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Smallpox's antiquity in doubt

Published online by Cambridge University Press:  16 September 2022

Timothy P. Newfield Open the ORCID record for Timothy P. Newfield [Opens in a new window] ,
Ana T. Duggan Open the ORCID record for Ana T. Duggan [Opens in a new window]  and
Hendrik Poinar Open the ORCID record for Hendrik Poinar [Opens in a new window]
Timothy P. Newfield
Affiliation:
Department of History, Department of Biology, Georgetown University
Ana T. Duggan
Affiliation:
McMaster Ancient DNA Centre, Department of Anthropology, Department of Biochemistry and Biomedical Sciences, McMaster University
Hendrik Poinar
Affiliation:
McMaster Ancient DNA Centre, Department of Anthropology, Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University
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Abstract

Smallpox, caused by the variola virus (VARV), is prominent in modern histories of the ancient Mediterranean world. The disease, or the diagnosis of it, has shaped estimations of the scale and significance of epidemics and pandemics, notably the 2nd-c. Antonine plague, and the burden of disease in large cities and regions densely populated in antiquity. Here we synthesize recent paleogenetic and evolutionary biological literature that casts significant doubt on the existence of a VARV that caused a disease we would recognize – clinically, ecologically, or epidemiologically – as smallpox in antiquity. On the basis of current data, it is time archaeologists and historians began to eradicate smallpox from their histories of the ancient world.

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Journal of Roman Archaeology , Volume 35 , Issue 2 , December 2022 , pp. 897 - 913
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

The place of smallpox in the history of the ancient Mediterranean is rarely contested. Although Enlightenment-era physicians and medical historians debated whether Greco-Roman populations knew the disease,Footnote 1 most who commented on smallpox's history before 1850 found little reason to think it was anywhere to be found in the Mediterranean region in antiquity.Footnote 2 Yet, gradually, from the mid-19th c., well-known ancient plagues, like the Athenian and Antonine plagues,Footnote 3 and less-discussed epidemics, like those encountered in Aëtius of Amida's medical compendium and dated to Trajan's reign, and in Eusebius's Church History and fixable to 310–11,Footnote 4 were identified as smallpox. The Cyprianic and Justinianic plagues also emerged, on occasion, in scholarship as potential outbreaks of smallpox,Footnote 5 though those diagnoses no longer hold favor.Footnote 6 In this paper, we synthesize recent literature in the fields of paleogenomics and evolutionary biology that casts doubt on smallpox's antiquity and, thereby, on retrospective smallpox diagnoses of ancient plagues. We draw particular attention to the Antonine plague, as a smallpox diagnosis has been assigned some significance in histories of that pandemic.

Retrospectively diagnosing ancient plagues is no straightforward matter.Footnote 7 Without paleogenomic support, which remains hard to obtain for those disease outbreaks for which we have written sources,Footnote 8 no modern diagnosis of a disease reported in an ancient text is unequivocal.Footnote 9 Yet, disease identifications, no matter how disputable, have carried significant weight in histories of ancient disease, shaping our efforts to understand the demographic and economic impact, and determinants, of poor health in antiquity. A prominent example is the smallpox diagnosis of the Antonine plague. Although opinion on the diagnosis of that plague has begun to pivot in recent scholarship, as discussed below, no other ancient disease outbreak is as commonly or confidently identified as smallpox as is the 2nd-c. pandemic.Footnote 10

Reference to smallpox in scholarship on the Antonine plague, which appears to have commenced in the reign of Marcus Aurelius,Footnote 11 is often fleeting.Footnote 12 That said, the identification of the Antonine plague as smallpox has been used in a variety of ways in modern histories of the pandemic. Most significantly, the diagnosis has been employed to support the idea that the 2nd-c. outbreak sickened and killed widely, as then contemporary (and particularly non-contemporaryFootnote 13) ancient authors claim.Footnote 14 The diagnosis has, as such, shored up the thinking that the multiple and varied references we possess to epidemic disease in the 160s–180s, the bulk of which make no reference to symptoms and can therefore be difficult to connect to one another, refer to a singular pandemic-scale disease outbreak, as opposed to multiple discrete epidemics.Footnote 15

Some uses of the diagnosis are in opposition. Scholars convinced that there is no evidence for smallpox in the Mediterranean region in the centuries or decades leading up to the Antonine plague have employed the diagnosis to argue that the smallpox of the 2nd-c. pandemic would have been especially devastating, as the population, without previous exposure, would have been immunologically naïve.Footnote 16 Conversely, scholars convinced that the Roman world was already acquainted with smallpox have proposed that the outbreak, while demographically significant because it was smallpox, was not as demographically significant as it could have been had the population not been previously exposed.Footnote 17 A smallpox diagnosis of the Antonine plague has additionally informed speculation on the pandemic's case fatality rateFootnote 18 and on the population cohorts worst affected.Footnote 19 It has also influenced conjecture on the pandemic's geographical originsFootnote 20 and association with climate change,Footnote 21 not to mention its seasonality and ecology.Footnote 22 The diagnosis has even underpinned ideas about the outbreak's duration, periodicity, and relation to the 3rd-c. Cyprianic plague.Footnote 23 Considering all of this, it is not surprising that the smallpox diagnosis of the 2nd-c. pandemic has been regarded as “potentially a matter of great significance.”Footnote 24 Indeed, the diagnosis has amassed considerable weight.

That a smallpox identification can support these arguments rests on the knowledge we have of smallpox's more recent history, as well as on the idea that the pathogen that causes smallpox existed in antiquity and then manifested and recognizably behaved as smallpox did in the centuries leading up to its eradication in the 1970s.Footnote 25 Smallpox is caused by the variola virus (VARV), a highly infectious orthopoxvirus that is host specific (it only infects and causes disease in humans), transmitted primarily via respiratory secretions, and capable of spreading rapidly.Footnote 26 VARV causes severe disease, though its presentation can vary. A noncontagious incubation period averaging 10–12 days results in fever, body aches, and malaise before a spotted rash forms in the mouth and subsequently spreads to the face, extremities, and appendages before the trunk. A few days later, the spots fill with a cloudy, dense fluid, eventually becoming hard and pustular, “like peas under the skin.”Footnote 27 Five or so days later, the pustules start to crust and scab. For three weeks, from the appearance of the rash to the flaking of the scabs, the sufferer is infectious, though infectivity varies over that period.Footnote 28

In naïve populations, VARV is thought to have caused large-scale outbreaks resulting in significant excess mortality.Footnote 29 Without prior infection, or widespread variolation or vaccination, the disease could be highly prevalent, with case fatality rates reaching 25–30 percent (or higher).Footnote 30 That said, considerable variation in VARV prevalence and mortality between regions, settlements, and subpopulations is to be expected in outbreaks, owing to an array of cultural, demographic, and ecological factors, such as population density and distribution, mobility, housing, and preexisting disease burden. In populations where VARV was endemic,Footnote 31 and the adults had some immunity, VARV could still apply near-constant demographic pressure, claiming the lives of many infants and children on an annual basis and, in certain circumstances, irrupting as epidemics.Footnote 32

This is, in large part, how smallpox manifested in recent centuries. For generations, historians, both armchair and professional, as well as physicians, have looked for this smallpox in antiquity. But can we superimpose this smallpox onto the distant past? What of this smallpox should we expect to be able to identify in ancient sources? Our ability to overlay our modern knowledge of smallpox onto the ancient world and diagnose ancient plagues as novel emergences of VARV,Footnote 33 or surmise that VARV was endemic in large Roman-era cities and regions densely populated in antiquity,Footnote 34 requires careful consideration of the available evidence, most notably newly emergent data from paleogenomics.

