A Phase 2 clinical trial (NCT02075203) involving 990 previously BCG-vaccinated adolescents showed that BCG re-vaccination was necessary for the prevention of TB infection in un-infected populations (Table 2) [60]. BCG was also assessed as an adjuvant combined with the COVID-19 pathogenic antigen (SARS-CoV-2 derived peptide from non-structural protein 3), to activate the adaptive immune response and provide lasting protection [62,152]. vaccine development and the importance of immune stimulants drives the emergence of novel and more effective adjuvants. This article highlights recent advances in vaccine adjuvant development and provides detailed data from pre-clinical and clinical studies specific to infectious diseases. Future perspectives into vaccine adjuvant development are also highlighted. Keywords: immunological adjuvants, infectious diseases, pre-clinical and clinical trials 1. Introduction Infectious (or communicable) diseases are caused by infectious agents passed from one Rolitetracycline person (or animal) to another, and these play a huge impact on the health of humans worldwide. These infections are caused by bacteria, Rolitetracycline parasites, viruses, or fungi (or their toxic by-products), where transmission occurs directly, indirectly or by means of a vector (e.g., mosquitoes). According to the World Health Organisation (WHO), the top ten primary causes of death in low-income countries (which account for 36% of the worlds population) are associated with primary infectious diseases, including malaria, tuberculosis, human immunodeficiency virus (HIV) and influenza (e.g., H1N1 and H5N1), all of which have seriously affected global economies over the past decade(s). More recently, COVD-19 (from the SARS-CoV-2 coronavirus family) was first observed in Wuhan City (China) and has now Rolitetracycline dominated the worldwide headlines after being Rolitetracycline deemed a pandemic by the WHO on 11 March 2020. A review by Baker et al. highlighted the impacts of urbanisation on infectious diseases, and the effects of climatic, technological, and demographic change on disease emergence, dynamics and spread [1]. In previous decades, the transmission of pathogens occurred between wild and/or domestic animals and the human population, causing severe and fatal epidemics worldwide (e.g., HIV-1, HIV-2, the 1918 influenza, and Middle East respiratory syndrome coronavirus). Agricultural and animal husbandry expansion has led to the overuse of antibiotics in domestic animals and pesticides, leading to negative effects on the health of the human population [1]. There is an interface between the ageing population with declining immune function and a potentially increased task of containing infectious diseases that increase the probability of pathogen emergence. With this globally changing landscape, the increased evidence for drug and antibiotic resistance has evolved (e.g., antimalarial resistance) [2]. Although antimicrobials/antibiotics have shown increased efficacy for the treatment of several infectious diseases (e.g., septicemia, meningitis, diphtheria), vaccines are seen as the best method for the long-term prevention (and/or treatment) of infectious Cspg2 diseases worldwide, as vaccines play a key role in limiting Rolitetracycline disease outbreak and disease burden [3]. Vaccines, a result from pioneering research in the late 18th century by Jenner et al. who investigated the development of a vaccine against the cowpox virus [4], are now the most effective public health strategies used to stimulate protective immunity against infectious diseases worldwide, and have been attributed to saving millions of lives each year [5,6,7,8]. Although a range of successful vaccines have been developed based on attenuated or killed microorganisms (or their toxins), effective vaccines are still absent for the treatment and/or prevention of many infectious diseases known today [9]. With the advancement in vaccine development, from traditional vaccines comprised of whole, killed (or live-attenuated) organisms, to the recent discovery of subunit vaccines using small specific parts of the infectious antigen, vaccines show immense commercial potential with minimal side effects [10]. As the majority of vaccine candidates in clinical development are highly purified proteins and peptides, due to their poor immunogenicity alone (primarily related to the removal of danger signals and their small size), immunological adjuvants (immune stimulants) are required to enhance and/or direct immune responses [11]. However, despite the acknowledged.