Emergence and reemergence of smallpox: The need for development of a new generation smallpox vaccine
Introduction
Smallpox is a dangerous infectious disease, known to the mankind since ancient times, which has taken more lives than any other infections or numerous wars. Only in the 20th century over incomplete eight decades with the mass vaccination and intensive struggle with the disease, no less than 300 million people died of smallpox [1].
It was smallpox to protect from which Edward Jenner proposed in 1796 inoculation with the cowpox infectious specimens, referred to as vaccination (from the Latin vache for cow). Moreover, smallpox was the first and yet only dangerous human infectious disease that has been eradicated on a global scale. The causative agent of smallpox is variola virus (VARV), a member of the genus Orthopoxvirus, family Poxviridae. VARV is a strictly anthroponotic virus. The genus Orthopoxvirus also contains three species of zoonotic viruses pathogenic for humans, namely, monkeypox virus (MPXV), cowpox virus (CPXV), and vaccinia virus (VACV). Orthopoxviruses are immunologically cross-reactive and cross-protective, so that the infection with any member of this genus provides protection against infection with any other member of the genus [2].
In 1980 the 33rd World Health Assembly declared the global smallpox eradication and recommended to stop vaccination against smallpox [3], [4]. Currently, the population cohort in all countries of the world with an age before 30 lacks any immunity against both the smallpox caused by VARV and the other human orthopoxvirus diseases. As for the older population cohort earlier vaccinated against smallpox, their immunity against orthopoxvirus infections is weakened [4]. Thus, year after year, the mankind becomes ever less protected against the zoonotic orthopoxvirus infections. Most likely, in last years this is the reason of numerous reports about human diseases caused by the zoonotic viruses MPXV [5], [6], [7], CPXV [7], [8], [9], [10], [11], and VACV-like [12], [13], [14] in various countries. An expanded circulation in human populations can allow these viruses to acquire new properties, thereby making them epidemically dangerous for the mankind.
This brief review summarizes the old archive data on smallpox, history of ancient civilizations, and the most recent data on the genome organization of orthopoxviruses, their evolutionary relationships, and the time points of smallpox emergence. The performed analysis provides the grounds for the hypothesis that smallpox could have emerged several times as a result of evolutionary changes in a zoonotic ancestor virus.
Section snippets
Cross-species virus transmission and emergence of new epidemic diseases
Before considering possible events in the VARV evolutionary history, we will brief the main mechanisms of human viral infections emergence detected so far.
The majority of emerging human pathogens are zoonotic [15], [16], [17], [18]. Most zoonotic pathogens are either not transmissible (directly or indirectly) between humans at all (i.e., humans are a dead-end host) or are only minimally transmissible. Substantial minorities of zoonotic pathogens are capable of some person-to-person transmission
Human zoonotic orthopoxvirus infections
After the global smallpox eradication, the question on possible reemergence of VARV or VARV-like agent became the most topical [19].
Important specific feature of smallpox is that it is an anthroponotic infection, i.e., it can be transmitted only from human to human, and has no natural reservoir. This infection is highly contagious, i.e., it is efficiently transmitted from ill to healthy persons. The other human orthopoxvirus infections, including cowpox and monkeypox, are zoonotic, i.e., the
When did smallpox emerge?
VARV determined very specific clinical manifestations and caused so large-scale epidemics with high mortality rate that many historians and physicians left documentary records about this disease. Part of these records has remained until now and makes it possible with a certain probability to logically assume when and where smallpox emerged [20], [44], [45]. The first nucleotide sequences of complete VARV genome were published in 1993 [33], [34], [42], [46] followed by genome sequencing of other
The stages of VARV evolution
Note that the available archive records are fragmentary and scattered. Moreover, it is not always possible to determine from these records the particular infection that caused a particular epidemic outbreak in the far past. That is why the putative oldest unmistakable descriptions of smallpox date back to the 4th century AD in China and 7th century AD in India and Mediterranean [20]. These descriptions determine smallpox as a primarily child infection, which indicates its stable endemicity as
Conclusions
Our analysis of the genome structure of the orthopoxviruses pathogenic for humans, their evolutionary relationships, and ancient archive records suggests that the highly pathogenic anthroponotic VARV had most likely emerged repeatedly during the history of the mankind. The direct ancestor of VARV is a zoonotic orthopoxvirus with a wide host range that had acquired the ability to infect humans by about 4000 YBP. We postulated that a high human-to-human transmission efficiency of VARV is directly
Acknowledgement
Conflict of interest statement: The author wishes to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
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