Evidence for smallpox in antiquity is primarily textual. Apart from the quasi-pox-like rashes visible on some New Kingdom Egyptian mummiesFootnote 35 (which though often mentioned in the literature have yet to yield VARV DNAFootnote 36), reports of osteomyelitis variolosaFootnote 37 (a nonspecific bony lesion associated with VARV infection which remains very rarely attested in the archaeological record), or the great age of variolation (and insufflation) purported for several regions of Asia in epidemiologically orientalist writing on smallpox's past,Footnote 38 what we have are infrequent references to: i) smallpox-like disease, such as Thucydides's small ulcers and pustules,Footnote 39 Galen's ulcerated and scarring exanthem,Footnote 40 Eusebius's severe carbuncles,Footnote 41 Ge Hong's disfiguring epidemic pustules,Footnote 42 and Gregory of Tours's malignant pustules and vesicles;Footnote 43 and ii) sequelae associated with recovery from smallpox, mainly pox-scarred skin and blindness.Footnote 44 Although more evidence of symptoms and sequelae may yet be recovered,Footnote 45 textual references have been and will continue to be incapable of providing the evidentiary basis needed to definitively confirm or deny the presence of smallpox in antiquity. Other data, however, novel and largely independent of archaeological and textual indications of ancient smallpox,Footnote 46 now strongly suggest that the disease we know as smallpox in fact did not exist in antiquity,Footnote 47 but rather has a more recent evolutionary history.

To date, paleogenomics have both solidified some old thinking about ancient diseaseFootnote 48 and upended some traditional narratives.Footnote 49 As our understanding of the evolutionary history and historical geography of pathogenic disease advances with paleogenomics, historians and archaeologists must remain abreast of developments and, as necessary, reconsider our histories of ancient disease. The ability to detect, capture, and sequence remnants of pathogens continues to improve, but robust results in the subfield of pathogen paleogenomics have been standard now for over a decade.Footnote 50 Although bacterial pathogens causing acute disease, like Yersinia pestis (the cause of plague), have been more often reportedFootnote 51 than double- or single-stranded DNA viruses,Footnote 52 or viruses containing highly fragile RNA,Footnote 53 all have now been identified owing to the refinement and ever-increasing sensitivity of paleogenomic methods.

There are, presently, a handful of VARV paleogenomes that have been drafted using decades-to-centuries-old human remains from archaeological contexts and medical archives.Footnote 54 These paleogenomes, some of which are only partial (or poorly phylogenetically resolved),Footnote 55 date to the 17th–20th c. and provide unequivocal evidence for VARV before the modern era. They can be studied alongside the ~45 genome-scale sequences obtained from samples taken in the mid-20th c.Footnote 56

Recent phylogenetic analyses using modern 20th-c. genomes coupled with the reconstructed paleogenomes have refined estimates of VARV's evolutionary history. Inferences of these analyses are historically significant. They show, for instance, that the two prominent groups of VARV strains eradicated in the 20th c., variola major (Clade I) and variola minor (Clade II/alastrim), shared a recent common ancestor some 200 or so years ago, potentially the result of a vaccination-induced population bottleneck.Footnote 57 In addition, these analyses have emphasized the recentness of the evolutionary history of variola minor, which caused a less-acute variety of smallpox but granted immunity to more virulent varieties of the disease.Footnote 58 Although a scarcity of VARV paleogenomes continues to hamper our understanding of VARV's evolutionary history, we have also learned, most importantly in relation to ancient pandemics, that VARV associated with smallpox appears to be centuries old not millennia old.

The inactivation of genes (rendering them non-functioning) in orthopoxviruses has been associated with both host specificity and virulence. All inactivated genes found in 17th- and 18th-c. VARV paleogenomes are also found in all sequenced 20th-c. strains. We can be sure, in other words, that the VARV paleogenomes which have been drafted to date caused smallpox.Footnote 59 This contrasts sharply with recently identified “sister lineages” of VARV – the four oldest orthopoxvirus paleogenomes yet recovered.Footnote 60 These early 7th–late 10th-c. genomesFootnote 61 are genetically distinct from the VARV we know to cause smallpox, so much so that when they were reported in 2020 they were identified as “aVARV” (“ancient VARV”), as opposed to VARV (or “mVARV” for “modern VARV”).Footnote 62 These strains, while ancestral to the reconstructed 17th–20th-c. VARV paleogenomes, contain a different pattern of inactivated genes than the strains associated with clinical smallpox, including some genes known to be associated with virulence.Footnote 63 Clinically and epidemiologically, therefore, the disease the millennium-old aVARV strains caused is likely to have differed, perhaps considerably, from smallpox as we know it.Footnote 64 Evolutionary analyses of, and genetic relationships between, orthopoxvirus sequences now reconstructed from ancient human remains and medical archives have taught us that it is improbable that a variola virus like the VARV associated with the disease we know as smallpox (“mVARV”) existed in any similar sense in antiquity. As sister lineages, aVARV should not be considered the direct ancestor of mVARV, and it must be underscored that our knowledge of any shared ancestors, intermediary forms, and historical host distributions remains unclear and likely to be clarified only by paleogenomics.

Pathogens evolve, and as they do their host specificity, transmission mechanics, and infectivity, as well as the disease they cause can, among other things, change. DNA viruses, like VARV, may not evolve as fast as RNA ones, but our ongoing experience with the pathogen SARS-CoV-2, the cause of the disease COVID-19, has made clear the ability of viruses to mutate in meaningful ways.Footnote 65 As the evolutionary history of quickly evolving viruses begins to come into focus, our accounts of their past must remain alert to the limits of our knowledge and sensitive to the weight of the terms we use to describe disease caused by pathogens not suffered and studied in the modern era.

As nomenclature may mislead, to be clear, the recently detected VARV “sister lineages” are not the VARV that caused smallpox. The aVARV paleogenomes neither evidence the discovery of smallpox in ancient or Late-Antique human remains nor raise the possibility of the existence or circulation of smallpox in antiquity.Footnote 66 Rather, aVARV is an orthopoxvirus, now presumably extinct, to which humans were susceptible. Whether it was zoonotic, rodent-borne, or dependent on a nonhuman reservoir, as speculated,Footnote 67 remains uncertain,Footnote 68 but that it has been discovered in early medieval northern Europe, where there were no population centers or regions with a population density even close to approaching the size needed to maintain smallpox, indicates how epidemiologically different aVARV could have been. Its degree of virulence and clinical manifestation are likewise unclear.Footnote 69

What we know for certain is that the sequences of VARV so far obtained from 17th-c. and later samples are remarkably similar to the VARV we understand causes smallpox, so much so that they have been collectively referred to as mVARV. On the other hand, aVARV sequences are more distantly related but, barring intervention and subdivision from the International Committee for Taxonomy of Viruses, must be considered of a single species and taxonomic unit with mVARV. Nevertheless, the genomic content of aVARV DNA, and the inferences for its virulence, and the uncertainty of its host specificity and/or reservoirs, suggest that its expression and behavior are very likely not that of smallpox but rather something for which we do not have a name. These semantics are important. Indiscriminate use of “smallpox” confuses matters. Recent scholarship notably continues to use “smallpox” in its discussion of the Antonine plague and aVARV. This loose usage has a long tradition: over 175 years ago, Haeser suggested smallpox symptoms may have differed in antiquity.Footnote 70 Yet, if the symptoms and epidemiology differed, the diagnosis loses its value, interpretive and heuristic, and becomes a hazard, as diagnoses, certainly ones of smallpox, carry considerable cultural, demographic and epidemiological weight.

Importantly, the aVARV sequences help us to pinpoint a minimum date range for the window during which VARV emerged as the virulent and highly infectious pathogen later described as the etiological agent of smallpox. These “time to the most recent common ancestor” (tMRCA) analyses are Bayesian analyses that attempt to estimate a date that reflects the point in time when aVARV and mVARV shared a common ancestor. Current analyses date this theoretical ancestor – with large confidence intervals – to the 4th c. CE.Footnote 71 Crucially, we do not know whether this theoretical ancestor resembled mVARV or was capable of causing a disease we would recognize as smallpox. A smallpox-causing VARV, therefore, could have emerged in the 4th c. or after the 4th c., not by the 4th c.Footnote 72 Molecular-clock analyses can only estimate the evolutionary history of sampled pathogen diversity, however, and on the basis of all available reconstructed mVARV and aVARV sequences, we must presently conclude that a VARV capable of causing smallpox could have emerged any time between the 4th c. and 16th c. CE. The time frame suggested by all available sequence data (paleogenomes and genomes), suggests a tMRCA closer to the early modern period than the Late-Antique one.Footnote 73 As such, smallpox's antiquity is very much in doubt and its Late Antiquity is in doubt too.Footnote 74

That smallpox, as known to modern biomedical science, first appeared as recently as 500 years or so ago is not set in stone. We remain in the midst of a paleogenomic revolution, and many more VARV and related orthopoxvirus sequences will yet be drafted from old soft tissues, teeth and bones, guaranteeing that our understanding of VARV's evolutionary history will continue to evolve. However, it must currently be regarded as unlikely that the emergence of a VARV that we understand to have caused smallpox will be pushed back to antiquity or Late Antiquity.

Without smallpox – pandemic, epidemic, or endemic – ancient Mediterranean populations should seem healthier to us.Footnote 75 So should societies in other world regions the disease is likewise thought to have long afflicted.Footnote 76 We are only beginning to grasp the pathogenic load suffered in antiquity anywhere, but the implications of a smallpox-less ancient world are many. For instance, several areas long stigmatized as ancient “cradles” of the disease based on exceptionally weak or nonexistent evidence,Footnote 77 and speculatively othered as sources of ancient Mediterranean smallpox epidemics,Footnote 78 can no longer carry that burden. In the absence of smallpox diagnoses, ancient disease outbreaks will also seem less familiar and understandable. Not being able to employ smallpox, what we know of its symptomatology or epidemiology, in our arguments regarding the demographic import, chronology, origins, or periodicity of ancient epidemics and pandemics will be a challenge to overcome. This is especially true for the Antonine plague, on account of the many roles a smallpox diagnosis has been assigned in our histories of that pandemic.

One option to confront this challenge, albeit one not recommended, would be to assume that plagues previously diagnosed as smallpox were in fact aVARV, or another VARV ancestor, which happened to manifest and behave a lot like VARV.Footnote 79 Although one might propose that the written evidence we have for ancient smallpox-like plagues (Galen, Eusebius, Ge Hong, etc.) corroborates this thinking, the idea is problematic. We know so very little about VARV ancestors – their ecology, epidemiology, or symptomatology – that such a diagnosis is not only unsubstantiated and unhelpful, but also misleading, as the continuity this proposal suggests between a VARV ancestor and VARV is wholly conjectural and not supported by available evidence. Another option would be to reject diagnosis, to adopt agnosticism and interpret the primary evidence on its own, without the superimposition of modern science.

Whether or not one pursues this second option, they should remain alert to the aspects of our histories of ancient plagues that have been built or buttressed with a smallpox diagnosis. Concerning the Antonine plague, we cannot simply abandon the diagnosis from our histories and move on. We will have to reckon with how the loss of the diagnosis will cause our accounts of that pandemic to change – our confidence regarding its origins, periodicity, and breadth will weaken, and a few ideas present in our histories will have to be given up, like questions concerning the 2nd-c. plague's demographic profile and density dependence.

The Mediterranean antiquity of smallpox gained favor in academic writing from the mid-19th c., when the disease was, in many world regions, in steep decline. On the verge of VARV's eradication, smallpox identifications of ancient plagues gained currency. Commentators on smallpox's past who lived when and where the disease was prevalent, to the contrary, found no place for it in the Greco-Roman past. Paleogenomic data and evolutionary biological analyses now lend support to that thinking and indicate it is time to eradicate smallpox from our histories of the ancient world and ancient plagues from our histories of smallpox.

Footnotes

1 E.g., Hahn Reference Hahn1733; Werlhof Reference Werlhof1735.

2 E.g., Sennert Reference Sennert1633, 464; Sydenham Reference Sydenham1685, 260–61; Porchon Reference Porchon1688, 8–9; le Clerc Reference le Clerc1723, 776–77; Freind Reference Freind1727a, 274; Freind Reference Freind1727b, 188–89; Mead Reference Mead1747, 2; Paulet Reference Paulet1768a, 2, 4, 25, 44–45, 51, 57; Woodville Reference Woodville1796, 4–6. Rarely have authoritative studies postdating 1850 also held that smallpox was unknown to Greeks and Romans. Some exceptions: von Becker Reference von Becker1879, 22, 42, 46, 49; Dixon Reference Dixon1962, 187.

