Modified Vaccinia Virus Ankara-Based Vaccines: Comparison
Please note this is a comparison between Version 2 by Sirius Huang and Version 3 by Sirius Huang.

Modified vaccinia virus Ankara (MVA) is a promising viral vector for vaccine development. MVA is well studied and has been widely used for vaccination against smallpox in Germany. 

  • viral vector vaccines
  • poxvirus
  • smallpox vaccine
  • vaccine development

1. Introduction

In recent years, viral vectors have become widely used in the development of new vaccines. This is due, first, to the high immunogenicity of these vectors, which mimic a natural infection and thus effectively stimulate two main arms of the adaptive immune response, as well as cell-mediated immunity. Another important factor is the high safety of viral vector vaccines compared to live attenuated vaccines. The most widely used viral vectors are derived from adenovirus, vaccinia virus, measles virus, herpes virus, and vesicular stomatitis virus. Among them, the vaccinia virus (VACV) is the only virus that was not originally a human pathogen. On the contrary, it became the first vaccine in human history directed against the smallpox virus. It is thanks to the massive worldwide vaccination with VACV that smallpox was eradicated. Studies of VACV led to the production of new strains, one of which, modified vaccinia virus Ankara (MVA), has been widely used as a vaccine vector since, along with the high immunogenicity typical of VACV, it had a high level of safety. 

2. History of the Origin of the Vaccinia Strain MVA and Its Properties

Until the 1960s, strains of VACV, which varied greatly in their biological properties, were used in different countries for smallpox vaccination [1]. The first strains of VACV were named after the health care institution, country, or area of origin. The most widely used strains are shown in Table 1 which was adapted from Sanchez-Sampredo et al [2]. Detailed information about the history of smallpox and the origin of VACV can be found in the study by Kaynarcalidan et al. [3].
Table 1. List of the first VACV strains used for vaccination [2].
For the preparation of the first-generation vaccine, a live virus produced on the skin of calves was used [4], so there was a high probability of microbial contamination of the preparations. In addition, such vaccines contained animal proteins, which often caused allergies in patients. Later, the cultivation of vaccine strains began to be carried out on the chorioallantoic membrane of chicken embryos or in various cell lines. This method led to the emergence of second-generation vaccines [2].
Numerous studies have shown that the use of cell cultures to grow viruses allowed for better control of vaccine production. This led to the stable production of the virus and an increase in the purity of the vaccine preparation due to the elimination of contamination by bacteria and animal proteins. However, the frequency of side effects that are characteristic of viral infections (e.g., fever, headache, malaise, and muscle aches) remained high with the second-generation vaccines. In addition, in rare cases, severe side effects such as post-vaccination encephalitis, myocarditis, and pericarditis, which required hospitalization and could lead to death, were observed [2][5][6]. Given the poor safety profile of the second-generation VACV vaccines, efforts have been made to improve their safety, leading to the third-generation vaccines [7].
Multiple passaging of the parental vaccine strain has been used to generate random mutations and deletions, which in turn have led to the attenuation of VACV and the emergence of new strains such as Lister-16m8 (LC16m8) [8], Dairen I (DIs) [9], M65 and M101 [10], NYVAC [11], ACAM3000 [4], and modified vaccinia virus Ankara (MVA) [12]. The origins of these strains and their genetic features are described in detail in the review by Kaynarcalidan et al. [3]. Of all the strains, only MVA and NYVAC are unable to replicate in human cells [13].
MVA was developed by Anton Mayr and Eberhard Munz in the 1960s as a result of sequential infection of primary chicken embryo fibroblasts (PEFs) with the chorioallantois VACV Ankara (CVA) vaccine strain, which was used for smallpox vaccination in Turkey and Germany [14]. After 516 passages, a highly attenuated laboratory virus was obtained and given the name MVA. The new virus differed from the parental CVA by the phenotype of the virus-infected chicken embryo cells. As a result of CVA infection, the fusion of squamous cells occurred, and continuous lysis was observed. In the case of MVA infection, infected cells took on a spherical shape, and the formation of individual plaques (limited areas with lysed cells) was observed. Most importantly, during the process of attenuation, MVA completely lost its ability to replicate in mammalian cells (with the exception of the Syrian hamster fibroblast cell line (BHK-21)) [2][15][16]. It is the inability to replicate in mammalian cells that distinguishes MVA from the other third-generation vaccinia strains; thus, MVA is currently considered one of the safest strains of the vaccinia virus.
