This article is part of the Research Topic Community Series in Development and Harmonization of Assays and Models to Assess Immunogenicity and Correlates of Protection of Vaccines Against Pathogens Causing Respiratory Infections: Volume 2
Authors:
Alessandra Buoninfante & Marco Cavaleri, Public Health Threats Department, European Medicines Agency, Amsterdam, Netherlands
Vaccines are complex biological medicinal products developed with the aim to generate protective immunity against specific infectious diseases in a particular target population. Regulatory authorities, who have the role of approving vaccines, ensure that these meet the agreed criteria for quality, safety and efficacy, and assess their benefit and risk profile before and after a marketing authorization is granted. In the European Union/European Economic Area, the vast majority of the vaccines currently available has been approved on the basis of clinical efficacy or immunogenicity data relying on humoral immune responses. Per contrary, there are no vaccines approved based on immunogenicity endpoints exclusively focused on cell mediated immunity, despite the known relevance of T cells immunity for protection against a variety of infectious diseases. We here review a few relevant cases of vaccines targeting infectious diseases for which data on cell mediated immunity have been considered in the context of regulatory filing, and provide our perspective on the way forward.
1 Introduction
Vaccines against infectious diseases aim to protect us from pathogens by activating antigen specific B and T cell responses. B cells produce antibodies, which can neutralize the pathogen by direct binding or by blocking certain functions of the pathogen and can exert immunological effector functions.
T cells recognize foreign antigens as short peptides presented on the cell surface in complex with human leukocyte antigen (HLA) class I or class II molecules, which confers them high specificity. Upon recognition of their cognate peptide presented by HLA molecules, memory T cells can rapidly elaborate effector functions to suppress replication, limit infection, and prevent spreading of pathogens within the host (1). Therefore, when designing vaccines against infectious diseases ideally both B and T cell responses should be targeted.
The European Medicines Agency (EMA) is the regulatory body responsible for the evaluation of centralized marketing authorization applications of medicinal products in the European Union/European Economic Area. This includes the evaluation of all new vaccines, and with its committees, EMA assesses their quality, safety and efficacy. The EMA assesses the scientific data submitted by developers on a specific products and grant its approval only if the benefit/risk ratio is considered positive for a defined indication of use. For vaccine approval, if an immune correlate of protection (CoP) defined as a type and amount of immunological response that correlates with vaccine-induced protection against an infectious disease (2) is available, it is deemed suitable to infer protection and demonstrate clinical benefit. Alternatively, if there is no established CoP and field efficacy studies are problematic, another approach to support approval of new vaccines is to use immune markers that are likely to predict protection even if the correlate of protection is not fully established.
All currently licensed vaccines generate humoral immune responses and work by either preventing infection or disease. Several approved vaccines have defined levels of serum antibodies that can be easily quantified and serve as correlates or surrogates of protective immunity. For these vaccines analysis of serum antibody titers provides clear and reliable information on vaccine efficacy and protection from disease. Emblematic representative cases are the correlates of protection of Hepatitis A, Hepatitis B, Hemophilus influenzae, where defined levels of antigen specific antibody levels measured by ELISA have been linked to protective efficacy and are used to support the authorization of a given product (3). Assays such as ELISA or neutralization assays which measure antibody titers have been standardized and used for licensure over the last decades. Differently than antibody responses, analysis of antigen specific CD4+ and CD8+ T cell responses and defining their contribution to vaccine-mediated immunity have been and remains a challenge. This is primarily due to the existence of many different sub- types of T cells with not completely defined functions and to their different tissue distribution. Additional challenges are encountered when trying to establish reproducible and reliable quantitative measurements.
In this article we reflect on the importance of eliciting T cells immunity with vaccination and provide a regulatory perspective on current state of play when it comes to documentation of T cells responses for regulatory submissions and decisions for vaccines, using specific case-examples.
