In brief

Fewer neutralising antibodies against the receptor-binding domain of SARS-CoV-2 may result in breakthrough infections, prompting the design of future ‘variant-resistant’ vaccines.

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Breakthrough infections from a memory lapse

22 Mar 2023

Vaccinated people affected by COVID-19 variants have different memory B cell responses than their close contacts who remain healthy.

COVID-19 vaccines deliver a message to the body’s immune system: “If you see this virus in the future, destroy it.” Intricate details about the virus such as its molecular structure are then locked away in an immune database via memory B cells. In the case of breakthrough infections, however, it seems that the immune system forgets these details.

Vaccines significantly lower the chances of infections in most people, but vaccinated people catching COVID-19—particularly by SARS-CoV-2 variants—seems to be on the rise, noted Lisa F. P. Ng, Executive Director of the A*STAR Infectious Disease Labs (ID Labs). “Vaccine breakthrough infections are very common right now, because variants such as XBB1.5 and BQ1.1 have acquired the ability to evade immune responses,” she explained.

Questions around how exactly variants are penetrating vaccine-initiated immune defences have lingered, prompting Ng and colleagues to investigate. In their study, the team recruited 55 vaccine breakthrough patients in Singapore alongside 86 of their vaccinated close contacts who didn’t get infected. The Delta variant was responsible for most of the cases in the study.

The researchers analysed blood samples from the participants in search of differences in the dynamics of their memory B cells—immune cells that self-replicate and churn out antibodies in response to viral attacks. Interestingly, plasma antibody levels were similar in both the breakthrough group and their close contacts. “Plasma antibodies refer to all antibodies found in the blood, and these antibodies primarily come from B cells that reside in the bone marrow and specialise in secreting antibodies,” said Ng.

A closer look revealed subtle differences in the immune responses in patients with breakthrough infections: there were fewer memory B cells specific to the SARS-CoV-2 receptor binding domain (RBD) and lower levels of inflammatory cytokines such as interleukin-1β and TNF.

These results imply that memory B cells in breakthrough cases have ‘forgotten’ the optimal way of preventing infection (by producing neutralising antibodies targeting the RBD). Also, even in breakthrough infections, vaccines can provide some protection against severe COVID-19. These critical findings could influence the design of future vaccines that activate stronger memory B cell responses, Ng suggested.

The success of this study would not have been possible without Singapore’s contact tracing efforts, Ng said. “The contact tracing efforts allowed us to very rapidly identify individuals with COVID-19, allowing us to collect samples at extremely early timepoints during infection.”

The team is currently investigating whether a similar memory B cell phenomenon could be behind breakthrough infections by highly immune evasive variants such as XBB1.5 in those who have received the bivalent vaccine booster.

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Tay, M.Z., Rouers, A., Fong, S.-W., Goh, Y.S., Chan, Y.-H. et al. Decreased memory B cell frequencies in COVID-19 delta variant vaccine breakthrough infection, EMBO Molecular Medicine 14, e15227 | article

About the Researchers

Lisa F.P. Ng obtained her PhD in molecular virology in coronaviruses from the National University of Singapore (NUS) in 2002. After joining A*STAR’s Genome Institute of Singapore (GIS) in 2002 as a Postdoctoral Fellow, she worked on viral diseases such as hepatitis, severe acute respiratory syndrome and influenza. Ng is currently the Executive Director at A*STAR Infectious Diseases Labs (ID Labs) where she focuses on the immune responses to arthritic arboviruses that are epidemic or highly endemic in the tropical region. Ng has won numerous accolades for her research, including the ASEAN ‘International Young Scientist and Technologist Award’ in 2008 and A*STAR’s ‘Most Inspiring Mentor Award’ in March 2013.
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Laurent Renia

Senior Fellow and Principal Investigator

A*STAR Infectious Diseases Labs (ID Labs)
Laurent Renia is the Founding Director and now Senior Fellow at the A*STAR Infectious Diseases Labs (ID Labs), established on 1 July, 2020. He earned his PhD degree in 1991 at the University Pierre et Marie Curie in Paris, France, where he studied immune response against malaria. Before joining A*STAR, Renia was a Research Director at the French National Institute of Health and Medical Research (INSERM) and Director of the Department of Immunology at the Institut Cochin. After joining A*STAR’s Singapore Immunology Network (SIgN) in 2007, he served as its Executive Director from 2014 to 2020. He has published more than 350 articles and book chapters on research topics on infection, immunity and immune-oncology.

This article was made for A*STAR Research by Wildtype Media Group