A replicon RNA vaccine can induce durable protective immunity from SARS-CoV-2 in nonhuman primates after neutralizing antibodies have waned

Author summaryAn ideal COVID-19 vaccine should reduce the risk of transmission, provide protection from severe respiratory disease, and elicit strong and long-lasting immunity against SARS-CoV-2. Currently, neutralizing antibodies are thought to be the main component of the immune response contributing to protection by currently licensed COVID-19 vaccines. Here we tested a novel COVID-19 self-amplifying replicon RNA vaccine in a nonhuman primate model. We found that various doses of the vaccine and different vaccine regimens were able to protect against infection as demonstrated by reduced levels of SARS-CoV-2 in the upper and lower respiratory tract. Additionally, we found that some animals were protected even when neutralizing antibodies were not present at the time of infection, which suggests a protective role of other immune responses including binding antibodies and T-cells. Overall, our study provides evidence that a self-amplifying replicon RNA vaccine can be protective against SARS-CoV-2 and is able to provide immunity for greater than 6 months. The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses against homologous virus. We also observed broad binding antibody against heterologous contemporary and ancestral strains, but neutralizing antibody responses were primarily targeted to the vaccine-homologous strain. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels in some animals after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels.