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Product Development

Gritstone sending a mixed-modality COVID vaccine to Phase I

The regimen is optimized to induce strong T cell responses as well as strong antibody responses

Jan 20, 2021 | 3:00 AM GMT

NIAID and the Gates Foundation are betting Gritstone’s antigen delivery and T cell epitope prediction technologies can yield a COVID-19 vaccine with both potent CD8+ T cell immunity and neutralizing antibody responses.

The approach could also serve as a shield against the rise of SARS-CoV-2 variants resistant to the first tranche of vaccines.

Gritstone Oncology Inc. (NASDAQ:GRTS) more than doubled its market value Tuesday, gaining $15.88 (249%) to $22.27 after revealing it would advance a pair of second-generation COVID-19 vaccine candidates out of its heterologous vector platform. The two will be tested as part of the same regimen, with the first dose a chimpanzee adenoviral (ChAd) vector vaccine, followed by a boost with a self-amplifying RNA (SAM).

CEO Andrew Allen told BioCentury the use of multiple modalities could provide “the best of both worlds.” The company has data showing that in non-human primates, self-amplifying RNA does not prime T cell responses as well as the ChAd vector; conversely, it is harder to get robust antibody responses with the adenoviral vector.

Phase II/III testing of the COVID vaccine could begin next half, raising the possibility that the vaccine could leapfrog the company’s lead cancer neoantigen therapies: a personalized neoantigen candidate and a shared neoantigen candidate, both in the Phase II portions of their respective Phase I/II trials GRANITE-001 and SLATE-001.

Neoantigen vaccines for cancer have yet to be clinically validated, as was the case with mRNA vaccines when NIH supported development of what ultimately became the modaltiy’s first authorized product: Moderna COVID-19 vaccine (mRNA-1273) from Moderna Inc. (NASDAQ:MRNA).

NIH’s National Institute of Allergy and Infectious Diseases is supporting Phase I testing of the COVID program, dubbed CORAL, through the Infectious Diseases Clinical Research Consortium (IDCRC). The Bill & Melinda Gates Foundation is supporting preclinical development through a grant.

The first vaccine candidate encodes a codon-optimized spike with mutations to stabilize the antigen’s prefusion structure and to remove the furin cleavage site involved in cell entry; it is slated to being Phase I testing this quarter. The second candidate, expected to enter the clinic in 2Q21, delivers the spike and broadens the antigen set with a cassette encoding non-spike CD8+ T cell epitopes.

All of the authorized COVID-19 vaccines from Western developers including  COVID-19 Vaccine AstraZeneca — a chimpanzee adenoviral vector vaccine from the University of Oxford and AstraZeneca plc (LSE:AZN; NASDAQ:AZN) — target only the SARS-CoV-2 spike.

The debut of Gritstone’s candidates comes amid growing concern over rapidly spreading viral variants with spike mutations. At least one, the E484K mutation that is in the South African S.501Y.V2 variant, has been linked to a drop in neutralization potency in some convalescent serum samples; whether it affects the authorized vaccines has not yet been determined.

Allen said Gritstone’s approach “of broadening the set of antigens within the vaccine, and broadening the immune response to include both neutralizing antibodies and CD8+ T cells, is a sensible approach to reducing the risk of a resistant variant spreading rapidly through a vaccinated population.”

During a webcast Tuesday morning, EVP of Research and CSO Karin Jooss presented mouse and non-human primate data showing the heterologous prime-boost regimens evoked strong anti-spike antibody responses and potent T cell responses against spike and non-spike peptides.

Also during Tuesday’s presentation, EVP and CTO Roman Yelensky said the mutations in SARS-CoV-2 variants “that have arisen so far do not affect the CD8 epitopes that we've included in the vaccine.”

The T cell epitopes include validated ones licensed from the La Jolla Institute for Immunology plus peptides identified with Gritstone’s EDGE platform, which can predict HLA-presented peptides using machine learning. Yelensky said the EDGE model covers over 100 HLA alleles, which “is particularly useful to expand the HLA coverage for individuals of diverse ancestries.” The vaccine’s T cell epitopes are predicted to cover over 90% of individuals with African, Asian or Pacific Islander, Hispanic or European ancestry.

HLA – Human leukocyte antigen

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