3 Willan Reference Willan and Smith1821 found smallpox almost everywhere he looked in Greco-Roman sources. Shortly thereafter Haeser Reference Haeser1845, 17, 78–79, 143, 251, 255, thought ancients knew the disease, though he had doubts about a smallpox identification of the Athenian and Antonine plagues and proposed smallpox is invisible in ancient texts partly because of “wie unbestimmt die Terminologie…ist.” Hirsch Reference Hirsch and Hirsch1860, 214–16, initially thought “Andeutungen” of smallpox were discernible in Greco-Roman texts, but that if Galen knew the disease, he did not describe it. Later, in the second edition of his Handbuch, Hirsch (Reference Hirsch and Hirsch1881, 90–91) more confidently identified smallpox in Galen's writings. Smallpox diagnoses of ancient plagues subsequently became more numerous. Baas Reference Baas1876, 147–48, considered Roman-era Mediterranean plagues possibly smallpox, but 20th-c. and post-20th-c. scholarship has repeatedly identified the Athenian and Antonine plagues as smallpox: e.g., Zinsser Reference Zinsser1935, 122–24, 127, 137; Littman and Littman Reference Littman and Littman1969; Littman and Littman Reference Littman and Littman1973; McNeill Reference McNeill1976, 103–5; Littman Reference Littman1984, 110–11, 115–16; Sallares Reference Sallares1991, 230, 233, 247–49; Hopkins 2002, 19–23; Zelener Reference Zelener2003, 83; Gourevitch Reference Gourevitch2005, 64–65; Sallares Reference Sallares, Scheidel, Saller and Morris2007, 37; Little Reference Little and Little2007, 4; Cunha and Cunha Reference Cunha, Cunha, Raoult and Drancourt2008, 9–13; Littman Reference Littman2009, 458–59, 464; Andorlini Reference Andorlini and Lo Cascio2012, 16, 24; Bruun Reference Bruun and Lo Cascio2012, 131; Livi Bacci Reference Livi Bacci and Lo Cascio2012, 341; Harper Reference Harper2015, 223; Harper Reference Harper2017, 67–68, 102–3, 104–7; Green Reference Green and Ludden2018, 8; Harper Reference Harper, Izdebski and Mulryan2018, 305–6; Harper Reference Harper2021, 194; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 387–91. In 2017 and 2018, Harper initially offered caution against pursuing a smallpox diagnosis, but then pursues one. For alleged artistic evidence of a smallpox diagnosis: Sabbatani and Fiorino Reference Sabbatani and Fiorino2009, 266. Doubts about the Athenian diagnosis are not uncommon, despite its popularity: e.g., Leven Reference Leven1991, 142–43; Papagrigorakis et al. Reference Papagrigorakis, Yapijakis, Synodinos, Raoult and Drancourt2008; Little Reference Little and Little2007, 4. Fewer doubt the Antonine plague's identity. Bruun Reference Bruun and Lo Cascio2012, 131, 131 n. 44, has commented on the popularity of the Antonine plague's smallpox diagnosis, but earlier observed (2007, 201) that the diagnosis was not definitive. Silver Reference Silver2012, 214–25, argued for plague, and Flemming Reference Flemming and Petit2019, 226, 232–34, offered a rare rebuke of this smallpox diagnosis, drawing in part on paleogenomic data available at the time. Littman and Littman Reference Littman and Littman1973 and Zelener Reference Zelener2003 have been influential. So confident were Littman and Littman in a smallpox diagnosis of the 2nd-c. pandemic that they used it to argue (245 n. 7) that “smallpox seems to have undergone the least change in the course of history.” Similarly, Duncan-Jones Reference Duncan-Jones1996, 109, suggested the “disease environment” of the ancient Mediterranean “did not necessarily change significantly in kind between antiquity and much later times” and pointed specifically to smallpox.

4 E.g., Hirsch Reference Hirsch and Hirsch1881, 90; Brown and McLean Reference Brown and McLean1962, 765; Hopkins 2002, 22, 23; Stathakopoulos Reference Stathakopoulos2004, 181; Harper Reference Harper2015, 247; Harper Reference Harper2016, 474–75; Harper Reference Harper2017, 141, 174.

5 In whole or in part, e.g., Willan Reference Willan and Smith1821, 12–13, 16; Schnurrer Reference Schnurrer1823, 126; Zinsser Reference Zinsser1935, 147; Hopkins 2002, 23.

6 E.g., Scheidel Reference Scheidel and Scheidel2001b, 31; Stathakopoulos Reference Stathakopoulos2004, 111, 126–67; Wagner et al. Reference Wagner, Klunk, Harbeck, Devault, Waglechner, Sahl, Enk, Birdsell, Kuch, Lumibao, Poinar, Pearson, Fourment, Golding, Riehm, Earn, DeWitte, Rouillard, Grupe, Wiechmann, Bliska, Keim, Scholz, Holmes and Poinar2014; Harper Reference Harper2015, 245–48; Harper Reference Harper2016, 474–75; Harper Reference Harper2017, 141; Keller et al. Reference Keller, Spyrou, Scheib, Neumann, Kröpelin, Haas-Gebhard, Päffgen, Haberstroh, Lacomba, Raynaud, Cessford, Durand, Stadler, Nägele, Bates, Trautmann, Inskip, Peters, Robb, Kivisild, Castex, McCormick, Bos, Harbeck and Krause2019; Huebner Reference Huebner2021, 170–71; cf. Benedictow Reference Benedictow2021, 108–11.

7 Arrizabalaga Reference Arrizabalaga2002; Cunningham Reference Cunningham2002; Leven Reference Leven, Horstmanshoff and Stol2004; Stein Reference Stein2006.

8 Considering both the current limits of paleogenomics (e.g., the commonness of false negatives and the difficulty in identifying viral pathogens, especially those containing RNA) and the problems inherent in attempting to marry what are often very roughly dated molecular results to precisely dated written records of disease outbreaks.

9 Marciniak and Poinar Reference Marciniak, Poinar, Lindqvist and Rajora2019, 123–24; Spyrou et al. Reference Spyrou, Bos, Herbig and Krause2019, 323, 329, 336. As Duncan-Jones Reference Duncan-Jones1996, 109, noted: textual limitations “make attempts to identify ancient epidemics relatively hazardous.”

10 A possible exception is the once infamous smallpox-like pandemic concurrent with outbreaks of first-pandemic plague in the 6th c.: Newfield et al. Reference Newfield, Marciniak, Cameron-Steinke and Oram2022. Most recently, McCormick Reference McCormick2021, 60, saw smallpox in Gregory of Tours's writings, which have been considered integral to the alleged 6th-c. smallpox pandemic for centuries: e.g., Paulet Reference Paulet1768a, 79–87; Zinsser Reference Zinsser1935, 124–25 n. 8; Dixon Reference Dixon1962, 190; Hopkins 2002, 24–25. This pandemic co-occurred with plague outbreaks in the 560s through 580s. Catalogues of first pandemic plague outbreaks: Biraben and Le Goff Reference Biraben and Le Goff1969; Stathakopoulos Reference Stathakopoulos2004, 110–54; Harper Reference Harper2017, 304–15.

11 Nearly all scholarship on the pandemic has the outbreak starting in 165, but Harper Reference Harper2017, 99, suggests a vague report of a disease outbreak in Arabia in 156 CE recounted in the Historia Augusta may be the earliest mention of the Antonine plague.

12 E.g., Duncan-Jones Reference Duncan-Jones1996, 109, 116 n. 88; Scheidel Reference Scheidel2001a, 95, 162; Scheidel Reference Scheidel and Scheidel2001b, 31, 74; Greenberg Reference Greenberg2003, 413; Bruun Reference Bruun, Hekster, de Kleijn and Slootjes2007, 201 n. 2; Scheidel Reference Scheidel, Scheidel, Saller and Morris2007, 49; Elliott Reference Elliott2016, 5 n. 8; Erdkamp Reference Erdkamp, Erdkamp, Gilbert Manning and Verboven2021, 435.

13 Emphasized in Gilliam Reference Gilliam1961, 227, 231–34, 248. Cf. Marino Reference Marino and Lo Cascio2012, 53, 56.

14 E.g., Littman and Littman Reference Littman and Littman1973, 254; Lo Cascio Reference Lo Cascio1994, 124–25; Scheidel Reference Scheidel2002, 108; Zelener Reference Zelener2003, 90, 95, 109, 110, 111; Rossignol and Durost Reference Rossignol and Durost2007, 420; Sallares Reference Sallares, Scheidel, Saller and Morris2007, 37; Zelener Reference Zelener and Lo Cascio2012, 168–71, 175–76; Harper Reference Harper2015, 245 (cf. 246 smallpox has “the communicability and fatality rates witnessed” in Cyprianic plague passages); Harper Reference Harper2017, 67–68, 108–9, 116, 229; Duncan-Jones Reference Duncan-Jones2018, 44; Vlach Reference Vlach, Erdrich, Komoróczy, Madejski and Vlach2020, 29, 32, 36.

15 The possibility of concurrent epidemics: Zinsser Reference Zinsser1935, 136–37; Gilliam Reference Gilliam1961, 227; Littman and Littman Reference Littman and Littman1973, 243 n. 3; Newfield Reference Newfield2021.

16 E.g., McNeill Reference McNeill1976, 103, 105; Zelener Reference Zelener2003, 55, 55 n. 124, 85; Rossignol and Durost Reference Rossignol and Durost2007, 420; Livi Bacci Reference Livi Bacci and Lo Cascio2012, 341–44; Zelener Reference Zelener and Lo Cascio2012, 169, 171; Harper Reference Harper2017, 68, 115–16; Duncan-Jones Reference Duncan-Jones2018, 44; Séguy Reference Séguy, Verhagen, Joyce and Groenhuijzen2019, 34. Bagnall Reference Bagnall2013, 714 comments on the popularity of this view.

17 Littman and Littman Reference Littman and Littman1973, 254; Zelener Reference Zelener2003, 55, 55 n. 124, 85; Zelener Reference Zelener and Lo Cascio2012, 169–71; Livi Bacci Reference Livi Bacci and Lo Cascio2012, 341–44, 345. The former argue that the 2nd-c. pandemic (only) killed 7–10 million people because “it was not attacking a virgin population.” Zelener and Livi Bacci also stress the significance of familiarity with smallpox. Bruun Reference Bruun and Lo Cascio2012, 132, suggests that a smallpox diagnosis should cause us to pull back on the alleged significance of the pandemic; had it been plague, for example, Bruun suggests we could expect a higher mortality.

18 E.g., Zelener Reference Zelener2003, 109, 112; Zelener Reference Zelener and Lo Cascio2012, 169, 171; Harper Reference Harper2017, 110.

19 E.g., Littman and Littman Reference Littman and Littman1973, 255; Scheidel Reference Scheidel2001a, 165; Bruun Reference Bruun and Lo Cascio2012, 125; Harper Reference Harper2017, 109, 111, 229; Duncan-Jones Reference Duncan-Jones2018, 44, 50; Vlach Reference Vlach, Erdrich, Komoróczy, Madejski and Vlach2020, 35.

20 Harper Reference Harper2017, 91–93, 99, argued the pandemic originated in East Africa. This idea is rooted in the aforementioned reference to an epidemic in Arabia in Antoninus Pius's reign and, more primarily, a now dated molecular clock study that speculated VARV emerged in East Africa some 3,000–4,000 years ago: Babkin and Babkina Reference Babkin and Babkina2015, 1100, 1104, 1107, 1108. This molecular-clock analysis has proved popular among disease historians (Green Reference Green and Ludden2018; Green and Jones Reference Green, Jones, Campbell and Knoll2020, 38–39; Harper Reference Harper, Izdebski and Mulryan2018, 306; Harper Reference Harper2021, 195–96; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 388, 390), but its divergence estimate does not take into consideration all VARV diversity known now and is not calibrated with paleogenomes (none were available). The analysis also rests on a number of assumptions, for instance, that VARV and related orthopoxviruses have the same substitution rate and that orthopoxviruses have shown great consistency regarding host specificity. The East Africa origin hypothesis assumes that the naked sole gerbil was always, as it is now, the only host of taterapox. Cf. Duggan et al. Reference Duggan, Perdomo, Piombino-Mascali, Marciniak, Poinar, Emery, Buchmann, Duchêne, Jankauskas, Humphreys, Golding, Southon, Devault, Rouillard, Sahl, Dutour, Hedman, Sajantila, Smith, Holmes and Poinar2016 and Porter et al. Reference Porter, Duggan, Poinar and Holmes2017 on VARV molecular clocks.

21 McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 374, 385, 393. Cf. Rossignol and Durost Reference Rossignol and Durost2007, 420.

