Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency

doi:10.21203/rs.3.rs-1693355/v1

T-cell immunity is central for the control of COVID-19, in particular in patients incapable to mount a humoral immune response. We previously reported on the favorable safety profile and efficacy in terms of induction of SARS-CoV-2-specific T-cell responses by CoVac-1, a peptide-based T-cell activator, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15¹. We conducted a Phase I/II open-label trial recruiting 54 patients with congenital or acquired B-cell deficiency who received one single subcutaneous dose of CoVac-1. Immunogenicity until day 28 in terms of CoVac-1-induced T-cell responses was the primary endpoint; safety until day 56 was assessed as secondary endpoint. Neither serious nor grade 4 CoVac-1-related adverse events were observed. The expected local granuloma formation was observed in 94% of study subjects, whereas systemic reactogenicity was mostly mild or absent. SARS-CoV-2-specific Tcell responses were induced in 86% of the patients and directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4⁺ T cells. CoVac-1-induced T-cell responses exceeded spike-specific T-cell responses after vaccination with mRNA vaccines in B-cell deficient patients and also that of immunocompetent COVID-19 convalescents with and without seroconversion. CoVac-1 induces broad and potent T-cell responses in patients with Bcell/antibody deficiency independently of current variants of concern, with a favorable safety profile. Our data warrant advancement to a pivotal Phase II/III safety and efficacy evaluation.

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prompted the development of several vaccines which protect billions of people from severe course of disease in particular by induction of humoral, i.e. antibody-mediated immunity.^2–5 Patients unable to mount humoral immune responses, neither to natural infection nor to prophylactic vaccination, are at high risk for a dismal outcome of COVID-19.^6–9 This comprises individuals with congenital B-cell deficiency, but also cancer patients with disease or treatment related B-cell depletion. Beyond humoral immunity mediated by B cells, T cells are key for COVID-19 outcome and maintenance of immunity to SARS-CoV-2.^10–17

In a Phase I trial, our peptide-based T-cell activator CoVac-1 showed a favorable safety profile and induced broad and long-lasting T-cell immunity that by far exceeded T-cell responses after SARS-CoV-2 infection as well as after vaccination with any approved vaccine.¹ CoVac-1 is composed of multiple SARS-CoV-2 human leukocyte antigen (HLA)-DR Tcell epitopes, which are derived from different viral proteins (spike, nucleocapsid, membrane, envelope, open reading frame (ORF) 8)^10,11,18 and, thus, induce T-cell immunity that is independent of existing variants of concern (VOCs).¹

We here report the results of the open-label Phase I/II trial evaluating immunogenicity along with safety and reactogenicity of CoVac-1 in the high-risk population of patients with congenital or acquired B-cell deficiency.

Patients

From July 6^th, 2021 to January 13^th, 2022, a total of 94 patients with congenital or acquired B-cell deficiency underwent screening at three study sites in Germany. A total of 54 patients received CoVac-1, 14 patients in the Phase I safety run-in, and 40 patients in the subsequent Phase II part of the trial. 28% of patients were female. Median patient age was 61.8 (range 37-90) years. 93% of study patients suffered from cancer-related, acquired B-cell deficiency, with chronic lymphocytic leukemia (CLL, 30%), mantle cell lymphoma (MCL, 24%) and follicular lymphoma (FL, 20%) as the most common diagnoses. Application of an approved COVID-19 vaccine prior to study inclusion was reported for 83% of patients with a median of two vaccinations per patient (Table S6). CD4⁺ T-cell counts in the study population ranged from 123-2,501/µl (median 458/µl). All patients received one dose of CoVac-1 on day 1 and were available for safety analyses until day 56 (Fig. 1). 49 patients were eligible for immunogenicity analysis until day 28. One major protocol violation occurred (missed study visit day 28). Analyses of follow-up safety and long-term immunogenicity data (until month 6) are ongoing. Demographic and clinical characteristics of the patients are provided in Table 1, S6 and S7.

