Heterologous versus homologous boosting elicits qualitatively distinct, BA.5–cross-reactive T cells in transplant recipients
Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, Trevor S. Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox
Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, Trevor S. Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox
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Clinical Research and Public Health COVID-19 Vaccines

Heterologous versus homologous boosting elicits qualitatively distinct, BA.5–cross-reactive T cells in transplant recipients

Abstract

Background The SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.Methods We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).Results Homologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.Conclusion Boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses.Funding Ben-Dov Family; NIH National Institute of Allergy and Infectious Diseases (NIAID) K24AI144954, NIAID K08AI156021, NIAID K23AI157893, NIAID U01AI138897, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007713, and National Cancer Institute 1U54CA260492; Johns Hopkins Vice Dean of Research Support for COVID-19 Research in Immunopathogenesis; and Emory COVID-19 research repository.

Authors

Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, Trevor S. Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox

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Figure 2

CD4+ T cells maintain cross-reactivity against BA.5, with higher responses following mRNA boost.

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CD4+ T cells maintain cross-reactivity against BA.5, with higher respons...
Peripheral blood mononuclear cells (PBMCs) were stimulated overnight with overlapping peptides (15-mers overlapping by 11) against ancestral or BA.5 spike (S) protein. S protein–specific CD4+ T cell responses were evaluated in participants who received 2 doses of an mRNA COVID-19 vaccine followed by adenoviral vector boost (Ad boost, blue, n = 40) or a third mRNA dose (mRNA boost, red, n = 35). Samples were collected approximately 2 weeks following the third dose and run in 2 batches with participants evenly distributed between both batches. (A) Representative gating for CD4+ T cell responses, including phenotype of IL-21+ cells and relation to PD-1+CXCR5+ expression that defines peripheral T follicular helper (pTfh) cells. PD-1, programmed death 1. (B) Frequency of memory CD4+ T cells producing any cytokine (TNF, IFN-γ, IL-2, or IL-21) or each individual cytokine. All values are with unstimulated DMSO-only control levels subtracted. Samples with negative or 0 values were converted to the lowest detected value for visualization purposes. Significance tested using Mann-Whitney U test. (C) Sample paired comparison of CD4+ responses recalled by ancestral or BA.5 S peptides. Significance tested using Wilcoxon matched pairs signed-rank test. *P < 0.05. All data shown as mean ± SEM with each dot representing 1 individual.