CLINICAL MATTERS
Delta plus is a word combination that sent many people into a panic when it was reported in media in October. To those familiar with the havoc that the Delta variant wreaked in India and globally, the only thing that could possibly be worse is the Delta plus.
Delta plus, or specifically AY.4.2 in this case, is a second-generation sublineage of Delta. This makes it the figurative grandchild of the original Delta. Delta plus has been used to loosely refer to any Delta sublineage showing one or more significant mutations, with proven onward transmission of the mutation or mutations. Sublineages arise as more people are infected by a lineage and new mutations accumulate. Since Delta is the most transmissible and the most widespread SARS-CoV-2 variant to date, it has spawned many, many sublineages.
Delta is officially designated as B.1.617.2 in the PANGO lineage system. PANGO lineage is one of the more widely used nomenclature systems developed to keep track of variants. AY.4.2 can also technically be written as B.1.617.2.4.2. The first generation of Delta sublineages could technically have been designated B.1.617.2.x. PANGO lineage nomenclature rules state that when there are more than three numbers after the letter of the lineage, a new letter or combination of letters is assigned.
AY was the assigned letter combination for sublineages of Delta. As of the time of this writing, there are at least 95 first-generation sublineages of Delta numbered AY.1 to AY.95. The parent sublineage of AY.4.2 is AY.4. AY.4 was first described in India but has been circulating most prominently in the UK. It has not been designated a variant of concern apart from being a sublineage of Delta, and it has not yet exhibited increased transmissibility or immune evasion beyond Delta. It has the signature mutation C7851T, which has not been shown to confer any survival advantage over the Delta variant for now.
AY.4.2 is the second sublineage of AY.4 and was first described in the UK. It has additional mutations on the spike protein Y145H and A222V. Scientists started tracking AY.4.2 when it was noted that an increasing proportion of the viruses being sequenced in the UK was AY.4.2. When this phenomenon occurs, it suggests that a lineage may have a survival advantage over other circulating lineages. Since the predominant circulating variant in the UK currently is Delta, AY.4.2 may have a potential advantage over and above Delta. Preliminary estimates put this possible increased transmissibility of AY.4.2 at about 10 to 15 percent more than that of Delta. While this is nothing like the two to three-fold increase in transmission of Delta compared to the original Wuhan virus, the baseline transmission being at least at the level of Delta is concerning. The rate of increase in proportion of sequences isn’t as large as the previously demonstrated rapid replacement of Alpha by Delta. In the US and the UK, Delta almost completely replaced Alpha as the dominant variant in just a few weeks. It remains to be seen if AY.4.2 will sustain its slow takeover or just stabilize or fade away.
The message here is that it is still too early to determine if AY.4.2 is a more dangerous lineage than Delta. The World Health Organization (WHO) designates three levels of risk for variants in decreasing order: variants of concern (VOCs), variants of interest (VOIs), and variants under monitoring (VUMs). VOCs are proven to have either increased transmission or increased immune evasion or both. AY.4.2 is a sublineage of Delta so it is at the very least as dangerous as Delta and is considered a VOC equivalent. If there is emerging evidence that AY.4.2 has further advantages over Delta, it may be designated as a new VOC. There is currently not enough data to make this determination, and vaccines and public health standards targeted toward Delta should still work. Meanwhile, closer monitoring is warranted to track its spread and minimize its potential impact, especially if it turns out to be a new VOC.
A variant under monitoring that was recently detected in the Philippines and made some headlines is B.1.1.318. It has been reported in many countries. It has multiple spike protein mutations, which may enable better immune system evasion. It was detected in a returning overseas Filipino during facility-based quarantine. Currently, there is no evidence of onward community transmission. This case shows how important it is to continue genomic surveillance and proper quarantine procedures for returning travelers.
Two lineages that were recently in the news in the Philippines were Lambda (C.37) and P.3 (formerly the VOI Theta). Lambda remains on the VOI list along with one other variant. There have been no further detections of Lambda in the country since the first case, and it does not seem to be gaining headway against Delta globally. Lambda and the circumstances of its detection locally were discussed in a previous column (mb.com.ph/2021/08/24/whos-afraid-of-lambda/). As predicted, it has not really been as problematic as Delta. P.3 continues to be detected locally but has neither achieved dominance nor exhibited any significant immune evasion or increased transmissibility, which is why it was removed by WHO from the VOI list.
Mutations for SARS-CoV-2 are a fact of life. Lineages and sublineages will emerge and expand as long as there continue to be COVID-19 infections. Fortunately, widespread vaccination is starting to have an impact on the diversity of SARS-CoV-2. Even with the risk of breakthrough infections from the Delta variant, preliminary data show that breakthrough infections in fully vaccinated individuals are less likely to generate new variants than infections among the unvaccinated. The source of new variants will likely be from countries with low vaccination rates. Therefore, a global effort to reduce the transmission of COVID-19 in all countries will benefit everyone. The best way to prevent the emergence of variants is to deny the virus susceptible hosts. Prioritizing primary vaccination of all eligible populations will decrease the risk of variant emergence. Ending the pandemic and the emerging threat of new variants is best achieved by ensuring equitable distribution and access to COVID-19 vaccines.