United States

Smallpox vaccination in the United States began in 1800, but its routine widespread use did not occur until this century. It was first demonstrated by Waterhouse in Boston in July 1800, with material provided by Jenner, ¹⁴³ and its use was actively promoted by President Thomas Jefferson. ¹⁴⁴ Because propagation of the virus at that time was primarily dependent on arm-to-arm transfer of material from a successful vaccinee to others, vaccination was practiced sporadically. Epidemics of variola major continued to occur at intervals, depending on population density and frequency of importations.

Toward the end of the 19th century in the United States, vaccinia virus began to be propagated on the flank of a calf, thus making vaccination more readily and widely available. By 1897, smallpox had largely been eliminated, ³ the result of vaccination and outbreak control. That summer, however, an outbreak of variola minor occurred in Pensacola, Florida, and within 4 years, this variety of smallpox had spread across the country. ¹⁴⁵ Although outbreaks of variola major continued to occur until about 1927, most cases of smallpox were caused by variola minor. Because the disease was mild and the case fatality rate was only 0.3 to 1.0%, interest in vaccination waned. To control the disease, public health authorities sought to compel vaccination as a requirement for school entry, an action upheld by the Supreme Court, ¹⁴⁶ a highly effective measure. ¹⁴⁷ However, antivaccinationist sentiment and antipathy toward compulsory measures prevailed in many states, most of which passed no legislation or prohibited compulsory vaccination. Reported cases of smallpox declined from 102,791 in 1921 to 30,151 in 1931, and between 1932 and 1939, 5000 to 15,000 cases were reported annually, with 23 to 52 deaths. During the following decade, reported cases steadily diminished, the last occurring in 1949. This progress occurred in the absence of any nationally coordinated smallpox control effort, and little is known about the extent of vaccination immunity in the country during the 1940s or about the epidemiology of smallpox. However, improved smallpox control, and eventually its elimination, is attributed by Leak ¹⁴⁸ to the wider availability of better refrigeration and, consequently, better preservation of the vaccine. Routine vaccination continued in the United States until 1971 as a protection in case smallpox was imported and was enforced in most states by compelling vaccination as a requirement for school entry. Beginning in the 1960s, the Centers for Disease Control and Prevention urged the routine vaccination of hospital staff, a group at high risk if smallpox was imported, but few hospitals complied. After the global eradication of smallpox, distribution of vaccine was restricted to the military and to the few laboratories that were working with orthopoxviruses.

Other Industrialized Countries

Through the 1800s, the experience with vaccination in other industrialized countries was similar to that in the United States. After an initial surge of enthusiasm for vaccination in the early 1800s, vaccination was less uniformly and extensively practiced in most countries until near the close of the century, when the vaccinia virus began to be propagated on calves. By 1900, a number of countries in northern Europe became smallpox free, and by 1914, the incidence in most countries had decreased to comparatively low levels. Even so, during the period from 1910 to 1914, Russia experienced a reported 200,000 deaths, and nearly 25,000 deaths were recorded in other European countries. ^{149, 150} World War I led to a resurgence of smallpox in Russia and its spread from there to many other countries. During the 1920s, vaccination programs led to the interruption of smallpox transmission in many European countries, and by the mid-1930s, smallpox occurred only after importations except in Spain and Portugal. Endemic smallpox persisted in these countries until 1948 and 1953, respectively.

Of the other major industrialized countries, as they are often referred to today, Canada interrupted transmission of smallpox in the early 1940s and Japan about 1950. Vaccination continued in all the industrialized countries, as it did in the United States, until the mid to late 1970s as a protection in case smallpox was reintroduced. Australia and New Zealand were two notable exceptions. These countries, protected by distance and strict quarantine measures, never vaccinated widely but also never became endemic for smallpox.

Eradication from the World

The first commitment to smallpox eradication as such was made in 1950 by the Pan American Sanitary Organization, which decided that year on a hemisphere-wide effort. ¹⁵¹ Freeze-dried vaccine produced by an improved commercial process ³⁰ was employed in mass vaccination campaigns, which during the succeeding decade eliminated smallpox from all countries except Argentina, Brazil, Colombia, and Ecuador.

In 1958, the Soviet Union proposed to the World Health Assembly that the WHO undertake a global eradication program, ³² a proposal that was agreed on in 1959. ³³ During the succeeding 7 years, a number of countries embarked on mass vaccination campaigns, and several countries, including China, were successful in eliminating the disease (Fig. 6-6). Overall, however, progress was disappointing, especially in Africa and in the Indian subcontinent. Few countries voluntarily contributed resources, and the WHO, then preoccupied with a costly and disappointing global malaria eradication program, provided few of its own resources and little support.

Figure 6-6

Countries with endemic smallpox in 1967 when the intensified program was initiated.

