Vaccines and antivirals are the primary strategies used to combat viral infections in humans and emerging pandemics. HIV-1, influenza and more recently, the emergence of Zika and SARS-CoV-2, pose significant challenges. For HIV-1, infected individuals harbor a substantial array of HIV-1 variants, a situation that presents a daunting challenge for developing vaccines and therapies. Similarly, the worldwide variability in flu reservoirs makes it difficult to predict which flu strain might acquire the ability to infect the human population, and due to the narrow timeframe between detecting a human infection and the “predict and produce” method for generating the vaccine each season, current influenza vaccines will likely be inadequate for preventing the next flu pandemic. Furthermore, transmission of viruses form mosquitos, such as Zika or from animals, such as SAR-CoV-2 pose a constant threat and new vaccine and antiviral technologies capable or rapidly responding to these threats are urgently needed. In an effort to address these issues, we are investigating new vaccine and antiviral concepts aimed at achieving broader, more universal protection against a wider range of highly variable viruses. Toward this goal, we have designed a therapeutic HIV DNA vaccine that when administered in combination with antiretroviral drugs to nonhuman primates infected with a primary isolate of SIV, induces profound control of viral replication that persists after antivirals are withdrawn. Viral control in this model correlated with strong mucosal CD8 responses localized in the gut, and this finding has more recently led us to investigate new DNA vaccine approaches that can more precisely focus CD8 against highly conserved epitopes and novel genetic adjuvants that can localize these responses to the gut, which is a primary source of residual virus. Similarly, using DNA and RNA vaccines and antivirals designed to precisely target highly conserved regions in influenza, we have shown significant protection against a wide range of influenza strains in mice, ferrets and nonhuman primates. More recently, we have shown that DNA and RNA vaccines can be rapidly developed in response to an emerging pandemic such as COVID-19. These studies demonstrate the feasibility of these new platforms for achieving broad protection against HIV and influenza and as a rapid response to emerging pandemics.. Studies currently in progress in the Fuller lab aim to elucidate mechanisms of protection mediated by these strategies and investigate various approach including novel adjuvants, DNA and RNA vaccine delivery approaches and combinatorial regimens to further improve these outcomes. Results from our work has resulted in over a dozen patents and two start-up biotechnology companies.