SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

Mudd, Philip A.; Minervina, Anastasia A.; Pogorelyy, Mikhail V.; Turner, Jackson S.; Kim, Wooseob; Kalaidina, Elizaveta; Petersen, Jan; Schmitz, Aaron J.; Lei, Tingting; Haile, Alem; Kirk, Allison M.; Mettelman, Robert C.; Crawford, Jeremy Chase; Nguyen, Thi H. O.; Rowntree, Louise C.; Rosati, Elisa; Richards, Katherine A.; Sant, Andrea J.; Klebert, Michael; Suessen, Teresa; Middleton, William D.; Wolf, Joshua; Teefey, Sharlene A.; O’Halloran, Jane A.; Presti, Rachel; Kedzierska, Katherine; Rossjohn, Jamie; Thomas, Paul G.; Ellebedy, Ali H.

doi:10.1016/j.cell.2021.12.026

Cited by 195 publications

(193 citation statements)

References 60 publications

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“…SARS-CoV-2 spike-specific CD4 + T cell responses were measured for all donors at all available timepoints utilizing two previously described flow cytometry activation-induced marker (AIM) assays (OX40 + CD137 + and OX40 + surface CD40L + (sCD40L)) ( Figures 3A, 3D, and S2-S3 ) and separate intracellular staining (ICS) for cytokines (IFNγ, TNFα, IL-2), granzyme B (GzB), and intracellular CD40L (iCD40L) ( Figures 3C, 3F, 4 and S4 ). SARS-CoV-2 spike-specific circulating follicular helper T (cTfh) cells were measured at all time points ( Figures 3B, 3E, S2A and S2D ), as this subpopulation of CD4 + T cells is crucial for supporting antibody responses following vaccination (Crotty, 2019; Lederer et al, 2022; Mudd et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

Humoral and cellular immune memory to four COVID-19 vaccines

Zhang

Mateus

Coelho

et al. 2022

Preprint

119

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Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 were examined longitudinally for 6 months. 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though memory CD8+ T cells were only detectable in 60-67% of subjects at 6 months. Ad26.COV2.S was not the strongest immunogen by any measurement, though the Ad26.COV2.S T cell, B cell, and antibody responses were relatively stable over 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in neutralizing antibodies, while memory T cells and B cells were comparatively stable over 6 months. These results of these detailed immunological evaluations may also be relevant for vaccine design insights against other pathogens.

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Section: Resultsmentioning

confidence: 99%

Humoral and cellular immune memory to four COVID-19 vaccines

Zhang

Mateus

Coelho

et al. 2022

Preprint

119

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“…The immune response elicited by vaccines relies strongly on the production of neutralizing antibodies by B cells and ideally also on the induction of memory cells for longer (potentially lifelong) durability 20,21 . Furthermore, specific T cells can be induced by the available vaccines to varying degrees 21 ; these might persist for >6 months and seem to be less affected by antigenic drift [22][23][24] . Vaccine-induced immune responses occurred in most participants (>90%) in the trials testing all of the available vaccines 10,15,25,26 .…”

Section: Effectiveness In the General Populationmentioning

confidence: 99%

“…Currently approved COVID-19 vaccines elicit robust CD4 + and CD8 + T cell responses in trial participants [21][22][23] . This effect occurs to a similar extent in patients with cancer 65,66 .…”

mentioning

confidence: 99%

COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety

et al. 2022

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Patients with cancer have a higher risk of severe coronavirus disease (COVID-19) and associated mortality than the general population. Owing to this increased risk, patients with cancer have been prioritized for COVID-19 vaccination globally, for both primary and booster vaccinations. However, given that these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, and the extent of humoral and cellular immune responses in these patients, as well as the risks of vaccine-related adverse events. In this Review, we summarize the current knowledge generated in studies conducted since COVID-19 vaccines first became available. We also highlight critical points that might affect vaccine efficacy in patients with cancer in the future.

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confidence: 99%

Germinal centre-driven maturation of B cell response to mRNA vaccination

Kim

Zhou

Horváth

et al. 2022

Nature

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220

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Germinal centres (GC) are lymphoid structures where B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells (BMPCs) [1][2][3][4][5] . SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans [6][7][8] . The fate of responding GC B cells as well as the functional consequences of such persistence have not been elucidated. We detected SARS-CoV-2 spike (S)-specific MBCs in 42 individuals who had received two doses of BNT162b2, a SARS-CoV-2 mRNA vaccine six months earlier. S-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies (mAbs), we tracked the evolution of 1540 S-specific B cell clones. We show that early blood S-specific plasmablasts -on averageexhibited the lowest SHM frequencies. In comparison, SHM frequencies of S-specific GC B cells increased by 3.5-fold within six months after vaccination. S-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-S antibody avidity in blood and affinity as well as neutralization capacity of BMPC-derived mAbs. This study documents how the striking persistence of SARS-CoV-2 vaccination-induced GC reaction in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus. B cell response to mRNA vaccinationWe have previously shown that vaccination of humans with The Pfizer-BioNTech SARS-CoV-2 mRNA vaccine, BNT162b2 induces a robust but transient circulating plasmablast (PB) response and a persistent germinal centre (GC) reaction in the draining lymph nodes 6 . Whether these persistent GC responses lead to the generation of affinity-matured memory B cells (MBCs) and long-lived bone marrow-resident plasma cells (BMPCs) remains unclear. To address this question, we analyzed long-term B cell responses in the participants enrolled in our previously described observational study of 43 healthy participants (13 with a history of SARS-CoV-2 infection) who received two doses of BNT162b2 (Extended Data Tables 1) 6,7 . Long-term blood samples (n=42) and fine needle aspirates (FNAs) of the draining axillary lymph nodes (n=15) were collected 29 weeks post-vaccination (Fig. 1a). Bone marrow aspirates were collected 29 (n=11) and 40 weeks (n=2) post-vaccination, with the latter time point used only for B cell receptor (BCR) repertoire profiling (Fig. 1a). None of the participants who contributed FNA or bone marrow specimens had SARS-CoV-2 infection history. GC B cells were detected in FNAs from all 15 participants (Fig. 1b, c, left panels, Extended Data Fig. 1a, Extended Data Table 2). All 14 participants with FNAs collected prior to week 29 generated S-binding GC B cell responses of varying magnitudes (Fig 1b, c, r...

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SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

Cited by 195 publications

References 60 publications

Humoral and cellular immune memory to four COVID-19 vaccines

Humoral and cellular immune memory to four COVID-19 vaccines

COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety

Germinal centre-driven maturation of B cell response to mRNA vaccination

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