Authored by, , , Zdenek Jezek and Ivan Danilovich Ladnyi, the chief architects who led its successful global Smallpox eradication program, the WHO’s massive, >1000-page, 1988 tome (Fenner, Frank, et al. Smallpox and its eradication. Vol. 6. Geneva: World Health Organization, 1988), is probably the first and last word about the subject. The information and figures used in this answer in this answer are from its chapter 11, Fenner, F., et al. “Smallpox vaccine and vaccination in the intensified smallpox eradication programme.” Smallpox and its eradication (1988): 539-592. .
This answer briefly outlines
- How different countries were already using different virus strains and vaccinifers (vaccine sources) to produce Smallpox vaccine.
- How the WHO developed and implemented novel quality control procedures and distribution systems to ensure vaccine of consistently high quality and safety were used in its Smallpox Eradication program.
Though the Vaccinia virus increasingly became a mainstay as Smallpox eradication efforts gathered steam during the 20th century, virtually every country tried to eliminate against Smallpox using a combination of inoculation with Smallpox itself, vaccination using cowpox, horsepox and other poxes, as well as isolation and quarantine. Thus, by the time the WHO launched its Intensified Smallpox Eradication Programme in 1967, Smallpox remained endemic in only 31 countries.
The WHO’s 1967 Smallpox outlook estimated ~300 million people needing to be vaccinated annually in the 31 endemic countries and their neighbors. The three main sources of Smallpox vaccine were
- Endemic countries producing vaccine for their own local use.
- A few producer countries producing vaccine to donate to the WHO, following a 1959 resolution at the 12th World Health Assembly.
- Vaccine supplied to developing countries through a number of bilateral aid programs.
While Smallpox vaccination started with Jenner in 1798, standardized vaccine production and reliable procedures and assays to assess vaccine quality control only began to be developed from the 1950s onwards.
The WHO’s survey of vaccine producers in February 1967 yielded data from 59 labs in 44 countries out of a total of 77 labs in 52 countries. This survey and tests of the various Vaccinia virus vaccines produced by these different labs showed results all over the map (see below).
- Different strains of Vaccinia virus and different sources were used to produce Smallpox vaccine: 39 used the skin of calves, 12 that of sheep, 6 that of water-buffaloes, 3 the chorioallantoic membrane of chick embryos, and 3 bovine embryo fibroblast tissue cultures
- Even the lyophilization (process of freeze-drying) equipment itself was produced by at least 11 different manufacturers based in either Czechoslovakia, France, West and East Germany, Japan, UK, USA. While France, Indonesia and the Netherlands started to produce air- or freeze-dried vaccines from the 1920s, Smallpox vaccine was largely produced in liquid form elsewhere. Problem is liquid vaccine loses potency within few days unless refrigerated while freeze-dried could retain potency for > a month even in the tropics. By the 1950s, more vaccine producers around the world became capable of producing freeze-dried vaccines, and it became the norm from 1971.
- Vaccinia virus vaccine from different labs had different potency, different number of doses per container (vial or ampule), different heat stability, and even different bacterial count. The latter is an important point since most of the Smallpox vaccine used in the eradication program was produced in animal skin. This meant that strict bacteriological sterility wasn’t possible.
To improve this situation and ensure production of vaccine of consistently high quality, potency and safety, the WHO put in place several key processes that helped streamline vaccine production, quality control measures, and distribution pipelines.
- A Smallpox Eradication unit set up in Geneva in 1967 helped streamline distribution.
- The WHO contracted with two labs to conduct quality control tests on its behalf. In a sense, these labs became reference labs for the WHO Smallpoxeradication program. They were the Connaught Medical Research Labs in the University of Toronto, Canada, and the National Institute of Public Health, Bilthoven, Netherlands.
Choice of Vaccinia virus strains and methods used in the WHO’s Smallpox eradication program
Although chick embryos and cultured cells had been successfully used in producing Smallpox vaccine by 1968, the WHO’s document on its Smallpox eradication program retained focus on the older, traditional method, using animal skin, rationale being it was simpler, more straightforward and practical to implement across a variety of vaccine producers around the world. OTOH, at the time the newer methods still had many kinks to be worked out such as reproducible titers and heat stability.
Many Vaccinia virus strains were available as choice of vaccine. Since different countries already had a tradition of working with different Vaccinia strains, rather than mandating use of single one, the WHO simply recommended using one that
- Induced adequate immunity with as few side effects as possible.
- Produced compact, clearly visible white pocks on chicken chorioallantoic membrane, i.e., an easy assay to assess potency.
Four Vaccinia virus strains ended up being the most widely used (see below).
If asked, the WHO’s Smallpox Eradication unit advised to use either the Lister or the New York City Board of Health Vaccinia strain. In addition, the WHO’s guiding document also provided detailed instructions on
- The use of seed lots and how to prepare them.
- How to prepare the vaccinifer (animal skin) for producing the Smallpoxvaccine.
- How to administer the vaccine using the scarification method.
- How to prepare the vaccine, freeze-dry it, and even the ampules, vials and stoppers to use to distribute it.
- How to reconstitute the freeze-dried vaccine using what fluid.
Thus, the WHO’s Intensified Smallpox Eradication Programme represents the first time the WHO put in place ‘an effective world-wide quality control programme for biological products‘ (see below).
2578 vaccine production batches were tested between 1967 and 1980, with consistent year on year improvement in vaccine quality (see below), specifically, vaccine potency, heat stability and bacterial count.
Culmination of these efforts was the resolution of 8 May 1980 at the 33rd World Health Assembly that declared Smallpox eradicated globally.