22 E.g., if the plague was smallpox, it had no animal reservoirs (Rossignol 2012, 463) and did not afflict other animals, as some sources claim (Marino Reference Marino and Lo Cascio2012, 38), and it would have been most prevalent in winter (Duncan-Jones Reference Duncan-Jones2018, 44; Vlach Reference Vlach, Erdrich, Komoróczy, Madejski and Vlach2020, 28; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 391–93, 400).

23 E.g., Scheidel Reference Scheidel2002, 108; Zelener Reference Zelener2003, 48, 90, 92, 98–109, 110; Livi Bacci Reference Livi Bacci and Lo Cascio2012, 341; Zelener Reference Zelener and Lo Cascio2012, 171, 174; Harper Reference Harper2015, 246; Harper Reference Harper2017, 110–11; Flemming Reference Flemming and Petit2019, 224. On the Cyprianic plague, see Harper Reference Harper2015; Huebner Reference Huebner2021.

24 Bagnall Reference Bagnall2013, 714.

25 Zelener Reference Zelener2003, 84; Harper Reference Harper2017, 102.

26 Presentation and epidemiology of VARV: Fenner et al. Reference Fenner, Henderson, Arita, Jezek and Ladnyi1988, 1–68, 169–208; www.cdc.gov/smallpox.

27 Wertenbaker Reference Wertenbaker1902, 349.

28 Regarding VARV infectivity, there are many variables to consider. The R0 (number of people an infected individual can be expected to infect) for smallpox (or more specifically a variola virus that causes smallpox) is debated, with values ranging from 1.5 to 20, depending on a myriad of circumstances; values between 3 and 6 are favored for a fully susceptible population. Serial interval estimates likewise vary. Gani and Leach Reference Gani and Leach2001; Eichner and Dietz Reference Eichner and Dietz2003; LeGrand et al. Reference LeGrand, Viboud, Boelle, Valleron and Flahault2003, 21, 23–24; MacIntyre Reference MacIntyre2020.

29 E.g., Rigau-Pérez Reference Rigau-Pérez1982, 423, 429; Fenner et al. Reference Fenner, Henderson, Arita, Jezek and Ladnyi1988, 1069–1102; Duncan et al. Reference Duncan, Scott and Duncan1993, 406, 407, 409, 410–11, 419; Krebsbach Reference Krebsbach1996, 30–31; Hopkins 2002, 8; Piper and Sandlos Reference Piper and Sandlos2007, 764, 765, 786 n. 24; Livi Bacci Reference Livi Bacci2008, 50, 59, 179, 211, 215, 221; White Reference White2018, 139.

30 Littman and Littman Reference Littman and Littman1973, 254; Fenner et al. Reference Fenner, Henderson, Arita, Jezek and Ladnyi1988, 227, 244, 246; Banthia and Dyson Reference Banthia and Dyson1999, 652–53, 668–69, 677. Some, however, have proposed that smallpox case fatality might surpass 50 percent at first contact.

31 VARV is thought to have been able to achieve endemicity in settlements with at least 200,000–300,000 people or in a tightly knit network of smaller settlements with a total population of that sort, e.g., Fenner et al. Reference Fenner, Henderson, Arita, Jezek and Ladnyi1988, 118; Bartlett Reference Bartlett1960, 37, 42. Some wager smaller centers of 100,000 would be enough: Newson Reference Newson2009, 11.

32 For cyclical epidemics in endemic areas and children as the primary smallpox deaths in endemic areas, e.g., Jannetta Reference Jannetta1987, 20, 57, 77, 88–89; Duncan et al. Reference Duncan, Scott and Duncan1993, 405, 407, 415–17, 420–21; Banthia and Dyson Reference Banthia and Dyson1999, 663–67, 677; Scheidel Reference Scheidel2001a, 94; Krylova and Earn Reference Krylova and Earn2020. Influxes of unexposed persons, possibly in the context of a food shortage or a siege, when previously less-exposed rural populations may have flocked to cities, could, like a build-up of births, result in epidemics.

33 In the Mediterranean region (or in general), as in Zinsser Reference Zinsser1935, 137; Littman and Littman Reference Littman and Littman1973; McNeill Reference McNeill1976, 103–5; Hopkins 2002, 22–23; Harper Reference Harper2017, 67–68, 91–92, 111.

34 E.g., Scheidel Reference Scheidel2001a, 96; Scheidel Reference Scheidel2002, 108; Hopkins 2002, 8, 20; Zelener Reference Zelener2003, 62, 63, 109–10; Andorlini Reference Andorlini and Lo Cascio2012, 16, 24; Zelener Reference Zelener and Lo Cascio2012, 174. Cf. Harper Reference Harper2017, 116, 127; Vlach Reference Vlach, Erdrich, Komoróczy, Madejski and Vlach2020, 33. Zelener Reference Zelener2003, 110, notes that urban mortality in the Antonine plague may have prevented smallpox from establishing endemicity in those cities after the plague.

35 Ruffer and Fergusson Reference Ruffer and Ferguson1911; Smith Reference Smith1912; Ruffer Reference Ruffer1914.

36 Hopkins Reference Hopkins1980; McCollum et al. Reference McCollum, Li, Wilkins, Karem, Davidson, Paddock, Reynolds and Damon2014.

37 E.g., Eeckels et al. Reference Eeckels, Vincent and Seynhaeve1964; Darton et al. Reference Darton, Richard and Truc2013; Tang et al. Reference Tang, Shao, Liu, Wen, Wang, Wang, Peng, Yao and Zuo2021.

38 E.g., d'Entrecolles Reference d'Entrecolles1731; Arouet (Voltaire) Reference Arouet1761, 74; Holwell Reference Holwell1767, 7–8; Cibot Reference Cibot1779, 392, 397; Haeser Reference Haeser1845, 255; Hirsch Reference Hirsch and Hirsch1860, 215–16; Zinsser Reference Zinsser1935, 106–7, 107 n. 1; Dixon Reference Dixon1962, 188.

39 Thuc. 2.48.

40 Littman and Littman Reference Littman and Littman1973, 246–47.

41 Euseb. Hist. eccl. 9.8.1–12.

42 Lien-Teh Reference Lien-Teh1931, 132.

43 Gregory of Tours Hist. 5.34, 6.8, 6.14, 6.15, 8.15, 8.18.

44 Naturally, relevant passages must be read in full. That some clinical and epidemiological features appear smallpox-like and others not has long problematized text-based diagnoses.

