He has also worked to identify easily detectable and quantifiable markers for effective immune responses against vaccinia that may be used as a surrogate of immunity to smallpox infection. In the event of a biological attack with smallpox, the results of Dr. In another project, MVM researchers have applied a new technology to identify the vaccinia virus antigens that are responsible for the anti-smallpox humoral and cell-mediated immunity that confers protection against smallpox infection.
The goal of this work has been to identify antigens that would be candidates for use in developing new smallpox vaccines. The technology is called the TAP Transcriptionally Active PCR Express TM system and is a tool that allows hundreds or thousands of antigen genes to be individually amplified in a transcriptionally active form so that their biological function or DNA vaccine immunological potency can be quickly analyzed.
MVM researchers have been applying this technology to the production of all the proteins encoded by vaccinia virus to identify antigens that might be useful for the production of DNA vaccines to smallpox. MVM investigators have also participated in smallpox vaccine trials. They have tested two different smallpox vaccines - the freeze-dried live virus commercial smallpox Dryvax vaccine Wyeth-Lederle Vaccines currently approved for use in the United States and the frozen smallpox vaccine APSV produced by Aventis Pasteur.
Both vaccines were prepared more than 30 years ago. Approximately subjects have participated to date in these studies at BCM. Importantly, these studies showed that the vaccines could remain potent following a fold dilution, effectively increasing a 15 million dose stockpile to million doses. Wendy Keitel. These groups are also planning to evaluate a new generation of smallpox vaccines Modified Vaccinia Ankara and LC16m8 that produce fewer adverse reactions.
The high lethality rate of smallpox is another factor that favors a recent origin of VARV. This feature is frequently typical of viruses that have recently adapted to new hosts. In many cases, further evolution of such viruses leads to decreases in the case fatality rate [ 24 , 25 , 26 ].
An example of such evolution is the history of the application of the myxoma virus genus Leporipoxvirus to control the European rabbit Oryctolagus cuniculus population in Australia. In this case, the lethality rate of myxomatosis rapidly decreased [ 27 , 28 , 29 ]. The origin of the West African MPXV subtype is an additional illustration of the evolutionary strategy of orthopoxvirus.
The emergence of this virus is dated to approximately years ago [ 30 ]. The loss of the complement-binding protein differentiated this subtype from the Central African MPXV strains and resulted in a reduction in the case fatality rate [ 31 ].
Reconstructions of the evolutionary histories of viruses are based on comparisons of their nucleotide or amino acid sequences using the numbers of distinctions as a measure of evolutionary divergence [ 14 , 32 ]. The only successful attempt was that by Biagini et al. Despite a considerable degree of degradation, the extracted specimens were appropriate for sequencing and analyses of the structure of the ancient virus genome; however, this study is not yet complete.
Consequently, the evolutionary history of VARV can be dated based on either the dates from which the VARV-containing samples were isolated or the assumed dates when the different VARV subtypes diverged from their ancestors. It is known that smallpox was exported to Central and South America from West Africa in the early 16th century and caused high case fatality epidemics among the local population.
Subsequent smallpox outbreaks in America had low lethality, and the virus that caused these epidemics acquired the name variola minor alastrim [ 3 , 7 ]. Babkina et al. Importantly, the West African and alastrim VARV strains clustered into two different phylogenetic branches, which led to the assumption of their independent evolution over a certain period of time. The phylogenetic relationships between VARV strains were later confirmed by sequencing of their genomes [ 15 ].
Based on data from RFLP analysis [ 36 ], Babkin assumed that variola minor alastrim originated from the West African VARV strains, and the first attempt to estimate the rate of poxvirus evolution was based on this assumption [ 37 ].
This analysis involved the central conserved region of the orthopoxvirus genomes and was conducted using a strict molecular clock and the maximum likelihood method. Li et al. These authors only analyzed the SNPs that met the requirement of seven nucleotides surrounding an SNP and conserved nucleotides on both its sides.
The complete orthopoxvirus genomes were studied in the evolutionary analysis described in this paper, which included the terminal variable regions of the genomes that were subjected to recombination [ 15 ] and the encoding of the virulence genes, many of which are under adaptive selection [ 16 , 17 , 39 ].
The first analysis was based on the assumption that VARV was imported to the south of Africa in and then colonized the overall continent. However, there are numerous documented records of earlier smallpox spread on this continent; regarding North Africa, VARV was present there at least as early as the 7th century AD [ 3 , 7 ].
The second assumption was based on a description of smallpox in an ancient Chinese manuscript dated to the 4th century AD. Consequently, the authors inferred that VARV either emerged 16, years ago according to in the first case, or 68, years ago in the second case using a strict molecular clock.
The authors suggested that smallpox appeared on the American continent long before Columbus discovered America. This contradicts the historical records that the American population was reduced by almost nine million people over 10 years of colonization due primarily to smallpox [ 3 , 7 ]. Additionally, it is difficult to imagine that the population of VARV-sensitive hosts reached a sufficient density 68, years ago.
In and , Babkin et al. In the former work, the following constraints were used: the time period of the divergence of the VARV alastrim strains from the West African strains did not exceed years, and the time of VARV emergence was less than 10, years ago. The time scale for orthopoxvirus divergent evolution was assessed using a Bayesian dating method and Multidivtime software.
In the latter work, an expanded set of various orthopoxvirus strains was considered. Babkin et al. VARV emergence was estimated to have occurred approximately 3, years ago, and the rate of mutation accumulation was estimated to be 2. Chronogram of the maximum credibility tree for the orthopoxviruses generated with BEAST based on the central conserved regions of their genomes.
