Project Description
Trial Title: A Phase I study to determine safety, tolerability and immunogenicity of intranasal administration of the COVID vaccine ChAdOx1 nCOV-19 in healthy UK adults
Chief Investigator: Dr Alexander Douglas
Funder: University of Oxford
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China and were later confirmed to be infected with a novel coronavirus, known as 2019-nCoV [1]. The virus was subsequently renamed to SARS-CoV-2 because it is similar to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV), a lineage B betacoronavirus. SARS-CoV-2 shares more than 79% of its sequence with SARS-CoV, and 50% with the coronavirus responsible for Middle East respiratory syndrome (MERS-CoV), a member of the lineage C betacoronavirus[2]. COVID-19 is the infectious disease caused by SARS-CoV-2. By January 2020 there was increasing evidence of human to human transmission as the number of cases rapidly began to increase in China. Despite unprecedented containment measures adopted by the Chinese government, SARS-CoV-2 rapidly spread across the world. The WHO declared the COVID-19 outbreak a public health emergency of international concern on 30th January 2020. As of 9th Feb 2021, over 106,125,682 cases have been reported to the WHO, with more than 2,320,497deaths worldwide [3].
Coronaviruses (CoVs) are spherical, enveloped, large positive-sense single-stranded RNA genomes. One-fourth of their genome is responsible for coding structural proteins, such as the spike (S) glycoprotein, envelope (E), membrane (M) and nucleocapsid (N) proteins. E, M, and N are mainly responsible for virion assembly whilst the S protein is involved in receptor binding, mediating virus entry into host cells during CoVs infection via different receptors.[4] SARS-CoV-2 belongs to the phylogenetic lineage B of the genus Betacoronavirus and it recognises the angiotensin-converting enzyme 2 (ACE2) as the entry receptor [5]. It is the seventh CoV known to cause human infections and the third known to cause severe disease after SARS-CoV and MERS-CoV.
The spike protein is a type I, trimeric, transmembrane glycoprotein located at the surface of the viral envelope of CoVs, which can be divided into two functional subunits: the N-terminal S1 and the C-terminal S2. S1 and S2 are responsible for cellular receptor binding via the receptor binding domain (RBD) and fusion of virus and cell membranes respectively, thereby mediating the entry of SARS-CoV-2 into target cells.[4] The roles of S in receptor binding and membrane fusion make it an ideal target for vaccine and antiviral development, as it is the main target for neutralising antibodies.
ChAdOx1 nCoV-19 vaccine consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the structural surface glycoprotein (Spike protein) antigen of the SARS CoV-2 (nCoV-19), with a leading tissue plasminogen activator (tPA) signal sequence. ChAdOx1 nCoV-19 expresses a codon-optimised coding sequence for the Spike protein from genome sequence accession GenBank: MN908947. The tPA leader sequence has been shown to be beneficial in enhancing immunogenicity of another ChAdOx1 vectored CoV vaccine (ChAdOx1 MERS) [6].
