Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We demonstrate the construction of a vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we use this vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. We show that mice immunized with these sMVA vectors develop robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.
Second-generation COVID-19 vaccines could contribute to establish protective immunity against SARS-CoV-2 and its emerging variants. We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara-based SARS-CoV-2 vaccine that co-expresses spike and nucleocapsid antigens. Here, we report COH04S1 vaccine efficacy in animal models. We demonstrate that intramuscular or intranasal vaccination of Syrian hamsters with COH04S1 induces robust Th1-biased antigen-specific humoral immunity and cross-neutralizing antibodies (NAb) and protects against weight loss, lower respiratory tract infection, and lung injury following intranasal SARS-CoV-2 challenge. Moreover, we demonstrate that single-dose or two-dose vaccination of non-human primates with COH04S1 induces robust antigen-specific binding antibodies, NAb, and Th1-biased T cells, protects against both upper and lower respiratory tract infection following intranasal/intratracheal SARS-CoV-2 challenge, and triggers potent post-challenge anamnestic antiviral responses. These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clinical trials.
Second-generation COVID-19 vaccines could contribute to establish protective immunity against SARS-CoV-2 and its emerging variants. We developed COH04S1, a synthetic multiantigen Modified Vaccinia Ankara-based SARS-CoV-2 vaccine that co-expresses spike and nucleocapsid antigens. Here, we report COH04S1 vaccine efficacy in animal models. We demonstrate that intramuscular or intranasal vaccination of Syrian hamsters with COH04S1 induces robust Th1-biased antigen-specific humoral immunity and cross-neutralizing antibodies (NAb) and protects against weight loss, lower respiratory tract infection, and lung injury following intranasal SARS-CoV-2 challenge. Moreover, we demonstrate that single-dose or two-dose vaccination of non-human primates with COH04S1 induces robust antigen-specific binding antibodies, NAb, and Th1-biased T cells, protects against both upper and lower respiratory tract infection following intranasal/intratracheal SARS-CoV-2 challenge, and triggers potent post-challenge anamnestic antiviral responses. These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clinical trials.
Immunocompromised recipients of allogeneic hematopoietic stem cell transplant (HCT) are at increased risk of severe COVID-19. 1 During the first year of a successful HCT, circulating T-cells arise from donor CD34 + cells and can react to antigens exposed to the donor through natural infection or vaccination before transplantation. Therefore, donor pathogen exposure or vaccination pre-graft can be beneficial to the recipient when mounting cellular and humoral response to augment immune reconstitution and control post-HCT natural infection or increase vaccination responses. 2 Here, we present evidence of transfer and expansion of SARS-CoV-2-specific adaptive immunity from three matched unrelated donors (MUDs), vaccinated with licensed COVID-19 vaccines to unvaccinated and vaccinated recipients. The 10/10 matched (with permissive HLA-DPB1 locus mismatch) MUDs and their recipients did not have COVID-19 history nor developed active infection through study completion (d + 180). All three recipients engrafted and achieved full donor chimerism (>95%) 3 by d + 30.The patient from MUD/R1 pair (Table 1S) was a 29-year-old Hispanic male, with body mass index of 40.07 kg/m 2 , hypertension, diabetes, diagnosed with Philadelphia like B-cell acute lymphoblastic leukemia, with cytokine receptor-like factor 2 rearrangement. The mRNA-1273 vaccinated MUD donor was a 33-year-old male. The recipient underwent a myeloablative HCT soon after CD-19 CAR T-cell therapy, while in second complete remission (CR2) with negative measurable residual disease (MRD), using fractionated total body irradiation with etoposide. He received GVHD prophylaxis of tacrolimus and sirolimus (tacro/siro). He developed grade 1 skin GVHD around d + 24, which resolved with topical therapy. He did not receive a COVID-19 vaccine because prior to HCT, the patient was unstable and not ambulatory.Patient from MUD/R2 pair was a 74-year-old Caucasian male with history of hypertension, diagnosed with acute myeloid leukemia with deletion Y and SRSF2 mutation, who was in CR1 with negative MRD after receiving hypomethylating agent and venetoclax. The BNT162b2 mRNA vaccinated MUD donor was a 30-year-old female.The recipient underwent reduced intensity HCT using fludarabine and melphalan conditioning (FM), with tacro/siro GVHD prophylaxis in combination with itacitinib JAK-1 inhibitor (NCT04339101). He devel-
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic that upended existing protocols and practices, including those for allogeneic hematopoietic stem cell transplantation (HCT). Here we describe the successful clinical course and multiple key interventions administered to an acute lymphoblastic leukemia patient, who tested SARS-CoV-2 positive by RT-PCR on day -1 of matched unrelated donor (SARS-CoV-2 IgG negative) T-cell-replete HCT. This experience allowed for implementing a virologic and immunomonitoring panel to characterize the impact of SARS-CoV-2 on the recipient's nascent humoral and cellular immune response. The finding of robust, functional, and persistent levels of SARS-CoV-2 specific T-cells, starting early after transplant was unexpected, and in combination with the clinical strategy may have contributed to the favorable outcome. Additionally, it is plausible that pre-existing cross-reactive endemic coronavirus immunity in the allogeneic graft reduced recipient susceptibility to COVID-19 disease. This case supports the critical role that T-cell responses may play in mitigating SARS-CoV-2 infection, even in the context of transplant immunosuppression, in which reconstitution of humoral response is commonly delayed. Interventional approaches to transfer SARS-CoV-2-specific cellular immunity such as HCT donor vaccination and adaptive cellular therapy could be of benefit.
To enhance protective cytomegalovirus (CMV)‐specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post‐HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non‐replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV‐seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 108 pfu/ml of Triplex before cell harvest (median 15, range 11–28 days). Donor and recipient pairs who committed to participation in the trial resulted in exceptional adherence to the protocol. Triplex was well‐tolerated with limited adverse events in donors and recipients, who all engrafted with full donor chimerism. On day 28 post‐HCT, levels of functional vaccinia‐ and CMV‐specific CD137+ CD8+ T cells were significantly higher (p < .0001 and p = .0174, respectively) in recipients of Triplex vaccinated MRD than unvaccinated MRD (control cohort). Predominantly, central and effector memory CMV‐specific T‐cell responses continued to steadily expand through 1‐year follow‐up. CMV viremia requiring antivirals developed in three recipients (18%). In summary, this novel approach represents a promising strategy applicable to different HCT settings for limiting the use of antiviral prophylaxis, which can impair and delay CMV‐specific immunity, leading to CMV reactivation requiring treatment.
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