Heterologous vaccination with inactivated and mRNA vaccines increases B and T cell responses to SARS-CoV-2

Abstract Background There has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines. Methods The levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples. Results A booster dose of an mRNA vaccine significantly increased the specific antibody response to the wild-type and VOCs including Omicron (by 14-fold), in individuals who had previously received two doses of inactivated vaccines. The levels of specific antibodies in the heterologous vaccination group were similar to those in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Furthermore, this heterologous vaccination regime significantly improved the specific memory B and T cell responses. Conclusions Heterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron.

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Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Viruses ◽

10.3390/v13081490 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1490

Author(s):

Victoria Matyushenko ◽

Irina Isakova-Sivak ◽

Igor Kudryavtsev ◽

Arina Goshina ◽

Anna Chistyakova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Natural Infection ◽

Intracellular Cytokine Staining ◽

T Cell Responses ◽

Effector Memory ◽

Memory T Cell ◽

Cell Responses ◽

Stimulation Of

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA−CCR7− phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.

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IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

Nature Communications ◽

10.1038/s41467-018-06804-y ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 14

Author(s):

Lyssia Belarif ◽

Caroline Mary ◽

Lola Jacquemont ◽

Hoa Le Mai ◽

Richard Danger ◽

...

Keyword(s):

T Cell ◽

Chronic Inflammation ◽

T Cell Responses ◽

Receptor Blockade ◽

Memory T Cell ◽

Cell Responses ◽

Specific Memory

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Norovirus-Specific Memory T Cell Responses in Adult Human Donors

Frontiers in Microbiology ◽

10.3389/fmicb.2016.01570 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 20

Author(s):

Maria Malm ◽

Kirsi Tamminen ◽

Timo Vesikari ◽

Vesna Blazevic

Keyword(s):

T Cell ◽

T Cell Responses ◽

Memory T Cell ◽

Cell Responses ◽

Adult Human ◽

Specific Memory

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Imatinib Mesylate Inhibits Antigen-Specific Memory CD8 T Cell Responses In Vivo

The Journal of Immunology ◽

10.4049/jimmunol.178.4.2028 ◽

2007 ◽

Vol 178 (4) ◽

pp. 2028-2037 ◽

Cited By ~ 24

Author(s):

Parisa Sinai ◽

Rance E. Berg ◽

J. Marshall Haynie ◽

Merrill J. Egorin ◽

Robert L. Ilaria ◽

...

Keyword(s):

T Cell ◽

Imatinib Mesylate ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Specific Memory ◽

Memory Cd8 T Cell

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COVID-19 convalescents exhibit deficient humoral and T cell responses to variant of concern Spike antigens at 12 month post-infection

10.1101/2021.11.08.21266035 ◽

2021 ◽

Author(s):

Pablo Garcia-Valtanen ◽

Christopher Martin Hope ◽

Makutiro Ghislain Masavuli ◽

Arthur Eng Lip Yeow ◽

Harikrishnan Balachandran ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Post Infection ◽

T Cell Responses ◽

Memory B Cells ◽

Pseudotyped Virus ◽

Cell Responses ◽

Specific Memory ◽

Cell Functionality

Background The duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination. Methods Serum and PBMC were collected from mild-COVID-19 convalescents at ~6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens. Findings At 12 months after mild-COVID-19, >90% of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in >50% of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4+ and 0.11-0.35% in CD8+ T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike 'high-responder' convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected. Interpretations SARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses.

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Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

10.21203/rs.3.rs-101480/v1 ◽

2020 ◽

Author(s):

Jianmin Zuo ◽

Alex Dowell ◽

Hayden Pearce ◽

Kriti Verma ◽

Heather Long ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Antibody Level ◽

Primary Infection ◽

Natural Infection ◽

T Cell Responses ◽

Symptomatic Infection ◽

Cell Responses ◽

Cell Immunity

Abstract The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

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Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine

10.1101/2021.07.14.452381 ◽

2021 ◽

Author(s):

Suhas Sureshchandra ◽

Sloan A. Lewis ◽

Brianna Doratt ◽

Allen Jankeel ◽

Izabela Ibraim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Single Cell ◽

Cd8 T Cells ◽

Natural Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Cell Responses

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

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Antibody Avidity in Humoral Immune Responses in Bangladeshi Children and Adults following Administration of an Oral Killed Cholera Vaccine

Clinical and Vaccine Immunology ◽

10.1128/cvi.00341-13 ◽

2013 ◽

Vol 20 (10) ◽

pp. 1541-1548 ◽

Cited By ~ 6

Author(s):

Mohammad Murshid Alam ◽

Daniel T. Leung ◽

Marjahan Akhtar ◽

Mohammad Nazim ◽

Sarmin Akter ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Responses ◽

Memory B Cell ◽

Antibody Avidity ◽

Memory T Cell ◽

Cell Responses ◽

Specific Memory ◽

Iga Antibodies ◽

Specific Igg

ABSTRACTAntibody avidity for antigens following disease or vaccination increases with affinity maturation and somatic hypermutation. In this study, we followed children and adults in Bangladesh for 1 year following oral cholera vaccination and measured the avidity of antibodies to the T cell-dependent antigen cholera toxin B subunit (CTB) and the T cell-independent antigen lipopolysaccharide (LPS) in comparison with responses in other immunological measurements. Children produced CTB-specific IgG and IgA antibodies of high avidity following vaccination, which persisted for several months; the magnitudes of responses were comparable to those seen in adult vaccinees. The avidity of LPS-specific IgG and IgA antibodies in vaccinees increased significantly shortly after the second dose of vaccine but waned rapidly to baseline levels thereafter. CTB-specific memory B cells were present for only a short time following vaccination, and we did not find significant memory B cell responses to LPS in any age group. For older children, there was a significant correlation between CTB-specific memory T cell responses after the second dose of vaccine and CTB-specific IgG antibody avidity indices over the subsequent year. These findings suggest that vaccination induces a longer-lasting increase in the avidity of antibodies to a T cell-dependent antigen than is measured by a memory B cell response to that antigen and that early memory T cell responses correlate well with the subsequent development of higher-avidity antibodies.

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