The Delta variant of the SARS-CoV-2 virus, also known as B.1.617.2, has become the dominant strain of COVID-19 worldwide. First detected in India in late 2020, Delta spread rapidly and led to devastating outbreaks in India and elsewhere. The Delta variant is more transmissible and able to evade some immune responses compared to previous variants. This led many to wonder – could there be an even more dangerous version of Delta emerging? Scientists have continued tracking new variants that are descendants of Delta, several of which have attracted attention as potentially more transmissible or able to evade immunity further. Here we review the data on Delta sublineages to determine which one may represent the strongest version of Delta.
Delta Plus
One notable Delta descendant is known as Delta Plus or AY.1. This sublineage was first detected in India in April 2021 and drew concern due to a mutation in the spike protein called K417N. This same mutation is also found in the Beta variant and is suspected to help the virus evade neutralizing antibodies. Initial reports suggested Delta Plus may be more transmissible than Delta. However, Delta Plus has remained very rare globally. It has been detected in the United States, United Kingdom, India, Japan, Nepal, Poland, Portugal, Russia, and Switzerland among other countries, but represents only a tiny fraction of sequenced cases. There is not sufficient evidence that Delta Plus is significantly more dangerous or transmissible than Delta itself.
AY.4.2
Another Delta sublineage called AY.4.2 has attracted more attention. AY.4.2 was first detected in India in December 2020 but began rising in prevalence in the UK during summer 2021. It is sometimes referred to as “Delta Plus” as well, although it is distinct from the AY.1 Delta Plus lineage. AY.4.2 accounts for Y% of recently sequenced cases in the UK. Initial studies suggested it may be around 10-15% more transmissible than Delta, owing to mutations affecting the spike protein. However, more recent research from the UK Health Security Agency found no evidence AY.4.2 has a significant transmission advantage over Delta. Regarding immune evasion, again early reports suggested it may evade immunity somewhat better than Delta, but the UKHSA found no evidence it is associated with significantly reduced vaccine effectiveness. While AY.4.2 has shown some signs of growth advantages, it does not appear to be substantially more dangerous than Delta itself.
AY.33
AY.33 is another notable Delta sublineage that may pose increased danger. It was first observed in India in late 2020. In August 2022, it accounted for around 20% of cases in the United States. AY.33 contains spike protein mutations that may help it evade neutralizing antibodies. However, direct comparative studies have not yet confirmed that AY.33 is substantially more threatening than other Delta sublineages. More evidence is still needed regarding its transmissibility and immune evasion capabilities before designating it as more dangerous than ordinary Delta.
BF.7
The BF.7 sublineage of Delta was first detected in China in October 2021. Preliminary studies found that it grows faster in human bronchial epithelial cells than BA.5, suggesting a higher replication rate. In autumn 2022, BF.7 began causing increasing shares of COVID-19 infections in countries like Belgium, Germany, France, and Denmark. By October 2022, it accounted for around 10% of new cases in the US as well. BF.7 contains a mutation called R346T in the spike protein, which modeling suggests may substantially enhance ACE2 receptor binding. Along with other mutations, this could plausibly make BF.7 the most immune-evasive Delta subvariant so far. However, concrete lab studies directly comparing BF.7’s antigenic escape properties to other Delta sublineages are still lacking. More research is warranted on whether BF.7 may overtake other Delta descents in the near future.
Key Delta Sublineages
| Sublineage | First detected | Notable mutations | Potential transmission advantage over Delta | Potential immune evasion advantage over Delta |
|---|---|---|---|---|
| Delta Plus (AY.1) | April 2021, India | K417N | Unclear, inconsistent evidence | Suspected but not yet confirmed |
| AY.4.2 | December 2020, India | A222V, Y145H | Likely not significant | Likely not significant |
| AY.33 | Late 2020, India | K26R, V27L, D614G, R646S | Unknown | Plausible but unconfirmed |
| BF.7 | October 2021, China | Q493K, R346T, N501Y | Plausible but unconfirmed | Plausible but unconfirmed |
Transmission Potential
Delta is already an extremely transmissible variant, with its R0 estimated to be around 6-7 compared to 2-3 for the original SARS-CoV-2 ancestral strain. This makes the prospect of a variant with even greater transmission potential concerning. Of the Delta sublineages, BF.7 currently has the most theoretical evidence supporting it being more transmissible than ordinary Delta. The R346T mutation may facilitate ACE2 receptor binding and viral entry, while other mutations could also play a role. However, direct comparative studies of the growth kinetics and cell-to-cell spread between BF.7 and other Delta sublineages are still needed. Real-world epidemiological data shows BF.7 comprises an increasing fraction of cases in multiple countries, but discerning cause and effect is challenging. More controlled studies will be valuable to determine if BF.7 does indeed hold a transmission advantage. For other Delta descendants like AY.4.2 and Delta Plus, the evidence is much weaker that they spread significantly faster than Delta itself.
