The World Health Organization (WHO) is considering classifying the monkeypox outbreak in non-endemic countries as a Public Health Emergency of International Concern (PHEIC). It is the highest global alert level, a distinction exhibited by covid-19 and polio.
The motives? From May 6 to June 22, 2022 More than 3,300 cases of monkeypox have been confirmed in at least 42 different countries.. The disease is endemic in West and Central African countries, and until now confirmed cases outside these regions have been associated with importations from endemic areas. Now the situation is different, so the outbreak is considered unusual and worrying.
For this reason, international efforts have focused on sequencing the virus causing the outbreak, to characterize the pathogen, identify the origin, track its distribution, analyze genetic diversity, guide diagnosis, conduct research, evaluate viral dynamics and learn the evolutionary trajectory of the pathogen, among other facets.
It belongs to clade 3, of low lethality
The results obtained have confirmed that all the strains in the current outbreak are closely grouped and that they belong to clade 3 of monkeypox virus. Clade 3, like clade 2, is included in the lineage formerly called “West Africa”. Clade 2 and 3 monkeypox virus is most frequently reported from areas from western Cameroon to Sierra Leone. It generally has a case fatality rate of less than 1%. In contrast, clade 1 viruses, formerly designated the “Central African” lineage, are more aggressive and achieve a case-fatality rate greater than 10%.
The fast increase in cases is disturbing. The strong clustering of sequences suggests that the ongoing outbreak has a single initial origin. Silent person-to-person transmission does not seem feasible, considering the known characteristics of the disease, which generally involves localized or generalized skin lesions in affected individuals. Cryptic transmission in an animal host in a non-endemic country also does not seem likely.
However, it is possible that the rapid overflow and magnification of the disease has occurred through superspreading events, such as mass social gatherings with mass sexual encounters.
It’s mutating at high speed
In addition, the current situation leads us to a worrying fact, and that is that the monkeypox viruses responsible for the outbreak diverge an average of 50 SNPs (Single Nucleotide Polymorphism) regarding the most related monkeypox viruses that were responsible for the outbreaks that occurred in the years 2018 and 2019 in the United States, Israel and Singapore. A SNP is a point mutation in the DNA sequence that affects a single nucleotide of a genome sequence. Previous estimates of the mutation rate in orthopoxviruses, such as the monkeypox virus, used 1 to 2 substitutions per site per year, so fifty changes in such a short time could represent a accelerated evolution of the virus.
Many of the mutations found so far are silent because they don’t change any of the viral proteins. However, at least twenty-one of the mutations found cause changes in these proteins. At present it is difficult to predict the effect that these individual mutations may have on the virus, but based on the known function of viral proteins from other orthopoxviruses, and with the aim of being analyzed and closely monitored, they can be classified into low, medium and high priority.
Of these mutations, there are three (D209N, P722S, M1741I), which are located in the B21 protein, which produce changes in three amino acids and which are ranked high priority. Previous studies indicate that monkeypox B21/22 family glycoproteins could be a important target for antibodies.
A mutant that eludes the immune system?
Although outbreak clade mutations are distributed throughout the genome, the existence of a small subset of mutations in important proteins that may be involved in virus transmission, virulence, or interaction with antiviral drugs is of concern.
On the other hand, the observed hypermutation may suggest the potential action of APOBEC3-type enzymes, which are part of the innate defense system. These enzymes have the ability to edit viral DNA and block virus replication so they can inhibit a wide range of viruses by introducing mutations. However, on some occasions, they fail to completely stop virus replication. This increases the probability that hypermutated (“edited” by the enzymes) but viable variants will emerge, with altered characteristics that allow them, among other things, to escape the immune response.
Whether the excess mutations observed in monkeypox virus is a direct consequence of APOBEC3-mediated genome editing in the human host cannot be discerned at this time.
Given the scenario, the current trajectory of disease incidence is uncertain. But it seems logical to think that the first signs of microevolution of this virus have appeared during human-to-human transmission, so adaptation of the pathogen to humans may be ongoing.