Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

Chen, Yuan; Mason, Georgina H; Scourfield, David Oliver; Greenshields‐Watson, Alexander; Haigh, Tracey A.; Sewell, Andrew K.; Long, Heather M.; Gallimore, Awen; Rizkallah, P.J.; MacLachlan, Bruce J.; Godkin, Andrew

doi:10.1016/j.celrep.2023.112827

Cited by 5 publications

(2 citation statements)

References 99 publications

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“…These results suggest immunological imprinting through exposure to the ancestral strain of SARS-CoV-2 impairs the cross-reactivity of the response to emerging variants of SARS-CoV-2. In addition, Omicron variants can bind in a separate register to the HLA-II heterodimer and abrogate T cell responses, which could further explain these results [ 39 ]. In contrast, we show a combined multi-clustering analysis of T cells responding to both Wuhan and Omicron found no significant differences in phenotype between Wuhan and Omicron-responsive T cells.…”

Section: Discussionmentioning

confidence: 99%

Lower Humoral and Cellular Immunity Following Asymptomatic SARS-CoV-2 Infection Compared to Symptomatic Infection in Education (The ACE Cohort)

Hopkins,

Gomez,

Tucis

et al. 2024

J Clin Immunol

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Purpose Asymptomatic SARS-CoV-2 infections were widely reported during the COVID-19 pandemic, acting as a hidden source of infection. Many existing studies investigating asymptomatic immunity failed to recruit true asymptomatic individuals. Thus, we conducted a longitudinal cohort study to evaluate humoral- and cell-mediated responses to infection and vaccination in well-defined asymptomatic young adults (the Asymptomatic COVID-19 in Education [ACE] cohort). Methods Asymptomatic testing services located at three UK universities identified asymptomatic young adults who were subsequently recruited with age- and sex-matched symptomatic and uninfected controls. Blood and saliva samples were collected after SARS-CoV-2 Wuhan infection, and again after vaccination. 51 participant’s anti-spike antibody titres, neutralizing antibodies, and spike-specific T-cell responses were measured, against both Wuhan and Omicron B.1.1.529.1. Results Asymptomatic participants exhibited reduced Wuhan-specific neutralization antibodies pre- and post-vaccination, as well as fewer Omicron-specific neutralization antibodies post-vaccination, compared to symptomatic participants. Lower Wuhan and Omicron-specific IgG titres in asymptomatic individuals were also observed pre- and post-vaccination, compared to symptomatic participants. There were no differences in salivary IgA levels. Conventional flow cytometry analysis and multi-dimensional clustering analysis indicated unvaccinated asymptomatic participants had significantly fewer Wuhan-specific IL-2 secreting CD4+ CD45RA+ T cells and activated CD8+ T cells than symptomatic participants, though these differences dissipated after vaccination. Conclusions Asymptomatic infection results in decreased antibody and T cell responses to further exposure to SARS-CoV-2 variants, compared to symptomatic infection. Post-vaccination, antibody responses are still inferior, but T cell immunity increases to match symptomatic subjects, emphasising the importance of vaccination to help protect asymptomatic individuals against future variants.

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Section: Discussionmentioning

confidence: 99%

Lower Humoral and Cellular Immunity Following Asymptomatic SARS-CoV-2 Infection Compared to Symptomatic Infection in Education (The ACE Cohort)

Hopkins,

Gomez,

Tucis

et al. 2024

J Clin Immunol

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“…We also observed in immunological studies from literature the striking differences in CD4+ epitope immunogenicity when in vitro studies such as (IFN)-γ ELISPOT are conducted. The envelope peptide (a CD4+ epitope) which we have chosen in our design has shown good immunogenicity in one study [ 36 ], but negligible immune binding in another study [ 77 ]. This anomaly may be due to lack of proper structure which cannot be monitored in the peptide epitopes in solution driven by random movement.…”

Section: Future Prospectsmentioning

confidence: 99%

De novo design of anti-variant COVID-19 vaccine

Goswami,

Kumar,

Ullah

et al. 2023

Biology Methods and Protocols

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Recent studies highlight the effectiveness of hybrid SARS-CoV-2 vaccines combining wild-type nucleocapsid and Spike proteins. We have further enhanced this strategy by incorporating delta and omicron variants’ spike protein mutations. Both delta and omicron mark the shifts in viral transmissibility and severity in unvaccinated and vaccinated patients. So their mutations are highly crucial for future viral variants also. Omicron is particularly adept at immune evasion by mutating spike epitopes. The rapid adaptations of Omicron and sub variants to spike based vaccines and simultaneous transmissibility underline the urgency for new vaccines in the continuous battle against SARS-CoV-2. Therefore, we have added three persistent T-cell stimulating nucleocapsid peptides similar to homologous sequences from seasonal Human Coronaviruses (HuCoV) and an envelope peptide that elicits strong T-cell immune response. These peptides are clustered in the hybrid spike's cytoplasmic region with non-immunogenic linkers, enabling systematic arrangement. AlphaFold (Artificial intelligence-based model building) analysis suggests omitting the transmembrane domain enhances these cytoplasmic epitopes’ folding efficiency which can ensure persistent immunity for CD4+ structural epitopes. Further molecular dynamics simulations validate the compact conformation of the modeled structures and a flexible C-terminus region. Overall, the structures show stability and less conformational fluctuation throughout the simulation. Also, the AlphaFold predicted structural epitopes maintained their folds during simulation to ensure specificity of CD4+ T-cell response after vaccination. Our proposed approach may provide options for incorporating diverse anti-viral T-cell peptides, similar to HuCoV, into linker regions. This versatility can be promising to address outbreaks and challenges posed by various viruses for effective management in this era of innovative vaccines.

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Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

Binayke,

Zaheer,

Vishwakarma

et al. 2024

Journal of Medical Virology

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Emerging evidence shows increased humoral response post‐omicron surge, but research on T cell responses is limited. This study investigated the durability, magnitude, and breadth of SARS‐CoV‐2‐spike‐specific T cell responses in 216 two‐dose vaccinated individuals pre‐ and post‐omicron surge. Post‐surge samples showed enhanced T cell responses, indicating widespread asymptomatic exposure to omicron. Further analysis of 105 individuals with multiple exposures to SARS‐CoV‐2 through boosters or infections showed that post‐omicron, two‐dose vaccinated individuals had T cell responses comparable to those of COVID‐19 convalescents or boosted individuals. Additionally, we report cross‐reactive T cell responses against omicron sub‐variants, including BA2.86, remained strong, with preserved frequencies of spike‐specific stem‐cell‐like memory T cells. In silico prediction indicates that mutated epitopes of JN.1 and KP.2 retain over 95.6% of their HLA binding capability. Overall, our data suggests that T cell responses are sustained, enhanced, and cross‐reactive against emerging SARS‐CoV‐2 variants following symptomatic or asymptomatic omicron infection.

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Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

Cited by 5 publications

References 99 publications

Lower Humoral and Cellular Immunity Following Asymptomatic SARS-CoV-2 Infection Compared to Symptomatic Infection in Education (The ACE Cohort)

Lower Humoral and Cellular Immunity Following Asymptomatic SARS-CoV-2 Infection Compared to Symptomatic Infection in Education (The ACE Cohort)

De novo design of anti-variant COVID-19 vaccine

Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

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