A new smallpox vaccine has produced encouraging results in tests on monkeys and mice.
The current vaccine can have side effects
Scientists hope it may provide an alternative to humans who cannot receive the current options.
Research, published in Nature, showed the vaccine protected monkeys from the related condition monkeypox.
And a Proceedings of the National Academy of Sciences study suggests it may be better tolerated by people with weakened immune systems.
Researchers from the US National Institute of Allergy and Infectious Diseases treated monkeys with a vaccine called modified vaccinia virus Ankara (MVA).
They found that the MVA jab alone was enough to protect them from monkeypox.
However, they found that a combination of MVA and the existing smallpox jab Dryvax gave even better protection.
They suggest that MVA could be used as a "prevaccine" to which Dryvax could be added in the event of a specific smallpox threat - for instance if it was used as a biological weapon.
The researchers also believe that MVA could provide an alternative for people who are unable to take Dryvax for medical reasons.
Dryvax is not recommended for people with weakened immune systems - including diabetics, transplant recipients, elderly people, small children, and HIV-positive people - because they are more susceptible to its dangerous side-effects.
To test this theory, they carried out a second study to examine the effect of the vaccine on immunocompromised mice.
They found that mice which were given Dryvax developed severe side-effects such as extreme weight loss and skin sores. Some died.
However, immunocompromised mice remained healthy even when treated with 1,000 times as much MVA.
Lead researcher Dr Bernard Moss told BBC News Online: "Although Dryvax is highly protective, it has serious and life threatening side-effects particularly in those with immunodeficiencies.
"Second generation vaccines that are made under modern conditions are currently being tested. However, these are likely to have similar kinds of complications.
"An alternative vaccine, such as MVA, with improved safety is needed to immunize those at high risk of side-effects with the current vaccine."
The UK has stockpiled supplies of smallpox vaccine for use in an emergency.
However, it is accepted that a mass vaccination programme would lead to a small number of deaths, as it would be inevitable that some people would suffer an adverse reaction.