Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19

Juno, Jennifer A; Tan, Hyon-Xhi; Lee, Wen Shi; Reynaldi, Arnold; Kelly, Hannah G.; Wragg, Kathleen; Esterbauer, Robyn; Kent, Helen E; Batten, C. Jane; Mordant, Francesca L; Gherardin, Nicholas A.; Pymm, Phillip; Dietrich, M.H.; Scott, Nichollas E.; Tham, Wai‐Hong; Godfrey, Dale I.; Subbarao, Kanta; Davenport, Miles P.; Kent, Stephen J.; Wheatley, Adam K.

doi:10.1038/s41591-020-0995-0

Cited by 442 publications

(559 citation statements)

References 49 publications

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“…In sum, the data suggest that vaccine platforms inducing T h 1 CD4 helper and T fh helper responses are likely to succeed in eliciting robust CD8 T cell and antibody responses against SARS-CoV-2. Similar observations of circulating T fh cells in vaccinated and infected humans support this hypothesis 14,35,36 .…”

Section: Discussionsupporting

confidence: 59%

SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

Elizaldi

Lakshmanappa

Roh

et al. 2020

Preprint

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CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that SARS-CoV-2 infection resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. We observed the generation of germinal center Tfh cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.

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Section: Discussionsupporting

confidence: 59%

SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

Elizaldi

Lakshmanappa

Roh

et al. 2020

Preprint

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“…As the SARS-CoV-2 S protein is the major target on the virus for neutralising antibodies 29,3,4,30,5,31,32,33 and has also been shown to be highly immunogenic for T cell responses in infected individuals 13,14,15,34 HLA-DR-bound and a further 16 HLA-DP-bound peptides. ~75% of the HLA-DR bound peptides identified were predicted to bind to at least one of the donor's HLA-DRB1 alleles, consistent with the higher expression and more dominant antigen presenting role of HLA-DRB1 versus HLA-DRB3, 4 and 5 molecules 17 . Whilst HLA-II binding predictions suggested that the two HLA-DRB1 alleles expressed in some donors made roughly equal contributions to the repertoire of unique peptides presented, in other donors a much greater proportion of the unique peptides detected were predicted to bind to one of their HLA-DRB1 alleles, with DRB1*04:01, a prevalent allele in European populations, appearing to play a more dominant role in antigen presentation in both of the donors expressing this allele.…”

Section: Discussionmentioning

confidence: 68%

“…S is also highly immunogenic for T cells, with many studies suggesting that although infected individuals mount CD4 + and CD8 + T cell responses to epitopes throughout the viral proteome, S is often at the top of the antigenic hierarchy 13,14,15 . The relative roles of CD4 + and CD8 + T cells in disease control or pathogenesis and impact of their protein and epitope specificity are unknown; but given the importance of CD4 + T cells (particularly CD4 + T follicular helper (Tfh) cells) in providing help for antibody responses 16 , and the correlation of memory B cell/nAb responses to S with circulating CD4 + Tfh responses in recovered COVID patients 17 , induction of potent Tfh cell responses to the S protein is likely to be crucial for the success of nAbinducing vaccines. CD4 + T cells are initially activated in response to recognition of specific peptides presented with major histocompatibility complex class II (MHC-II) molecules on professional antigen presenting cells such as dendritic cells (DCs) 18 .…”

Section: Introductionmentioning

confidence: 99%

Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells

Parker

Partridge

Wormald

et al. 2020

Preprint

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Understanding and eliciting protective immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent priority. To facilitate these objectives, we have profiled the repertoire of human leukocyte antigen class II (HLA-II)-bound peptides presented by HLA-DR diverse monocyte-derived dendritic cells pulsed with SARS-CoV-2 spike (S) protein. We identify 209 unique HLA-II-bound peptide sequences, many forming nested sets, which map to sites throughout S including glycosylated regions. Comparison of the glycosylation profile of the S protein to that of the HLA-II-bound S peptides revealed substantial trimming of glycan residues on the latter, likely introduced during antigen processing. Our data also highlight the receptor-binding motif in S1 as a HLA-DR-binding peptide-rich region. Results from this study have application in vaccine design, and will aid analysis of CD4+ T cell responses in infected individuals and vaccine recipients.

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“…Immunisation with OVA induced intermediate frequencies of BCL-6 + (median 1.1%; IQR 0.8-1.5) and GL7 + (median 32.0%; IQR 28.2-38.1) B cells, with minimal detection of GC formation in RBD-immunised animals (BCL-6 + ; median 0.3%; IQR 0.2-0.4) (GL7 + ; median 15.9%; IQR 12.1-21.1). The specificity of GC B cells (IgD -B220 + GL7 + CD38 lo ) was examined using recombinant S and RBD probes, as previously described (Juno et al, 2020). Both S-specific (S + RBD -) and RBD-specific (S + RBD + ) were reliably detected in S-immunised animals, constituting 21.5% 3) and 1.2% (IQR 0.47-2.27) of GC B cells respectively ( Figure 1D).…”

Section: Sars-cov-2 Spike But Not Rbd Is Potently Immunogenic In Micementioning

confidence: 81%

Prime-boost protein subunit vaccines against SARS-CoV-2 are highly immunogenic in mice and macaques

Tan

Juno

Lee

et al. 2020

Preprint

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SummarySARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assessed prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD was associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augmented neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines were comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.

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Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19

Cited by 442 publications

References 49 publications

SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells

Prime-boost protein subunit vaccines against SARS-CoV-2 are highly immunogenic in mice and macaques

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