The numbers on nodes indicate the time to the most recent common ancestor of the clades years ago. Legend and figure reproduced from [ 30 ]. In , Hughes et al. Firth et al. These authors established the substitution accumulation rates in the genomes of different VARV strains based on the times of their isolations. They obtained slightly higher evolution rates than those reported in previous articles [ 30 , 41 , 42 ], which can be explained by the terminal highly variable regions of the genomes, which were used in the analysis [ 16 , 17 , 39 ].
Kerr et al. The authors studied the attenuation of the myxoma virus following its introduction with the goal of achieving biological control of the European rabbit populations in Australia and Europe. The computed rates for myxoma virus evolution were two- to threefold higher than those of the orthopoxviruses, which is explainable by the rapid adaptation of this virus to its new host, the European rabbit.
One can conclude that most researchers have obtained similar orthopoxvirus evolutionary rates and dates of VARV origin using different approaches. A high density of susceptible hosts was necessary for the origin of these viruses [ 7 , 23 , 24 ]. It is known that the naked sole gerbil Gerbilliscus kempi , which lives in the savannas and dry forests of Africa, is the only host for TATV, whereas the common gerbil Meriones unguncuilatus is not sensitive to TATV [ 47 ].
The fact that these three viruses are closely related suggests the existence of a common ancestral virus with a broad host range. Presumably, this virus affected rodents and was able to infect various representatives of the order Rodentia because the natural hosts of the majority of the current Old World orthopoxviruses e.
The putative natural source of VACV is the horsepox virus, which is known to be pathogenic for rodents [ 48 ]. It is known that CPXV has the broadest range of susceptible hosts and the longest genome of all known orthopoxviruses, and CPXV contains all of the orthopoxviral genes [ 17 , 19 ]. It is currently believed that all orthopoxviruses evolved from a CPXV-like progenitor via the shortening of the genome and mutations of some genes.
These processes resulted in the emergence of narrower, specialized pathogens [ 18 , 39 , 46 ]. The CPXV strains are so genetically diverse that it has been suggested that they should be assigned to separate orthopoxvirus species [ 49 , 50 ]. Researchers have tended to associate the site of VARV emergence with the first historical evidence describing smallpox and with the appearance of the first civilizations that produced large human settlements that allowed a new virus to emerge. Previously, it was noted that the Indian strains did not form a common cluster on the phylogenetic tree [ 52 ].
However, this fact could be explained by the large-scale smallpox epidemics in India in recent times and the subsequent spread of this virus to other Asian regions. Note that the genetic distances between the Indian strains are small on the phylogenetic tree. Indeed, as mentioned above, these three viruses originated from a common ancestral virus. Most probably, this virus was a CPXV-like virus that was able to infect rodents and other mammals. It is known that the naked sole gerbil is the only host of TATV [ 47 ], this rodent species is distributed from West Africa to Ethiopia, and its distribution range is confined by tropical forests in the south and the Sahara Desert in the north Figure 3 [ 53 , 54 ].
Domesticated camels were imported for the first time to Africa, specifically, the Horn of Africa, — years ago, further advanced to Egypt in the 6th—7th century BC, and subsequently spread to other regions of the African continent [ 55 , 56 ]. There is evidence that large settlements existed approximately years ago in the Horn of Africa [ 57 ]. Consequently, the putative area in which these three orthopoxvirus species emerged from a common progenitor might be the Horn of Africa.
This hypothesis supports the dating of VARV emergence because the camel and naked sole gerbil did not meet in the same area before years ago. Babkin and Babkina [ 30 ] assumed that the evolution of a CPXV-like ancestral virus and its further separation into three highly specialized species were triggered by the introduction of the camel, a new potential host with unique antibodies [ 58 , 59 ], and the need for the virus to adjust to changing conditions.
World map. The Black circle denotes the putative region of the origin of the camelid Camelidae ancestors approximately 45 MYA [ 60 ]. The direction of their migration is shown with arrows: 1, migration of the camel ancestors from North America to Asia 2—3 MYA [ 61 ]; and 2, introduction of domesticated camels into East Africa approximately 4 TYA [ 55 , 56 ]; hatched oval: the distribution area of naked sole gerbils [ 53 , 54 ].
The most recognized drivers of pathogen emergence are climate change, destruction of the environment of potential hosts, penetration of the pathogen into a new area, pathogen spread to other populations of hosts, and interactions with the host immune system [ 62 ]. This eruption was one of the largest volcanic events on Earth in recorded history and caused considerable climate changes [ 64 ] that presumably caused the migrations of various mammals and might have forced the evolution of the VARV ancestor.
However, the coincidence of the timing of these climate changes and the emergence of VARV does not prove the relationship between these events. Some authors have focused on the question of which particular changes in the genetic structure of the ancestral virus enable the emergence of VARV and the adaptation to humans. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
You will be subject to the destination website's privacy policy when you follow the link. CDC is not responsible for Section compliance accessibility on other federal or private website. Cancel Continue. Thanks to the success of vaccination, the last natural outbreak of smallpox in the United States occurred in In , the World Health Assembly declared smallpox eradicated eliminated , and no cases of naturally occurring smallpox have happened since.
Smallpox research in the United States continues and focuses on the development of vaccines, drugs, and diagnostic tests to protect people against smallpox in the event that it is used as an agent of bioterrorism.
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