Genomic studies have shown that the parental CVA strain lost approximately 15% of its genome [12], reducing the genome length from 208 kb in CVA to 177 kb in MVA [17]. Six large genomic deletions were identified, ranging in length from 2.6 kb to 10.2 kb, as well as many shorter deletions, insertions, and point mutations, leading to fragmentation, truncation, or deletion of open reading frames (ORFs) (Figure 1) [18]. As a result of these modifications, MVA ceased to encode many virulence factors, including factors that suppress the immune response to the vaccinia virus, such as viral receptors for γ-interferon, α/β interferons, and CC chemokines [19].
Figure 1. Generation of MVA strain from CVA strain. Location of the major deletion sites.
In 2019 [20] and 2020 [21], restoration of the C12L and C16L/B22R genes was identified as necessary to restore the ability of MVA to productively infect mammalian cells. The functions of these genes have not yet been studied enough, but it is known that they affect the synthesis and processing of the late structural proteins of the virus. In the absence of these genes in human and other mammalian cells, the virus replicates its DNA and has undisturbed expression of early and intermediate genes, as well as of most of the late genes, but further development is blocked at the stage of virion assembly [18], which makes it impossible to form infectious progeny [22][23][24][25].

3. Safety of Smallpox Vaccines Based on the MVA Strain

A smallpox vaccine based on the MVA strain was first used in Germany in 1977. Due to its high safety profile, it was used for children, the elderly, and people with weakened immune systems [1][26]. In just a few years, more than 120,000 people were vaccinated.
Vaccinated patients experienced mild local reactions, such as redness at the injection site, but did not develop blisters, pustules, or ulcers, as was observed with the second-generation smallpox vaccines [27][28][29][30]. In 2.3% of cases, vaccination caused a fever, and in 4.1% of cases, it led to the development of other non-specific systemic reactions [26], but no severe side effects were detected. Since vaccination was carried out at a time when smallpox was no longer present in Germany, its effectiveness remained unexplored [31].
Another smallpox vaccine based on the MVA strain, MVA-BN (V00083008), was licensed by the European Medicines Agency in 2013 under the brand name IMVAMUNE and by the US Food and Drug Administration (FDA) in 2019 under the brand name Jynneos [32]. According to several clinical studies in immunocompromised people, including those with atopic dermatitis or HIV infection, the MVA-BN vaccine has been shown to be completely safe and highly immunogenic [33][34][35][36][37]. The vaccine was recommended in the US and Canada in 2022 to prevent monkeypox [38]. These authorizations were based on the results obtained in the study by Earl et al. [39]. This work showed that two vaccinations with MVA-BN completely protect cynomolgus monkeys from a lethal monkeypox infection.
One of the most serious complications when using the first- and second-generation smallpox vaccines was neurotoxicity. The frequency of post-vaccination encephalitis varied depending on the vaccine strain. In the past, the heavily used Lister and Dryvax® vaccines averaged 2.6 and 2.9 cases of vaccinal encephalitis per million doses, respectively [40][41]. Although the incidence of encephalitis after vaccination was extremely low, a quarter of these cases ended in death, and in another quarter, irreversible neurological disorders developed [5][42][43][44]. No cases of neurotoxicity were recorded with third-generation LC16m8 or MVA vaccines [45]. Animal studies have also demonstrated that intracerebral inoculation of MVA does not lead to encephalitis, and, moreover, immunization with MVA prevents the risk of developing encephalitis after vaccination with a replication-competent vaccine [16][46][47].
The most commonly reported severe adverse events with the first- and second-generation smallpox vaccines were myocarditis and pericarditis, which occurred at a rate of 120 cases per million [48][49][50]. The MVA strain vaccine has not been shown to increase the risk of myo- or pericarditis [36][51][52].
Moreover, preliminary vaccination with MVA has been shown to be able to attenuate skin lesions caused by the first-generation Dryvax vaccine based on the replication-competent vaccinia strain NYCBOH.
It was further shown that the safety of the MVA virus depends on its homogeneity. MVA obtained by Mayr [15] has long been considered incapable of replication in mammalian cells [12][23]. However, in 2009, new data showed that at least some MVA strains deposited in different collections, such as MVA-572 (ECACC), MVA-I721 (National Collection of Cultures of Microorganisms, CNCM, Pasteur Institute Paris), MVA VR-1508 (ATCC), are heterogeneous and contain virus variants that can replicate in human cell lines and even cause lethality in immunodeficient mice [28][53][54]. At the same time, it was shown that the MVA-BN strain, obtained as a result of six rounds of purification of the MVA-584 strain by the selection of individual plaques (viral clones), was not able to replicate in any of the human cell lines considered in the study or in mice with suppressed immunity [53]. The obtained data indicate the need for a careful assessment of the homogeneity of those strains that are planned for use in clinical practice.
