An angel's trumpet: Development of the heat stable smallpox vaccine

Abstract

Towards the end of the eighteenth century, Edward Jenner proved that inoculation with live cowpox virus immunises against smallpox. The induction of immunity depends on the ability of cowpox - and the related vaccinia viruses that superseded it - to replicate in the recipient. Like most viruses, these agents are inactivated quite rapidly at temperatures much above 0°C and so, from Jenner's time onward, means for preserving smallpox vaccine were explored. The earliest methods, used by Jenner and others, included direct arm to arm transfer, and drying material from vaccination lesions on glass, ivory, or silver surfaces. Within a few years, bulk vaccine was being prepared in animals, and in the early nineteenth century a method was devised for testing its potency. Many workers tried to preserve smallpox vaccine, the main methods being the addition of so called 'protective substances' to liquid vaccine; drying from the liquid state; and drying from the frozen state (freeze drying). The first two were of little or no value. My own researches at the Lister Institute of Preventive Medicine centred on freeze drying by the centrifugal method. After much experimentation, it was found that a freeze dried, partially purified suspension of vaccinia virus propagated in sheep and containing 5% peptone was highly thermostable. This property was largely a result of the addition of peptone, which also prevented inactivation of the virus during drying caused by 'salting out' of the phenol added to destroy bacterial contaminants. Vaccines prepared in this way withstood storage for over a year at 45°C. By parallel titrations of vaccine in chick embryos and in groups of humans, a minimum standard of potency was established that had to be met after storage for at least one month at 37°C. Other criteria for the dried vaccine included reproducibility of performance from batch to batch, economic production, and simplicity of use in the field. In comparative tests with other vaccines, the Lister Institute method performed best and was eventually adopted by the World Health Organization for the global smallpox eradication programme. Despite the success of the freeze dried smallpox vaccine, the preservation of other live virus vaccines still poses problems. Our knowledge of the factors preventing inactivation of viruses at ambient temperatures remains largely empirical. Nevertheless, some of the newer subunit vaccines show promise of stability during long term storage and may provide at least a partial solution.