Safety and reactogenicity

Data regarding solicited and unsolicited AEs were available for all patients from diary cards (for 28 days after CoVac-1 application) and safety visits (until day 56). No patient discontinued the trial because of an AE. No vaccine-related SAEs and no grade 4 AEs were reported. Until day 56 reactogenicity in terms of solicited AEs occurred in all trial patients (Fig. 2). Local events were normal to moderate (grade 0 to 2) in 87% of study patients. 94% of patients showed the expected formation of a granuloma/induration at the injection site, which persisted beyond day 56. Severe AEs (grade 3) comprised local erythema in 11% of patients. 4% of patients reported localized inguinal lymphadenopathy. Local skin ulceration at the injection site was reported by 2% of patients. No fever or other systemic inflammatory solicited AEs were reported. Other systemic solicited AEs occurred in 26% of patients. 93% of the reported systemic solicited AEs were mild, with transient fatigue being the most frequently reported (17% of patients). One patient suffered from unrelated (chemotherapy-induced) grade 4 neutropenia. In 36% of patients, acute phase reaction with elevated C-reactive protein was observed until day 56.

67 unsolicited AEs occurred, which were predominantly mild (79%, Extended Data Table 1). Of all unsolicited AEs, three were judged to be related to CoVac-1, comprising two viral reactivations (herpes simplex and varizella zoster virus) and one formation of a blister at injection site (grade 1). Of the unsolicited AEs, three were reported as SAE not related to CoVac-1 application (details in the Supplementary Appendix, Extended Data Table 1).

No immune-mediated AE was observed in any of the patients. Until day 56, two SARS-CoV-2 infections occurred, with reportedly mild disease course (detailed case narratives in the Supplementary Appendix) and resolved without sequel.

Immunogenicity

Immunogenicity was determined in terms of T-cell responses to the six SARS-CoV-2 HLA-DR CoVac-1 T-cell epitopes^1,10,11 using ELISPOT assays. T-cell responses were assessed in all eligible patients at baseline (day 1), on day 7, day 14, and day 28 after CoVac-1 application. The immunogenicity endpoint was reached: CoVac-1-induced IFN-g T‑cell responses were documented in 86% of patients on day 28, with a 36‑fold increase (median positive calculated spot counts: 4 (day 1) to 144 (day 28)) from baseline (Fig. 3a). Vaccine-induced T‑cell responses were directed to multiple CoVac-1 peptides, with median 4/6 peptides recognized by patients` T cells on day 28 (Fig. 3b). The CoVac-1 peptide P6_ORF8 most frequently induced T-cell responses (75%), followed by P3_spi (69%), P5_mem and P4_env (both 52%, Extended Data Fig. 1). 12% and 44% of the study patients showed low-frequent pre-existing SARS-CoV-2 T‑cell responses ex vivo and after 12 days in vitro stimulation at baseline, respectively, in particular to the spike-derived peptide P3_spi (Extended Data Fig. 1 and 2). This may be explained by prior vaccination with approved COVID-19 vaccines as well as by cross-reactive T-cell responses to human common cold coronaviruses (HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1)^10,17.

CoVac-1-induced CD4⁺T cells displayed a multifunctional T-helper 1 (Th1) phenotype with positivity for IFN-g, tumor necrosis factor (TNF), interleukin-2 (IL-2), and CD107a (Fig. 3c). Frequency of functional CD4⁺ T cells was increased up to 38-fold after in vitro expansion (e.g. 0.03% (ex vivo) to 1.15% (median positive samples) CoVac-1-specific CD107a⁺CD4⁺ T cells), indicative of potent expandability of the induced T cells upon SARS-CoV‑2 exposure (Extended Data Fig. 3).

Subgroup analysis showed higher response rates and frequencies of CoVac-1-induced T cells on day 28 for patients with acquired B-cell deficiency (87% response rate, median calculated spot count 151) compared to patients with congenital B-cell deficiency (75% response rate, median calculated spot count 81), with highest frequencies of T cells observed in patients with FL and diffuse large B-cell lymphoma (DLBCL) (median calculated spot counts 401 and 663, respectively, Fig. 3d). No relevant difference in the frequency and intensity of CoVac-1-induced T-cell responses was observed between cancer patients with or without ongoing anti-CD20 therapy (85% vs 88% response, median calculated spot count 151 vs. 164, Fig. 3d).

Beyond T-cell responses, induction of low-level SARS-CoV-2 anti-spike IgG antibodies was observed on day 28 in 8 patients (Fig. 3e).

The intensity of CoVac-1-induced IFN‑g T-cell responses (median calculated spot count 144) exceeded spike-specific T-cell responses induced by approved mRNA-based vaccines (median calculated spot count 45) in B-cell deficient patients prior to CoVac-1 application (Fig. 4a, Table S6). Such pre-existing spike-specific T-cell responses after mRNA vaccination were boosted by CoVac-1, and expanded to various CoVac-1 peptides derived from other SARS-CoV-2 proteins (Fig. 4b, c). Notably, none of the variant-defining or associated mutations of the Omicron variants (BA.1, BA1.1, BA.2, BA.3, Fig. 4d, Table S8)²² affected any of the CoVac-1 peptides.

