SARS-CoV-2 epitope–specific CD4
            <sup>+</sup>
            memory T cell responses across COVID-19 disease severity and antibody durability

Nelson, Ryan; Chen, Yuezhou; Venezia, Olivia; Majerus, Richard M; Shin, Daniel S.; Carrington, Mary; Yu, Xu G.; Wesemann, Duane R.; Moon, James J.; Luster, Andrew D.; Abayneh, Betelihem A.; Allen, Patrick; Alter, Galit; Antille, Diane; Armstrong, Katrina; Balazs, Alejandro; Bals, Julia; Barbash, Max; Bartsch, Yannic C.; Boucau, Julie; Boyce, Siobhan; Braley, Joan; Branch, Kelley R.; Broderick, Katherine; Carney, Julia; Chan, Andrew; Chevalier, Josh; Chowdhury, Fatema Z.; Daley, George Q.; Davidson, Susan; Dougan, Michael; Drew, David A.; Einkauf, Kevin; Elliman, Ashley; Fallon, Jon; Fedirko, Liz; Finn, Kelsey; Flaherty, Keith T.; Flannery, Jeanne; Forde, Pamela; García-Broncano, Pilar; Gettings, Elise; Golan, David; Griffin, Amanda; Grimmel, Sheila; Grinke, Kathleen; Hall, Kathryn; Hartana, Ciputra Adijaya; Healy, Meg; Heller, Howard M.; Henault, Deborah; Holland, Grace; Jiang, Chenyang; Jilg, Nikolaus; Kapłonek, Paulina; Karpell, Marshall; Kayitesi, Chantal; Lam, Evan C.; LaValle, Vlasta; Lefteri, Kristina; Lian, Xiaodong; Lichterfeld, Mathias; Lingwood, Daniel; Liu, Huan; Liu, Jinqing; Lu, Yuting; Luthern, Sarah; Ly, Natasha; Marchewka, Jordan; Martino, Brittani; McNamara, Roseann; Michell, Ashlin; Millstrom, Ilan; Miranda, Noah; Nambu, Christian; Nelson, Susan C.; Noone, Marjorie; O’Callaghan, Claire; Ommerborn, Christine; Osborn, Matthew; Pacheco, Lois Chris; Phan, Nicole; Pillai, Shiv; Porto, Falisha A.; Rassadkina, Yelizaveta; Reissis, Alexandra; Rosenthal, Alex; Ruzicka, Francis F.; Ryan, Edward T.; Seiger, Kyra; Selleck, Kathleen; Sessa, Libera; Sharpe, Arlene; Sharr, Christianne; Shin, Sally; Singh, Nishant K.; Slaughenhaupt, Sue; Sheppard, Kimberly Smith; Sun, Weiwei; Sun, Xiaoming; Suschana, Elizabeth; Ticheli, Hannah; Trocha-Piechocka, Alicja; Wilson, Vivine; Wong, C. Jason; Worrall, Daniel; Zhu, Alex; Manickas-Hill, Zachary; DeMers, Edward; Judge, Kelly; Ghebremichael, Musie; Lai, Peggy S.; Li, Jonathan; Walker, Bruce D.; Martin, Maureen P.; Yuki, Yuko

doi:10.1126/sciimmunol.abl9464

Cited by 42 publications

(36 citation statements)

References 43 publications

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“…One interpretation is that, in addition to leaving an imprint in the memory B cell pool, prior and/or recent endemic coronavirus infection may have resulted in an immune system better prepared to handle SARS-CoV-2 invasion (shorter symptom duration) and support an environment more conducive for LLPC differentiation (durable antibody response). Recent findings showing greater spike specific cTfh cells enriched in sustainers ( 28 ) is consistent with the possibility that sustainers may be equipped for a more robust GC response and memory retention. Noteworthy is that essentially all the highly mutated, cross-reactive memory B cells bind S2 and not RBD.…”

Section: Discussionsupporting

confidence: 73%

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

et al. 2022

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Key features of immune memory are greater and faster antigen-specific antibody responses to repeat infection. In the setting of immune-evading viral evolution, it is important to understand how far antibody memory recognition stretches across viral variants when memory cells are recalled to action by repeat invasions. It is also important to understand how immune recall influences longevity of secreted antibody responses. We analyzed SARS-CoV-2 variant recognition, dynamics of memory B cells and secreted antibody over time after infection, vaccination, and boosting. We find that a two-dose SARS-CoV-2 vaccination regimen given after natural infection generated greater longitudinal antibody stability and induced maximal antibody magnitudes with enhanced breadth across Beta, Gamma, Delta and Omicron variants. A homologous 3 rd mRNA vaccine dose in COVID-naïve individuals conferred greater cross-variant evenness of neutralization potency with stability that was equal to the hybrid immunity conferred by infection plus vaccination. Within unvaccinated individuals who recovered from COVID, enhanced antibody stability over time was observed within a subgroup of individuals that recovered more quickly from COVID and harbored significantly more memory B cells cross-reactive to endemic coronaviruses early after infection. These cross-reactive clones map to the conserved S2 region of SARS-CoV-2 spike with higher somatic hypermutation levels and greater target affinity. We conclude that SARS-CoV-2 antigen challenge histories in humans influence not only the speed and magnitude of antibody responses, but also functional cross-variant antibody repertoire composition and longevity.

