Nanoparticle-Mediated Mucosal Vaccination: Harnessing Nucleic Acids for Immune Enhancement.

Recent advancements in in vitro transcribed mRNA (IVT-mRNA) vaccine manufacturing have attracted considerable interest as advanced methods for combating viral infections. The respiratory mucosa is a primary target for pathogen attack, but traditional intramuscular vaccines are not effective in generating protective ion mucosal surfaces. Mucosal immunization can induce both systemic and mucosal immunity by effectively eliminating microorganisms before their growth and development. However, there are several biological and physical obstacles to the administration of genetic payloads, such as IVT-mRNA and DNA, to the pulmonary and nasal mucosa. Nucleic acid vaccine nanocarriers should effectively protect and load genetic payloads to overcome barriers i.e., biological and physical, at the mucosal sites. This may aid in the transfection of specific antigens, epithelial cells, and incorporation of adjuvants. In this review, we address strategies for delivering genetic payloads, such as nucleic acid vaccines, that have been studied in the past and their potential applications.

Quantifying the effectiveness of betaherpesvirus-vectored transmissible vaccines.

Transmissible vaccines have the potential to revolutionize how zoonotic pathogens are controlled within wildlife reservoirs. A key challenge that must be overcome is identifying viral vectors that can rapidly spread immunity through a reservoir population. Because they are broadly distributed taxonomically, species specific, and stable to genetic manipulation, betaherpesviruses are leading candidates for use as transmissible vaccine vectors. Here we evaluate the likely effectiveness of betaherpesvirus-vectored transmissible vaccines by developing and parameterizing a mathematical model using data from captive and free-living mouse populations infected with murine cytomegalovirus (MCMV). Simulations of our parameterized model demonstrate rapid and effective control for a range of pathogens, with pathogen elimination frequently occurring within a year of vaccine introduction. Our results also suggest, however, that the effectiveness of transmissible vaccines may vary across reservoir populations and with respect to the specific vector strain used to construct the vaccine.

Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drives rapid and potent immunogenicity capable of single-dose protection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines.