Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review

Marnie L Elizaga, Sandhya Vasan, Mary A Marovich, Alicia H Sato, Dale N Lawrence, Bernard R Chaitman, Sharon E Frey, Michael C Keefer, MVA Cardiac Safety Working Group, David D Ho, Sarah J Schlesinger, Paul Chaplin, Robert Johnson, Artur Kalichman, Ann Duerr, Julie McElrath, Li Qin, Molly Swenson, Lindsey Baden, Massimo Cardinali, Phumla Adesanya, Patricia Fast, Arlene Hurley, Claudia Schmidt, Soe Than, Viseth Ngauy, Bonnie Slike, Lei Zhu, Geoffrey Gorse, Gwendolyn Pendleton, Karen Stocke, Janice Tennant, Jonathan Fuchs, Paul Goepfert, Paulo Barroso, William Blattner, Mhorag Hay, Catherine Bunce, Spyros Kalams, Marnie L Elizaga, Sandhya Vasan, Mary A Marovich, Alicia H Sato, Dale N Lawrence, Bernard R Chaitman, Sharon E Frey, Michael C Keefer, MVA Cardiac Safety Working Group, David D Ho, Sarah J Schlesinger, Paul Chaplin, Robert Johnson, Artur Kalichman, Ann Duerr, Julie McElrath, Li Qin, Molly Swenson, Lindsey Baden, Massimo Cardinali, Phumla Adesanya, Patricia Fast, Arlene Hurley, Claudia Schmidt, Soe Than, Viseth Ngauy, Bonnie Slike, Lei Zhu, Geoffrey Gorse, Gwendolyn Pendleton, Karen Stocke, Janice Tennant, Jonathan Fuchs, Paul Goepfert, Paulo Barroso, William Blattner, Mhorag Hay, Catherine Bunce, Spyros Kalams

Abstract

Background: Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines.

Methods: Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine.

Results: Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine.

Conclusions: Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.

Trial registration: ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Overview of clinical trial designs.
Figure 1. Overview of clinical trial designs.
Schema for each of the 6 clinical trials with prospective cardiac safety assessments included in this report, A) US Military HIV Research Program study [NCT00376090] , B) National Institutes of Health Division of Microbiology and Infectious Disease/St. Louis University study [NCT00082446] , C) Aaron Diamond AIDS Research Center/International AIDS Vaccine Initiative study [NCT00252148] , D) HIV Vaccine Trials Network 055 study [NCT00083603] , E) HIV Vaccine Trials Network 065 study [NCT00301184] , and F) HIV Vaccine Trials Network 067 study [NCT00428337] . ‘Arrows’ indicate time of vaccination; ‘X’ indicates time of routine ECGs; ‘N’ indicates total number of study participants included in this analysis; ‘A:P’ indicates ratio of participants who received active vaccination (A) to placebo (P).
Figure 2. Participant Flow.
Figure 2. Participant Flow.
Flow diagram of participants screened, enrolled and followed with prospective cardiac safety assessments among the 6 trials included in this report. ‘MVA’ indicates MVA alone or an MVA-HIV recombinant candidate vaccine, whereas ‘Placebo’ was a buffered sterile saline solution.

