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Third-generation Smallpox Vaccine LC16m8 Proven Safe and Immunogenic

By Amesh A. Adalja, MD, March 20, 2009

The Journal of the American Medical Association recently published a study conducted by a team of Japanese researchers who vaccinated more than 3,000 Japanese military personnel from 2002-2005 with LC16m8, a tissue-cultured third-generation smallpox vaccine. In the 1970s, LC16m8 was used in Japan to immunize approximately 100,000 infants, with no reported adverse events detected via passive surveillance.1 Third generation smallpox vaccines, as discussed in a prior issue of the CBN Report, are attenuated vaccine strain viruses that possess a reduced tendency to elicit adverse reactions, as compared with first and second generation vaccines. They are thought to have an improved safety profile in patients with HIV, atopic skin diseases, and other immune system abnormalities that have historically precluded use of the earlier generation vaccines. Since the third generation vaccines have been available only since smallpox was eradicated, their efficacy in humans cannot be definitively established.

Japanese Military Recruits Selected as Study Subjects

The objective of the current study was to assess the immunogenicity and safety profile of LC16m8 in both vaccinated and unvaccinated adults. The study subjects were recruits in the Japan Self Defense Forces during the years 2002-2005. Six selection rounds were performed, with 350 to 700 healthy adults aged 18 to 55 years recruited in each round. Immunosuppression (including the use of immunosuppressive drugs) and current eczema were among the exclusion criteria. Individuals with atopic dermatitis with stable skin lesions were vaccinated.1

Stratification by Prior Smallpox Vaccination

The researchers stratified subjects based on age as a surrogate for vaccination history. Given that routine smallpox vaccination with 3 inoculations with a first generation vaccine stopped in 1976, different birth cohorts had different vaccination histories. Four groups with varied vaccination histories ultimately were identified: never vaccinated, vaccinated once, vaccinated twice, and fully vaccinated with 3 doses.1

Study subjects were vaccinated with 1 dose of the LC16m8 vaccine and then were monitored for 30 days. Appearance of a skin reaction (pustule, induration, congestion) at the site of vaccination 10 to 14 days after inoculation indicated success, that is, a clinical “take.” Serum was also analyzed for neutralizing antibody titers. General health interviews, electrocardiography (ECG), and troponin assays at 30 days post-vaccination were also performed. The ECG and troponin testing were administered to identify cases of myopericarditis, a known complication of the vaccine currently licensed in the U.S.1

Primary Vaccinees Had Higher Take Rates and Seroconversion

In all, 3,221 individuals were vaccinated, 4 of whom had atopic dermatitis. Approximately 50% had never been vaccinated, 98.4% were men, and all were Asian. Clinical take rates were significantly increased in primary vaccinees as compared with re-vaccinees (94.4% vs. 86.6%); however, primary vaccinee age did not affect the likelihood of a clinical take. Re-vaccinees who had only 1 prior vaccination displayed take rates higher than those who had received 2 or 3 prior vaccinations.  A higher propensity for seroconversion (4-fold titer increase) in those who had not been previously vaccinated was found; however, titers of neutralizing antibodies against LC16m8 were not significantly different between primary vaccinees and revaccinees. Overall, the vaccine displayed high levels of vaccine take in primary vaccinees and provoked an effective booster response in some re-vaccinees.1

 Naïve
Re-vaccinees
Vaccine take in recipients1,443/1,529
(94.4%)
1,465/1,692
(86.6%)
Seroconversion and/or boost
in those with vaccine take
37/41
(90.2%)
93/155
(60%)

               

No Adverse Events Requiring VIG

No severe adverse events were noted during the vaccination period, and there was no need for vaccinia immuneglobulin (VIG) use. However, in the 30-day post-vaccination follow-up, 2 possibly severe events occurred: 1 case of allergic dermatitis and 1 case of erythema multiforme. No ECG abnormalities or elevations of troponin levels were detected.1

Should the U.S. Diversify the Strategic National Stockpile to Include LC16m8?

The results of this study are important in light of the recent decisions by the U.S. government to pursue third generation vaccines, as evidenced by the award of a contract to Bavarian Nordic, the manufacturer of Imvamune (see CBN Report, 1-08-2009). While neither vaccine has been tested against human smallpox cases in vivo, LC16m8 has been used without ill effect several times since the large-scale use in the 1970s mentioned above.

While the advantages of one third generation vaccine over another have not been elucidated, additional data on use in immunocompromised individuals may be the deciding factor, given that 4% of Americans are immunocompromised and 10% to 15% have atopic skin disease. The first and second generation vaccines are contraindicated in both groups.

While the safety data for LC16m8 are impressive, it is the case that in this study, ECGs were performed only at 30 days post-vaccination, which means that asymptomatic cases of myopericarditis that may have occurred within 7 to 14 days of vaccination would have been missed. However, the clinical significance of detection of these asymptomatic cases is debatable.

Given the results of this study, it may be prudent to diversify the U.S. stockpile of smallpox vaccines to include LC16m8.

Reference

Saito T, Fujii T, Kanatani Y, et al. Clinical and immunological response to attenuated tissue-cultured smallpox vaccine LC16m8. JAMA 2009;301:1025-1033. http://jama.ama-assn.org/cgi/content/full/301/10/1025. Accessed March 16, 2009.