Furthermore, there were concerns about the possible restoration of MVA replication as a result of its recombination with circulating orthopoxviruses in vivo, for example, when vaccinating animals. This situation was simulated in vitro by infecting cells permissive to MVA with replication-competent Norwegian vaccinia strain No-H1 simultaneously with MVA [55]. A hybrid MVA that could propagate in human cells could only be obtained by infecting the cell line with high doses of both viruses (multiplicity of infection = 5), an extremely unlikely event in vivo. It should be noted that no occurrence of a replication-competent MVA strain has been reported in any preclinical or clinical study [56].

4. Recombinant Vaccines Based on MVA

In addition to being used as a smallpox vaccine, the MVA virus can also serve as a vector for vaccines against other pathogens. MVA is considered a promising viral vector due to its ability to incorporate up to 25 kb of foreign DNA into its genome, to express a wide range of transgenes with correct post-translational modification, due to its high immunogenicity in vivo [57][58], and also because of its safety profile.
To date, a large number of candidate vaccines have been developed based on the MVA vector, including vaccines against HIV [59][60], tuberculosis [61], malaria [62][63][64], Ebola [65][66][67][68][69], RSV [70][71], MERS [72], CMV [73], and influenza [74][75][76], which are being studied in the late stages of clinical trials. Significantly more candidate vaccines against a variety of other human diseases appear in preclinical studies [2][18][77]. MVA is also an attractive and efficient viral vector for the development of recombinant veterinary vaccines [78][79][80][81][82][83][84][85][86][87].

References

  1. Fenner, F.; Henderson, D.A.; Arita, I.; Jezek, Z.; Ladnyi, I.D. Smallpox and Its Erradication; World Health Organization: Geneva, Switzerland, 1988; pp. 1–1460.
  2. Sánchez-Sampedro, L.; Perdiguero, B.; Mejías-Pérez, E.; García-Arriaza, J.; Di Pilato, M.; Esteban, M. The evolution of pox-virus vaccines. Viruses 2015, 7, 1726–1803.
  3. Kaynarcalidan, O.; Mascaraque, S.M.; Drexler, I. Vaccinia Virus: From Crude Smallpox Vaccines to Elaborate Viral Vector Vaccine Design. Biomedicines 2021, 9, 1780.
  4. Orenstein, W.; Offit, P.; Edwards, K.M.; Plotkin, S. Plotkin’s Vaccines, 7th ed.; Elsevier: Amsterdam, The Netherlands, 2017.
  5. Belongia, E.A.; Naleway, A.L. Smallpox Vaccine: The Good, the Bad, and the Ugly. Clin. Med. Res. 2003, 1, 87–92.
  6. Kennedy, R.B.; Ovsyannikova, I.; Poland, G.A. Smallpox vaccines for biodefense. Vaccine 2009, 27, D73–D79.
  7. Jacobs, B.L.; Langland, J.O.; Kibler, K.V.; Denzler, K.L.; White, S.D.; Holechek, S.A.; Wong, S.; Huynh, T.; Baskin, C.R. Vaccinia virus vaccines: Past, present and future. Antivir. Res. 2009, 84, 1–13.
  8. Kenner, J.; Cameron, F.; Empig, C.; Jobes, D.V.; Gurwith, M. LC16m8: An attenuated smallpox vaccine. Vaccine 2006, 24, 7009–7022.
  9. Tagaya, I.; Kitamura, T.; Sano, Y. A New Mutant of Dermovaccinia Virus. Nature 1961, 192, 381–382.
  10. Sánchez-Sampedro, L.; Gómez, C.E.; Mejías-Pérez, E.; Pérez-Jiménez, E.; Oliveros, J.C.; Esteban, M. Attenuated and replica-tion-competent vaccinia virus strains M65 and M101 with distinct biology and immunogenicity as potential vaccine candidates against pathogens. J. Virol. 2013, 87, 6955–6974.
  11. Tartaglia, J.; Perkus, M.E.; Taylor, J.; Norton, E.K.; Audonnet, J.-C.; Cox, W.I.; Davis, S.W.; Van Der Hoeven, J.; Meignier, B.; Riviere, M.; et al. NYVAC: A highly attenuated strain of vaccinia virus. Virology 1992, 188, 217–232.
  12. Meyer, H.; Sutter, G.; Mayr, A. Mapping of deletions in the genome of the highly attenuated vaccinia virus MVA and their influence on virulence. J. Gen. Virol. 1991, 72, 1031–1038.