The intensity of CoVac-1-induced IFN-g T-cell responses in B-cell deficient patients at day 28 (B-CoVs, median calculated spot count 144) was similar or even higher than T-cell responses to CoVac-1 peptides (median calculated spot count 55), to SARS-CoV-2-specific (median calculated spot count 61) and to cross-reactive (median calculated spot count 105) T‑cell epitopes^10,11 in immunocompetent HCs, with asymptomatic and mild disease^1,10 (Fig. 4e, Table S5). The same held true for the comparison of CoVac-1-induced T-cell responses in B-cell deficient patients with a cohort of immunocompetent HCs¹⁰ with asymptomatic and mild disease that did not develop a humoral anti-spike IgG response upon infection (Fig. 4f), indicating that CoVac-1-induced T-cell responses in B-cell deficient patients might be sufficient to provide immunity against severe COVID-19 in this highly immunocompromised population.

Recently, evaluation of the peptide-based T-cell activator CoVac-1 in healthy adults showed promising safety and immunogenicity in terms of profound and long-lasting SARS-CoV-2-specific T-cell responses that are not affected by VOCs.¹ This prompted clinical evaluation in patients with congenital or acquired B-cell deficiency, the latter comprising patients receiving B-cell depleting therapy, e.g. in leukemia and lymphoma. This patient population is unable to mount sufficient humoral immune response upon vaccination with approved vaccines^7–9 and is at high risk for a severe course of COVID-19.^23–27

Here we report on the Phase I/II clinical trial evaluating CoVac-1 in patients with congenital or acquired B-cell deficiency, which confirmed the favorable safety profile and documented potent de novo induction of T-cell responses after one single administration even in this highly immunocompromised study population. Of note, beyond B-cell deficiency, 50% of patients additionally presented with CD4⁺ T cell counts below 500/µl, further emphasizing the severe immunodeficiency of the trial population.²⁸ Local granuloma formation was observed in 94% of study subjects displaying an expected and intended local reaction after Montanide administration,^21,29 which enables continuous local stimulation of SARS-CoV2-specific T cells required for induction of long-lasting T-cell responses without systemic inflammation¹⁹. In line with the findings in healthy volunteers,¹ CoVac-1 induced a Th1 CD4⁺ T-cell response in the B-cell deficient patients, precluding the theoretical risk of vaccine-associated enhanced respiratory disease, which has been associated with a T-helper 2 (Th2)-driven immune response.³⁰ CoVac-1-induced T-cell responses showed high diversity targeting multiple vaccine peptides derived from different viral proteins, which is of high relevance for anti-viral defense and disease outcome in viral infections including SARS-CoV2.^10,18,31,32 The broad T-cell responses induced by CoVac-1 are not affected by any of the current SARS-CoV-2 VOCs¹, including the latest Omicron variants,²² which are associated with loss of neutralizing antibody capacity and reduced efficacy of approved vaccines.^33,34

CoVac-1-induced T-cell responses exceeded spike-specific T-cell responses induced by mRNA vaccination^3,4,35 in B-cell deficient patients. Moreover, CoVac-1 was able to boost such pre-existing spike-specific T-cell responses.

Subgroup analysis showed higher frequency and intensity of T-cell responses in cancer patients with acquired B-cell deficiency compared to patients with congenital B-cell deficiency. This could be the consequence of additional T-cell defects in patients with congenital immune defects (e.g. Common Variable Immunodeficiency, CVID).^36,37

Even after receipt of two or more doses of approved vaccines, none of the patients showed any humoral immune response to SARS-CoV-2 at study inclusion; after CoVac-1 application, induction of low-level SARS-CoV-2 anti-spike IgG antibodies was observed in single patients, despite consistently negative results in sequential SARS-CoV-2 PCRs. This finding may be due to stimulation of pre-existing³⁸ or vaccine-induced low frequent B cells by CoVac-1-induced CD4⁺ T cells.

