Scientists have identified alterations in the mpox virus genome that potentially correlate with changes in viral transmissibility observed in the 2022 outbreak (Nat Commun 2024;15[1]. doi:10.1038/s41467-024-46949-7).
Mount Sinai scientists with researchers from the Carlos III Health Institute in Madrid, Spain, analyzed samples from 46 patients infected with mpox whose diagnosis and sequencing were carried out at the institute early in the 2022 mpox outbreak. The team sequenced each study participant’s complete mpox virus genome to determine possible correlations between genomic variations in the different groups of sequences and epidemiological links associated with the virus’s ability to evolve, transmit and infect.
According to the research team, recurrent observed genomic changes were in areas of the genome that could be related to viral adaptation. Those specific locations would contribute to modulating the viral replication cycle, adaptability, and path of entry and egress. These alterations appear in areas known as low-complexity genomic regions, which are particularly difficult to sequence and analyze, explaining why they were overlooked before. This highly sophisticated complete genome sequencing was made possible with two advanced sequencing technologies:
- single-molecule, long-read sequencing (to cover highly repetitive regions), and
- deep short sequencing reads (to provide accuracy and depth).
The virus uses a unique evolutionary method that expands and contracts its genome, known as the genomic accordion.
“This reveals significant variation in short tandem repeats within LCRs [low-complexity regions]. We demonstrate that LCR entropy in the MPXV [mpox virus] genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. Silico analyses indicate that expression, translation, stability or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204 and OPG208, could be affected in a manner consistent with the established ‘genomic accordion’ evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability,” the researchers wrote in the paper.
Tpoxx Effective in PLWH
Data from a retrospective cohort study presented at CROI 2024, in Denver, suggest tecovirimat (Tpoxx, SIGA Technologies) is effective in arresting the progression of mpox infection in people living with HIV (PLWH).
“For people living with HIV with known or suspected mpox, especially those with more advanced HIV or more severe mpox (e.g., mucosal involvement at presentation), starting tecovirimat within seven days of symptom onset appears to reduce the risk of mpox progression,” said Bruce Aldred, MD, an assistant professor in the Division of Infectious Diseases at Emory University School of Medicine, in Atlanta, who presented the results (poster 419).
Researchers studied 112 PLWH diagnosed with mpox at four hospitals in Atlanta, between June 1 and Oct. 7, 2022. Half of the patients received tecovirimat within seven days of symptom onset, and the other half was treated either later than seven days after symptom onset or did not receive tecovirimat. Mpox progression occurred in three (5.4%) patients taking tecovirimat in the first seven days compared with 15 (26.8%) in the late or no tecovirimat group.
The study population enrolled 54 of 56 (96.4%) cisgender males in both cohorts and two of 56 (3.6%) transgender females in both cohorts. Among participants, 109 of 112 (97.3%) reported having sex with cisgender male partners, and 84.8% identified as Black. No cisgender females or transgender males were included in the study, “which was simply due to the fact that these populations were much less affected by the 2022 mpox outbreak in the U.S.,” Dr. Aldred explained.
In the early tecovirimat group, the median age was 35 years; 54 were cisgender men, 46 were Black and 10 were other races. In the late or no tecovirimat group, the median age was 36 years; 54 were cisgender men, 49 were Black and seven reported other races or unknown race.
By detailing the alterations within these repetitive genomic sequences and linking them to critical viral functions, the researchers provide a plausible explanation for the increased transmissibility observed during the 2022 mpox outbreak.
“These findings might be offering the first hints to help us understand the unique features of the strains associated with sustained human-to-human transmission, which has not ever been observed in these agents,” said Gustavo Palacios, PhD, a professor of microbiology at the Icahn School of Medicine at Mount Sinai, in New York City, and a senior author of the study. “Better understanding of the doors that facilitate transmission of viral agents and impact their clinical presentations will enable us to develop more effective prevention and treatment strategies.”
Mpox virus is a double-stranded DNA virus that can infect animals and humans. Symptoms include fever, swollen lymph nodes and a rash. Most cases are mild, and patients tend to recover without treatment; however, mpox can be very painful and may lead to permanent scarring.
First encountered in 1958 in crab-eating macaque monkeys imported to Belgium, mpox virus has caused sporadic human disease outbreaks since the 1970s in Central and Western Africa. In May 2022, multiple countries, including the United States, reported an increasing number of mpox infections and associated disease, including clusters in cases with subclade IIb mpox, which were potentially linked to super-spreading events in Belgium, Spain and the United Kingdom.
Although the number of new cases associated with the 2022 spillover has decreased over time, cases are still occurring among unvaccinated individuals, including a current increase in Central Africa due to a new spillover. As the virus’s circulation in humans increases, the risk for emergence of a more transmissible variant capable of becoming endemic in the human population increases, the researchers said.
“Biopreparedness and virological surveillance involves studying the causes that favor zoonotic spillover and facilitates human-to-human transmission. When we observe significant changes in basic epidemiological features of a viral agent like mpox, it should reinvigorate our interest in understanding those transmission conditions. The increasing number of cases currently happening in Africa, and the 2022 epidemic, should be clear alert signals,” Dr. Palacio said.
Dr. Palacio reported no relevant financial disclosures.
This article is from the June 2024 print issue.