Immune Evasion Potential
The Delta variant already exhibited increased ability to evade neutralizing antibodies compared to previous SARS-CoV-2 strains. However, its descendants could potentially erode immune protections further. Again, BF.7 is one of the leading candidates based on its mutations and growth trends. The R346T mutation falls within a known antibody epitope region and could modulate antibody binding. Epidemiological data suggests a growth advantage even in highly vaccinated populations. But direct comparisons of antibody evasion to other Delta sublineages are needed. AY.33 also has concerning mutations that could plausibly decrease neutralization. And early reports suggested Delta Plus may modestly reduce neutralization, although subsequent studies found conflicting evidence. Determining which Delta descendant has the most worrisome immune escape properties remains an active area of investigation. Vaccine effectiveness studies and detailed lab testing of antibody evasion will shed more light on this question.
Prevalence and Spread
Despite some Delta sublineages showing potential increased transmissibility or immune evasion, none have yet outpaced ordinary Delta in global or regional prevalence. Delta remains dominant at over 90% of sequenced cases worldwide. The Delta sublineages discussed here have shown some signs of growth advantages in particular countries, but not enough to overtake original Delta anywhere yet. For instance, AY.4.2 rose to about 10% of UK cases but then leveled off. BF.7 and AY.33 are increasing in prevalence in parts of the US and Europe, but still represent a minority of infections. With Delta already being hyper-transmissible, it is a tall order for newer sublineages to demonstrate a substantial enough transmission boost to displace it. More time is needed to assess if any Delta descendants have the evolutionary fitness needed to truly outcompete their progenitor variant. Continued genomic surveillance combined with lab studies will shed light on whether an up-and-coming subvariant can become dominant globally.
Implications for COVID vaccines, treatments, and tests
While Delta sublineages show varying degrees of potential immune evasion, COVID-19 vaccines still provide protection, especially against severe disease and death. For instance, vaccines were 70-75% effective against symptomatic AY.4.2 infection and 90%+ effective against hospitalization. Effectiveness is anticipated to remain high against Delta descendants unless they gain very major new mutations. Vaccine protection may wane faster against newly emerging variants, supporting booster shots. Some antibody therapies are likely to become less effective against sublineages like BF.7. Thus, antiviral pills like Paxlovid and updated RBD-targeting antibody cocktails will grow in importance. Viral tests like PCR should still detect Delta sublineages accurately since they target conserved genomic regions. Overall, vaccines, treatments, and diagnostics continue working against Delta descendants but with possible decreased efficacy in some regards.
Conclusion
Delta remains the overwhelmingly dominant SARS-CoV-2 variant worldwide. But some of its sublineages demonstrate early signs of greater transmissibility, immune escape potential, and growth advantages in certain geographic settings. The strains to watch most closely as potentially the strongest Delta descendants are AY.33, Delta Plus, and especially BF.7. However, definitive conclusions cannot yet be drawn about their advantage over original Delta. More comparative, controlled studies of properties like transmission, cell entry mechanisms, and antibody neutralization are needed to determine if any Delta offspring can meaningfully outcompete their progenitor. With Delta already being massively fit and transmissible, it will likely take a substantial edge in transmission and/or immune evasion capacity for another sublineage to overtake it. Continued genomic surveillance combined with lab follow-up on variants of interest will clarify over time if a descendant of Delta emerges as an even stronger version. The COVID-19 pandemic continues evolving, but vaccines, treatments, and public health measures can still mitigate the toll of SARS-CoV-2, even as new variants arise.