Pro recently showed that the sequence homology between antigens and the human microbiome can either dampen (tolerogenic effect, most dominant) or increase (inflammatory effect) T-cell epitope immunogenicity; this occurs via molecular mimicry and is partially determined by bacterial genus. vaccine studies. In addition, we describe key KL1333 factors that may influence cell-mediated immunity and how antigen-specific responses are measured quantitatively and qualitatively, at both cellular and molecular levels. Finally, we discuss how we can harness this emerging knowledge and novel CD117 tools to inform the design and testing of the next generation of improved infant pertussis vaccines. (antigens that they contain, their dose, as well as their formulation; currently licenced variations contain alum adjuvant and between one to five purified, stabilised, and chemically or genetically modified (detoxified) pertussis antigens, including pertussis toxin (PT, at least), filamentous haemagglutinin (FHA), pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). From the 1990s, therefore, aP began to be rolled out globally by the World Health Organisation (WHO) and was incorporated into the primary immunisation schedule of most high-income countries (HICs) [7,8]. Despite high vaccine coverage rates (especially in HICs), however, there has been a resurgence in disease worldwide and it remains a primary cause of vaccine-preventable KL1333 death [9,10]. Recent models have indicated that there were 24.1 million pertussis cases and 160,700 deaths in children younger than 5 years worldwide in 2014, with the highest burden in sub-Saharan Africa, although these are estimates given the paucity of pertussis epidemiological data to date [11]. In many low-to-middle-income countries (LMICs), KL1333 the suboptimal pertussis control is thought to be primarily due to limited access to vaccines and inadequate healthcare resources, with poor diagnostic tools [12,13,14]. In HICs, the situation is more complex, and several reasons have been postulated for the increased reporting, including improved diagnostics, enhanced KL1333 surveillance, changes in immunisation strategy and administration schedules, differences in vaccine composition and immune responses induced, and antigenic variation in the circulating strains of due to vaccine selection pressure, reviewed extensively elsewhere [4,10,15,16]. The most plausible explanation is the switch in infant primary immunisation from wP to aP vaccines, which has been linked to less effective protection (particularly against colonisation, infection and transmission) and waning immunity [10,17,18,19,20,21]. The data to support this hypothesis primarily stems from both epidemiological studies and animal infection/transmission models. Infection in predominantly aP-vaccinated settings peaks in two age groups: (1) infants too young to have received the primary immunisation schedule and who should, therefore, benefit from herd immunity, suggesting that sterilising immunity is not achieved through immunisation; colonisation (often asymptomatic) can thus still occur, facilitating bacterial transfer to vulnerable, unprotected cohorts (2) adolescents and adults, although the clinical presentation is less severe, indicating that different specific long-term immune memory is elicited by the vaccines, with pertussis-specific immunity waning more rapidly following aP vaccination. Observational studies have shown that older children primed with aP compared to wP vaccines in infancy had a 2-to 5-fold greater risk of pertussis diagnosis [22,23,24]. Moreover, a US case control study demonstrated that, among adolescents who have only received DTaP vaccines in childhood, vaccine effectiveness following Tdap booster was 68.8% during the first year after vaccination, rapidly declining to 8.9% by 4 years after vaccination [25]. Nevertheless, even wP vaccines do not seem to establish as effective or long-lasting immunity as natural infection [26]. Pertussis outbreaks in these two cohorts have, therefore, led to the introduction of multiple boosters in some countries (particularly in the primary school and adolescent age groups) and routine maternal vaccination in pregnancy to protect the new-born in early life, prior to their first priming vaccine dose [27,28]. 1.2. Differences in Vaccine Composition and Host Immune Responses Go Hand-in-Hand Differences between KL1333 vaccines are multifactorial and interrelated. Key contributing factors are the underlying qualitative and quantitative immunological mechanisms that mediate effectiveness and longevity of vaccine-induced safety, particularly in the respiratory mucosal interface. Animal models have shown that memory CD4+ T-cells of T-helper (Th-)1 and Th17 phenotype facilitate long-term safety, which are elicited by natural infection as well as immunisation with wP [29,30,31,32]. In contrast, aP vaccination is definitely associated with a predominant Th2 response in humans [33,34,35,36,37]. Beyond Th-cell polarisation, additional qualitative changes in cellular reactions may result in suboptimal and/or shorter effectiveness [21,38,39,40,41]. For instance, given that wP vaccines appear to prevent colonisation in animal models, they may induce immune reactions that home to and/or take action more effectively in the mucosal.