Safety and immunogenicity of LC16m8, an attenuated smallpox vaccine in vaccinia-naive adults

Jeffrey S Kennedy, Marc Gurwith, Cornelia L Dekker, Sharon E Frey, Kathryn M Edwards, Julie Kenner, Michael Lock, Cyril Empig, Shigeru Morikawa, Masayuki Saijo, Hiroyuki Yokote, Kevin Karem, Inger Damon, Mark Perlroth, Richard N Greenberg, Jeffrey S Kennedy, Marc Gurwith, Cornelia L Dekker, Sharon E Frey, Kathryn M Edwards, Julie Kenner, Michael Lock, Cyril Empig, Shigeru Morikawa, Masayuki Saijo, Hiroyuki Yokote, Kevin Karem, Inger Damon, Mark Perlroth, Richard N Greenberg

Abstract

Introduction: LC16m8 is an attenuated cell culture-adapted Lister vaccinia smallpox vaccine missing the B5R protein and licensed for use in Japan.

Methods: We conducted a phase I/II clinical trial that compared the safety and immunogenicity of LC16m8 with Dryvax in vaccinia-naive participants. Adverse events were assessed, as were electrocardiography and laboratory testing for cardiotoxicity and viral culturing of the vaccination sites. Neutralization titers to vaccinia, monkeypox, and variola major were assessed and cell-mediated immune responses were measured by interferon (IFN)-γ enzyme-linked immunosorbent spot and lymphoproliferation assays.

Results: Local and systemic reactions after vaccination with LC16m8 were similar to those reported after Dryvax. No clinically significant abnormalities consistent with cardiac toxicity were seen for either vaccine. Both vaccines achieved antivaccinia, antivariola, and antimonkeypox neutralizing antibody titers >1:40, although the mean plaque reduction neutralization titer of LC16m8 at day 30 after vaccination was significantly lower than Dryvax for anti-NYCBH vaccinia (P < .01), antimonkeypox (P < .001), and antivariola (P < .001). LC16m8 produced robust cellular immune responses that trended higher than Dryvax for lymphoproliferation (P = .06), but lower for IFN-γ ELISPOT (P = .02).

Conclusions: LC16m8 generates neutralizing antibody titers to multiple poxviruses, including vaccinia, monkeypox, and variola major, and broad T-cell responses, indicating that LC16m8 may have efficacy in protecting individuals from smallpox. Clinical Trials Registration. NCT00103584.

Figures

Figure 1.
Figure 1.
Study flow diagram. CMI, cell-mediated immune; NYCBH, New York City Board of Health; PRNT, plaque reduction neutralization titer.
Figure 2.
Figure 2.
Anti-Dryvax (Focus) plaque reduction neutralization titer (PRNT) response by day and vaccine. The first 50 volunteers were enrolled (41 LC16m8 and 9 Dryvax vacinees); a subset of 4 Dryvax nonseroconverters was not included. P values at timepoints are noted to reflect level of significance for differences between groups. Abbreviations: CI, confidence interval; GMT, geometric mean titer.
Figure 3.
Figure 3.
Comparison of interferon (IFN)–γ enzyme-linked immunosorbent spot and lymphoproliferation assay responses following vaccination with Dryvax versus LC16m8. A, Geometric mean number of IFN-γ–producing cells by vaccine and time from vaccination. B, Lymphocyte proliferation: geometric mean stimulation index by vaccine and time from vaccination. Abbreviations: CI, confidence interval; GM, geometric mean; IFN, interferon; PBMC, peripheral blood mononuclear cell.

