Vaccines for preventing smallpox

Smallpox is an acute viral infection unique to humans. A worldwide smallpox campaign (including mass vaccination, patient isolation, and surveillance) contributed to the eradication of the disease by 1980. However, there is growing concern that the virus could now be used as a biological weapon. Smallpox spreads from one person to another by infected saliva droplets. The incubation period is 7 to 17 days. The symptoms begin with severe headache, backache, and fever up to 40 °C, all beginning abruptly. Then a rash appears on the face and spreads, the spots become watery blisters containing pus that form scabs and leave pitted scars when they fall off. The infected person is contagious until the last smallpox scab has fallen off, although most of the transmission occurs in the first week. Most people with smallpox recover, but some do die and the risk depends on the strain of virus. The early vaccines were effective, but they had a number of adverse effects, including headache, fever, and reaction at the infection site, and also the possibility of death. New vaccines continue to be developed. The review identified 10 trials that involved 2412 participants. Overall, the quality of the trials was not high but the review showed that stockpiles of the vaccines maintained their effectiveness even when diluted. New second-generation vaccines seemed to be effective but still have adverse events. There were too few participants overall to be able to assess rare outcomes. Further research is needed, particularly on the third-generation vaccines.

Authors' conclusions: 

The evidence shows that stockpiled vaccines have maintained their immunogenicity and new cell-cultured vaccines are similar to stockpiled vaccines in terms of vaccination success rate and immunogenicity. First- and second-generation vaccines diluted to at least 1:10 are as effective as undiluted vaccine in terms of clinical success rate and immunogenicity. Dilution did not reduce the frequency of adverse events. Success rate and immunogenicity were similar in naive and previously vaccinated persons, but there were fewer adverse events in previously vaccinated persons. The rate of adverse events found in this review reveals the need for further development and improvement of smallpox vaccines.

Read the full abstract...

Smallpox was eradicated by 1980, but its possible use as a bioweapon has rekindled interest in the development of protective vaccines. Therefore, stockpiled calf lymph-derived vaccines and recently developed cell-cultured vaccines have been investigated to contribute information to smallpox emergency response plans, while newer (non-replication competent) vaccines are developed.


To assess the effects of smallpox vaccines in preventing the disease, in inducing immunity, and in regard to adverse events.

Search strategy: 

In December 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 4), MEDLINE, EMBASE, LILACS, and Current Controlled Trials, and handsearched Index Medicus. We also searched three databases of vaccine safety in December 2005.

Selection criteria: 

Randomized controlled trials of smallpox vaccines versus placebo, other smallpox or non-smallpox vaccine, no intervention, or different dose of the same vaccine in people receiving smallpox vaccination irrespective of age.

Data collection and analysis: 

Both authors independently assessed trial quality and extracted data. We combined dichotomous data using risk ratio with a random-effects model.

Main results: 

Ten trials involving 2412 participants were included. The vaccines investigated were calf-lymph derived first-generation vaccines (Dryvax, APVS, Lancy-vaxina, Lister), and cell-cultured second-generation vaccines (ACAM, CCSV). Vaccines were investigated in different dilutions. All undiluted vaccines induced a reaction in 95% of people vaccinated in terms of pustule and immunogenicity. Also 1:10 dilutions were fully efficient when the starting concentration was defined. Serious adverse events were reported in 1% to 2% of the volunteers. Fever was observed in 11% to 22% of participants, and headache in roughly half of the participants. Fever was less frequent when new vaccines were administered, but rates of headache were similar in new and old vaccines.