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Immunogenicity and Efficacy of the COVID-19 Candidate Vector Vaccine MVA-SARS-2-S in Preclinical Vaccination

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Immunogenicity and Efficacy of the COVID-19 Candidate Vector Vaccine MVA-SARS-2-S in Preclinical Vaccination Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA-SARS-2-S in preclinical vaccination Alina Tschernea,b,1, Jan Hendrik Schwarza,1, Cornelius Rohdec,d,1, Alexandra Kupkec,d,1, Georgia Kalodimoua,b,1, Leonard Limpinsela, Nisreen M. A. Okbae, Berislav Bošnjakf, Inga Sandrockf, Ivan Odakf, Sandro Halwec,d, Lucie Sauerheringc,d, Katrin Brosinskia, Nan Lianglianga, Elke Duella,b, Sylvia Janya, Astrid Freudensteina, Jörg Schmidtc,d, Anke Wernerc,d, Michelle Gellhorn Serrac,d, Michael Klüverc,d, Wolfgang Guggemosg, Michael Seilmaierg, Clemens-Martin Wendtnerg, Reinhold Försterf,h,i, Bart L. Haagmanse, Stephan Beckerc,d, Gerd Suttera,b,2, and Asisa Volza,b,j aDivision of Virology, Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, 80539 Munich, Germany; bDivision of Virology, Department of Veterinary Sciences, German Center for Infection Research, 80539 Munich, Germany; cInstitute of Virology, Philipps University Marburg, 35037 Marburg, Germany; dInstitute of Virology, Marburg, German Center for Infection Research, 35392 Giessen-Marburg-Langen, Germany; eDepartment of Viroscience, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; fInstitute of Immunology, Hannover Medical School, 30625 Hannover, Germany; gMunich Clinic Schwabing, Academic Teaching Hospital, Ludwig-Maximilians-Universität München, 80804 Munich, Germany; hInstitute of Immunology, German Center for Infection Research, 30625 Hannover, Germany; iCluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany; and jInstitute of Virology, University of Veterinary Medicine, Hannover, 30559 Hannover, Germany Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved May 23, 2021 (received for review December 20, 2020) Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) for SARS-CoV-2 cell entry. As a class I viral fusion protein, it has emerged as the infectious agent causing the pandemic coronavi- mediates virus interaction with the cellular receptor angiotensin- rus disease 2019 (COVID-19) with dramatic consequences for global converting enzyme 2 (ACE2), and fusion with the host cell mem- human health and economics. Previously, we reached clinical evalua- brane, both key steps in infection. Thus, infection can be prevented tion with our vector vaccine based on modified vaccinia virus Ankara by S-specific antibodies neutralizing the virus (6–9). (MVA) against the Middle East respiratory syndrome coronavirus Among the front-runner vaccines are new technologies such as MICROBIOLOGY (MERS-CoV), which causes an infection in humans similar to SARS messenger RNA (mRNA)-based vaccines and nonreplicating adeno- and COVID-19. Here, we describe the construction and preclinical char- virusvectorvaccines(10–13). First reports from these SARS-CoV-2- acterization of a recombinant MVA expressing full-length SARS-CoV-2 S–specific vaccines in phase 1/2 clinical studies demonstrated spike (S) protein (MVA-SARS-2-S). Genetic stability and growth char- acceptable safety and promising immunogenicity profiles, and by acteristics of MVA-SARS-2-S, plus its robust expression of S protein as now data from large phase 3 clinical trials show promising levels antigen, make it a suitable candidate vaccine for industrial-scale pro- of protective efficacy (4, 12–14). In December 2020, the first duction. Vaccinated mice produced S-specific CD8+ T cells and serum antibodies binding to S protein that neutralized SARS-CoV-2. Prime- Significance boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. The highly attenuated vaccinia virus MVA is licensed as small- MVA-SARS-2-S is currently being investigated in a phase I clinical trial pox vaccine; as a vector it is a component of the approved as aspirant for developing a safe and efficacious vaccine against adenovirus-MVA–based prime-boost vaccine against Ebola vi- COVID-19. rus disease. Here, we provide results from testing the COVID-19 candidate vaccine MVA-SARS-2-S, a poxvirus-based vector vac- vaccine vector | vaccinia virus | poxvirus | nonclinical testing cine that proceeded to clinical evaluation. When administered by intramuscular inoculation, MVA-SARS-2-S expresses and safely evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), delivers the full-length SARS-CoV-2 S protein, inducing balanced Sthe causal agent of coronavirus disease 2019 (COVID-19), first SARS-CoV-2–specific cellular and humoral immunity, and protec- emerged in late 2019 in China (1). SARS-CoV-2 exhibits extremely tive efficacy in vaccinated mice. Substantial clinical experience efficient human-to-human transmission, the new pathogen rapidly has been gained with MVA vectors using homologous and het- spread worldwide, and within months it caused a global pan- erologous prime-boost applications, including the immunization demic, changing daily life for billions of people. The COVID-19 of children and immunocompromised individuals. Thus, MVA- case fatality rate of ∼2–5% makes the development of counter- SARS-2-S represents an important resource for developing fur- measures a global priority. In fact, the development of COVID- ther optimized COVID-19 vaccines. 