systems) have opened the door to the delivery of improved and new vaccines against re-emerging and difficult pathogens. Adjuvant Systems concept started through serendipity. The access to new developments in technology, microbiology and immunology have been instrumental for the dicephering of what they do and how they do it. This knowledge opens the door to more rational vaccine design with implications for developing new and better vaccines.

Vaccine safety evaluation: Practical aspects in assessing benefits and risks

Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls. Unfounded vaccine scares such as those associating the combined measles-mumps-rubella vaccine with autism, and whole-cell pertussis vaccines with encephalopathy, can also have massive impacts, resulting in reduced vaccine uptake and disease resurgence. The safety assessment of vaccines is exhaustive and continuous; beginning with non-clinical evaluation of their individual components in terms of purity, stability and sterility, continuing throughout the clinical development phase and entire duration of use of the vaccine; including post-approval. The breadth and depth of safety assessments conducted at multiple levels by a range of independent organizations increases confidence in the rigour with which any potential risks or side-effects are investigated and managed. Industry, regulatory agencies, academia, the medical community and the general public all play a role in monitoring vaccine safety. Within these stakeholder groups, the healthcare professional and vaccine provider have key roles in the prevention, identification, investigation and management of adverse events following immunisation (AEFI). Guidelines and algorithms aid in determining whether AEFI may have been caused by the vaccine, or whether it is coincidental to it. Healthcare providers are encouraged to rigorously investigate AEFIs and to report them via local reporting processes. The ultimate objective for all parties is to ensure vaccines have a favourable benefit-risk profile.

Safety assessment of adjuvanted vaccines: Methodological considerations

Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines.

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

This opinion paper describes 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). 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 vaccines. Adjuvants can be used to amplify the immune response to vaccine antigens. The combination of antigens with more than one adjuvant (referred to as “Adjuvant System”), can lead to the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. The Adjuvant System AS04 contained in the two licensed vaccines against HPV and HBV described here is a combination of the TLR4 agonist MPL and aluminium salt. Clinical results from these AS04 adjuvanted vaccines are described in light of other vaccines adjuvanted with aluminium salts only. The vaccines formulated with AS04 have been shown to enhance the immune responses while maintaining a clinically acceptable reactogenicity and safety profile.

Hepatitis B virus vaccine in chronic kidney diseases: improved immunogenicity by adjuvants? Limits of a meta-analysis.

The meta-analysis by Fabrizi et al. [1] highlights the importance f including fundamentals of immunology and vaccinology in the ethodology, otherwise inaccurate conclusions can be drawn. The meta-analysis aims to evaluate the immunogenicity of djuvanted versus non-adjuvanted HBV vaccines in patients with hronic kidney disease. However, this assumption is inaccurate as ll recombinant HBV vaccines are adjuvanted. In reality the authors ctually assess here the benefit of adding or replacing adjuvant ompared with aluminium-salt-adjuvanted HBV vaccines. This inaccuracy is compounded further because the clinical trials elected have considerable differences in vaccine formulation and tudy design precluding meaningful interpretation of data. The adjuvants listed in this analysis are very different in nature nd trigger different immunological pathways. Of the adjuvants ncluded, only one, AS04, is approved as a vaccine adjuvant. Delivery of vaccine antigen and adjuvant defines how the mmune system is activated and what types of immune cells are mpacted. Mode of action studies have revealed that adjuvants ust be spatially and temporally co-localised with the antigen 2,3]. In the studies considered in the meta-analysis, HBV antiens were administered intramuscularly with aluminium salt, ut some additional adjuvants were given orally (levamisole and mmunoferon®), administered as a separate intramuscular (IFN 2b, L-2, GM-CSF and -IFN) or subcutaneous injection (GM-CSF), forulated with the antigen (HBV-AS04 and HBV-AS02), and in two ther studies, the route was not specified. Patient populations were not homogenous. Although all studies ere targeting patients with renal impairment, 5 of the 10 studes were actually focusing on non-responders. This translated in a arge range of total vaccine doses the patients had received. Nonesponders constitute a specific population, with a higher degree of mmune deficiency compared to unvaccinated population selected n the other studies. Moreover, benefit of adjuvants is mainly seen uring primary vaccination, through enhancement of the strength nd quality of the immune response; when given as booster the djuvanted-vaccines recall previously elicited immune responses. The only primary outcome measure retained for the metanalysis is seroprotection rate calculated at completion of the vacciation schedule and over follow-up. As all studies differed in schedle, number of doses (1–4) and length of follow-up, homogeneity

Life-course immunization as a gateway to health

ABSTRACT Introduction: Extending the benefits of vaccination against infectious diseases from childhood throughout the entire life-span is becoming an increasingly urgent priority in view of the world’s aging population, emergence and reemergence of infectious diseases, and the necessity to invest more on prevention versus cure in global healthcare. Areas covered: This perspective discusses how life-course immunization could benefit human health at all stages of life. To achieve this, the current vaccination paradigm should be changed and all stakeholders have a role to play. Expert commentary: To enhance immunization confidence in the population, it is essential that stakeholders eliminate complacency toward infectious diseases, improve vaccination convenience, remove barriers among different healthcare specialties, and address prevention as a single entity. They must also consider societal and cultural mindsets by understanding and including public viewpoints. A new “4Cs’ model encompassing convenience, confidence, complacency, and cultural acceptance is proposed to convert ‘vaccine availability’ to ‘vaccination acceptance’ throughout life. Life-course vaccination should become the new social norm of a healthy life-style, along with a healthy diet, adequate physical exercise, and not smoking. We are ‘all in’ to make life-course immunization a gateway for all people to lead longer, healthier lives.