In the nineteenth century, the cowpox virus in the vaccine was replaced by the vaccinia virus, which also belongs to the orthopox virus family. The vaccinia virus was grown on the skin of newborn calves, which created a risk of contamination with other pathogens and so this smallpox vaccine was far from ideal. But the vaccinia vaccine allowed health authorities around the world to embark on a massive vaccination campaign in the 1960s. The last natural case of smallpox was documented in Somalia in 1977, and in 1980 the World Health Organization (WHO) officially declared the smallpox eradicated.
By this time, many countries had already stopped administering the smallpox vaccine, as the disease no longer posed a major threat to public health. ‘By that point it had already become an exotic disease that you could catch on long journeys,’ says Poland.
New smallpox vaccines
Still, concerns persisted that terrorists would use the virus as a biological weapon. While the US destroyed most of its doses of first-generation smallpox vaccines at the beginning of this century, a new vaccine was developed as a precaution: ACAM2000. That vaccine is based on viruses that have been grown in modern laboratories and is therefore free from the contaminants of the first-generation vaccines. But the drug has many side effects.
When the ACAM2000 vaccine was introduced in the US, 9/11 “The side effects quickly became obvious,” says Raina MacIntyre, an infectious disease expert at the University of New South Wales in Sydney and a member of the WHO’s Strategic Advisory Group of Experts on Immunization.
Although the side effects were rare, some people who had been vaccinated with the vaccine developed inflammation of the heart and brain. And like the first-generation vaccine, this vaccine also relied on live virus particles, which could multiply in the body, which was especially dangerous for people with weakened immune systems and other medical conditions.
Another disadvantage of ACAM2000 only became apparent after a while, namely when very few people were vaccinated against smallpox. “There were just very, very few people available in the US who knew how to administer this vaccine,” Poland says.
Fortunately, a new generation of smallpox vaccines has now been developed. In 2019, the US Food and Drug Administration (FDA) officially approved the use of the vaccine Jynneos, which is marketed in Europe as IMVANEX and in Canada as Imvamune. The vaccine is given in two doses and is based on a modified version of the vaccinia virus that does not replicate in the body, making it safer for people with underlying medical conditions, experts say. Meanwhile, Japan has authorized its own smallpox vaccine, LC16m8, which has also been modified to prevent it from multiplying easily in the body.
While many unanswered questions remain about these new vaccines, they offer some hope for a world currently struggling with an unprecedented outbreak of another orthopox virus, monkeypox.
A smallpox vaccine against monkeypox?
The monkeypox virus was discovered in 1958 in a population of monkeys used as laboratory animals. The first case of monkeypox in humans was documented in 1970 in the Democratic Republic of the Congo (DRC). This virus is less transmissible and less dangerous than smallpox, as it kills only three to six percent of those infected with it. Unlike smallpox, monkeypox circulates among animals, making it particularly difficult to eradicate the pathogen.
There is preliminary evidence that people who have been vaccinated with the smallpox vaccine become less ill with monkeypox. In 1988, researchers in Zaire analyzed cases of monkeypox in people who had and had not had a scar from a smallpox vaccination. That study showed that the smallpox vaccine was also effective against monkeypox in 85 percent of the cases.
According to MacIntyre, outbreaks of monkeypox in the past have always been rare and limited, meaning that at most a few or a few dozen people became infected. But that has changed in recent years. A 2010 study in the DRC found that the number of monkey pox cases in humans was 20 times higher than in the recent past, and that especially many young people were infected who had never been vaccinated against smallpox.
“We then saw very large outbreaks in Nigeria from 2017 and then in the Democratic Republic of Congo,” MacIntyre says. Her team’s investigation of the outbreak in Nigeria, from 2017 to 2020, found that these cases were linked to a lack of vaccination. Again, this mainly concerned young people who had never been vaccinated against smallpox and also elderly people who had received their smallpox shot decades ago and who now had hardly any immunity to the pathogen.
Still, the idea that smallpox vaccines would also work against monkeypox has not yet been confirmed by science, said Wafaa El-Sadr, founder director of ICAP,
an international health care institution of Columbia University. Although the studies mentioned seem to indicate that older people who have been vaccinated against smallpox also have some degree of protection against monkeypox, “we don’t have any hard data yet to definitively support that association,” she says.
The knowledge gap is particularly large with regard to the new vaccine Jynneos. The only studies that have shown this vaccine to be effective against monkey pox have been animal studies, not human studies, says El-Sadr. It is also unclear whether Jynneos is safe for children, who are vulnerable to a serious course of monkey pox. And while the US plans to extend the existing stock of smallpox vaccines by injecting smaller doses between layers of skin rather than into the fatty tissue beneath the skin, few data seem to indicate the benefit of this measure.
“There’s a whole laundry list of unanswered questions,” El-Sadr says. “The good news is that there is a vaccine available that is likely to be effective against monkeypox in humans.”
Who will get the new smallpox vaccines?
The monkeypox outbreak doesn’t mean that smallpox vaccine inoculations will return to routine anytime soon. After all, any decision to vaccinate involves weighing the risks against the benefits.
Jynneos may be safer than the older generation vaccines as it does not contain live virus particles, but the vaccine still carries some risks of side effects, including feverish symptoms or an allergic reaction. In addition, monkeypox is largely transmitted between men who have sex with other men, which means that the risk to the population as a whole is small. “If inoculation with a particular vaccine has no clear benefits, then any risk is one too many,” says Poland.
Experts also believe that there is currently no urgent need to administer the vaccine on a large scale as a precautionary measure, as has happened with vaccines against COVID-19. Smallpox vaccines are also effective if someone is already infected, so it makes more sense to only inject people who fear they have been infected.
Of course, the trade-off between risks and benefits would have to be reconsidered if the situation changes. “If the outbreak is contained and we can contain it at an early stage, it will be very difficult to argue for large-scale vaccination with this vaccine,” says El-Sadr.
But if Western countries fail to contain the monkeypox outbreak in the dams, perhaps more people should be vaccinated as a precaution—particularly if the virus enters the animal world’s reservoir and the disease becomes a widespread presence. Also, the recommendation for vaccination could change if monkeypox starts to spread among children, as the disease poses a higher risk for this group than for adults.
El-Sadr is hopeful that it will not come to that. “Fortunately, this virus is very different from smallpox and the consequences of monkeypox infection are much less dangerous than smallpox infection,” she says. “Certainly there is an outbreak, and that is worrying. But we have a test that we can use to diagnose monkeypox, we have a vaccine that we can use and hopefully scale up, and we have a treatment for the disease.”
This article was originally published in English on nationalgeographic.com.