Not only did the COVID cases demonstrate a ~70% decline in circulating B- and T-cells, but histological analysis backed by immunohistochemistry staining demonstrated comparable reduction in the number of germinal center B-cells and accompanying Bcl-6+ TFH cells.27 These findings are in agreement with the low levels of somatic hypermutation in 403 monoclonal antibodies that were developed from B-cells recovered from the blood of convalescent subjects by Brouwer demonstrated that administered lipid nanoparticles induce robust cooperation of TFH cells with germinal center B-cells.21,143,144 Similar effects were observed during the vaccination of rhesus macaques against influenza by Lindgren for influenza.154 The selection of potentially synergistic epitope combinations will benefit from the use immunoinformatics tools, as described above.65,94,99,100,102,104,109 This approach could include the use of tools that enable the design of appropriate linker and codon adjustment strategies for minigene design.64,102 Ultimately, it should be possible to use suitably designed nanocarriers to deliver multi-epitope peptide sequences or minigene nucleic acid constructs to the host immune system for antigen presentation. effective humoral and cellular immunity that prevents viral infection or controls disease severity. In addition to a brief description of the design features of unique cationic lipid and virus-mimicking nanoparticles for accomplishing spike protein delivery and presentation by the cognate immune system, we also discuss the importance of adjuvancy and design features to Piromidic Acid promote cooperative B- and T-cell interactions in lymph node germinal centers, including through the use of epitope-based vaccines. Although current vaccine efforts have demonstrated short-term efficacy and vaccine safety, key issues are now vaccine durability and adaptability against viral Piromidic Acid variants. We present a forward-looking perspective of how vaccine design can be adapted to improve durability of the immune response and vaccine adaptation to overcome immune escape by viral variants. Finally, we consider the impact of nano-enabled approaches in the development of COVID-19 vaccines for improve vaccine design against other infectious agents, including for pathogens that may lead to future pandemics. Keywords: COVID-19, vaccine, antigens, epitopes, lipid Piromidic Acid nanoparticles, adjuvants, immune escape, durability, viral variants, immunoinformatics Graphical Abstract The challenge of developing a SARS-CoV-2 vaccine capable of intervening in the alarming rate of spread and mortality, the likes of which has not been seen since the 1918 influenza contagion, has been a daunting task. Remarkably, the 4C14 year time frame that was required for developing mumps, measles, polio, or human papilloma virus vaccines was condensed into a year to accomplish the same task for COVID-19.1 Infectious disease experts have cautioned for years about the pandemic potential of coronaviruses. These concerns were confirmed by the emergence of SARS-CoV-1 in 2003, with a case fatality rate of 15%, and the Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) in 2012, with a fatality rate of 36%.2 These short-lived outbreaks stimulated interest in understanding coronavirus pathogenesis and immunity, leading to the development of experimental vaccines in animal models.3-8 Unfortunately, due to the finite duration of these disease episodes, none of the efforts resulted in vaccine development for human use. Nonetheless, these efforts provided critical information Rabbit polyclonal to GRB14 about the role of the trimeric spike (S) glycoprotein, which is responsible for SARS-CoV uptake into host cells through a binding interaction with angiotensin-converting enzyme 2 (ACE2) receptors (Figures 1 and ?and22).3,6,7,9-11 In particular, it was revealed that the development of neutralizing antibodies against the receptor-binding domain (RBD) of the SARS-CoV-1 or MERS-CoV spike were effective in blocking viral uptake. This finding was instrumental in earmarking the generation of neutralizing antibodies against the spike protein as a viable vaccine strategy against coronaviruses.3,6,7,9-11 Moreover, research on experimental SARS-CoV-1 and respiratory syncytial virus (RSV) vaccines helped to refine a structural vaccinology approach in which the spike or fusion proteins were engineered to obtain a stabilized antigen conformation that optimizes the generation of neutralizing antibodies.12-14 These attempts subsequently became a blueprint for expedited SARS-CoV-2 vaccine development. Open in a separate window Number 1. SARS-CoV-2 parts for generating protective antiviral immune responses.These include the spike or S glycoprotein, membrane or M protein, envelope or E protein, and nucleocapsid or N protein (associates with viral RNA genome; not shown). The current choice for vaccine generation is the S glycoprotein, which is definitely capable of generating neutralizing antibody reactions in addition to eliciting CD8+ and CD4+ T-cells. The spike protein exhibits a screw-like shape, composed of a larger head and a long, thin stalk.206 Three spike proteins interact to form a trimer that is held in place by a stalk (composed of S1 and S2 areas), which stands away from the viral surface and exhibits a host protease (furin) cleavage site, the part of which is explained in Number 2. Adapted with permission from ref 206. Copyright 2020 CAS. Open in a separate window Number 2. SARS-CoV-2 spike (S) glycoprotein.A. The S protein includes (i) the trimeric S1 subunit, which consists of 3 receptor-binding domains (RBDs) (two of which are lying down, with one standing up); (ii) the membrane-associated S2 subunit, which includes a fusion peptide; (iii) a transmembrane (TM) anchor and (iv) an intracellular tail.60 B. Schematic to show the early stage of viral uptake.60 Viral uptake commences with proteolytic cleavage by furin, which separates the S1 and S2 subunits, enabling one RBD to stand up. Next, the 2nd and then the 3rd RBD domains stand up. The achievement of a pre-fusion complex (with 3 RBDs standing up) prospects to two important results: (i) exposure and immune acknowledgement of S1 epitopes that were covered up from the RBDs in the lying down conformation; (ii) high affinity binding of RBDs to the sponsor hACE2 receptor to enable viral docking. Once docked onto.