T-cell-mediated immunity and, in particular CD4⁺ T cells, are indispensable for the generation of protective antibody responses, reinforcement of CD8⁺ T-cell responses,^39,40 as well as direct killing of virus-infected cells.^41,42 The relevance of anti-viral T-cell responses during acute infection and for long-term immunity was also proven specifically for SARS-CoV-2.^{10,11,14−17} Moreover, cases of asymptomatic SARS-CoV-2 infection, as well as reports from patients with congenital B-cell deficiency document cellular immune responses without seroconversion, providing evidence for the role of T-cell immunity in disease control, even in the absence of neutralizing antibodies.^15,43 Accordingly, CoVac-1 may well serve as a T-cell activator beyond current prophylactic approaches in immunocompromised patients comprising substitution of immunoglobulins and application of monoclonal SARS-CoV-2 antibody products.^44,45

To elucidate which frequencies and phenotypes of T cells are required to effectively combat COVID-19, a longitudinal Phase II/III efficacy study with CoVac-1 is presently in preparation. Evidence that CoVac-1-induced T-cell responses may confer immunity to severe COVID-19 in this highly immunocompromised population is provided by the phenotype of CoVac-1-induced T cells, which resembles that upon natural infection,^10–12 and the intensity of the CoVac-1-induced T-cell responses, which is similar and even higher compared to a cohort of immunocompetent HCs with asymptomatic and mild COVID-19 disease that did not develop a humoral anti-spike IgG response upon infection and thus likely were protected by a SARS-CoV-2-specific T-cell response alone. Despite lacking a humoral immune response to SARS-CoV-2, two study patients experienced a mild course of COVID-19 after CoVac-1 application.

Limitations of our trial include the small sample size, low ethnic diversity and exclusion of patients with autoimmune disease receiving B-cell depleting therapies. Safety and immunogenicity data over a longer observation period are presently being collected during the study follow-up where patients are monitored for up to 6 months.

In conclusion, the safety and immunogenicity data of our trial demonstrate that CoVac-1 is a promising T-cell activator for induction of SARS-CoV-2 T-cell immunity in patients with congenital or acquired B-cell defects and warrant advancement to a pivotal phase II/III safety and efficacy evaluation.

Trial design and oversight

The multi-center Phase I/II trial (ClinicalTrials.gov Identifier: NCT04954469) was conducted at the Clinical Collaboration Unit (CCU) Translational Immunology, University Hospital Tübingen, the Institute of Clinical Cancer Research, Krankenhaus Nordwest, University Cancer Center, Frankfurt and Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany. Men as well as non-pregnant women aged ≥ 18 years, with congenital or acquired B-cell deficiency, defined by either decreased IgG serum concentration, ongoing immunoglobulin substitution for hypogammaglobulinemia, or ongoing or following (up to six months) treatment regimens containing anti-CD20 immunotherapy (e.g. rituximab) were eligible. Patients were enrolled independently of COVID-19 vaccination status if negative for anti-spike SARS-CoV-2 antibodies at the time of inclusion. Individuals with history of SARS-CoV-2 infection (real-time polymerase chain reaction (PCR) or antibody test) were excluded. A detailed description of inclusion and exclusion criteria is provided in the Supplementary Appendix. Health status was based on medical history and laboratory values, vital signs and physical examination at screening. Prior to enrollment, all patients provided written informed consent. As safety and efficacy measure, a run-in Phase I trial was conducted with a follow-up period of 28 days after administration, followed by vaccination of further study patients in Phase II. Assessment of the run-in Phase I part included the decision to proceed with a single CoVac-1 administration (detailed description in Supplementary Appendix). The trial was open-label without a control arm and funded by the Federal Agency of Science, Research and the Arts (BMBF), Germany and the Ministry of Science, Research and the Arts Baden-Württemberg (MWK), Germany. The trial was approved by the local ethics committees under the lead of the Ethics Committee at the University Hospital Tübingen (255/2021AMG1) and the competent authority Paul Ehrlich Institute and performed in accordance with the International Council for Harmonization Good Clinical Practice guidelines.

Safety and immunogenicity assessment to proceed to Phase II was performed by an independent data safety monitoring board (DSMB).

T-cell activator peptides and adjuvant

CoVac-1, developed and produced by the Good Manufacturing Practices (GMP) Peptide Laboratory at the Department of Immunology, University of Tübingen, Germany, is a peptide-based T-cell activator comprising six HLA-DR-restricted SARS-CoV‑2 peptides¹ derived from various SARS-CoV-2 proteins (spike, nucleocapsid, membrane, envelope, and ORF8) and the synthetic lipopeptide adjuvant XS15, a TLR1/2 ligand^19,20 (manufactured by Bachem AG, Bubendorf, Switzerland) emulsified in Montanide^TM ISA51 VG²¹ (manufactured by Seppic, Paris, France).