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Section: Discussionsupporting

confidence: 73%

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

et al. 2022

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“…While a correlation between antibodies and CD4 + T cells, mainly follicular T cells (Tfh), would be expected, a recent study by Nelson et al. ( 27 ) analyzed memory T cell responses using peptide:HLA tetramers and did not find high associations between peak antibodies to SARS-CoV-2 and Tfh cells. Klarquist et al.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infected children form early immune memory responses dominated by nucleocapsid-specific CD8+ T cells and antibodies

et al. 2022

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This is the third year of the SARS-CoV-2 pandemic, and yet most children remain unvaccinated. COVID-19 in children manifests as mostly mild or asymptomatic, however high viral titers and strong cellular and humoral responses are observed upon acute infection. It is still unclear how long these responses persist, and if they can protect from re-infection and/or disease severity. Here, we analyzed immune memory responses in a cohort of children and adults with COVID-19. Important differences between children and adults are evident in kinetics and profile of memory responses. Children develop early N-specific cytotoxic T cell responses, that rapidly expand and dominate their immune memory to the virus. Children’s anti-N, but not anti-S, antibody titers increase over time. Neutralization titers correlate with N-specific antibodies and CD8+T cells. However, antibodies generated by infection do not efficiently cross-neutralize variants Gamma or Delta. Our results indicate that mechanisms that protect from disease severity are possibly different from those that protect from reinfection, bringing novel insights for pediatric vaccine design. They also underline the importance of vaccination in children, who remain at risk for COVID-19 despite having been previously infected.

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“…Our observation of two subsets of vaccinated individuals with different antibody dynamics over time resembles the observation of two subsets of COVID-19 convalescents, antibody sustainers , that exhibited the same or increasing antibody levels over time, and antibody decayers that lost antibody levels over the same time frame ( 38 ). A tetramer-based analysis of T follicular helper cells suggested a connection between Spike-specific CD4+ T cell responses and anti-Spike antibody durability ( 39 ). In addition, more memory B cell cross-reactivity with endemic coronaviruses was identified as a marker for more sustained antibody responses after infection ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

In-silico evaluation of adenoviral COVID-19 vaccination protocols: Assessment of immunological memory up to 6 months after the third dose

et al. 2022

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BackgroundThe immune response to adenoviral COVID-19 vaccines is affected by the interval between doses. The optimal interval is unknown.AimWe aim to explore in-silico the effect of the interval between vaccine administrations on immunogenicity and to analyze the contribution of pre-existing levels of antibodies, plasma cells, and memory B and T lymphocytes.MethodsWe used a stochastic agent-based immune simulation platform to simulate two-dose and three-dose vaccination protocols with an adenoviral vaccine. We identified the model’s parameters fitting anti-Spike antibody levels from individuals immunized with the COVID-19 vaccine AstraZeneca (ChAdOx1-S, Vaxzevria). We used several statistical methods, such as principal component analysis and binary classification, to analyze the correlation between pre-existing levels of antibodies, plasma cells, and memory B and T cells to the magnitude of the antibody response following a booster dose.Results and conclusionsWe find that the magnitude of the antibody response to a booster depends on the number of pre-existing memory B cells, which, in turn, is highly correlated to the number of T helper cells and plasma cells, and the antibody titers. Pre-existing memory T cytotoxic cells and antibodies directly influence antigen availability hence limiting the magnitude of the immune response. The optimal immunogenicity of the third dose is achieved over a large time window, spanning from 6 to 16 months after the second dose. Interestingly, after any vaccine dose, individuals can be classified into two groups, sustainers and decayers, that differ in the kinetics of decline of their antibody titers due to differences in long-lived plasma cells. This suggests that the decayers may benefit from a tailored boosting schedule with a shorter interval to avoid the temporary loss of serological immunity.

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SARS-CoV-2 epitope–specific CD4 ⁺ memory T cell responses across COVID-19 disease severity and antibody durability

Cited by 42 publications

References 43 publications

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

SARS-CoV-2 infected children form early immune memory responses dominated by nucleocapsid-specific CD8+ T cells and antibodies

In-silico evaluation of adenoviral COVID-19 vaccination protocols: Assessment of immunological memory up to 6 months after the third dose

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SARS-CoV-2 epitope–specific CD4 + memory T cell responses across COVID-19 disease severity and antibody durability

Cited by 42 publications

References 43 publications

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

SARS-CoV-2 infected children form early immune memory responses dominated by nucleocapsid-specific CD8+ T cells and antibodies

In-silico evaluation of adenoviral COVID-19 vaccination protocols: Assessment of immunological memory up to 6 months after the third dose

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SARS-CoV-2 epitope–specific CD4 ⁺ memory T cell responses across COVID-19 disease severity and antibody durability