Frustrated by lack of progress in the program, although skeptical about the feasibility of the concept of eradication itself, the World Health Assembly in 1966, decided, finally, to provide to the WHO a special allocation of $2.4 million annually for an intensified global smallpox eradication effort. ³⁴ The hope was expressed that the task might be accomplished within a 10-year period, that is, by December 1976. ³⁶

In the intensified program, the strategy emphasized two principles that ultimately proved to be critical to its success. The first was to ensure, through the use of international vaccine testing centers, that all vaccine in the program met accepted standards and, likewise, to ensure, through concurrent sample surveys, that a satisfactory vaccination coverage had been achieved and that the vaccinations had been successful. The second principle was the identification of the absence of cases as the program's principal objective and the need to measure progress not in terms of numbers of vaccinations performed, as had been the practice, but in terms of declining incidence of smallpox. This principle required the development of an effective case notification system and focused attention on measures to reduce incidence.

During 1967, the first year of the program, 44 countries, 31 of which were endemic, reported 131,789 cases of smallpox. The endemic countries were Brazil, most countries of Africa south of the Sahara, and five countries in Asia: Afghanistan, India, Indonesia, Nepal, and Pakistan (see Fig. 6-6). Later surveys revealed that only about 1% of all cases were then being reported; thus, it is estimated that between 10 and 15 million cases occurred that year in countries whose population was about 1.2 billion people.

Provision of adequate supplies of fully potent vaccine was a critical first problem. ^{152, 153} Early surveys revealed that not more than 10% of the vaccine being produced in or provided to the endemic countries met accepted international standards. Laboratories in Canada and the Netherlands agreed to test samples of all vaccine to be used in the program, manufacturers collaborated in developing a detailed production manual, and consultants and equipment were provided to laboratories in the endemic countries. Donations of vaccine, primarily from the Soviet Union and the United States, met initial needs, but by 1973, more than 80% of all vaccine for the program was being produced in the developing countries.

The traditional method of vaccination by scarification was changed. In 1967, jet injectors were introduced for programs in Brazil and western and central Africa. One year later, a new instrument, the bifurcated needle, developed by Wyeth Laboratories, was found to be effective in multiple-puncture vaccinations ¹⁵⁴ ; by 1969, it was in use in all countries. Vaccination with the bifurcated needle required only one fourth as much vaccine, even illiterate village volunteers required less than an hour's training in its proper use, and workers could vaccinate as many as 1000 persons per day.

Vaccination programs were developed or strengthened in all endemic and neighboring countries, the last of them beginning in 1971. Although the strategy also called for the improvement of national reporting systems and containment of outbreaks by special teams, such activities were slow to begin. It quickly became apparent, however, that these activities, referred to as the surveillance-containment program, could serve to interrupt smallpox transmission more easily and quickly than anyone had imagined, even where vaccinial immunity was low. ^{69, 155, 156}

With increasingly greater emphasis on surveillance-containment activities, endemic smallpox steadily receded (Fig. 6-7; see also Fig. 6-6). It was eliminated from 20 countries of western and central Africa by 1970, ⁷⁰ from Brazil in 1971, from Indonesia in 1972, and from the entire continent of Asia in 1975. Ethiopia stopped transmission in 1976 and Somalia on October 26, 1977. The last naturally occurring case of smallpox developed less than 1 year after the originally projected 10-year target date. WHO-organized international commissions visited each of the endemic countries and areas to confirm the fact of eradication, and in May 1980 the World Health Assembly, acting on the recommendation of a WHO Global Commission (Fig. 6-8), announced that worldwide eradication had been achieved and recommended that smallpox vaccination be used only for those working with orthopoxvirus in research laboratories. ¹ The WHO established an international stockpile of vaccine in the unlikely event that its use would ever again be required and encouraged laboratories to destroy their stocks of variola virus. As of 1997, variola virus remained in only two research laboratories—one in the United States and one in Russia.

Figure 6-7

Number of countries experiencing smallpox each year from 1967 to 1978. (From Fenner F, Henderson DA, Arita I, et al. Smallpox and Its Eradication. Geneva, World Health Organization, 1988, pp 517-538.)

Figure 6-8

The response to an initial infection occurs in three phases. Document signed on December 9, 1979, by members of the World Health Organization Global Commission, certifying that smallpox had been eradicated. (From Fenner F, Henderson DA, Arita I, et al. (more...)

The overall cost of the program was estimated to be about $300 million, of which $98 million represented international assistance. The savings, as a result of cessation of vaccination and quarantine measures, was estimated to be in excess of $1 billion annually. ⁴

With the eradication of smallpox, questions arose as to whether it might not be prudent to destroy the known remaining laboratory stocks of variola virus to provide added assurance that the virus might not accidentally or even deliberately be released into an unprotected world. This was considered in 1986 by a WHO Ad Hoc Committee on Orthopoxvirus Infections, which recommended a broader consultation with the international community and destruction of the virus if no serious objections were raised. ¹⁵⁷ Meanwhile, in preparation for possible destruction, a library of cloned DNA restriction fragments of selected strains was prepared, and later the genomes of a number of prototype strains were fully or partially sequenced. ¹⁵⁸

Arguments were advanced both supporting ¹⁵⁸ and objecting to ¹⁵⁹ destruction of the virus stocks. In 1994, the question was again reviewed in depth by the WHO Committee, which again recommended to the WHO Director General that the considerations, on balance, strongly favored destruction of the virus. ¹⁶⁰ It was ultimately decided in the 1996 World Health Assembly that destruction of the virus should take place on June 30, 1999.