CoVac-1 peptides (250 µg/peptide) and XS15 (50 µg) were prepared as water-oil emulsion 1:1 with Montanide^TM ISA51 VG with an injectable volume of 500 µL. Each patient received one subcutaneous injection of CoVac-1 at the abdomen on day 1. The dose was based on the safety and efficacy data of a Phase I trial in healthy adults.¹

Safety assessment

Primary safety outcomes reflect the nature, frequency, and severity of solicited adverse events (AEs) until day 56 after CoVac-1 application. Documentation was facilitated by a patient diary (covering 28 days after application) and graded by the investigators according to a modified Common Terminology Criteria for Adverse Events (CTCAE) V5.0 grading scale (Table S1). In addition, the number and percentage of trial patients with unsolicited events until day 56 was reported (according to CTCAE V5.0). Safety assessment included clinically significant changes in laboratory values (hematology and blood chemistry), serious adverse events (SAE), and adverse events of special interest (AESI), which included SARS-CoV-2 infection, COVID-19 manifestations, and immune-mediated medical conditions (Tables S2 and S3).

Immunogenicity assessment

The primary immunogenicity endpoint was defined by the induction of CoVac-1-specific T-cell responses in at least 70% of study patients to one or more of the CoVac-1 peptides or the combination of all six peptides, evaluated on day 7, day 14, and day 28 by interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay ex vivo and after in vitro T-cell expansion. For T-cell expansion, peripheral blood mononuclear cells (PBMCs) were pulsed with CoVac-1 peptides (5 mg/mL per peptide) and cultured for 12 days adding 20 U/mL interleukin-2 (IL-2, Novartis) on days 3, 5, and 7. For IFN-g ELISPOT (ex vivo or after in vitro expansion), cells were stimulated with 2.5 mg/mL of CoVac-1 peptides and analyzed in technical replicates. T-cell responses were considered positive (indicated as median of positive samples (pos)) if mean spot count was ≥ three‑fold higher than mean spot count of negative control and defined as CoVac-1-induced (indicated as response (%)) if the mean spot count post administration was ≥ two-fold higher than the respective spot count on day 1 (baseline, prior to vaccination). Patients without the general ability to mount antigen-specific T-cell responses (absence of CoVac-1-induced T-cell responses and no T-cell responses to HLA-DR T-cell epitope control panel including Epstein-Barr virus (EBV), cytomegalovirus (CMV) and adenovirus (ADV) peptides as previously described¹⁸ Table S4) were considered as not assessable (drop-out). CoVac-1-induced T-cell responses were further characterized using cell surface markers and intracellular cytokine staining (ICS). For the latter, cells were stimulated with 10 µg/mL per peptide. The gating strategy is provided in Fig. S1. Immunogenicity results were compared with those of immunocompetent healthy COVID-19 convalescents (HCs) with PCR-confirmed SARS-CoV-2 infection (Table S5). All assays were conducted in a blinded fashion and are described in detail in the Supplementary Appendix.

Statistical analysis

The total sample size calculation (n = 54 patients) of the trial was based on the following assumptions: For the analysis of safety in the first 14 patients (Phase I), incidence of SAE associated with administration of CoVac-1 exceeding a predetermined rate of 20% was investigated. The trial was expanded to Phase II after proving safety and sufficient T-cell response (> 80% of patients, with documented CoVac-1-induced T-cell responses) measured by IFN-γ ELISPOT on day 28. Here, the sample size (n = 40) based on the assumption that, in the unfavorable case of SARS-CoV-2 specific immune response induction in ≤ 50% of the patients, the treatment concept is extended with a probability of at most 5%. On the other hand, in the favorable case of peptide-specific immune response induction in ≥ 70% of patients, the concept would be followed with a probability of at least 80%. Safety data are summarized by counting every respective AE (lowest level term) that occurred in a patient only once. If the same AE occurred more than once, only the highest graded AE was counted. Data are displayed as mean ± standard deviation (SD), box plots as median with 25% or 75% quantiles and min/max whiskers. Details regarding statistical analysis plan and sample size calculation are provided in the Supplementary Appendix and the protocol.

Acknowledgement

We thank all the patients of this trial and the members of the data and safety monitoring board (Peter Brossart, Bonn; Hansjörg Schild, Mainz; Clemens Wendtner, Munich).

