B-pVAC-SARS-CoV-2: Study to Prevent COVID-19 Infection in Adults With Bcell/ Antibody Deficiency

Multicenter Phase I-II clinical trial

Phase I:

Part I: 14-patients will receive an open-label 500 μl subcutaneous injection via needle and syringe of the study IMP (CoVac-1). 28 days following vaccination of the

1th patient, there will be an interim analysis of safety and immunogenicity and a review by the data safety monitoring board (DSMB) before proceeding to Phase II Definition of sufficient immunogenicity after one dose of vaccination: T cell response to at least one CoVAC-1 vaccine peptide on day28 in ≥80% of study patients, with proven general ability to mount antigen-specific T cell responses (detection of T cell responses to EBV/CMV control peptides) assessed by Interferon gamma (IFN-γ) ELISpot.

• The time point (day28) for the assessment of CoVac-1 induced T cell responses was selected based on the results of the ongoing P-pVAC-SARS-CoV-2 study, where CoVac-1-induced SARS-CoV-2 T cell responses were observed in 100% of study subjects at day28.
• The threshold of 80% was introduced after considering recent findings about cancer patients with hematological malignancies (comprising patients with B cell or antibody deficiencies) vaccinated with BNT162b2. Here it was observed that only 50% of patients had a BNT162b2-induced T cell response, while this was achieved in 80% of the healthy donors. Thus, the threshold of 80% was chosen, with the aim of providing our study population an immunization comparable to the one achieved in the healthy population vaccinated with the approved vaccines. CoVac-1 induced T cell responses are defined as positive T cell response in Interferon gamm (IFN-γ) ELISPOT assay with spot count at least 2-fold higher than the baseline assay (Visit 1). T cell responses are considered to be positive when the mean spot count per well is at least 3-fold higher than the mean number of spots in the negative control wells (stimulated with a control peptide). Only patients with detectable T cell response to the viral peptide panel ex vivo or after in vitro T cell expansion, and thus general ability to mount an antigen-specific immune response will be considered for the evaluation of sufficient immune responses after one CoVac-1 vaccination. Part II (optional): If there is an insufficient immune response measured by Interferon gamma (IFN-γ) ELISpot in Part I of Phase I on day 28, an additional Part (Part II) of Phase I will start enrollment of 14 subjects receiving two open-label 500 μl subcutaneous injection via needle and syringe of the study IMP (CoVac-1) on day1 and day42.

Phase II (after an amendment to the protocol):

40 subjects will receive an open-label 500 μl subcutaneous injection via needle and syringe of the study IMP (CoVac-1) on d1 and, depending on the data collected in Phase I, a second vaccination on day42 if necessary.

Inclusion criteria

• Adult (≥18 years) male or non-pregnant, non-lactating female
• Primary antibody deficiency syndrome or Secondary antibody deficiency syndrome, defined by one of the following:

• IgG < 4 g/l
• Ongoing substitution of immunoglobline for hypogammaglobinemia
• Anti-CD20 antibody (monospecific) therapy for malignant disease:
• after combined Anti-CD20 antibody therapy with chemotherapy (e.g. fludarabin, cyclophosphamid, bendamustin, anthracycline, vincristin) or BTK-inhibitors or BCL2-inhibitors (within 1-6 months post therapy)
• ongoing single agent Anti-CD20 antibody therapy
• Anti-CD20 antibody maintenance therapy
• Ability to understand and voluntarily sign an informed consent form
• Ability to adhere to the study visit schedule and other protocol requirements
• Female patients of child bearing potential (FCBP) and male patients with partners of child bearing potential, who are sexually active, must agree to the use of two effective forms (at least one highly effective method) of contraception. This should be started from the signing of the informed consent and continue until three months after vaccination. Furthermore, contraception must be carried on by patients receiving B-cell depleting therapies for the whole duration of the treatment.
• Postmenopausal or evidence of non-child-bearing status. For women of childbearing potential: negative urine or serum pregnancy test within 7 days prior to study treatment. Postmenopausal or evidence of nonchildbearing status is defined as:

• Amenorrhoea for 1 year or more following cessation of exogenous hormonal treatments
• Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50

Exclusion criteria

• Pregnant or lactating females
• Participation in any clinical trial with intake of any nonregistered vaccine product
• Any concomitant disease affecting the effect of the therapeutic vaccine or interfering with the study primary endpoint:

• Active infection
• Psychiatric disorders
• Known systemic anaphylaxis
• Prior or current infection with SARS-CoV-2 as assessed by medical history and/or by throat/nose swab (PCR) or serologically documented immunization against SARSCoV- 2 (after infection or vaccination)
• Persisting symptoms developed after SARS-CoV-2 vaccination with an approved vaccine product at study inclusion
• History of Guillain-Barré syndrome
• HIV infection, chronic or active hepatitis B or C
• History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/haemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder, excluding febrile seizures as child)
• Baseline laboratory CD4+ T cell count < 100 μl
• The following pre-existing medical conditions:

• Chronic liver failure defined as Child-Pugh Score ≥B
• Chronic renal failure defined as GFR <40 ml/min/1,73m2
• Serious pre-existing cardiovascular disease such as NYHA ≥ III
• Sickle cell anemia
• Patients presenting with any clinical, laboratory or radiological signs of tumor-progression
• Patient receiving active treatment with small molecules, including Tyrosine Kinases-Inhibitors (e.g. Ibrutinib), Proteosome-Inhibitors (e.g. Bortezomib), Bcl-2- Inhibitors (e.g. Venetoclax), Phosphoinositid-3-Kinase- Inhibors (e.g. Idelalisib)
• Known hypersensitivity to any of the components included in the CoVac-1 vaccine
• Pre-existing auto-immune disease except for Hashimoto thyroiditis and mild (not requiring immunosuppressive treatment) psoriasis
• Intention of receiving one dose of an already approved vaccine against SARS-CoV-2 before day 56