Understanding XD, XE and XF
CLINICAL MATTERS
There has been a recent flurry of news articles on the latest twist in the Covid-19 saga—recombinant SARS-CoV-2 viruses. XD and XF, both recombinants of Omicron and Delta, have been unceremoniously dubbed “Deltacron” by the media. XE, a recombinant of the Omicron sublineages BA.1 and BA.2, has been found to be about 10 percent more transmissible than BA.2. There are fears that XE could cause the next round of Covid-19 spikes worldwide. As is usually the case in these sensationalist headlines, the truth is less alarming. Firm evidence that XD, XE, or XF are real threats is equivocal, and the probability of a major spike in cases from any of these recombinants is not likely if public health standards are observed.
Recombinants can occur when two SARS-CoV-2 lineages are co-circulating in a community. Occasionally, two lineages can simultaneously infect a person, and the viral genetic material can be mixed up during viral replication in the same cell. Covid-19 infection is relatively short-lived, so there is a limited amount of time for the two viral lineages to interact. Viruses in the body are rapidly cleared, especially among vaccinated and boosted persons. In immunocompromised hosts, especially those who are unvaccinated or partially vaccinated, however, viruses can persist in the body for a longer period. A simultaneous infection or superinfection (infected with a second lineage while the first lineage is still active) is more likely to occur under these circumstances and a new recombinant may be generated. These recombinants still need to be transmitted to another susceptible host to persist in the community. If there is no significant survival advantage to the recombinant over the dominant circulating variant, it will likely fizzle out and disappear.
There have probably been many instances of the formation of SARS-CoV-2 recombinants, especially with the enormous number of confirmed Covid-19 cases worldwide, currently numbering 500 million people. Most of these recombinants are sporadic and may not be detected if they do not have a significant advantage over the prevailing variants in the community. Increasing the amount and frequency of genomic surveillance may catch more sporadic recombinants, but these incidentally detected recombinants are mostly inconsequential.
Aside from XD, XE, and XF, there have been earlier recombinants designated XA, XB, and XC. XA is a recombinant of Alpha and B.1.177, XB is a recombinant of B.1.634 and B.1.631, and XC is a recombinant of Delta and Alpha. XD, XE, and XF are getting more attention because both parent sublineages are bad VOCs and are potentially more worrisome. XE is a recombinant of BA.1 and BA.2, which are both sublineages of Omicron. XD and XF are recombinants of BA.1 and Delta. Which parts of which lineages are incorporated into the recombinant’s genome can be seemingly random. There are likely more recombinants out there and more will occur as lineages co-circulate, especially in areas with high case numbers.
XD was previously inaccurately referred to as “Deltacron” by mainstream media. First detected in France in December 2021, it has since been found in Belgium and Denmark. XD has been designated a variant under monitoring (VUM) by the World Health Organization (WHO). It is currently the only recombinant among the VUMs. Since Delta and Omicron both have multiple sublineages, “Deltacron” is a misnomer and not very informative. In addition, the different Delta and Omicron sublineages can recombine in many ways and with differing proportions of the genome of each parent sublineage, so “Deltacron” can refer to any number of combinations of different Delta and Omicron sublineages. Moreover, the designation of Delta and Omicron as variants of concern (VOCs) is a result of these specific lineages exhibiting increased transmissibility and breakthrough infection. XD has not shown any unusual characteristics beyond the infectivity and decreased vaccine susceptibility of its parent sublineages.
If XD is eventually determined (though unlikely) to be a variant of concern, it would then be referred to as Pi (the next letter in the Greek alphabet) and not Deltacron, which is a portmanteau with no scientific significance. XD is more accurately referred to as a combination of the Delta sublineage AY.4 and the Omicron sublineage BA.1, written as AY.4/BA.1. Only the spike protein region of the genome is from BA.1, while the rest is from the Delta sublineage AY.4.
XE is a recombinant of two Omicron lineages BA.1 and BA.2. It consists of a short portion of BA.1 in the ORF1a region (the first part of the SARS-CoV-2 genome) while the rest of the genes are from BA.2. It was first detected in the UK. XE has made headlines recently because, based on modeling and estimates by the UK Health Security Agency, it is about 10 percent more transmissible than BA.2. BA.2 is in turn up to 75 percent more transmissible than the BA.1 Omicron sublineage. Thailand recently detected a patient with the XE recombinant, leading to some anxiety that XE would spread to the Southeast Asian region. The patient only had mild symptoms and recovered. WHO is closely monitoring XE and will determine whether it will receive a VUM, VUI, or VOC designation in the near future.
XF is a mix of BA.1 and Delta. The beginning portion of ORF1a is Delta while the rest of the genome is BA.1. It was first detected in the UK in February 2022. It does not seem to have any growth advantage over other variants of concern at this time. It does not seem to be spreading outside the UK.
The proportion of the genes that make up the different recombinants are shown in the figure below, as reported by the UK Health Security Agency (assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1063424/Tech-Briefing-39-25March2022_FINAL.pdf).
Will our vaccines work against all these new recombinants? At the very least, the current vaccines are expected to continue protecting at a high level (>80 percent) against severe disease, especially if a booster has been given. Since the spike proteins of these viruses are identical to one of their parent sublineages, it is unlikely that the recombinants will be more vaccine-resistant than their “parents.” The spike protein regions of XD and XF are identical to BA.1. The spike protein region of XE is identical to BA.2. We, therefore, expect that these recombinants will more or less respond in the same way to the vaccines (same level of breakthrough infections) as the parent virus with the same spike protein sequence.
This does not mean we should be complacent. The continued low case numbers in the Philippines is because of the adherence to multiple layers of protection—masks, vaccination, boosting, pre-departure testing, and genomic surveillance. The Philippine Genome Center is more than capable of detecting recombinant viruses, both present, and future. If any of these recombinants do make it into the Philippines, these viruses will not find us unprepared as long as we continue to comply with our public health standards.