Fernanda Tavares Da Silva

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.

Post-licensure safety surveillance for human papillomavirus-16/18-AS04-adjuvanted vaccine: more than 4 years of experience

To summarise post‐licensure safety surveillance over more than 4 years of routine use of the human papillomavirus‐16/18‐AS04‐adjuvanted vaccine (HPV‐16/18 vaccine: Cervarix®, GlaxoSmithKline, Belgium).

Optimal approaches to data collection and analysis of potential immune mediated disorders in clinical trials of new vaccines

BACKGROUND The potential for development of autoimmune diseases after vaccination with new vaccines containing novel adjuvants is a theoretical concern. Randomised, placebo-controlled trials are the best method for assessing a potential causal relationship between an adverse event and vaccination, but usually have a sample size too small to detect adverse events occurring in <1% of subjects. Incomplete case documentation may hamper definitive diagnoses, preventing accurate causality assessment. To date there are no guidelines for collection, documentation and monitoring of potential immune mediated disorders (pIMD) reported in the course of clinical trials with adjuvanted vaccines. OBJECTIVE This paper proposes a methodology for collection of pIMDs in clinical vaccine trials, with the objective of obtaining complete and reliable data using standardised methodology for its collection and analysis. RECOMMENDATIONS The role of the study investigator in prospective, standardised safety data collection is key and can be facilitated by providing a pIMD list in study documents and disease-specific standard questionnaires to assist timely and thorough documentation. External expert review of histopathology samples or other specialised diagnostic data would increase diagnostic accuracy. Centralised case ascertainment using standard case definitions would identify true cases of interest. We propose collection of safety data for at least 6 months and up to one year after the last vaccine dose. Bio-banking as a platform for collecting samples from enrolled patients for future use (e.g., to measure biomarkers of diagnostic, prognostic or predictive utility) could eventually provide valuable information in cases where a pIMD is diagnosed during the study period. CONCLUSION Standardised collection of safety data to allow appropriate analyses are optimal approaches for detecting rare events in clinical trials. Appropriate data analysis will then more reliably define potential causal relationships with vaccination.

Stillbirth: Case definition and guidelines for data collection, analysis, and presentation of maternal immunization safety data ☆

No abstract available Keywords: Adverse event; Case definition; Fetal death; Guidelines; Immunization; Stillbirth.

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.

Strategies for continuous evaluation of the benefit–risk profile of HPV-16/18-AS04-adjuvanted vaccine

The HPV types 16/18-AS04-adjuvanted cervical cancer vaccine, Cervarix® (HPV-16/18-vaccine, GlaxoSmithKline, Belgium) was first approved in 2007 and is licensed in 134 countries for the prevention of persistent infection, premalignant cervical lesions and cervical cancer caused by oncogenic HPV. Benefit–risk status requires continual re-evaluation as vaccine uptake increases, as the epidemiology of the disease evolves and as new information becomes available. This paper provides an example of benefit–risk considerations and risk-management planning. Evaluation of the benefit–risk of HPV-16/18-vaccine post-licensure includes studies with a range of designs in many countries and in collaboration with national public agencies and regulatory authorities. The strategy to assess benefit versus risk will continue to evolve and adapt to the changing HPV-16/18-vaccine market.

Signal detection based on time-to-onset: extending a new method from spontaneous reports to observational studies

A proof‐of‐concept study has previously highlighted the added value of a method using time‐to‐onset (TTO) for quantitative and non‐parametric signal detection on spontaneous report data. The aim of this study was to assess the added value of this new TTO signal detection method adapted to observational studies.

Signal management in pharmacovigilance and human risk assessment of CpG 7909, integrating embryo-fetal and post-natal developmental toxicity studies in rats and rabbits

The potential reproductive and developmental toxicity of the synthetic oligodeoxynucleotide (ODN) CpG 7909, a component of GSKs AS15 immunostimulant, was examined in rat and rabbit studies following intermittent intramuscular injections. Previous studies using subcutaneous and intraperitoneal injections in mice, rats and rabbits revealed that CpG ODNs induced developmental effects. To analyze the safety signal, GSK conducted additional animal studies using the intended clinical route of administration. CpG 7909 injections were administered intramuscularly to rats or rabbits 28 and 14days before pairing, on 4 or 5 occasions during gestation, and on lactation day 7. The No Observed Adverse Effect Level for female fertility, embryo-fetal and pre- and post-natal development was 4.2mg/kg in both species, approximately 500-fold higher than the anticipated human dose. In conclusion, the anticipated risk to humans is considered low for sporadic intramuscular exposure to CpG 7909.

Development of adjuvanted recombinant zoster vaccine and its implications for shingles prevention

ABSTRACT Introduction: GSK has developed a two-dose adjuvanted recombinant zoster vaccine (Shingrix, RZV) to protect people aged ≥50 years (50+) against herpes zoster (HZ) and its complications. RZV showed >90% efficacy against HZ, sustained over 4 years of follow-up, in all studied age groups. Areas covered: This article reviews the scientific rationale underlying the design of RZV; the clinical evidence demonstrating immunogenicity, safety, and efficacy in persons 50+; and the public health implications and cost-effectiveness. Expert commentary: A decline in varicella zoster virus (VZV) immunity is associated with increased risk of HZ in adults 50+ and immunocompromised individuals. RZV was designed to restore levels of anti-VZV cellular and humoral immunity to prevent VZV reactivation. RZV includes the recombinant gE glycoprotein antigen, and Adjuvant System AS01B which promotes cellular and antibody responses. In two Phase III studies in subjects aged 50+ and 70+ years, RZV efficacy against HZ compared to placebo was >90% and ≥89% against post-herpetic neuralgia (PHN). RZV is expected to dramatically impact HZ morbidity including its complications, and associated health-care costs. In the US population aged 50+ years, vaccination with RZV can be cost-effective compared to no vaccination and cost-saving compared to the currently available live-attenuated HZ vaccine (Zostavax, Merck). Video abstract Read the transcript Watch the video on Vimeo