Recent advances in the study of live attenuated cell-cultured smallpox vaccine LC16m8

Significance Statement

Smallpox was one of the most feared infectious diseases in the world. It is caused by the variola virus, an orthopoxvirus, which results in high fever and progressive rashes all over the body, killing up to 30% of the infected patients.
In the 1960s, World Health Organization (WHO) launched a global eradication campaign using first-generation smallpox vaccines, consisting of vaccinia virus, and declared the eradication of smallpox in 1980. Consequently, routine vaccination programs were discontinued.However, owing to terrorist events in the USA in the beginning of this century, the need for the smallpox vaccine had to be reconsidered. Several countries have since stockpiled the smallpox vaccine as a measure against bioterrorism.
Since 2002, Japan has re-produced and stockpiled LC16m8, a live attenuated third-generation vaccine, which was developed as a safer alternative in the 1970s because of the adverse effects of the first-generation smallpox vaccines.

Repeated evaluations of LC16m8 have demonstrated an excellent safety profile, and an efficacy comparable to that of first-generation vaccines. Severe adverse events attributable to the vaccine have not been reported so far, and the vaccine has been safely administered even to immunodeficient animals. Additionally, LC16m8 has beneficial properties for practical use: induction of visible major cutaneous reactions, signs of successful vaccination, and easy administration using bifurcated needles.

Detailed information on the safety and efficacy of LC16m8 is critical for public health decision-makers to plan strategic vaccination programs in case of a possible emergent outbreak of smallpox. Even after eradication, possibilities of a re-occurrence of the disease exist, under intended or unintended circumstances. Therefore, a vaccine stockpile and updated research are necessary public health measures.

An established vaccine may also be useful against related diseases. The routine vaccination of smallpox vaccines were effective against monkeypox, another disease caused by orthopoxvirus in Africa. The discontinuation of the smallpox vaccination program has decreased the immunity of populations against both smallpox and monkeypox, leading to concerns regarding possible outbreaks of the disease; thus, preparedness for these possibilities is desirable.

Although LC16m8 conferred protective effects against monkeypox in macaques, its efficacy against monkeypox in humans has not been evaluated. Additionally, LC16m8 has not been evaluated in immunocompromised patients. Further studies are expected for the evaluation of LC16m8 in these applications.


Journal Reference

Vaccine. 2015. pii: S0264-410X(15)01179-2.

Eto A1, Saito T1, Yokote H2, Kurane I3, Kanatani Y4.

[expand title=”Show Affiliations”]
  1. Department of Health Crisis Management, National Institute of Public Health, 2-3-6 Minami, Wako-shi, 351-0197, Saitama, Japan.
  2. Chemo-Sero-Therapeutic Research Institute (Kaketsuken), 1-6-1 Okubo, Kita-ku, Kumamoto-shi, 860-8568, Kumamoto, Japan.
  3. National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, 162-8640, Tokyo, Japan.
  4. Department of Health Crisis Management, National Institute of Public Health, 2-3-6 Minami, Wako-shi, 351-0197, Saitama, Japan. Electronic address: [email protected].


LC16m8 is a live, attenuated, cell-cultured smallpox vaccine that was developed and licensed in Japan in the 1970s, but was not used in the campaign to eradicate smallpox. In the early 2000s, the potential threat of bioterrorism led to reconsideration of the need for a smallpox vaccine. Subsequently, LC16m8 production was restarted in Japan in 2002, requiring re-evaluation of its safety and efficacy. Approximately 50,000 children in the 1970s and about 3500 healthy adults in the 2000s were vaccinated with LC16m8 in Japan, and 153 adults have been vaccinated with LC16m8 or Dryvax in phase I/II clinical trials in the USA. These studies confirmed the safety and efficacy of LC16m8, while several studies in animal models have shown that LC16m8 protects the host against viral challenge. The World Health Organization Strategic Advisory Group of Experts on Immunization recommended LC16m8, together with ACAM2000, as a stockpile vaccine in 2013. In addition, LC16m8 is expected to be a viable alternative to first-generation smallpox vaccines to prevent human monkeypox.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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Recent advances in the study of live attenuated cell-cultured smallpox vaccine LC16m8. Global Medical Discovery feature