For those in public health, it is time to seriously work with the affected African countries and relevant supranational organisations and help reduce the burden of mpox. It is not acceptable to think this will never be a problem here, or that mpox is a mild disease.

This is relevant to the ongoing mpox outbreak in central Africa, this time caused by a clade Ib virus, which also seems to be accumulating APOBEC3-driven mutations, although we don’t know yet what consequences this is having on the virus.

So it appears that as these enzymes are doing their job introducing mutations to weaken the virus, they also provide novel properties. Definitely an aspect to consider as MPXV continues to evolve.

For those in genomics, there are only 46 nucleotide differences between the 186,000 nucleotide genomes of these viruses! And they are not replication errors, but mutations introduced by human defense enzymes, likely APOBEC3.

It is very difficult to say how these properties contributed to B going global (we discuss some possibilities in the manuscript). However, available reports with clinical data show B generally caused fewer, localised lesions, whereas A caused more lesions with higher dissemination.

Surprisingly, we found the opposite. B disseminated worse than A in cell culture; B had poorer control of several host innate immune pathways than A; and, consistent with all these, B caused milder disease than A in an animal model of infection.

We then studied these viruses side-by-side in the lab at multiple levels. At that point, if anything, we predicted that B, having gone global, would have higher fitness and be more competitive than A in many of these assays.

In 2022 a global outbreak of mpox occurred causing >100,000 cases. The MPXV that caused it (technically, clade IIb lineage B.1) evolved from an MPXV circulating and endemic to West Africa (lineage A.1). So B evolved from A. Remember: A for ancestor.

Thanks to very many who helped, particularly to @Pirbright_Inst and their excellent CL3 facilities. This was led by Becky Sumner (now PI @KCL) and was another fantastic collaboration with @iviromics. A small thread 👇