A stabilized MERS-CoV spike ferritin nanoparticle vaccine elicits robust and protective neutralizing antibody responses

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified as a human pathogenic virus in 2012 and is causing ongoing sporadic infections as well as outbreak clusters. Despite case fatality rates (CFRs) of over 30% and the pandemic potential associated with betacoronaviruses, a safe and efficacious vaccine has not been developed for prevention of MERS in at-risk individuals. Here we report the design, in vitro characterization, and preclinical evaluation of MERS-CoV antigens. Our lead candidate comprises a stabilized spike ectodomain displayed on a self-assembling ferritin nanoparticle that can be produced from a high-expressing, stable cell pool. This vaccine elicits robust antibody titers in BALB/c mice as measured by MERS-CoV pseudovirus and live-virus neutralization assays. Immunization of non-human primates (NHPs) with a single dose of Alhydrogel-adjuvanted vaccine elicits >103geometric mean titer (GMT) of pseudovirus neutralizing antibodies that can be boosted with a second dose. These antibody levels are durable, with GMTs that surpass the post-prime levels for more than 5 months post-boost. Importantly, sera from these NHPs exhibits broad cross-reactivity against lentiviruses pseudotyped with spike proteins from MERS-CoV clades A, B, and C as well as a more distant pangolin merbecovirus. In an established alpaca challenge model, immunization fully protects against viral infection. This protein-based MERS-CoV nanoparticle vaccine is a promising candidate for advancement to clinical development to protect at-risk individuals and for future use in a potential outbreak setting.Key pointsMERS coronavirus (MERS-CoV) is an important betacoronavirus that continues to pose a risk to regional and global human health as demonstrated by recent fatal infections in the Middle East.A novel, stabilized MERS-CoV spike antigen displayed on a multimeric nanoparticle platform demonstrates robust immunogenicity in multiple animal models (mouse, NHP, and alpaca) and complete protection in an established animal challenge model (alpaca).Following a prime and boost in NHPs, this MERS-CoV nanoparticle vaccine induced durable and broad immunogenicity, with cross-clade neutralization against clades A, B, and C MERS-CoV pseudoviruses as well as a distant pangolin merbecovirus.This MERS-CoV nanoparticle vaccine is temperature and pH stable, can be expressed at high yield in a cGMP stable cell pool, and is based on a platform with established clinical safety. Thus, this vaccine candidate is well-suited for rapid clinical development against this important human pathogen.