References

    1. Greenberg RN, Kennedy JS. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008;17:555–64.
    1. Kennedy JS, Greenberg RN. IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev Vaccines. 2009;8:13–24.
    1. Kenner J, Cameron F, Empig C, Jobes DV, Gurwith M. LC16m8: an attenuated smallpox vaccine. Vaccine. 2006;24:7009–22.
    1. Meseda CA, Mayer AE, Kumar A, et al. Comparative evaluation of the immune responses and protection engendered by LC16m8 and Dryvax smallpox vaccines in a mouse model. Clin Vaccine Immunol. 2009;16:1261–71.
    1. Hashizume S Chiba Serum Institute. Special edition future of vaccination: everything about attenuated vaccines. Basics of new attenuated vaccine strain LC16m8. Clin Virus. 1975;3:229–35.
    1. Hirayama M. In search of attenuated vaccine. Clinical special edition: vaccination in future—everything about attenuated vaccine. Clin Virus. 1975;3:269–79.
    1. Saito T, Fujii T, Kanatani Y, et al. Clinical and immunological response to attenuated tissue-cultured smallpox vaccine LC16m8. JAMA. 2009;301:1025–33.
    1. Newman FK, Frey SE, Blevins TP, et al. Improved assay to detect neutralizing antibody following vaccination with diluted or undiluted vaccinia (Dryvax) vaccine. J Clin Microbiol. 2003;41:3154–7.
    1. Bell E, Shamim M, Whitbeck JC, Sfyroera G, Lambris JD, Isaacs SN. Antibodies against the extracellular enveloped virus B5R protein are mainly responsible for the EEV neutralizing capacity of vaccinia immune globulin. Virology. 2004;325:425–31.
    1. Viner KM, Isaacs SN. Activity of vaccinia virus-neutralizing antibody in the sera of smallpox vaccinees. Microbes Infect. 2005;7:579–83.
    1. Damon IK, Davidson WB, Hughes CM, et al. Evaluation of smallpox vaccines using variola neutralization. J Gen Virol. 2009;90:1962–6.
    1. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265–74.
    1. Military Vaccine Agency, Army Medical Command, U.S. Dept of Defense. National Immunization Program, CDC. Cardiac adverse events following smallpox vaccination–United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:248–50.
    1. Artenstein AW, Grabenstein JD. Smallpox vaccines for biodefense: need and feasibility. Expert Rev Vaccines. 2008;7:1225–37.
    1. Engelstad M, Howard ST, Smith GL. A constitutively expressed vaccinia gene encodes a 42-kDa glycoprotein related to complement control factors that forms part of the extracellular virus envelope. Virology. 1992;188:801–10.
    1. Empig C, Kenner JR, Perret-Gentil M, et al. Highly attenuated smallpox vaccine protects rabbits and mice against pathogenic orthopoxvirus challenge. Vaccine. 2006;24:3686–94.
    1. Midgley CM, Putz MM, Weber JN, Smith GL. Vaccinia virus strain NYVAC induces substantially lower and qualitatively different human antibody responses compared with strains Lister and Dryvax. J Gen Virol. 2008;89:2992–7.
    1. Benhnia MR, McCausland MM, Su HP, et al. Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine. J Virol. 2008;82:3751–68.
    1. Saijo M, Ami Y, Suzaki Y, et al. LC16m8, a highly attenuated vaccinia virus vaccine lacking expression of the membrane protein B5R, protects monkeys from monkeypox. J Virol. 2006;80:5179–88.
    1. Casey CG, Iskander JK, Roper MH, et al. Adverse events associated with smallpox vaccination in the United States, January–October 2003. JAMA. 2005;294:2734–43.
    1. Morgan J, Roper MH, Sperling L, et al. Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January–October 2003. Clin Infect Dis. 2008;46(Suppl 3):S242–50.
    1. Mack TM, Noble J, Jr, Thomas DB. A prospective study of serum antibody and protection against smallpox. Am J Trop Med Hyg. 1972;21:214–8.
    1. Sarkar JK, Mitra AC, Mukherjee MK. The minimum protective level of antibodies in smallpox. Bull World Health Organ. 1975;52:307–11.
    1. Sirven P, Castelli FA, Probst A, Szely N, Maillere B. In vitro human CD4+ T cell response to the vaccinia protective antigens B5R and A33R. Mol Immunol. 2009;46:1481–7.
    1. Tang J, Murtadha M, Schnell M, Eisenlohr LC, Hooper J, Flomenberg P. Human T-cell responses to vaccinia virus envelope proteins. J Virol. 2006;80:10010–20.
    1. Gordon SN, Cecchinato V, Andresen V, et al. Smallpox vaccine safety is dependent on T cells and not B cells. J Infect Dis. 2011;203:1043–53.
    1. Weinzierl AO, Rudolf D, Maurer D, et al. Identification of HLA-A*01- and HLA-A*02-restricted CD8+ T-cell epitopes shared among group B enteroviruses. J Gen Virol. 2008;89:2090–7.
    1. Yue Y, Gui J, Xu W, Xiong S. Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization. Mol Immunol. 2011;48:706–13.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa