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The recent emergence and rapid response to severe acute respiratory syndrome coronavirus 2 was enabled by prototype pathogen and vaccine platform approaches, driven by the preemptive application of RNA vaccine technology to the related Middle East respiratory syndrome coronavirus. Recently, the National Institutes of Allergy and Infectious Diseases identified nine virus families of concern, eight enveloped virus families and one nonenveloped virus family, for which vaccine generation is a priority. Although RNA vaccines have been described for a variety of enveloped viruses, a roadmap for their use against nonenveloped viruses is lacking. Enterovirus D68 was recently designated a prototype pathogen within the family Picornaviridae of nonenveloped viruses because of its rapid evolution and respiratory route of transmission, coupled with a lack of diverse anti-enterovirus vaccine approaches in development. Here, we describe a proof-of-concept approach using a clinical stage RNA vaccine platform that induced robust enterovirus D68–neutralizing antibody responses in mice and nonhuman primates and prevented upper and lower respiratory tract infections and neurological disease in mice. In addition, we used our platform to rapidly characterize the antigenic diversity within the six genotypes of enterovirus D68, providing the necessary data to inform multivalent vaccine compositions that can elicit optimal breadth of neutralizing responses. These results demonstrate that RNA vaccines can be used as tools in our pandemic-preparedness toolbox for nonenveloped viruses. Editor's summary: mRNA vaccines have been shown to be successful for many enveloped viruses, including SARS-CoV-2 and RSV. However, their ability to confer protection against nonenveloped viruses, such as picornaviruses, remains to be seen. Here, Warner et al. developed and tested a series of self-amplifying mRNA vaccines targeting different subclades of enterovirus D68 (EV-D68). The authors found that the vaccines elicited antibodies that could neutralize their homologous subclade, with some evidence of heterologous protection. These data, coupled with a series of immunogenicity and challenge studies in mice and nonhuman primates, suggest that multivalent EV-D68 vaccines may confer broad protection against this prototype pathogen. —Courtney Malo [ABSTRACT FROM AUTHOR]