  13. Nájera, J.L.; Gomez, C.E.; Domingo-Gil, E.; Gherardi, M.M.; Esteban, M. Cellular and Biochemical Differences between Two Attenuated Poxvirus Vaccine Candidates (MVA and NYVAC) and Role of the C7L Gene. J. Virol. 2006, 80, 6033–6047.
  14. Mayr, A.; Munz, E. Changes in the vaccinia virus through continuing passages in chick embryo fibroblast cultures. Zent. Bakteriol Orig 1964, 195, 24–35.
  15. Mayr, A.; Hochstein-Mintzel, V.; Stickl, H. Passage history, properties and applicability of the attenuated vaccinia virus strain MVA. Infection 1975, 3, 6–14.
  16. Mayr, A.; Stickl, H.; Müller, H.K.; Danner, K.; Singer, H. The smallpox vaccination strain MVA: Marker, genetic structure, experience gained with the parenteral vaccination and behavior in organisms with a debilitated defence mechanism. Hyg. Betr. Prav. Med. 1978, 167, 375–390.
  17. Antoine, G.; Scheiflinger, F.; Dorner, F.; Falkner, F. The complete genomic sequence of the modified vaccinia ankara strain: Comparison with other orthopoxviruses. Virology 1998, 244, 365–396.
  18. Volz, A.; Sutter, G. Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development. Adv. Virus Res. 2017, 97, 187–243.
  19. Blanchard, T.J.; Andrea, P.; Alcami, A.; Smith, G.L. Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: Implications for use as a human vaccine. J. Gen. Virol. 1998, 79, 1159–1167.
  20. Liu, R.; Mendez-Rios, J.D.; Peng, C.; Xiao, W.; Weisberg, A.S.; Wyatt, L.S.; Moss, B. SPI-1 is a missing host-range factor re-quired for replication of the attenuated modified vaccinia Ankara (MVA) vaccine vector in human cells. PLoS Pathog 2019, 15, e1007710.
  21. Peng, C.; Moss, B. Repair of a previously uncharacterized second host-range gene contributes to full replication of modified vaccinia virus Ankara (MVA) in human cells. Proc. Natl. Acad. Sci. USA 2020, 117, 3759–3767.
  22. Sutter, G.; Moss, B. Nonreplicating vaccinia vector efficiently expresses recombinant genes. Proc. Natl. Acad. Sci. USA 1992, 89, 10847–10851.
  23. Carroll, M.W.; Moss, B. Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia virus: Propaga-tion and generation of recombinant viruses in a nonhuman mammalian cell line. Virology 1997, 238, 198–211.
  24. Drexler, I.; Wahren, B.; Sutter, G.; Heller, K.; Erfle, V. Highly attenuated modified vaccinia virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but not in various human transformed and primary cells. J. Gen. Virol. 1998, 79, 347–352.
  25. Okeke, M.I.; Nilssen, Ø.; Traavik, T. Modified vaccinia virus Ankara multiplies in rat IEC-6 cells and limited production of mature virions occurs in other mammalian cell lines. J. Gen. Virol. 2006, 87, 21–27.
  26. Meyer, H. Summary Report on First, Second and Third Generation Smallpox Vaccines; World Health Organization: Geneva, Switzerland, 2013.
  27. Frey, S.E.; Newman, F.K.; Kennedy, J.S.; Sobek, V.; Ennis, F.A.; Hill, H.; Yan, L.K.; Chaplin, P.; Vollmar, J.; Chaitman, B.R.; et al. Clinical and immunologic responses to multiple doses of IMVAMUNE® (Modified Vaccinia Ankara) followed by Dryvax® challenge. Vaccine 2007, 25, 8562–8573.
  28. Kennedy, J.S.; Greenberg, R.N. IMVAMUNE®: Modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev. Vaccines 2009, 8, 13–24.
  29. Walsh, S.R.; Dolin, R. Vaccinia viruses: Vaccines against smallpox and vectors against infectious diseases and tumors. Expert Rev. Vaccines 2011, 10, 1221–1240.
  30. Rosenbaum, P.; Tchitchek, N.; Joly, C.; Stimmer, L.; Hocini, H.; Dereuddre-Bosquet, N.; Beignon, A.-S.; Chapon, C.; Levy, Y.; Le Grand, R.; et al. Molecular and Cellular Dynamics in the Skin, the Lymph Nodes, and the Blood of the Immune Response to Intradermal Injection of Modified Vaccinia Ankara Vaccine. Front. Immunol. 2018, 9, 870.
  31. Slifka, M.K. The Future of Smallpox Vaccination: Is MVA the key? Med. Immunol. 2005, 4, 2.
  32. FDA Approves First Live, Non-Replicating Vaccine to Prevent Smallpox and Monkeypox. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-first-live-non-replicating-vaccine-prevent-smallpox-and-monkeypox (accessed on 22 June 2022).
