Allogeneic partially HLA-matched dendritic cells (DC) as a vaccine in metastatic renal cell cancer (mRCC): Final analysis of a clinical phase I/II study.

e15053 Background: Despite novel kinase inhibitors, prognosis of metastatic RCC remains poor and new experimental approaches are warranted. Our aim was to evaluate a DC-based vaccine, which exploits alloreactivity as a means to amplify specific anti-tumor immune responses. Methods: Allogeneic, partially HLA-matched DC were generated in our GMP facility. DC were loaded with autologous tumor lysate. 8 patients with progressive mRCC were included, 7 patients were immunized repetitively with 107 DC s.c. over 20 weeks. Low-dose IL-2 (3 Mio U s.c. qd) was used concomitantly. Endpoints of the study were feasibility, safety, immunological and clinical responses. T cell responses against HLA-A2-restricted RCC-associated antigens were evaluated by proliferation assays, ELISpot and cytokine bead array (CBA). T cell repertoire was analysed by T cell receptor γ and –β PCR. Results: Vaccination was feasible and safe, no treatment-related grade 3/4 toxicity or clinically relevant autoimmunity was observed. No objective responses were observed, however, 2/7 patients showed stable disease, one a minimal clinical response. The mean TTP was 24.6 weeks (range 5 to 96). Delayed-type hypersensitivity was detected in 3/7 and HLA antibodies were induced in 3/7 patients. In 3/7 patients T cell responses against RCC-associated antigens such as TYMS, G250, vimentin, surviving and cyclin-D1 were induced by vaccination. These antigen-specific T cells showed a predominant TH1-cytokine profile. Interestingly, a clonally expanded T cell population could be detected by γ- and –β PCR in one patient with both a minimal clinical response and a T cell response. This clone is currently persisting for more than 80 months, its specificity is under investigation. Conclusions: Vaccination with allogeneic tumor-lysate-loaded DC was feasible, safe and was able to induce TH1-polarized immune responses against RCC-associated antigens. Tumor vaccination might be a promising approach in minimal residual disease, possibly in combination with antibodies against CTLA-4 or PD-1.

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Potent HIV-1-Specific CD8 T Cell Responses Induced in Mice after Priming with a Multiepitopic DNA-TMEP and Boosting with the HIV Vaccine MVA-B

Viruses ◽

10.3390/v10080424 ◽

2018 ◽

Vol 10 (8) ◽

pp. 424 ◽

Cited By ~ 5

Author(s):

Beatriz Perdiguero ◽

Suresh C. Raman ◽

Cristina Sánchez-Corzo ◽

Carlos Oscar S. Sorzano ◽

José Ramón Valverde ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Effective Vaccine ◽

T Cell Epitopes ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Hiv 1

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I prophylactic and therapeutic clinical trials, but was unable to prevent viral rebound after antiretroviral (ART) removal. To potentiate the immunogenicity of MVA-B, here we described the design and immune responses elicited in mice by a new T cell multi-epitopic B (TMEP-B) immunogen, vectored by DNA, when administered in homologous or heterologous prime/boost regimens in combination with MVA-B. The TMEP-B protein contained conserved regions from Gag, Pol, and Nef proteins including multiple CD4 and CD8 T cell epitopes functionally associated with HIV control. Heterologous DNA-TMEP/MVA-B regimen induced higher HIV-1-specific CD8 T cell responses with broader epitope recognition and higher polyfunctional profile than the homologous DNA-TMEP/DNA-TMEP or the heterologous DNA-GPN/MVA-B combinations. Moreover, higher HIV-1-specific CD4 and Tfh immune responses were also detected using this regimen. After MVA-B boost, the magnitude of the anti-VACV CD8 T cell response was significantly compromised in DNA-TMEP-primed animals. Our results revealed the immunological potential of DNA-TMEP prime/MVA-B boost regimen and supported the application of these combined vectors in HIV-1 prevention and/or therapy.

