It’s been three months since the first case of Omicron was identified in the US. Initial reports that Omicron is more contagious but causes less severe disease appear to be substantiated. Fortunately, surges in cases and hospitalizations have peaked in many regions.
Omicron is undoubtedly not the last variant that will arise out of the pandemic. News reports of an Omicron subvariant, dubbed BA.2 or stealth Omicron, are already circulating. One of the main concerns with any new variant is whether the immunity people have built up, either from vaccination or previous infection, will continue to provide protection.
It is becoming clear that T cells may be the key to long-term immunity and cross-reactivity against viral variants, potentially paving the way to more effective, or universal vaccines.
Antibody effectiveness wanes as the virus mutates
Until recently, neutralizing antibodies, which bind to the SARS-CoV-2 spike protein and limit its ability to invade host cells, have been one of the primary measures of immunity. However, as the virus mutates, antibodies developed against earlier variants simply do not work as well.
This realization has led the FDA to revise the authorization of two monoclonal antibody treatments in January because “these treatments are highly unlikely to be active against the omicron variant”.
With regard to Omicron, a new study in Cell shows that “Fully vaccinated people have fewer memory B cells and neutralizing antibodies against the Omicron variant.” (1,2) This decrease ultimately leads to more breakthrough infections. However, as we have repeatedly seen, vaccines developed against early SARS-CoV-2 strains continue to protect against severe disease and death.
T cells—the key to long-term COVID-19 immunity?
Luckily, the immune system has another weapon against infection, namely T cells. The importance of T cells in SARS-CoV-2 infection was recognized early in the pandemic.
The longevity of T-cell responses was confirmed in a study showing commercial vaccines can elicit long-lasting T-cell responses effective against both Delta and Omicron variants. (2) Study author Shane Crotty explained to Newswise, “These cells won’t stop you from getting infected, but in many cases, they are likely to keep you from getting very ill.” (1)
Understanding the biology of long-lasting T-cell-mediated immunity
As SARS-CoV-2 continues to mutate, tools that predict how those mutations impact the immune response are critical for future vaccination strategies and development.
As part of the ImmuneCODE™ project, Adaptive Biotechnologies has mapped T-cell targeting to hundreds of viral SARS-CoV-2 antigens and amassed TCR sequencing results from thousands of patients following infection or vaccination. (4)
Together, these datasets showed that, despite mutations in Omicron, up to two-thirds of the T-cell response is maintained. T cells and antibodies recognize different antigens. Antibodies are more likely to recognize surface proteins, like the spike protein, while T cells recognize a broader range of antigens.
The majority of Omicron mutations occur in the spike region of the virus. Since the CD8+ T-cell response to SARS-CoV-2 infection targets a broad range of antigens across the viral genome, researchers expect this response will remain robust against Omicron. (4)
This study, now published on medRxiv, highlights the significance of T-cell immunosequencing in assessing vaccine-mediated cellular immunity. The findings also have important implications for identifying people at higher risk of developing severe illness from new variants.
For more on how T cells can protect against SARS-CoV-2 variants, read our blog article on SARS-CoV-2 Variants and Vaccine Immune Responses.
Cross-reactive T cells: hope for a pan-coronavirus vaccine
Countless households across the globe have observed an intriguing phenomenon—why do some members test positive while others remain negative?
Two new studies suggest that cross-reactive T cells may hold the answer.
A recent study by Dr. Rhia Kundu from Imperial College London found that previous exposure to other coronaviruses, like those that cause the common cold, can lead to “high levels of pre-existing T cells [that] can protect against COVID-19 infection.” (5)
In another study, Becerra-Artiles et al. identified highly conserved epitopes in cross-reactive T cells isolated from pre-pandemic samples that were recognized by CD4+ T cells in previously infected and never infected samples (6). The authors identified “a pan-coronavirus epitope that could be responsible for the cross-reactive T cell response.” (7)
Future research focused on such pan-coronavirus epitopes may inform the development of broadly active vaccines with the potential to protect against current and future variants.
T-cell repertoire profiling may inform vaccine response
It’s clear that understanding the T-cell response is critical to understanding immune protection. Immunosequencing provides a profile of the T-cell repertoire that can be used to understand the impact of disease, treatment, and vaccination.
In a recent study published in eLife, researchers used immunosequencing to profile the CD4+ T-cell repertoire in individuals before receiving a hepatitis B virus (HBV) vaccine. Subjects with a higher number of pre-existing memory CD4+ T cells developed immunity faster and produced more antibodies following vaccination. Pre-vaccination T-cell levels could predict immune response to the vaccine. (8) These results have important implications, not just for HBV vaccines but for vaccination strategies as a whole. Additional research on T-cell immunity “may lead to new ways for scientists and clinicians to [infer] which individuals [may] be protected by vaccination against hepatitis B infection, and who may have a delayed or inadequate immune response.” (9)
For Research Use Only. Not for use in diagnostic procedures.
1. La Jolla Institute for Immunology. Current vaccines teach T cells to fight Omicron. Newswise. Published January 24, 2022.
2. Tarke A, Coelho CH, Zhang Z, Dan JM, Yu ED, Methot N, et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell 2022. [Epub ahead of print].
3. Lin J, Law R, Korosec CS, Zhou C, Koh WH, Ghaemi MS, et al. Longitudinal Assessment of SARS-CoV-2 Specific T Cell Cytokine-Producing Responses for 1 Year Reveals Persistence of Multi-Cytokine Proliferative Responses, with Greater Immunity Associated with Disease Severity. bioRxiv. 2022 January 20;2022.01.18.476864
4. May DH, Rubin BER, Dalai SC, Patel K, Shafiani S, Elyanow R, et al. Immunosequencing and epitope mapping reveal substantial preservation of the T cell immune response to Omicron generated by SARS-CoV-2 vaccines. medRxiv. 2021 December 27;2021.12.20.21267877.
5. Head E. T cells from common colds cross-protect against infection with SARS-CoV-2. Imperial News. Published January 10.
6. Becerra-Artiles A, Calvo-Calle JM, Co M, Nanaware PP, Cruz J, Weaver GC, et al. Broadly-recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles. bioRxiv. 2022 January 22;2022.01.20.477107.
7. Bhowmik S. Evaluation of cross-reactive T cell responses between SARS-CoV-2 and common-cold human coronaviruses. News Medical. Published January 25, 2022.
8. Elias G, Meysman P, Bartholomeus E, De Neuter N, Keersmaekers N, Suls A, et al. Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination. eLife 2022;11:e68388.
9. Ogunjimi B, Meysman P. Pre-existing immune cells can predict early response to hepatitis B vaccine. EurekAlert! Published January 25, 2022.