  33. Greenberg, R.N.; Hurley, M.Y.; Dinh, D.V.; Mraz, S.; Vera, J.G.; Von Bredow, D.; Von Krempelhuber, A.; Röesch, S.; Virgin, G.; Arndtz-Wiedemann, N.; et al. Correction: A multicenter, open-label, controlled phase II study to evaluate safety and immunogenicity of MVA smallpox vaccine (IMVAMUNE) in 18–40 year old subjects with diagnosed atopic dermatitis. PLoS ONE 2015, 10, e0142802.
  34. Overton, E.T.; Stapleton, J.; Frank, I.; Hassler, S.; Goepfert, P.A.; Barker, D.; Wagner, E.; von Krempelhuber, A.; Virgin, G.; Meyer, T.P.; et al. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Expe-rienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial. Open Forum Infect. Dis. 2015, 2, ofv040.
  35. Von Sonnenburg, F.; Perona, P.; Darsow, U.; Ring, J.; von Krempelhuber, A.; Vollmar, J.; Roesch, S.; Baedeker, N.; Kol-laritsch, H.; Chaplin, P. Safety and immunogenicity of modified vaccinia Ankara as a smallpox vaccine in people with atop-ic dermatitis. Vaccine 2014, 32, 5696–5702.
  36. Overton, E.T.; Lawrence, S.J.; Wagner, E.; Nopora, K.; Rösch, S.; Young, P.; Schmidt, D.; Kreusel, C.; De Carli, S.; Meyer, T.P.; et al. Immunogenicity and safety of three consecutive production lots of the non repli-cating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial. PLoS ONE 2018, 13, e0195897.
  37. Overton, E.T.; Lawrence, S.J.; Stapleton, J.T.; Weidenthaler, H.; Schmidt, D.; Koenen, B.; Silbernagl, G.; Nopora, K.; Chaplin, P. A randomized phase II trial to compare safety and immunogenicity of the MVA-BN smallpox vaccine at various doses in adults with a history of AIDS. Vaccine 2020, 38, 2600–2607.
  38. Rao, A.K.; Petersen, B.W.; Whitehill, F.; Razeq, J.H.; Isaacs, S.N.; Merchlinsky, M.J.; Campos-Outcalt, D.; Morgan, R.L.; Damon, I.; Sánchez, P.J.; et al. Use of JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for Preex-posure Vaccination of Persons at Risk for Occupational Exposure to Orthopoxviruses: Recommendations of the Advisory Committee on Immunization Practices—United States. Morb. Mortal. Wkly. Rep. 2022, 71, 734–742.
  39. Earl, P.L.; Americo, J.L.; Wyatt, L.S.; Eller, L.A.; Whitbeck, J.C.; Cohen, G.H.; Eisenberg, R.J.; Hartmann, C.J.; Jackson, D.L.; Kulesh, D.A.; et al. Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature 2004, 428, 182–185.
  40. Kretzschmar, M.; Wallinga, J.; Teunis, P.; Xing, S.; Mikolajczyk, R. Frequency of adverse events after vaccination with dif-ferent vaccinia strains. PLoS Med. 2006, 3, e272.
  41. Wiser, I.; Balicer, R.D.; Cohen, D. An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies. Vaccine 2007, 25, 976–984.
  42. Centers for Disease Control and Prevention (CDC). Update: Adverse events following civilian smallpox vaccination--United States. MMWR Morb. Mortal. Wkly. Rep. 2004, 53, 106–107.
  43. Gurvich, E.B.; Vilesova, I.S. Vaccinia virus in postvaccinal encephalitis. Acta Virol. 1983, 27, 154–159.
  44. Rockoff, A.; Spigland, I.; Lorenstein, B.; Rose, A.L. Postvaccinal encephalomyelitis without cutaneous vaccination reaction. Ann. Neurol. 1979, 5, 99–101.
  45. Zhang, C.X.; Sauder, C.; Malik, T.; Rubin, S.A. A mouse-based assay for the pre-clinical neurovirulence assessment of vac-cinia virus-based smallpox vaccines. Biologicals 2010, 38, 278–283.
  46. McCurdy, L.H.; Larkin, B.D.; Martin, J.E.; Graham, B.S. Modified Vaccinia Ankara: Potential as an Alternative Smallpox Vaccine. Clin. Infect. Dis. 2004, 38, 1749–1753.
  47. Werner, G.T.; Jentzsch, U.; Metzger, E.; Simon, J. Studies on poxvirus infections in irradiated animals. Arch Virol. 1980, 64, 247–256.