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Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

Journal of Virology ◽

10.1128/jvi.01992-17 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 16

Author(s):

Bobby Brooke Herrera ◽

Wen-Yang Tsai ◽

Charlotte A. Chang ◽

Donald J. Hamel ◽

Wei-Kung Wang ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Dengue Virus ◽

Zika Virus ◽

Cell Response ◽

Vaccine Development ◽

T Cell Responses ◽

T Cell Response ◽

Zikv Infection ◽

Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

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Dissecting The Potential Role Of Prevnar As An Anti-Myeloma Vaccine

Blood ◽

10.1182/blood.v122.21.1980.1980 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1980-1980

Author(s):

Kimberly Noonan ◽

Lakshmi Rudraraju ◽

Anna Ferguson ◽

Amy Sidorski ◽

Andrea Casildo ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Clinical Response ◽

Plasma Cells ◽

T Cell Responses ◽

Fold Increase ◽

T Cell Response ◽

Cell Phenotype ◽

Cell Responses

Abstract Background Prevnar, is a multi-valent conjugate vaccine given to children and adults over 50 for the prevention of Streptococcus pneumonia, otis media and pneumococcal pneumonia. The conjugate in Prevnar is a CRM-197 protein molecule which is a nontoxic recombinant Diphtheria toxin. Prevnar serves as an excellent tool in monitoring overall immune response changes in myeloma patients’ pre and post treatment. Humoral B-cell responses can be measured by antibody responses to the pneumococcal antigens, while T cell responses to CRM-197. Clinical Study We previously conducted a study to determine the efficacy of lenalidomide to augment vaccine specific responses in patients with myeloma. Two cohorts of patients were studied. In cohort A (N=10), the first Prevnar vaccine was given two weeks prior to starting lenalidomide and the second vaccine on day 14 of cycle 2 of lenalidomide. In cohort B (N=7), both Prevnar vaccines were given on lenalidomide (day 14 of cycle 2 and 4). As we previously reported patients in cohort B had an overall better B and T cell response to Prevnar compared to cohort A. These responses were due to an overall change in B and T cell phenotype attained with lenalidomide therapy. Results Prospectively, patients in cohort B also had an unexpected overall increase in disease response and in response duration. In Cohort A only 10% of patients responded to therapy while 60% of patients in Cohort B had a clinical response. The patients with a measurable clinical response had a 5-fold increase in the percentage of tumor specific bone marrow (BM) T cells after two vaccinations with Prevnar whereas the non-responding patients had no increase in tumor specific BM T cells. Parelleling the anti-tumor response, responders showed a 15 fold increase in CRM-197 specific BM T cells after the second vaccination. Patients with no clinical response showed minimal CRM-197 T cell immunity. CRM-197 is a specific inhibitor of HB-EGF; syndecan-1 (CD138) is an HB-EGF co-receptor as well as a marker for myeloma plasma cells. We hypothesized that HB-EGF specific responses produced by vaccination with the Prevnar vaccine, and CRM-197 specifically, may have contributed to the overall increased clinical responses in our clinical trial. Responding patients had a 5-fold increase in HB-EGF specific BM T cells after vaccine 2 while clinical non-responders had no increase in HB-EGF specific BM T cells. T cells specificity for purified HB-EGF correlated with both CRM-197 and tumor specific responses. Finally the myeloma cell lines U266, H929, KMS-11 and KMS-12 co-stained for CD138 and HB-EGF with 47% of CD138+ myeloma cells co-expressing HB-EGF. Conclusions We hypothesize that the CRM-197 moiety of the Prevnar vaccine can prime T cell responses against HB-EGF on plasma cells. This immune response, in turn, weakens the tumor stromal interactions in the tumor microenvironment and potentially enhances the anti-tumor efficacy of immunomodulatory drugs such as lenalidomide. Therefore, Prevnar may possibly serve as a candidate anti-myeloma vaccine. Disclosures: No relevant conflicts of interest to declare.