19 vaccine candidates is advancing at an international level with unprecedented speed. About 1 y after the first known cases of Author contributions: G.S. and A.V. designed research; A.T., J.H.S., C.R., G.K., L.L., N.L., S.J., COVID-19, we can account for >80 SARS-CoV-2–specific vaccines A.F., G.S., and A.V. performed research; N.M.O., B.B., I.S., I.O., S.H., L.S., J.S., A.W., M.G.S., > M.K., W.G., M.S., C.-M.W., R.F., and B.L.H. contributed new reagents/analytic tools; A.T., in clinical evaluations and 10 candidate vaccines already in phase J.H.S., C.R., A.K., G.K., N.M.A.O., B.B., I.O., K.B., E.D., R.F., B.L.H., S.B., G.S., and A.V. ana- III trials (2–4). However, we still lack information on the key im- lyzed data; and A.T., J.H.S., C.R., A.K., S.B., G.S., and A.V. wrote the paper. mune mechanisms needed for protection against COVID-19. A The authors declare no competing interest. better understanding of the types of immune response elicited upon This article is a PNAS Direct Submission. natural SARS-CoV-2 infections has become an essential compo- This open access article is distributed under Creative Commons Attribution License 4.0 nent to assess the promise of various vaccination strategies (5). (CC BY). The SARS-CoV-2 spike (S) protein serves as the most impor- 1A.T., J.H.S., C.R., A.K., and G.K. contributed equally to this work. tant target antigen for vaccine development based on preclinical 2To whom correspondence may be addressed. Email: [email protected]. research on candidate vaccines against SARS-CoV or Middle East This article contains supporting information online at https://www.pnas.org/lookup/suppl/ respiratory syndrome coronavirus (MERS-CoV). The trimeric S doi:10.1073/pnas.2026207118/-/DCSupplemental. protein is a prominent structure at the virion surface and essential Published June 23, 2021. PNAS 2021 Vol. 118 No. 28 e2026207118 https://doi.org/10.1073/pnas.2026207118 | 1of9 Downloaded by guest on September 30, 2021 mRNA-based COVID-19 vaccines received emergency use au- antibody directed against the 9-aa HA-tag at the C terminus of thorization or conditional licensing by the US Food and Drug the recombinant SARS-2-S protein revealed highly specific staining in Administration and European Medicines Agency (11, 15, 16). By permeabilized cells corresponding to the expected intracellular local- March 2021, two adenovirus vector-based COVID-10 vaccines ization of the S-protein C-terminal end. A SARS-CoV-1-S–specific had been approved by regulatory authorities (17, 18). This is good monoclonal antibody showing cross-reactivity with SARS-CoV-2 (29) news because efficacious vaccines will provide a strategy to change in recognizing an epitope in the external domain of the SARS-CoV-2- SARS-CoV-2 transmission dynamics. In addition, multiple vac- S protein also allowed the specific staining of nonpermeabilized cine types will be advantageous to meet specific demands across MVA-SARS-2-S–infected Vero cells, suggesting that the SARS- different target populations. This includes the possibility of using 2-S protein was readily translocated to the plasma membrane heterologous immunization strategies depending on an individ- (Fig. 2A). ual’s health status, boosting capacities, and the need for balanced To examine the MVA-produced recombinant S protein in more humoral and Th1-directed cellular immune responses. detail, we prepared total lysates from MVA-SARS-2-S–infected MVA, a highly attenuated strain of vaccinia virus originating chicken embryonic fibroblasts (CEFs) or Vero cells for separation from growth selection on chicken embryo tissue cultures, shows a by SDS-PAGE and subsequent immunoblot analysis (Fig. 2). The characteristic replication defect in mammalian cells but allows mouse monoclonal antibody directed against the HA-tag at the C unimpaired production of heterologous proteins (19). At present, terminus of the recombinant SARS-2-S protein revealed two prom- MVA serves as an advanced vaccine technology platform for de- inent protein bands that migrated with molecular masses of ∼190 and veloping new vector vaccines against infectious disease including 90–100 kDa (Fig. 2B). As in the SDS-PAGE the detected protein emerging viruses and cancer (20). In response to the ongoing pan- bands migrated at molecular masses significantly higher than the demic, the MVA vector vaccine platform allows rapid generation of 145 kDa predicted for full-length SARS-CoV-2-S protein based experimental SARS-CoV-2–specific vaccines (21). Previous work on its amino acid sequence, we hypothesized that the proteins from our laboratory addressed the development of an MVA can- might be glycosylated.
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