45 Consider Flemming Reference Flemming and Petit2019.

46 “Largely,” as physical and written indications of smallpox have been problematically used in some molecular clock studies of VARV's evolutionary history (e.g., Li et al. Reference Li, Carroll, Gardner, Walsh, Vitalis and Damon2007). More recently, such studies have drawn only on irrefutable paleogenetic data (Duggan et al. Reference Duggan, Perdomo, Piombino-Mascali, Marciniak, Poinar, Emery, Buchmann, Duchêne, Jankauskas, Humphreys, Golding, Southon, Devault, Rouillard, Sahl, Dutour, Hedman, Sajantila, Smith, Holmes and Poinar2016; Pajer et al. 2017; Ferrari et al. Reference Ferrari, Neukamm, Baalsrud, Breidenstein, Ravinet, Phillips, Rühli, Bouwman and Schuenemann2020) but contextualize their findings with written evidence. Also “largely” as several of the reconstructed VARV genomes discussed below are dated on the basis of the archaeological context of the individuals whose remains they were recovered from (Mühlemann et al Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020, SI).

47 Flemming Reference Flemming and Petit2019, 236, 240, drew on the earliest of the VARV paleogenomes (Duggan et al. Reference Duggan, Perdomo, Piombino-Mascali, Marciniak, Poinar, Emery, Buchmann, Duchêne, Jankauskas, Humphreys, Golding, Southon, Devault, Rouillard, Sahl, Dutour, Hedman, Sajantila, Smith, Holmes and Poinar2016) and remarked that “the consensus around [the] smallpox [diagnosis of the Antonine plague] needs to be challenged and questions of identification re-opened” via, in part, further genomic work. We report on that work here.

48 E.g., Plasmodium falciparum, malaria, and Mycobacterium tuberculosis, human tuberculosis, in the ancient Mediterranean region: Marciniak et al. Reference Marciniak, Prowse, Herring, Klunk, Kuch, Duggan, Bondioli, Holmes and Poinar2016; Lalremruata et al. Reference Lalremruata, Ball, Bianucci, Welte, Nerlich, Kun and Pusch2013; Yersinia pestis, plague, in Late Antique Europe: Wagner et al. Reference Wagner, Klunk, Harbeck, Devault, Waglechner, Sahl, Enk, Birdsell, Kuch, Lumibao, Poinar, Pearson, Fourment, Golding, Riehm, Earn, DeWitte, Rouillard, Grupe, Wiechmann, Bliska, Keim, Scholz, Holmes and Poinar2014; Feldman et al. Reference Feldman, Harbeck, Keller, Spyrou, Rott, Trautmann, Scholz, Peaffgen, Peters, McCormick, Bos, Herbig and Krause2016; Keller et al. Reference Keller, Spyrou, Scheib, Neumann, Kröpelin, Haas-Gebhard, Päffgen, Haberstroh, Lacomba, Raynaud, Cessford, Durand, Stadler, Nägele, Bates, Trautmann, Inskip, Peters, Robb, Kivisild, Castex, McCormick, Bos, Harbeck and Krause2019.

49 E.g., Mycobacterium tuberculosis, human TB, in the Americas “pre-contact”: Bos et al. Reference Bos, Harkins, Herbig, Coscolla, Weber, Comas, Forrest, Bryant, Harris, Schuenemann, Campbell, Majander, Wilbur, Guichon, Wolfe Steadman, Collins Cook, Niemann, Behr, Zumarraga, Bastida, Huson, Nieselt, Young, Parkhill, Buikstra, Gagneux, Stone and Krause2014; human TB preceding bovine TB and not vice versa: Brosch et al. Reference Brosch, Gordon, Marmiesse, Brodin, Buchrieser, Eiglmeier, Garnier, Gutierrez, Hewinson, Kremer, Parsons, Pym, Samper, van Soolingen and Cole2002; TB and measles virus younger than expected: Furuse et al. Reference Furuse, Suzuki and Oshitani2010; Düx et al. Reference Düx, Lequime, Patrono, Vrancken, Boral, Gogarten, Hilbig, Horst, Merkel, Prepoint, Santibanez, Schlotterbeck, Suchard, Ulrich, Widulin, Mankertz, Leendertz, Harper, Schnalke, Lemey and Calvignac-Spencer2020; Sabin et al. Reference Sabin, Herbig, Vågene, Ahlström, Bozovic, Arcini, Kühnert and Bos2020.

50 Marciniak and Poinar Reference Marciniak, Poinar, Lindqvist and Rajora2019, 123–24; Spyrou et al. Reference Spyrou, Bos, Herbig and Krause2019. First pathogen genome: Bos et al. 2011.

51 Marciniak and Poinar Reference Marciniak, Poinar, Lindqvist and Rajora2019.

52 E.g., Krause-Kyora et al. Reference Krause-Kyora, Susat, Key, Kühnert, Bosse, Immel, Rinne, Kornell, Yepes, Franzenburg, Heyne, Meier, Lösch, Meller, Friederich, Nicklisch, Alt, Schreiber, Tholey, Herbig, Nebel and Krause2018; Ross et al. Reference Ross, Klunk, Fornaciari, Giuffra, Duchêne, Duggan, Poinar, Douglas, Eden, Holmes and Poinar2018; Guzmán-Solís et al. Reference Guzmán-Solís, Villa-Islas, Bravo-López, Sandoval-Velasco, Wesp, Gómez-Valdés, de la Luz Moreno-Cabrera, Meraz, Solís-Pichardo, Schaaf, TenOever, Blanco-Melo and Ávila Arcos2021; Kocher et al. Reference Kocher, Papac, Barquera, Key, Spyrou, Hübler and Rohrlach2021.

53 E.g., Düx et al. 2020; Gryseels et al. Reference Gryseels, Watts, Kabongo Mpolesha, Larsen, Lemey, Muyembe-Tamfum, Teuwen and Worobey2020. Fragility: Duchêne et al. Reference Duchêne, Ho, Carmichael, Holmes and Poinar2020, R1217–18.

54 Biagini et al. Reference Biagini, Thèves, Balaresque, Géraut, Cannet, Keyser, Nikolaeva, Gérard, Duchesne, Orlando, Willerslev, Alekseev, de Micco, Ludes and Crubézy2012; Duggan et al. Reference Duggan, Perdomo, Piombino-Mascali, Marciniak, Poinar, Emery, Buchmann, Duchêne, Jankauskas, Humphreys, Golding, Southon, Devault, Rouillard, Sahl, Dutour, Hedman, Sajantila, Smith, Holmes and Poinar2016; Pajer et al. 2017; Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020; Ferrari et al. Reference Ferrari, Neukamm, Baalsrud, Breidenstein, Ravinet, Phillips, Rühli, Bouwman and Schuenemann2020; Meffray et al. Reference Meffray, Ardagna, Sillano, Parmentier, Pouget, Signoli and Biagini2021.

55 Notably, Biagini et al. Reference Biagini, Thèves, Balaresque, Géraut, Cannet, Keyser, Nikolaeva, Gérard, Duchesne, Orlando, Willerslev, Alekseev, de Micco, Ludes and Crubézy2012; Meffray et al. Reference Meffray, Ardagna, Sillano, Parmentier, Pouget, Signoli and Biagini2021. Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020 likewise present some low-coverage paleogenomes.