  48. Arness, M.K.; Eckart, R.E.; Love, S.S.; Atwood, J.E.; Wells, T.S.; Engler, R.J.M.; Collins, L.C.; Ludwig, S.L.; Riddle, J.R.; Grabenstein, J.D.; et al. Myopericarditis following Smallpox Vaccination. Am. J. Epidemiol. 2004, 160, 642–651.
  49. Elizaga, M.L.; Vasan, S.; Marovich, M.A.; Sato, A.H.; Lawrence, D.N.; Chaitman, B.R.; Frey, S.E.; Keefer, M.C. MVA cardiac safety working group prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia ankara Vaccines: A systematic review. PLoS ONE 2013, 8, e54407.
  50. Parrino, J.; Graham, B.S. Smallpox vaccines: Past, present, and future. Basic Clin. Immunol. 2006, 118, 1320–1326.
  51. Zitzmann-Roth, E.-M.; Von Sonnenburg, F.; De La Motte, S.; Arndtz-Wiedemann, N.; Von Krempelhuber, A.; Uebler, N.; Vollmar, J.; Virgin, G.; Chaplin, P. Cardiac Safety of Modified Vaccinia Ankara for Vaccination against Smallpox in a Young, Healthy Study Population. PLoS ONE 2015, 10, e0122653.
  52. Greenberg, R.N.; Hay, C.M.; Stapleton, J.T.; Marbury, T.C.; Wagner, E.; Kreitmeir, E.; Röesch, S.; Von Krempelhuber, A.; Young, P.; Nichols, R.; et al. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects. PLoS ONE 2016, 11, e0157335.
  53. Sutter, M.; Meisinger-Henschel, C.; Tzatzaris, M.; Hülsemann, V.; Lukassen, S.; Wulff, N.H.; Hausmann, J.; Howley, P.; Chaplin, P. Modified vaccinia Ankara strains with identical coding sequences actually represent complex mixtures of virus-es that determine the biological properties of each strain. Vaccine 2009, 27, 7442–7450.
  54. Okeke, M.I.; Okoli, A.S.; Diaz, D.; Offor, C.; Oludotun, T.G.; Tryland, M.; Bøhn, T.; Moens, U. Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps? Viruses 2017, 9, 318.
  55. Hansen, H.; Okeke, M.I.; Nilssen, O.; Traavik, T. Recombinant viruses obtained from co-infection in vitro with a live vac-cinia-vectored influenza vaccine and a naturally occurring cowpox virus display different plaque phenotypes and loss of the transgene. Vaccine 2004, 23, 499–506.
  56. Verheust, C.; Goossens, M.; Pauwels, K.; Breyer, D. Biosafety aspects of modified vaccinia virus Ankara (MVA)-based vec-tors used for gene therapy or vaccination. Vaccine 2012, 30, 2623–2632.
  57. Earl, P.L.; Americo, J.L.; Wyatt, L.S.; Espenshade, O.; Bassler, J.; Gong, K.; Lin, S.; Peters, E.; Rhodes Jr, L.; Spano, Y.E.; et al. Rapid protection in a monkeypox model by a single injection of a replication-deficient vaccinia virus. Proc. Natl. Acad. Sci. USA 2008, 105, 10889–10894.
  58. Guerra, S.; González, J.M.; Climent, N.; Reyburn, H.; López-Fernández, L.A.; Nájera, J.L.; Gómez, C.E.; García, F.; Gatell, J.M.; Gallart, T.; et al. Selective induction of host genes by MVA-B, a candidate vaccine against HIV/AIDS. J. Virol. 2010, 84, 8141–8152.
  59. Joachim, A.; Nilsson, C.; Aboud, S.; Bakari, M.; Lyamuya, E.F.; Robb, M.L.; Marovich, M.A.; Earl, P.; Moss, B.; Ochsenbauer, C.; et al. Potent functional antibody responses elic-ited by HIV-I DNA priming and boosting with heterologous HIV-1 recombinant MVA in healthy Tanzanian adults. PLoS ONE 2015, 10, e0118486.
  60. Nilsson, C.; Godoy-Ramirez, K.; Hejdeman, B.; Bråve, A.; Gudmundsdotter, L.; Hallengärd, D.; Currier, J.R.; Wieczorek, L.; Hasselrot, K.; Earl, P.L.; et al. Broad and po-tent cellular and humoral immune responses after a second late HIV-modified vaccinia virus ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccines. AIDS Res. Hum. Retrovir. 2014, 30, 299–311.