We are grateful to the technical and clinical staff of the participating trial centers at the CCU Translational Immunology, Department of Internal Medicine, University Hospital Tübingen, the Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, University Cancer Center, Frankfurt and the Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, the team of the “Wirkstoffpeptid Labor”, Department of Immunology, Tübingen, the pharmacy of the University Hospital Tübingen, the data management team at the Institute for Clinical Epidemiology and applied Biometry, and the “Zentrum für Klinische Studien”, at the University Hospital Tübingen for support and coordination. We further thank EMC Microcollections GmbH for provision of XS15.

This work was supported by the Ministry of Science, Research and the Arts Baden-Württemberg, Germany (MWK, Sonderfördermassnahme COVID-19, TÜ17), Federal Agency of Science, Research and the Arts, Germany (BMBF, FKZ:01KI20130 and FKZ:16LW0004K), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Grant WA 4608/1-2), the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (Grant EXC2180‑390900677), the German Cancer Consortium (DKTK), the Wilhelm Sander Stiftung (Grant 2016.177.2), the José Carreras Leukämie-Stiftung (Grant DJCLS 05 R/2017), the Robert Bosch Stiftung, the BIH-Charité Clinician Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health, the Ernst- Jung-Preis für Medizin and the Landesforschungspreis Baden-Württemberg both awarded to H.-G. Rammensee.

Author Contribution

J.S.H., K.-H.W., H.-G.R., H.R.S. and J.S.W. were involved in the design of the overall study and strategy. C.M., I.F. and M.W.L. provided feedback on the study design. C.T., A.N., Y.M., J.B., J.R., M.W., S.S., N.H.G., Me.Ma., A.H., B.K., K.L.C., M.L. and S.Hol. performed the immunogenicity analyses. J.S.H., Ma.Ma., T.H., S.M.R., C.M.T., S.J., S.H., A.P., E.J. and J.S.W. conducted patient data and sample collection as well as medical evaluation and analysis. J.S.H., Ma.Ma., T.H., S.M.R., C.M.T., S.J., C.A.P., S.Ha., T.O.G., E.J., H.R.S. and J.S.W. collected data as study investigators. S.J., C.M. and I.F. developed the statistical design and oversaw the data analysis. M.D., M.R. and M.T.O. conducted GMP production of CoVac-1. J.S.H., C.T., Ma.Ma., H.R.S. and J.S.W. drafted the manuscript. All authors supported the creation of the manuscript by review and editing.

Competing Interests

J.S.H., H.R.S., A.N., H.-G.R., and J.S.W. are listed as inventors on a patent related to the SARS-CoV-2 T-cell epitopes included in CoVac-1. H.-G.R. and K.-H.W. are listed as inventor on a patent related to the adjuvant XS15 included in CoVac-1. The other authors declare no competing interests.

Data Availability Statement

Data supporting the findings of this study including de-identified patient data are available after final completion of the trial report and are shared according to data sharing guidelines upon reasonable request to the corresponding author J.S.W.

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Table 1: Patients’ characteristics

Characteristics		All	Phase I	Phase II
Patients - no.		54	14	40
Diagnosis - [no. (%)]
	Primary immunodeficiency
	CVID	2 (4)	1 (7)	1 (3)
	XLA	1 (2)	1 (7)	0 (0)
	Others*	1 (2)	0 (0)	1 (3)
	Secondary immunodeficiency
	CLL	16 (30)	4 (29)	12 (30)
	MCL	13 (24)	3 (21)	10 (25)
	FL	11 (20)	4 (29)	7 (18)
	DLBCL	5 (9)	0 (0)	5 (13)
	Others**	5 (9)	1 (7)	4 (10)
Age - [years]
	Median	61.8	62.5	61.5
	Range	37-90	40-80	37-90
Sex - no. (%)
	Female	15 (28)	4 (29)	11 (27)
	Male	39 (72)	10 (71)	29 (73)

Assessment was done at the time of screening. *Unspecified agammaglobulinemia. **Hodgkin’s lymphoma, marginal cell lymphoma, myeloproliferative syndrome, Waldenström’s macroglobulinemia. Abbreviations: CLL, chronic lymphocytic leukemia; CVID, common variable immunodeficiency; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; no., number; XLA, X-linked agammaglobulinemia.

Yes there is potential Competing Interest. J.S.H., H.R.S., A.N., H.-G.R., and J.S.W. are listed as inventors on a patent related to the SARS-CoV-2 T-cell epitopes included in CoVac-1. H.-G.R. and K.-H.W. are listed as inventor on a patent related to the adjuvant XS15 included in CoVac-1.

Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency

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Abstract

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Introduction

Results

Discussion

Methods

Declarations

References

Tables

Additional Declarations

Supplementary Files

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