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

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.

Figure 1.

Study flow diagram. CMI, cell-mediated immune; NYCBH, New York City Board of Health; PRNT, plaque reduction neutralization titer.

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.

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.