Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale up. Here, we developed an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti-SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.
Highlights
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged in December 2019 and within 3 months, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV2 infection, was declared a worldwide pandemic [1,2,3]
We evaluated the ability of replicon RNA (repRNA)-CoV2S to rapidly generate antibody and T cell responses in mice when formulated with a Lipid InOrganic Nanoparticle (LION) emulsion designed to enhance vaccine stability and intracellular delivery of the vaccine
Gel electrophoresis analysis of LION-formulated repRNA molecules extracted by phenol-chloroform treatment after a concentrated RNase challenge showed substantial protection from RNase-catalyzed degradation compared to unformulated repRNA (Fig. 1G)
Summary
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged in December 2019 and within 3 months, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV2 infection, was declared a worldwide pandemic [1,2,3]. The S protein mediates binding of coronaviruses to angiotensin converting enzyme 2 (ACE2) on the surface of various cell types including epithelial cells of the pulmonary alveolus [4,5,6]. Protection is thought to be mediated by neutralizing antibodies against the S protein [7, 8], as most of the experimental vaccines developed against the related SARS-CoV incorporated the S protein, or its receptor binding domain (RBD), with the goal of inducing robust, neutralizing antibody responses [9,10,11]. Previous reports have shown that human neutralizing antibodies protected mice challenged with SARS-CoV [12,13,14] and Middle East respiratory syndrome (MERS)-CoV [15] suggesting that protection against SARS-CoV-2 could be mediated through anti-S antibodies. SARS vaccines that drive Type 2 T helper cell (Th2) responses have been associated with enhanced lung immunopathology following challenge with SARS-CoV, whereas those with a Type 1 T helper cell (Th1)biased immune response are associated with enhanced
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