  61. Tameris, M.D.; Hatherill, M.; Landry, B.S.; Scriba, T.J.; Snowden, M.A.; Lockhart, S.; Shea, J.E.; McClain, J.B.; Hussey, G.D.; Hanekom, W.A.; et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previ-ously vaccinated with BCG: A randomised, placebo-controlled phase 2b trial. Lancet 2013, 381, 1021–1028.
  62. Hodgson, S.H.; Ewer, K.; Bliss, C.M.; Edwards, N.; Rampling, T.; Anagnostou, N.A.; De Barra, E.; Havelock, T.; Bowyer, G.; Poulton, I.D.; et al. Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals. J. Infect. Dis. 2014, 211, 1076–1086.
  63. Biswas, S.; Choudhary, P.; Elias, S.; Miura, K.; Milne, K.H.; De Cassan, S.C.; Collins, K.; Halstead, F.; Bliss, C.M.; Ewer, K.; et al. Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure. PLoS ONE 2014, 9, e107903.
  64. Sebastian, S.; Gilbert, S.C. Recombinant modified vaccinia virus Ankara-based malaria vaccines. Expert Rev. Vaccines 2015, 15, 91–103.
  65. Milligan, I.D.; Gibani, M.M.; Sewell, R.; Clutterbuck, E.A.; Campbell, D.; Plested, E.; Nuthall, E.; Voysey, M.; Silva-Reyes, L.; McElrath, M.J.; et al. Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA 2016, 315, 1610–1623.
  66. Tapia, M.D.; O Sow, S.; E Lyke, K.; Haidara, F.C.; Diallo, F.; Doumbia, M.; Traore, A.; Coulibaly, F.; Kodio, M.; Onwuchekwa, U.; et al. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: A phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect. Dis. 2015, 16, 31–42.
  67. Callendret, B.; Vellinga, J.; Wunderlich, K.; Rodriguez, A.; Steigerwald, R.; Dirmeier, U.; Cheminay, C.; Volkmann, A.; Bra-sel, T.; Carrion, R.; et al. A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates. PLoS ONE 2018, 13, e0192312.
  68. Wagstaffe, H.R.; Clutterbuck, E.A.; Bockstal, V.; Stoop, J.N.; Luhn, K.; Douoguih, M.J.; Shukarev, G.; Snape, M.D.; Pollard, A.J.; Riley, E.M.; et al. Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses. J. Clin. Investig. 2020, 130, 3936–3946.
  69. Fuentes, S.; Ravichandran, S.; Coyle, E.M.; Klenow, L.; Khurana, S. Human Antibody Repertoire following Ebola Virus In-fection and Vaccination. iScience 2020, 23, 100920.
  70. Sacks, D.; Baxter, B.; Campbell, B.C.V.; Carpenter, J.S.; Cognard, C.; Dippel, D.; Eesa, M.; Fischer, U.; Hausegger, K.; Hirsch, J.A.; et al. Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int. J. Stroke 2018, 13, 612–632.
  71. Jordan, E.; Lawrence, S.J.; Meyer, Y.P.H.; Schmidt, D.; Schultz, S.; Mueller, J.; Stroukova, D.; Koenen, B.; Gruenert, R.; Sil-bernagl, G.; et al. Broad Antibody and Cellular Immune Re-sponse From a Phase 2 Clinical Trial with a Novel Multivalent Poxvirus-Based Respiratory Syncytial Virus Vaccine. J. Infect. Dis. 2021, 223, 1062–1072.
  72. Koch, T.; Dahlke, C.; Fathi, A.; Kupke, A.; Krähling, V.; A Okba, N.M.; Halwe, S.; Rohde, C.; Eickmann, M.; Volz, A.; et al. Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: An open-label, phase 1 trial. Lancet Infect. Dis. 2020, 20, 827–838.
  73. Aldoss, I.; La Rosa, C.; Baden, L.R.; Longmate, J.; Ariza-Heredia, E.J.; Rida, W.N.; Lingaraju, C.R.; Zhou, Q.; Martinez, J.; Kaltcheva, T.; et al. Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients. Ann. Intern. Med. 2020, 172, 306.
  74. Kreijtz, J.H.; Goeijenbier, M.; Moesker, F.M.; van den Dries, L.; Goeijenbier, S.; De Gruyter, H.; Lehmann, M.H.; de Mutsert, G.; van de Vijver, D.; Volz, A.; et al. Safety and immu-nogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: A randomised, double-blind phase 1/2a clinical trial. Lancet Infect. Dis. 2014, 14, 1196–1207.