References

    1. Mayr A, Hochstein-Mintzel V, Stickl H (1975) Passage history, properties and use of the attenuated vaccinia virus strain Ankara. Infection 3: 6–14 (in German)..
    1. Stickl H, Hochstein-Mintzel V, Mayr A, Huber HC, Schafer H, et al. (1974) MVA vaccination against smallpox: clinical trials of an attenuated live vaccinia virus strain (MVA). Dtsch Med Wochenschr 99: 2386–92 (in German)..
    1. Mayr A, Danner K (1978) Vaccination against pox diseases under immunosuppressive conditions. Dev Biol Stand 41: 225–34.
    1. Fenner F, Henderson DA, Arita I, Jezek Z and Ladnyi ID (1988) History of International Public Health: smallpox and its eradication. Geneva: World Health Organization.
    1. Neff JM, Lane JM, Pert JH, Moore R, Millar JD, et al. (1967) Complications of smallpox vaccination*, I. National survey in the United States, 1963. N Eng J Med 276(3): 125–32.
    1. Morgan J, Roper MH, Sperling L, Schieber RA, Heffelfinger JD, et al. (2008) Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January-October 2003. Clin Infect Dis 46: S242–50.
    1. Mackett M, Smith GL, Moss B (1982) Vaccinia virus: a selectable eukaryotic cloning and expression vector. Proc Natl Acad Sci USA 79: 7415–9.
    1. Zagury D, Bernard J, Cheynier R, Desportes I, Leonard R, et al. (1988) A group specific anamnestic immune reaction against HIV-1 induced by a candidate vaccine against AIDS. Nature 332: 728–31.
    1. Wallack MK, McNally K, Michaelides M, Bash J, Bartolucci A, et al. (1986) A phase I-II SECSG (Southeastern Cancer Study Group) pilot study of surgical adjuvant immunotherapy with vaccinia-melanoma oncolysates (VMO). Am Surg 52: 148–51.
    1. McCurdy LH, Larkin BD, Martin JE, Graham BS (2004) Modified vaccinia Ankara: potential as an alternative smallpox vaccine. Clin Infect Dis 38: 1749–53.
    1. Frey SE, Newman FK, Kennedy JS, Sobek V, Ennis FA, et al. (2007) Clinical and immunologic responses to multiple doses of IMVAMUNE (modified vaccinia Ankara) followed by Dryvax challenge. Vaccine 25: 8562–73.
    1. Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, et al. (2004) A human immunodediciency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 85: 911–19.
    1. Bart PA, Goodall R, Barber T, Harari A, Guimaraes-Walker A, et al. (2008) EV01: a phase I trial in healthy HIV negative volunteers to evaluate a clade C HIV vaccine, NYVAC-C undertaken by the EuroVacc Consortium. Vaccine 26: 3153–61.
    1. Pialoux G, Excler JL, Riviere Y, Gonzalez-Canali G, Feuillie V, et al. (1995) A prime-boost approach to HIV prevent vaccine using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein 160 (MN/LAI). AIDS Res Hum Retroviruses 11: 373–81.
    1. Moorthy VS, Imoukhuede EB, Keating S, Pinder M, Webster D, et al. (2004) Phase 1 evaluation of 3 highly immunogenic prime-boost regimens, including a 12-month reboosting vaccination, for malaria vaccination in Gambian men. J Infect Dis 189: 2213–9.
    1. McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, et al. (2004) Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 10: 1240–4.
    1. Poland GA, Grabenstein JD, Neff JM (2005) The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program. Vaccine 23: 2078–81.
    1. US Department of Defense, Smallpox Vaccination Program (2012) Available: .Accessed 2012 Jun.
    1. Casey CG, Iskander JK, Roper MH, Mast EE, Wen XJ, et al. (2005) Adverse events associated with smallpox vaccination in the United States, January-October 2003. JAMA 294: 2734–43.
    1. Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, et al. (2003) Myopericarditis following smallpox vaccination among vaccinia-naïve US military personnel. JAMA 289: 3283–9.
    1. Eckart RE, Love SS, Atwood JE, Arness MK, Cassimatis DC, et al. (2004) Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination. J Am Col Cardiol 44: 201–5.
    1. CDC (2003) Cardiac adverse events following smallpox vaccination–United States, 2003. MMWR 52: 248–50.
    1. Acambis Inc. (2007) ACAM2000 Smallpox vaccine: Vaccines and Related Biological Products Advisory Committee [VRBPAC] Briefing Document.
    1. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, et al. (2004) Smallpox vaccination and myopericarditis: a clinical review. J Am Coll Cardiol 43: 1503–10.
    1. Carroll MW, Moss B (1997) Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia virus: propagation and generation of recombinant viruses in a nonhuman mammalian cell line. Virology 238: 198–211.
    1. Stittelaar KJ, Kuiken T, de Swart RL, van Amerongen G, Vos HW, et al. (2001) Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques. Vaccine 19: 3700–9.
    1. Keefer MC, Frey SE, Elizaga M, Metch B, DeRosa SC, et al. (2011) A phase I trial of preventive HIV vaccination with heterologous poxviral-vectors containing matching HIV-1 inserts in healthy HIV-uninfected subjects. Vaccine 29: 1948–1958.
    1. Goepfert PA, Elizaga ML, Sato A, Qin L, Cardinali M, et al. (2011) Phase I safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J Infect Dis 203: 610–9.
    1. Gorse GJ, Newman MJ, deCamp A, Hay CM, DeRosa SC, et al... (2012) DNA and Modified Vaccinia Ankara (MVA) Human Immunodeficiency Virus Type 1(HIV-1) Vaccines Encoding Multiple Cytotoxic and Helper T-Lymphocyte Epitopes Are Safe But Weakly Immunogenic in HIV-1-Uninfected, Vaccinia-Naive Adults. Clin Vaccine Immunol.
    1. Currier JR, Ngauy V, de Souza MS, Ratto-Kim S, Cox JH, et al. (2010) Phase I safety and immunogenicity evaluation of MVA-CMDR, a multigenic, recombinant modified vaccinia Ankara-HIV-1 vaccine candidate. PLoS One 5: e13983.
    1. Vasan S, Schlesinger SJ, Chen Z, Hurley A, Lombardo A, et al. (2010) Phase I safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1 B’/C candidate vaccine. PLoS One 5: e8816.
    1. CDC (2003) Update: Cardiac-related events during the civilian smallpox vaccination program – United States, 2003. MMWR 52: 492–6.
    1. Sano J, Chaitman BR, Swindle J, Frey SE (2009) Electrocardiography screening for cardiotoxicity after modified vaccinia Ankara vaccination. Am J Med 122: 79–84.
    1. Fortescue EB, Shin AY, Greenes DS, Mannix RC, Agarwal S, et al. (2007) Cardiac troponin increases among runners in the Boston Marathon. Ann Emerg Med 49: 137–43.
    1. Parrino J, McCurdy LH, Larkin BD, Gordon IJ, Rucker SE, et al. (2007) Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals. Vaccine 25: 1513–25.
    1. McCormack S, Stohr W, Barber T, Bart P-A, Harari A, et al. (2008) EV02: A phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to NYVAC-C alone. Vaccine 26: 3162–74.
    1. Peters BS, Jaoko W, Vardas E, Panayotakopoulos G, Fast P, et al. (2007) Studies of a prophylactic HIV-1 vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity. Vaccine 25: 2120–7.
    1. Guimaraes-Walker A, Mackie N, McCormack S, Hanke T, Schmidt C, et al. (2008) Lessons from IAVI-006, a phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers. Vaccine 26: 6671–7.
    1. Jaoko W, Nakwagala FN, Anzala O, Manyonyi GO, Birungi J, et al. (2008) Safety and immunogenicity of recombinant low-dosage HIV-1 A vaccine candidates vectored by plasmid pTHr DNA or modified vaccinia virus Ankara (MVA) in humans in East Africa. Vaccine 26: 2788–95.
    1. Ramanathan VD, Kumar M, Mahalingam J, Sathyamoorthy P, Narayanan PR, et al. (2009) A phase 1 study to evaluate the safety and immunogenicity of a recombinant HIV type-1 subtype C modified vaccinia Ankara virus vaccine candidate in Indian volunteers. AIDS Res Hum Retroviruses 25: 1107–16.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner