The current and future landscape of smallpox vaccines

Abstract

The potential use of smallpox as a weapon for bioterrorism has created a need for more and better smallpox vaccines. The first generation vaccines such as Dryvax were produced by crude methods that would not allow licensure today. Second generation vaccines, grown in modern safe tissue cultures but employing seed virus from first generation vaccines of known effectiveness, have been developed. One, ACAM2000, has been licensed and added to the US National Stockpile. These second generation vaccines can produce the same complications as first generation vaccines, and myopericarditis has been well documented as associated with ACAM2000. This has created advocacy for third and fourth generation smallpox vaccines. Third generation vaccines are those which have been attenuated either by serial passage in non-human cells, or by careful deletions of genes in the laboratory. Two of these, MVA (Modified Vaccinia Ankara), and LC16m8 (a derivative of Lister strain vaccinia), have been tested in various human trials. These seem to be ready to apply for licensure if there proves to be a market. Fourth generation vaccines, created as subunits of full strength vaccinia, or fully engineered non-replicating molecules which express various known epitopes of vaccinia and/or smallpox, have also been developed. It may be difficult or impossible to prove the efficacy of these vaccines because smallpox no longer exists and there is no animal model that accurately reflects the human disease. These fourth generation vaccines include several large stable DNA viruses into which immunogens from others agents such as HIV and malaria can be inserted, so they may have a future as vector vaccines for a variety of other agents besides smallpox.