“Replication Proteins” – New Target for Next-Generation COVID-19 Vaccines

Next-generation vaccines for Covid-19 should aim to induce an immune response against ‘replication proteins’, essential for the very early stages of the viral cycle, concludes new research conducted by scientists at University College London (UCL).

By designing vaccines that activate immune memory cells known as T cells to attack infected cells that express this part of the virus’s internal machinery, it may be possible to eliminate SARS-CoV-2 from the very beginning. and thus help stop its spread.

This approach could complement the Covid-19 vaccines currently approved in the UK, which only trigger immune responses to the spike protein protruding from the outside of the virus.

Researchers say the discovery, published in Nature, could lead to the creation of a pan-coronavirus vaccine, which protects not only against SARS-CoV-2 and its variants, but also against coronaviruses that cause the common cold, and against new emerging animal coronaviruses.

Senior author Professor Mala Maini (UCL Infection & Immunity) said: “Our research shows that individuals who naturally resisted detectable SARS-CoV-2 infection generated memory T cells that target infected cells that carry the replication expressing proteins, part of the virus’s internal machinery.

“These proteins – which are required for the earliest phase of the virus’s life cycle, once it enters a cell – are common to all coronaviruses and remain ‘highly conserved’, so they are unlikely to change or mutate.

“A vaccine that can prompt T cells to recognize and target infected cells expressing these proteins, critical to the success of the virus, would be more effective in eliminating early SARS-CoV-2, and could have the added benefit of recognizing other coronaviruses that are currently infecting humans or could do so in the future.”

Researchers say next-generation vaccines could be developed to induce both memory T cells to target replication proteins and antibodies to target the spike protein.

Professor Maini added: “T cells that recognize the virus’s replication machinery would provide an additional layer of protection beyond the peak-targeted immunity generated by the already highly effective current vaccines.

“This dual-action vaccine would provide more flexibility against mutations, and because T cells can live incredibly long, it could also provide longer-lasting immunity. By expanding pre-existing T cells, such vaccines could help to keep the virus in a very early stage.”

Discovering the T-cell response to replication proteins

This fundamental scientific discovery comes from an observational study led by UCL and St Bartholomew’s Hospital, COVIDsortium, which analyzed immune responses in a large cohort of London-based health professionals from the very beginning of the UK’s first wave of pandemic.

However, in a subset of health professionals who showed no sign of SARS-CoV-2 infection (repeatedly tested negative by PCR and antibody tests), there was an increase in T cells.

Rather than completely avoiding infection, a subset of health professionals appears to have had a transient (abortive) infection, which cannot be detected by routine testing, but generated T cells specific for SARS-CoV. 2; consistent with this, the same subjects also had a slight increase in another blood marker of viral infection.

Lead author, Dr. Leo Swadling (UCL Infection & Immunity), said: “We know that some individuals do not remain infected despite likely exposure to the virus. What we did not know is whether these individuals have actually managed to avoid the virus completely or whether they cleared the virus naturally before it could be detected by routine testing.

“By closely monitoring health professionals for signs of infection and immune responses, we identified a minority with this SARS-CoV-2 specific T cell response.

“What’s really informative is that the T cells detected in these individuals, where the virus failed to establish successful infection, preferentially target different regions of the virus than those after infection.”

Why might some individuals cure an infection better than others?

In a commentary, Dr. Swadling: “It could be due to the infection history of these individuals. The health professionals who were able to get the virus under control before it was detectable were more likely to have these T cells that recognize the internal machinery before the start of the pandemic. These pre-existing T cells are poised to recognize SARS-CoV-2.”

Where do these pre-existing T cells come from?

He added: “The regions of the virus that recognize these T cells are highly conserved among other members of the coronavirus family, such as those that cause the common cold every year. Previous exposure to the common cold may have given these individuals an edge against the virus, tipping the balance in favor of their immune systems eliminating the virus before it could start to multiply.”

Reference: “Pre-existing polymerase-specific T cells expand in failed seronegative SARS-CoV-2” by Leo Swadling, Mariana O. Diniz, Nathalie M. Schmidt, Oliver E. Amin, Aneesh Chandran, Emily Shaw, Corinna Pade, Joseph M. Gibbons, Nina Le Bert, Anthony T. Tan, Anna Jeffery-Smith, Cedric CS Tan, Christine YL Tham, Stephanie Kucykowicz, Gloryanne Aidoo-Micah, Joshua Rosenheim, Jessica Davies, Marina Johnson, Melanie P. Jensen, George Joy , Laura E. McCoy, Ana M. Valdes, Benjamin M. Chain, David Goldblatt, Daniel M. Altmann, Rosemary J. Boyton, Charlotte Manisty, Thomas A. Treibel, James C. Moon, COVIDsortium researchers, Lucy van Dorp , Francois Balloux, Áine McKnight, Mahdad Noursadeghi, Antonio Bertoletti and Mala K. Maini, Nov. 10, 2021, Nature.
DOI: 10.1038/s41586-021-04186-8

This research was funded by the NIHR and UKRI’s UK Coronavirus Immunology Consortium.

The COVIDsortium is supported by funding donated by individuals, charities and businesses, with institutional support from Barts Health NHS Trust and Royal Free NHS Foundation Trust, in partnership with University College London and Queen Mary University London.