The XBB.1.5 Omicron recombinant variant that was first detected in the U.S. (New York and Connecticut) in late October 2022 has now spread to at least 29 countries. It is rapidly increasing in number to become the dominant variant in the U.S., particularly in the northeast part of the country. It has been seen to have a growth advantage and has replaced other variants in a few countries in Europe, as well.
The XBB.1.5 variant has demonstrated a “stunning increase” in prevalence in the U.S, and went from “4% of sequences to 40% in just a few weeks”, Dr. Ashish Jha, White House COVID-19 Response Coordinator tweeted on January 4. As per CDC estimates, the variant is causing 75% of new cases in the northeast part of the U.S.
The XBB.1.5 variant is a descendant of XBB.1, which, in turn, descends from XBB. The XBB variant evolved through recombination of two descendants of the earlier Omicron BA.2 variant. If XBB and XBB.1 already had high transmissibility and higher immune escape, the XBB.1.5 variant is even more transmissible while retaining significant immune escape ability.
A study posted on preprint server BioRxiv, which is yet to be peer-reviewed, found that both XBB.1 and XBB.1.5 “significantly” evaded convalescent plasma samples from BA.1, BA.5, and BF.7 breakthrough infections. However, XBB.1.5 displayed slightly weaker immune evasion capability compared with XBB.1.
The XBB.1.5 variant was first found in India on December 30 last year, and as per INSACOG five XBB.1.5 variants have been detected so far — three cases in Gujarat and one each in Karnataka and Rajasthan.
“XBB.1.5 is the most transmissible variant that has been detected yet,” Dr. Maria Van Kerkhove, an epidemiologist and the WHO’s technical lead on COVID-19 said during a press briefing on January 4. “The reason for the high transmissibility of XBB.1.5 are the mutations within this recombinant sub-variant of Omicron.”
The higher transmissibility of XBB.1.5 will mean that it will be responsible for a larger fraction of COVID-19 cases in many countries and could also drive new surges. While it is too early to say if XBB.15 will have increased severity, there has been a sharp increase in hospitalisations in the U.S.
“The underlying mechanism for such high transmissibility remains unclear,” says Dr. Yunlong Cao from Peking University, Beijing, and one of the corresponding authors of the preprint. As per the authors, the XBB.1.5 variant carries an additional mutation compared with XBB.1 and is outcompeting BQ.1.1 and other XBB sub-lineages.
The additional mutation found on XBB.1.5 renders the virus with “substantially higher” binding affinity with the receptor compared with BQ.1.1 and XBB/XBB.1. And compared with XBB.1, the XBB.1.5 variant has “comparable” antibody evasion but displays distinct transmissibility suggesting that “enhanced receptor-binding affinity would indeed lead to higher growth advantages”.
With stronger immune escape ability than BQ.1.1 but limited by weaker binding affinity, XBB and XBB.1 were recorded only in a few countries. In contrast, with enhanced receptor-binding affinity but comparable antibody evasion, the prevalence of XBB.1.5 demonstrates that receptor-binding affinity will affect the transmissibility, the authors write.
Dr. Akiko Iwasaki, an immunologist at Yale University, says she is concerned because of the “putative ability of XBB.1.5 to have increased capacity to infect cell types that express even lower levels of ACE2”.
The additional mutation seen on XBB.1.5 is the S486P on the spike protein. “It took a longer time for major variants to emerge with mutations at site 486 — BA.4/5 with F486V in spring 2022, and then XBB with F486S later in 2022,” Dr. Jesse Bloom from the Fred Hutchinson Cancer Research Center, Washington tweeted.
The reason why the S486P mutation in XBB.1.5 is under spotlight is because of the rareness. “An amino acid is encoded by three nucleotides in a codon, and almost all mutations involve a change in just one nucleotide. Changes in two of the nucleotides are very rare,” Dr. Vinod Scaria, a senior scientist at the Delhi-based Institute of Genomics and Integrative Biology (CSIR-IGIB) tells The Hindu.
“It’s easy to understand why it took longer for variants to emerge at site 486; mutations at 486 reduce ACE2 [binding] affinity, so the benefit they provide in antibody escape comes at cost to receptor binding,” says Dr. Bloom. One-nucleotide change at the 486 site (F486S) was seen in XBB and XBB.1 variants, too. As expected, while the F486S mutation provided both XBB and XBB.1 variants with greater immune escape, the binding affinity was compromised.
The XBB.1.5 variant fixed the reduced binding affinity seen in XBB and XBB.1 by undergoing changes in two nucleotides to become S486P. “The S486P mutation [in XBB.1.5] only caused a slight reduction in immune evasion capability. However, the S486P mutation greatly enhanced ACE2 binding,” Dr. Cao tweeted. “The fact that XBB.1.5 showed a much superior growth advantage than XBB.1 suggests that receptor-binding affinity does play a big role in SARS-CoV-2 spreading.”
Another important observation made by the authors in the preprint is that the strong receptor binding ability of XBB.1.5 could enable its tolerance of further immune escape mutations. Dr. Cao elaborated this in a tweet: “XBB.1.5’s hACE2 binding affinity is almost comparable to that of BA.2.75, which may enable XBB.1.5 to gain more mutations, similar to what BA.2.75 had. It’s just that XBB.1.5 hasn’t felt much immune pressure yet.”