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Understanding and weaponizing immune responses to COVID-19

Data and insights on COVID-19 immunity from three leading academic researchers

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Human B and T cell responses to the novel coronavirus provide natural biomarkers and blueprints for COVID-19 countermeasures. Virtual presentations hosted Thursday by BioCentury and Repertoire Immune Medicines Inc. showcased emerging work on SARS-CoV-2 antigens and immune receptors that could help triage patients and optimize vaccines and mAbs against COVID-19.

Even as compounds that interfere with the virus’ life cycle begin to show hints of efficacy, there is a growing consensus that tackling pathology and spread of COVID-19 will also require interventions that draw from the host immunity side of the equation (see “Deal Flow, Diagnostics and Defeating COVID-19”).

In a webinar on the adaptive response to COVID-19, leading academic researchers presented data, models and collaborations that could help chart a path for B cell and T cell-based countermeasures, and weighed in on vaccine antigen choice, the likelihood of antibody-induced adverse events and how memory T cells against more common coronaviruses could influence clinical outcomes.

Fresh out of the lab

Galit Alter, a professor at the Ragon Institute of MGH MIT and Harvard, shared unpublished data on biochemical and functional differences in the early antibody responses of hospitalized COVID-19 patients who recovered from the disease, versus those who succumbed.

Among the findings was that 5-11 days after symptom onset, the sera of convalescent patients was enriched for antibodies against the SARS-CoV-2 spike protein, while deceased patients’ early immune responses were more focused on the virus’ nucleocapsid protein.

Massachusetts Institute of Technology professor Arup Chakraborty presented a physics-based model for predicting which viral epitopes stimulate cytotoxic CD8 T cell responses that had been trained on data capturing patient responses to HIV epitopes.

“For the antibody side, spike is the right target based on all this data. But it may be different for therapeutic indications as opposed to prevention by vaccination.”

Galit Alter, Ragon Institute

Applying that model to SARS-CoV-2 and four common human coronaviruses led his team to predict that epitopes shared by the new and established viruses are helping at least part of the population control viral load by inducing cross-reactive T cell responses. The model also predicted that the spike protein alone is unlikely to provide broad T cell-mediated immunity across the population.

Based on their results and evidence from other groups, Alter and Chakraborty think the optimal SARS-CoV-2 targets for immune-based interventions will vary depending on whether the goal is preventing infection via humoral immunity, or establishing long-lived T cell responses that kill infected cells.

“For the antibody side, spike is the right target based on all this data. But it may be different for therapeutic indications as opposed to prevention by vaccination,” Alter said.

A third presentation from La Jolla Institute for Immunology professor Erica Ollmann Saphire described the goals, workflows and policies of the Coronavirus Immunotherapeutics Consortium (CoVIC).

The collaboration seeks to identify potent neutralizing mAbs against SARS-CoV-2 by comparing candidates from different developers in blinded, standardized in vitro, cellular and in vivo assays; Ollmann Saphire led a similar initiative for Ebola.

CoVIC is funded with $1.7 million from the Bill & Melinda Gates Foundation as part of the COVID-19 Therapeutic Accelerator, and involves CROs Carterra LSA, Nexelis and the Just - Evotec Biologics unit of Evotec SE (Xetra:EVT).

Part of CoVIC’s work is identifying the characteristics -- such as antigen specificity and antibody isotype -- that make mAbs most effective against the virus, along with those that give unwanted effects.

Ollmann Saphire thinks concerns about antibody-dependent enhancement (ADE) of infection have been overblown, but other safety issues could emerge for immune-based COVID-19 therapies.

“In the initial studies we’ve seen, there hasn’t yet been strong evidence for ADE. I think the separate issue would be, might a vaccine induce severe respiratory disease through a Th2 mechanism,” she said.

Panelist Mojca Skoberne, head of immunology and early development at Repertoire, thinks understanding the antigen specificities that protect immune responses in convalescent patients could inform the next wave of COVID-19 vaccines.

Repertoire EVP of Corporate Development Tim Harris voiced a similar perspective in a commentary on the iterative nature of vaccine development (see “Vaccine Prospects for COVID-19”).

Repertoire uses a trio of platform technologies to identify what TCRs and antigens matter in disease (see “Repertoire Bets on Both Sides of TCR-Antigen Coin”).

Targets

SARS-CoV-2 N - SARS-CoV-2 nucleocapsid protein

SARS-CoV-2 S - SARS-CoV-2 spike protein

T cell receptor - TCR

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