Researchers analyzed the genomes of virus fragments found on smallpox vaccination kits used during the Civil War. The kits are housed at the Mütter Museum of the College of Physicians of Philadelphia. [JD Howell, McMaster University]

Scientists and historians working at McMaster University, the Mütter Museum, and the University of Sydney applied sophisticated sequencing techniques to reconstruct the genomes of viral strains that were recovered from the “vaccination kits” used during the time of the American Civil War. They say the work points to the importance of studying the diversity of wild virus strains, which could feasibly include strains that may protect against a wide range of viruses, including flu or coronaviruses. Their work could also lead to a new field of medical history study through the non-destructive examination of materials previously associated with biological samples.

“Understanding the history, the evolution, and the ways in which these viruses can function as vaccines is hugely important in contemporary times,” said evolutionary geneticist Hendrik Poinar, PhD, who is director of the McMaster Ancient DNA Centre, where the work was carried out, and a principal investigator at the university’s Michael G. DeGroote Institute for Infectious Disease Research. “This work points to the importance of looking at the diversity of these vaccine strains found out in the wild. We don’t know how many could provide cross protection from a wide range of viruses, such as flus or coronaviruses.”

Poinar and colleagues report their findings in Genome Biology, in a paper titled, “The origins and genomic diversity of American Civil War Era smallpox vaccine strains.”

Smallpox is caused by variola virus (VARV), a human-specific member of the Orthopoxvirus (OPXV) genus of the Poxviridae. Smallpox was one of the most devastating viral diseases ever to strike humankind, killing about three out of every 10 people who were infected. Those who survived infection frequently left disabled, blind, or disfigured.

The World Health Organization recently celebrated the 40th anniversary of the eradication of smallpox, the most successful campaign ever attempted. In fact, smallpox is the only human infectious disease that humans have managed to eradicate, thanks to widespread coordinated vaccination programs, and the effectiveness of the vaccine itself. “The World Health Organization’s success in eradicating smallpox using vaccinia virus (VACV; 1980) was in part due to the broad protective immunity induced by infection with one OPXV against subsequent infection by another,” the authors wrote.

Yet despite the historical importance of the achievement, little is known about the origins and diversity of viruses used in smallpox vaccination, the team continued. “Prior to the twentieth century, the method, source, and origin of smallpox vaccinations remained unstandardized and opaque … The lack of standardization in vaccination practices and propagation throughout most of its history means that historical vaccine strains may be any one of several OPXVs.”

The concept of widespread vaccination dates back to 1796, when English physician Edward Jenner observed that exposure to a milder illness (called cowpox)—thought to be transferred from cows with a similar pox-like illness on their udders to milkmaids—offered protection against future smallpox outbreaks. While “cowpox” is often referenced as the source of the first vaccination, little had been known about the specific origins and diversity of the virus strains used in early smallpox vaccination programs, and the method and source material used for early smallpox vaccinations remained unstandardized for over a century.

Ana Duggan, PhD, a former postdoc in the department of anthropology at McMaster and lead researcher on the study. [JD Howell, McMaster University]
“On the basis of Edward Jenner’s work, cowpox virus (CPXV) was assumed to have been involved in historical vaccination, although horsepox virus (HSPV) and ‘equination’ are also cited,” the authors continued. “In 1939, it was recognized that the smallpox vaccine strains being used in the twentieth century were distinct from CPXV and these VACV strains had become the predominant smallpox vaccines. However, both the origin of VACV and its natural host or reservoir are also unknown.”

For their study, researchers used sophisticated techniques developed at the McMaster Ancient DNA Centre to reconstruct and analyze the genomes of virus fragments recovered from vaccination kits used during the Civil War era. “To better characterize the origins of smallpox vaccination, we investigated the origin, diversity, and propagation of early smallpox vaccine strains by extracting and sequencing total DNA and analyzing both the virome and metagenome from these kits,” the investigators explained.

The kits, part of a medical collection at the Mütter Museum of the College of Physicians of Philadelphia, contained lancets and small glass plates for mixing fluid for vaccines that had been collected from blisters of deliberately infected subjects, and tin boxes with sliding lids to contain scab material. “Kits found in collections relating to the American Civil War correspond to a time of known medical crisis and intervention to prevent smallpox outbreaks,” the investigators noted. “We were kindly granted access to five historical kits from the Mütter Museum of the College of Physicians of Philadelphia that date to the mid-to-late nineteenth century (likely circa 1859–1873) and are associated with medical practices of the American Civil War era … Vaccination ‘kits’ and their biological contents (scabs, lymph) provide evidence of early vaccination methods and materials and remain in medical collections/archives across the globe.”

The techniques used by the scientists enabled them to successfully recover viral molecules from both organic sources, such as scab material, and also from the non-destructive sampling of inorganic materials, such as tin boxes and glass slides, which contained no evidence of organic residues.

The researchers were able to determine that in the 1860s and 1870s, medical practitioners in Philadelphia were using a vaccinia virus strain that was still being propagated in human subjects. The milder relative of the deadly smallpox pathogen was introduced into the body, usually by applying pus or scabs to a scratch or cut in the skin, where it helped recipients to develop immunity to smallpox.

So, within the historical context of American medical practices in the 1860s and 1870s, it seems that vaccination was a “uniquely human process,” the team noted. “Vaccination material was still being produced within humans and transferred directly from donors to patients, a process that changed in the following decades in response to public health concerns over iatrogenic disease spread and the for-profit industrialization of vaccine production through animals.”

An overriding concern about vaccine design is how close—from an evolutionary standpoint—the vaccine strain must be to the one causing disease for it to prevent illness. The vaccinia strains used for vaccination were in fact very distantly related to the virus that causes smallpox. The slow mutation rate of orthopox viruses (of which both vaccinia and variola are members) likely allows for this “distant” protection.

“Vaccination is a wonderful process with a rich medical history that we should celebrate,” said Ana Duggan, PhD, a former postdoc in the department of anthropology at McMaster, now at the Public Health Agency of Canada, who was lead researcher on the study. “Medical museums are incredible repositories of our past and of our collective history. The new tools we develop in this work allow us to begin to investigate how medical sources, procedures, and techniques have changed through time.”

The authors conclude that their work offers up a novel, non-destructive approach to recovering DNA which can preserve historical medical collection artifacts for further study. “The clear identification and reconstruction of near-complete genomes of VACV from these vaccination kits, which were in use during the American Civil War era, indicates that these strains were circulating within humans and via physician networks prior to the twentieth century.”

And as researchers around the world are working to develop a vaccine against COVID-19, the success of the smallpox campaign, and the findings reported by Poinar and colleagues, point to the value of vaccination, the team reasoned. They suggested other vaccines are waiting to be discovered among the viral relatives of today’s influenza and coronaviruses.

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