Third-Generation Smallpox Vaccines: Challenges in the Absence of Clinical Smallpox

Abstract

Smallpox, a disease caused by variola virus, is estimated to have killed hundreds of millions to billions of people before it was certified as eradicated in 1980. However, there has been renewed interest in smallpox vaccine development due in part to zoonotic poxvirus infections and the possibility of a re-emergence of smallpox, as well as the fact that first-generation smallpox vaccines are associated with relatively rare, but severe, adverse reactions in some vaccinees. An understanding of the immune mechanisms of vaccine protection and the use of suitable animal models for vaccine efficacy assessment are paramount to the development of safer and effective smallpox vaccines. This article focuses on studies aimed at understanding the immune responses elicited by vaccinia virus and the various animal models that can be used to evaluate smallpox vaccine efficacy. Harnessing this information is necessary to assess the effectiveness and potential usefulness of new-generation smallpox vaccines.

Keywords:

• animal model
• animal rule
• immune response
• orthopoxvirus
• smallpox vaccine
• vaccinia virus
• variola virus

Acknowledgements

We thank Carol Weiss and Marina Zaitzeva, CBER/FDA, for critically reviewing this manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The opinions expressed in this paper are solely those of the authors, and do not in any way represent the official position of the US FDA.

No writing assistance was utilized in the production of this manuscript.