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EBV-positive lymphoma patients have a selective deficiency in EBV immunity

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21032 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21032-21032

Author(s):

K. N. Heller ◽

P. G. Steinherz ◽

C. S. Portlock ◽

C. Münz

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Healthy Volunteers ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Specific Immune Response ◽

Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

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Immune Responses in Perforin Deficient Mice

10.26686/wgtn.16968397 ◽

2021 ◽

Author(s):

◽

Helen Mary Alys Simkins

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Influenza Infection ◽

T Cell Responses ◽

Nkt Cells ◽

T Cell Response ◽

Dependent Manner ◽

Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

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Immune Responses in Perforin Deficient Mice

10.26686/wgtn.16968397.v1 ◽

2021 ◽

Author(s):

◽

Helen Mary Alys Simkins

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Influenza Infection ◽

T Cell Responses ◽

Nkt Cells ◽

T Cell Response ◽

Dependent Manner ◽

Cell Responses

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TLR9 and Dendritic Cells Are Required for CD8+ T Cell Responses to the AAV Capsid

Blood ◽

10.1182/blood.v124.21.552.552 ◽

2014 ◽

Vol 124 (21) ◽

pp. 552-552 ◽

Cited By ~ 1

Author(s):

Geoffrey L. Rogers ◽

Roland W Herzog

Keyword(s):

Pattern Recognition ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Post Injection ◽

Cell Responses

Abstract CD8+ T cell responses to the adeno-associated virus (AAV) capsid have posed a significant barrier to transduction in clinical trials of AAV-mediated gene therapy for hemophilia B, as reactivation of a memory CTL response to the capsid is capable of eliminating transduced hepatocytes in the absence of immunosuppression. Recently, it has been suggested that innate immune responses induced by the toll-like receptor (TLR) pathway can influence the development of adaptive immune responses to AAV-mediated gene transfer. In particular, reports have implicated TLR2 (AAV capsid), TLR9 (AAV genome), and MyD88 (downstream signaling adaptor of both these TLRs). Herein, we have used a modified AAV2 with an insertion of the immunodominant MHC class I epitope of ovalbumin into the capsid (AAV2-SIINFEKL) to study the mechanism of CD8+ T cell responses to the AAV capsid. Using an H2-Kb-SIINFEKL tetramer reagent, we determined that anti-capsid CD8+ T cell responses depended on the TLR9-MyD88 pathway. While the frequency of circulating capsid-specific CD8+ T cells peaked around 7-10 days post-injection and subsided after about 21 days in wild type (WT) mice, tetramer-positive cells were not detected in TLR9-/- or MyD88-/- mice. The kinetics and magnitude of the response was unaltered in TLR2-/- mice. Mice deficient in STING, a downstream adaptor of multiple cytoplasmic DNA sensing pathways, also developed comparable capsid-specific CD8+ T cell frequencies to WT mice, suggesting that this is not a general effect of pattern recognition of DNA. Interestingly, the frequency of capsid-specific CD8+ T cells was not reduced in AP3-/- mice, which are deficient in type I IFN signaling downstream of TLR9. Adoptively transferred OVA-specific OT-1 T cells proliferated in WT but not TLR9-/- mice that received AAV2-SIINFEKL, confirming the importance of TLR9. The effect was antigen-specific, as OT-1 cells in WT mice that received AAV2 lacking SIINFEKL showed minimal proliferation comparable to TLR9-/- mice. In addition to pattern-recognition receptors, we also assessed the role of antigen-presenting cells in the CD8+ T cell response to capsid. The formation of capsid-specific CD8+ T cells was unaltered in mice that received gadolinium chloride to inactivate macrophages, or in B cell-deficient μMT mice. Depletion of B cells in WT mice prior to vector administration also failed to affect the anti-capsid CD8+ T cell response. However, transient depletion of dendritic cells (DCs) in CD11c-DTR mice resulted in a delayed development of capsid-specific CD8+ T cells. Seven days post-injection, DC-depleted mice had a significantly reduced frequency of tetramer-positive CD8+ T cells which recovered to normal by 10 days, likely due to the repopulation of DCs before the input capsid was completely cleared. Overall, our results show that TLR9 signaling, most likely in DCs, is required for the formation of de novo anti-capsid CD8+ T cell responses. Disclosures Herzog: Genzyme: AAV-FIX technology Patents & Royalties.