56 Esposito et al. Reference Esposito, Sammons, Frace, Osborne, Olsen-Rasmussen, Zhang, Govil, Damon, Kline, Laker, Li, Smith, Meyer, Leduc and Wohlhueter2006; Li et al. Reference Li, Carroll, Gardner, Walsh, Vitalis and Damon2007; Babkin and Babkina Reference Babkin and Babkina2015.

57 For inferences based on VARV's molecular clock: Firth et al. Reference Firth, Kitchen, Shapiro, Suchard, Holmes and Rambaut2010; Duggan et al. Reference Duggan, Perdomo, Piombino-Mascali, Marciniak, Poinar, Emery, Buchmann, Duchêne, Jankauskas, Humphreys, Golding, Southon, Devault, Rouillard, Sahl, Dutour, Hedman, Sajantila, Smith, Holmes and Poinar2016.

58 Cautious concern about the circulation of Clade II VARV in the 2nd c. (Livi-Bacci Reference Livi Bacci and Lo Cascio2012, 345) is, therefore, now unnecessary.

59 For this reason, those genomes are identified as VARV.

60 Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020.

61 Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020, Table I, SI.

62 Emphasized in Newfield et al. Reference Newfield, Duggan and Poinar2020.

63 The significance of aVARV strains not having the full suite of pseudogenized genes of virulent smallpox is hard to overstate.

64 Although the Antonine plague has long been associated with smallpox, that tentative diagnosis is not evidence that aVARV caused a recognizable “ancient form” of smallpox or that the Antonine plague was aVARV. That aVARV behaved and manifested something like smallpox, as has already been multiple times speculated (Harper Reference Harper2021, 195–96; McCormick Reference McCormick2021, 60; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 387–91), is not known.

65 González-Candelas et al. Reference González-Candelas, Shaw, Phan, Kulkarni-Kale, Paraskevis, Luciani, Kimura and Sironi2021; Karim and de Oliveira Reference Karim and de Oliveira2021.

66 Cf. Harper Reference Harper2021, 195, where these aVARV genomes are mischaracterized as both “ancient” and “smallpox,” and said to have a “close resemblance” to VARV. McCormick Reference McCormick2021, 60, assumes the novel aVARV genomes evidence smallpox.

67 Alcamí Reference Alcamí2020.

68 The available evidence of aVARV is scattered over multiple centuries and a large region of northern Europe. Whether aVARV spread quickly or slowly over northern Europe is not known.

69 That it was detected at all indicates that aVARV could, perhaps in concert with comorbidities, kill, but its virulence is unknown. Alcamí Reference Alcamí2020 proposed the disease aVARV caused was mild on the basis of activations of genes associated with virulence and immunomodulation detected by Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020.

70 Haeser Reference Haeser1845, 255.

71 Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020.

72 “By” the fourth century: McCormick Reference McCormick2021, 60.

73 This contrasts with speculation that a smallpox-causing VARV emerged in Late Antiquity: Harper Reference Harper2021, 195–96, and McCormick Reference McCormick2021, 60. That smallpox's emergence dates closer to 1500 than 500 was long ago suggested on the basis of historical evidence, Carmichael and Silverstein, Reference Carmichael and Silverstein1987. The place of Rhazes's detailed account of judari, long read as smallpox (Paulet Reference Paulet1768b, 1–102; Willan Reference Willan and Smith1821, 1–2; Dixon Reference Dixon1962, 187–88; Hopkins 2002, 27; Green Reference Green and Ludden2018, 8; McCormick Reference McCormick2021, 60; cf. Flemming Reference Flemming and Petit2019, 236–40), in the history of smallpox remains to be sorted out, so too other alleged early evidence of smallpox from other world regions.

74 That possible marine reservoir effects have not been accounted for in the radiocarbon dating of the human remains from which aVARV paleogenomes have been reconstructed (Mühlemann et al. Reference Mühlemann, Vinner, Margaryan, Wilhelmson, de la Fuente Castro, Allentoft, de Barros Damgaard, Hansen, Holtsmark Nielsen, Strand, Bill, Buzhilova, Pushkina, Falys, Khartanovich, Moiseyev, Schjellerup Jørkov, Østergaard Sørensen, Magnusson, Gustin, Schroeder, Sutter, Smith, Drosten, Fouchier, Smith, Willerslev, Jones and Sikora2020, SI, 5, 8) is an important issue, as emphasized in McCormick Reference McCormick2021, 60 n. 114, one which could very well pull those remains and the genomes recovered from them closer to the present. The implication is that, if marine reservoir effects have offset the radiocarbon dating, aVARV, and by extension mVARV, would have even less to do with antiquity than already emphasized here and less to do with Late Antiquity too.

75 The reverse was also true. Zelener Reference Zelener2003, 111, observed that to identify smallpox in the Roman world “significantly alters perceptions of Roman demography.” At the same time, the written, skeletal and paleogenetic evidence available for disease in antiquity does not suggest a light disease burden, smallpox or not.

76 Schnurrer Reference Schnurrer1823, 4, 16, 54, 156; Haeser Reference Haeser1845, 255; Zinsser Reference Zinsser1935, 105–6; Dixon Reference Dixon1962, 188; Fenner et al. Reference Fenner, Henderson, Arita, Jezek and Ladnyi1988, 118 (cf. 210); Hopkins 2002, 16–18. Cf. App Reference App2010, 297–362; Newfield et al. Reference Newfield, Marciniak, Cameron-Steinke and Oram2022.

77 Notably, East and South Asia, see, e.g., d'Entrecolles Reference d'Entrecolles1731; Holwell Reference Holwell1767, 7–8; Cibot Reference Cibot1779, 392, 397; and works cited in n. 76.

78 Epidemics reported in Chinese sources have been repeatedly connected to the Antonine plague, and East Asia has sometimes, but not always, been identified as the place of the Antonine plague's origins: e.g., McNeill Reference McNeill1976, 102–3; Duncan-Jones Reference Duncan-Jones1996, 115, 117; Gourevitch Reference Gourevitch2005, 59; Rossignol and Durost Reference Rossignol and Durost2007, 420; Andorlini Reference Andorlini and Lo Cascio2012, 24; Duncan-Jones Reference Duncan-Jones2018, 44–45; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 387.

79 It has been proposed, before and after the identification of aVARV, that the Antonine plague was instead a smallpox ancestor, possibly (in the 2021 publications) aVARV itself: Gourevitch Reference Gourevitch2005, 65; Harper Reference Harper2021, 195–96; McDonald Reference McDonald, Erdkamp, Manning and Verboven2021, 387–91.

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