DUBLIN – Spybiotech Ltd. has secured a first vaccine deal for its proprietary Spytag/Spycatcher protein conjugation technology. The Serum Institute of India Pvt. Co. Ltd. (SIIPL) is employing the technology in a COVID-19 virus-like-particle (VLP)-based vaccine, which recently entered a phase I/II trial in Australia. An initial data readout is expected in October or November. If successful, the vaccine could become a key part of India’s response to the COVID-19 pandemic. The country is now second only to the U.S. in numbers of confirmed cases, but its outbreak shows no signs of slowing down.

A 2017 spin-out from the Jenner Institute at the University of Oxford, Spybiotech was co-founded by vaccine researchers Sumi Biswas, Simon Draper and Jing Jin and by Mark Howarth, professor of protein nanotechnology at Oxford, who invented the Spytag/Spycatcher technology. Their initial proof-of-concept work was in malaria vaccine development, and that research that is ongoing at the Jenner Institute. Spybiotech has exclusive rights to the technology for all vaccine applications.

Its lead internal program comprises a vaccine for cytomegalovirus, which is slated to enter the clinic in either late 2021 or early 2022. Terms of the agreement with SIIPL have not been disclosed. Several other, as yet unlicensed, groups are using the system for COVID-19 vaccine development, including Copenhagen, Denmark-based Bavarian Nordic A/S, which earlier this year agreed to in-license a VLP-based vaccine from Hørsholm-based Adaptvac ApS. A phase I/IIa trial is due to get underway in the fourth quarter.

Sumi Biswas, co-founder, CEO and chief scientific officer, Spybiotech

The Spytag/Spycatcher technology comprises an engineered 10 kilodalton protein based on the fibronectin binding protein of Streptococcus pyogenes and an amino acid tag with which it spontaneously forms an isopeptide bond. The native protein contains a domain in which a spontaneous intramolecular bond forms between a lysine residue and an aspartic acid residue. That confers on the domain an exceptionally high level of stability – it retains its folding at pH2 or up to 100°C. Howarth’s group split that structure into two elements – the protein-based “catcher” and a 13-amino-acid “tag.” The sequence encoding the Spycatcher protein is included in the gene encoding the VLP, while the Spytag peptide sequence information is included in the gene that specifies the antigen of interest. Simply mixing the two gene products together allows the bond to form and the two components to be linked. “It’s a one-step conjugation,” said Biswas, Spybiotech’s CEO and chief scientific officer. The plug-and-display technology also allows for a relatively straightforward switch to a new antigen should SARS-CoV-2 undergo substantial mutation at any point in the future.

The simplicity of the process is its main advantage. Most conjugated vaccines – the best known are those involving polysaccharide antigens linked to immunogenic carrier proteins – rely on chemical conjugation methods and are not easy to produce. “The processes for those vaccines are very complicated,” Biswas told BioWorld. Each part of the SIIPL vaccine is produced in yeast. The VLP component comprises the surface antigen of hepatitis B virus (HBV), which is already widely used in licensed vaccines. The antigen forms the basis of recombinant HBV vaccines, but has also been deployed in VLP-based vaccines that carry heterologous antigens. One example is Mosquirix (RTS,S), the malaria vaccine developed by London-based Glaxosmithkline plc. “It’s proven – it works,” she said. “We know that VLPs are one of the best ways to include a strong antibody response.”

Race against COVID-19

Within the feverish climate of COVID-19 vaccine development, VLP-based efforts have received little attention to date, largely because their development lags those based on technologies such as mRNA, which can be deployed more rapidly. Medicago, a subsidiary of Osaka-based Mitsubishi Tanabe Pharma, has started a phase I trial in 180 volunteers of its plant-derived Coronavirus Virus-Like Particle vaccine candidate, which it is administering alone and in combinations involving two different adjuvants, GSK’s pandemic adjuvant and CpG 1018 from Emeryville, Calif.-based Dynavax Technologies Corp. It plans to move to a phase II/III trial in October. The Max Planck-Bristol Centre for Minimal Biology at the University of Bristol and Bristol, U.K.-based Imophoron Ltd. are in preclinical development with a synthetic VLP-based COVID-19 vaccine. New-York-based Ibio Inc. is also in preclinical development with IBIO-200, which also employs VLP technology.

Pune-based SIIPL, the world’s largest vaccine manufacturer in volume terms, is lining up several vaccine candidates for manufacturing as well as development. It has entered a $150 million agreement with Gavi, the Vaccine Alliance, and the Bill & Melinda Gates Foundation to produce initially up to 100 million doses of the Jenner Institute-developed “Oxford vaccine,” AZD-1222 (formerly ChAdOx1-nCov-19 vaccine), which Cambridge-based Astrazeneca plc has in-licensed, and NVX-CoV2373, the adjuvanted subunit vaccine in phase I/II development at Gaithersburg, Md.-based Novavax Inc. Those will be priced at no more than $3 per dose and will be available for distribution in India and in other low- and middle-income countries. SIIPL has also entered a partnership with Farmingdale, N.Y.-based Codagenix Inc. to co-develop a rationally designed live attenuated vaccine.

Although many media commentators have characterized current vaccine development efforts as a “race,” the real race is against the virus. Although clinical data has started to trickle out from the most advanced vaccine development programs, most of it is confined to preliminary measures of safety and immunogenicity. “We know fairly little about what kind of immune responses are going to be effective,” Biswas said. It will still take several months for a fuller picture to emerge.

Spybiotech, meanwhile, is currently raising a series A round. It previously raised £5 million (US$6.5 million) in seed financing from Oxford Sciences Innovation and GV, as well as £10 million from a convertible debt offering.

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