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Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection.

10.21203/rs.3.rs-226857/v2 ◽

2021 ◽

Author(s):

Donal T. Skelly ◽

Adam C. Harding ◽

Javier Gilbert-Jaramillo ◽

Michael L. Knight ◽

Stephanie Longet ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Natural Infection ◽

Vaccine Dose ◽

T Cell Responses ◽

T Cell Response ◽

Potential Threat ◽

Cell Responses ◽

Reference Isolate ◽

The Impact

Abstract Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417, escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks of the receptor-binding domain. To address the potential threat posed by VOC, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort sampled in the early convalescent stages after natural infection in the first wave of the pandemic in Spring 2020. We tested antibody and T cell responses against a reference isolate of the original circulating lineage, B, and the impact of sequence variation in the B.1.1.7 and B.1.351 VOC. Neutralization of the VOC compared to B isolate was reduced, and this was most evident for the B.1.351 isolate. This reduction in antibody neutralization was less marked in post-boost vaccine-induced responses compared to naturally induced immune responses and could be largely explained by the potency of the homotypic antibody response. After a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOC was completely abrogated in the majority of vaccinees. Importantly, high magnitude T cell responses were generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. These data indicate that VOC may evade protective neutralizing responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine dose, but the impact of the VOC on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants.

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Induction of High Levels of Specific Humoral and Cellular Responses to SARS-CoV-2 After the Administration of Covid-19 mRNA Vaccines Requires Several Days

Frontiers in Immunology ◽

10.3389/fimmu.2021.726960 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sergio Gil-Manso ◽

Diego Carbonell ◽

Luis López-Fernández ◽

Iria Miguens ◽

Roberto Alonso ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Vaccination Schedule ◽

T Cell Response ◽

Cell Responses ◽

Fast Development ◽

Specific Igg ◽

Cellular Immune

ObjectivesIn the context of the Covid-19 pandemic, the fast development of vaccines with efficacy of around 95% preventing Covid-19 illness provides a unique opportunity to reduce the mortality associated with the pandemic. However, in the absence of efficacious prophylactic medications and few treatments for this infection, the induction of a fast and robust protective immunity is required for effective disease control, not only to prevent the disease but also the infection and shedding/transmission. The objective of our study was to analyze the level of specific humoral and cellular T-cell responses against the spike protein of SARS-CoV-2 induced by two mRNA-based vaccines (BNT162b2 and mRNA-1273), but also how long it takes after vaccination to induce these protective humoral and cellular immune responses.MethodsWe studied in 40 healthy (not previously infected) volunteers vaccinated with BNT162b2 or mRNA-1273 vaccines the presence of spike-specific IgG antibodies and SARS-CoV-2-specific T cells at 3, 7 and 14 days after receiving the second dose of the vaccine. The specific T-cell response was analyzed stimulating fresh whole blood from vaccinated volunteers with SARS-CoV-2 peptides and measuring the release of cytokines secreted by T cells in response to SARS-CoV-2 stimulation.ResultsOur results indicate that the immunization capacity of both vaccines is comparable. However, although both BNT162b2 and mRNA-1273 vaccines can induce early B-cell and T-cell responses, these vaccine-mediated immune responses do not reach their maximum values until 14 days after completing the vaccination schedule.ConclusionThis refractory period in the induction of specific immunity observed after completing the vaccination could constitute a window of higher infection risk, which could explain some emerging cases of SARS-CoV-2 infection in vaccinated people.

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Natural and vaccine-induced antibody and cellular responses against emerging SARS-CoV-2 variants of concern

10.21203/rs.3.rs-224655/v1 ◽

2021 ◽

Author(s):

Donal T. Skelly ◽

Adam C. Harding ◽

Javier Gilbert-Jaramillo ◽

Michael L. Knight ◽

Stephanie Longet ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Natural Infection ◽

T Cell Responses ◽

T Cell Response ◽

Antibody Neutralization ◽

Potential Threat ◽

Cell Responses ◽

The Uk ◽

The Impact

Abstract Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.

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