In the majority of cases, smallpox is spread from one person to another by infected saliva droplets that expose a susceptible person having face-to-face contact with the ill person. People with smallpox are most infectious during the first week of illness, because that is when the largest amount of virus is present in saliva. However, some risk of transmission lasts until all scabs have fallen off.

A highly successful global immunisation programme begun in 1967 under the aegis of the World Health Organisation (WHO), succeeded in eradicating smallpox in 1977. In 1980 the World Health Assembly recommended that all countries cease vaccination. A WHO committee recommended that all laboratories destroy their stocks of variola virus or transfer them to one of two WHO reference laboratories – The Institute of Virus Preparations in Moscow, Russia and the Centre for Disease Control and Prevention (CDC) Atlanta, USA. All countries reported compliance.

The WHO committee later recommended that all virus stocks be destroyed in June 1999. The World Health Assembly authorised temporary retention of the remaining stocks to facilitate the possible development of a more attenuated, less reactogenic smallpox vaccine and an antiviral drug that could be used in treatment of patients with smallpox.

The vaccine against smallpox was the key tool in the eradication of the disease. The vaccine does not contain the variola virus, which causes smallpox, but a closely related live virus called vaccinia (VACV). When this vaccine is given to humans, the resulting immunity protects them against smallpox.

Most existing vaccine stocks and the vaccine used in the WHO eradication campaign consist of pulp scraped from vaccinia-infected animal skin, mainly calf or sheep, with phenol added to a concentration sufficient to kill bacteria but not so high as to inactivate the vaccinia virus (VACV). The vaccine is then freeze-dried and sealed in ampoules for later re-suspension in sterile buffer and subsequent intradermal inoculation by multiple puncture with a bifurcated needle.

A number of strains of seed virus have been used to produce smallpox vaccine, one of these the New York City Board of Health strain (NYCBH) of VACV substantially contributed to the global eradication of the disease. During the period 1967– 71, 152 million doses of NYCBH strain were delivered.

Previous methods of vaccine production that used calf lymph are no longer available. New generation vaccines will be manufactured by cell culture technology in serum reduced, serum free, or entirely protein free media therefore minimizing or, ideally, even eliminating the risk of contamination with adventious agents, such as BSE. Safety and efficacy must be evaluated against Wyeth Dryvax® commercially approved smallpox vaccine with a proven track record derived from the (NYCBH) strain of VACV.

During the WHO eradication programme 4 vaccinia strains were widely used for human immunization. No formal clinical trial has ever been performed and the efficacy of the different strains has never been directly compared. However there are other non-comparative data available, which indicate a high level of effectiveness and lower rates of adverse events for the NYCBH strain.

WHO conducted several key meetings of experts aimed at improving vaccine production, quality and performance worldwide and several key documents were prepared dealing with vaccine specifications (World Health Organization, Methodology of freeze-dried smallpox vaccines production, WHO, Geneva, SE/68.3 Rev.2, 1968; Fenner F Henderson DA, Arita A et al. Smallpox and its Eradication, WHO, Geneva, 1988). With regard to the strain of virus recommended for use in manufacture, the experts recommended: “…that a strain of vaccinia virus should be used which would induce immunity in man with as few ill effects as possible…. No particular strain [is] officially recommended but in response to inquiries, either the Lister or New York City Board of Health strain should be used…”

Apart from the aforementioned WHO eradication program strains, the MVA strain has been used in humans in local vaccination programs in non-endemic regions. The Modified Vaccinia Ankara strain is one of the most highly attenuated vaccinia strains. However, the vaccine does not cause pock lesions at the site of inoculation, and therefore shows no signs of a successful vaccination. The MVA strain was therefore never used as a sole vaccine but only as a primer prior to vaccination proper (usually with the Elstree strain) in an effort to reduce adverse reactions of the vaccination with the Elstree strain in the latter stages of the smallpox eradication programs in Germany and Turkey.

The Acambis / Baxter vaccine is a “state of the art” highly purified cell culture based smallpox vaccine. It is a live attenuated vaccinia vaccine produced from ACAM2000 seed stocks.

ACAM2000 is a biologically cloned vaccinia virus strain derived from the NYCBH strain. A strain that has known efficacy against smallpox virus. The NYCBH strain vaccine played a significant role in the global eradication programme. This vaccine strain had been supplied for the program in Africa A total of 152 million doses of NYCBH vaccine were delivered during the period 1967-71. As a result of this effort, smallpox was eradicated from the region.

The NYCBH strain has a very good safety profile. As quoted by Henderson et al 1999 “The frequency of complications associated with the use of the New York City Board of Health strain (the strain used throughout the United States and Canada [sic. and elsewhere] for vaccine is the lowest for any established vaccinia virus strain ...".

Vaccine lots for stockpile will be produced in Vero (African Green monkey kidney) cells propagated in entirely serum- and protein-free conditions therefore excluding the risk of contamination/transmission with adventitious agents such as BSE.

The new vaccine is a state of the art product.

• Highly purified
• Genetically highly homogeneous, and stable throughout manufacturing process
• Fully characterised Vero-cell culture
• Master and working cell and virus stock systems established
• Serum-free and protein free production process, excluding risk of contamination/transmission with adventitious agents
• Good safety profile
• Seroconversion equal or better than Dryvax® (Dryvax accepted as the comparative standard for clinical studies)
• Preclinical animal model data suggest lower pathogenicity when compared with Dryvax®
• Baxter has a proven record for an advanced large-scale manufacturing process of Vaccinia Virus using the latest biotechnology
• Baxter has experience in vaccine production and supply
• Baxter/Acambis have been awarded the largest contract to date – the US government contract for 155 million doses