  75. Lillie, P.J.; Berthoud, T.K.; Powell, T.J.; Lambe, T.; Mullarkey, C.; Spencer, A.J.; Hamill, M.; Peng, Y.; Blais, M.-E.; Duncan, C.; et al. Prelimi-nary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin. Infect. Dis. 2012, 55, 19–25.
  76. Puksuriwong, S.; Ahmed, M.S.; Sharma, R.; Krishnan, M.; Leong, S.; Lambe, T.; McNamara, P.S.; Gilbert, S.C.; Zhang, Q. Modified Vaccinia Ankara–Vectored Vaccine Expressing Nucleoprotein and Matrix Protein 1 (M1) Activates Mucosal M1-Specific T-Cell Immunity and Tissue-Resident Memory T Cells in Human Nasopharynx-Associated Lymphoid Tissue. J. Infect. Dis. 2019, 222, 807–819.
  77. Volz, A.; Sutter, G. Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies. Vaccine 2013, 31, 4235–4240.
  78. Alberca, B.; Bachanek-Bankowska, K.; Cabana, M.; Calvo-Pinilla, E.; Viaplana, E.; Frost, L.; Gubbins, S.; Urniza, A.; Mertens, P.; Castillo-Olivares, J. Vaccination of horses with a recombinant modified vaccinia Ankara virus (MVA) expressing African horse sickness (AHS) virus major capsid protein VP2 provides complete clinical protection against challenge. Vaccine 2014, 32, 3670–3674.
  79. Haagmans, B.L.; van den Brand, J.; Raj, V.S.; Volz, A.; Wohlsein, P.; Smits, S.L.; Schipper, D.; Bestebroer, T.M.; Okba, N.; Fux, R.; et al. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 2016, 351, 77–81.
  80. Lopera-Madrid, J.; Osorio, J.E.; He, Y.; Xiang, Z.; Adams, L.G.; Laughlin, L.C.; Mwangi, W.; Subramanya, S.; Neilan, J.; Brake, D.; et al. Safety and immunogenicity of mammalian cell de-rived and Modified Vaccinia Ankara vectored African swine fever subunit antigens in swine. Veter Immunol. Immunopathol. 2017, 185, 20–33.
  81. Zajac, M.; Zanetti, F.A.; Esusy, M.S.; Federico, C.R.; Zabal, O.; Valera, A.R.; Calamante, G. Induction of Both Local Immune Response in Mice and Protection in a Rabbit Model by Intranasal Immunization with Modified Vaccinia Ankara Virus Ex-pressing a Secreted Form of Bovine Herpesvirus 1 Glycoprotein D. Viral Immunol. 2017, 30, 70–76.
  82. Lorenzo, G.; López-Gil, E.; Ortego, J.; Brun, A. Efficacy of different DNA and MVA prime-boost vaccination regimens against a Rift Valley fever virus (RVFV) challenge in sheep 12 weeks following vaccination. Veter Res. 2018, 49, 1–12.
  83. Volz, A.; Fux, R.; Langenmayer, M.C.; Sutter, G. Modified vaccinia virus ankara (MVA)—development as recombinant vac-cine and prospects for use in veterinary medicine. Berl. Munch Tierarztl. Wochenschr. 2015, 128, 464–472.
  84. Marín-López, A.; Barreiro-Piñeiro, N.; Utrilla-Trigo, S.; Barrialesa, D.; Benavente, J.; Nogalesa, A.; Martínez-Costas, J.; Orte-go, J.; Calvo-Pinilla, E. Cross-protective immune responses against African horse sickness virus after vaccination with pro-tein NS1 delivered by avian reovirus muNS microspheres and modified vaccinia virus Ankara. Vaccine 2020, 38, 882–889.
  85. Calvo-Pinilla, E.; Marín-López, A.; Moreno, S.; Lorenzo, G.; Utrilla-Trigo, S.; Jiménez-Cabello, L.; Benavides, J.; Nogales, A.; Blasco, R.; Brun, A.; et al. A protective bivalent vaccine against Rift Valley fever and bluetongue npj. Vaccines 2020, 5, 1–12.
  86. Prkno, A.; Hoffmann, D.; Kaiser, M.; Goerigk, D.; Pfeffer, M.; Winter, K.; Vahlenkamp, T.W.; Beer, M.; Starke, A. Field Trial Vaccination against Cowpox in Two Alpaca Herds. Viruses 2020, 12, 234.
  87. Trigo, S.U.; Jiménez-Cabello, L.; Alonso-Ravelo, R.; Calvo-Pinilla, E.; Marín-López, A.; Moreno, S.; Lorenzo, G.; Benavides, J.; Gilbert, S.; Nogales, A.; et al. Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus. Vaccines 2020, 8, 346.
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