SARS-CoV-2 PQ.16.1.1, PJ.2.1, RF.5.4 Variants and Their Sub-lineages Will Lead a Global COVID-19 Surge That is Just Starting
Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 25, 2026 1 hour, 12 minutes ago
Thailand Medical News: Genomic surveillance networks around the world are registering a quiet but unmistakable uptick in three Omicron-descended lineages that, together with their proliferating sub-lineages, display the combination of geographic expansion, mutational density and early growth signals that historically preceded larger waves. RF.5, PJ.2.1 and PQ.16.1.1 have moved from niche detections to repeated recoveries across Asia, North America and Oceania during the first half of 2026. This
Thailand Medical News report examines their phylogenetic origins, defining genetic changes, sub-lineage diversification and the epidemiological patterns that suggest the early phase of a renewed global increase in SARS-CoV-2 circulation is already under way.
RF.5.4 - From JN.1 Through LF.7 and PY.1.1.1 into Regional Expansion
RF.5.4 belongs to the long BA.2.86/JN.1 continuum that has dominated global sequences since late 2023. Its formal Pango alias is B.1.1.529.2.86.1.1.16.1.7.9.1.1.1.1.5. The lineage path runs JN.1 → LF.7 → PY.1 → PY.1.1 → PY.1.1.1 → RF.5. PY.1.1.1 itself carries the spike mutation S:A435S and ORF1a:M3862I; RF.5 then adds S:M153I and the reversion S:K478T. The RF.5.4 – an Indian-focused branch defined by Orf1a:T1638N (nucleotide C5178A) has become especially prominent, accounting for a substantial share of recent sequenced samples in several Indian states.
Additional markers observed on RF.5 branches include Orf1b:T730I, Orf3a:P42L and N:R204Q.
The RF.5.4 lineage first drew official attention when Andhra Pradesh authorities confirmed four sequenced cases from Kadapa district that were processed at the National Institute of Virology in Pune. During the same mid-2026 window the state recorded sixteen COVID-19 cases and four deaths, all in patients with significant comorbidities. Indian officials claimed that RF.5 produces the familiar mild Omicron clinical picture of sore throat, cough, low-grade fever, headache, fatigue and myalgia and shows no evidence of elevated severity. However, some newer sub-lineages of the RF.5.4 are suspected of driving disease severity and deaths!
A number of Southeast Asian countries currently report higher absolute sequence counts of the variant, consistent with denser sequencing infrastructure and travel links. World Health Organization monitoring remains at the routine level, yet the successive accumulation of spike changes and the clear geographic broadening keep RF.5 under continuous scrutiny.
PJ.2.1: A Long-Branch Saltation Descendant of KP.3.1.1
PJ.2.1 stands out as one of the most mutationally extreme recent saltation or chronic-infection-style lineages. Phylogenetic placement shows it as a distant descendant of KP.3.1.1, itself nested inside the JN.1/BA.2.86 family. The earliest known sequence was recovered in Ontario, Canada, in early August 2025.
Subsequent wastewater detections have been repeated and strongest in the New York City metropolitan area, with additional signals appearing in Florida, Alabama and Utah. Relative to nearer parental branches such as MC.10.1.7, PJ.2.1 carries more than thirty nucleotide substitutions, three to four deletions and two insertions, resulting in over thirty amino-acid changes across the genome. Within the spike protein the most distinctive features are the rare two-nucleotide substitution W452K, the change H445P, and the insertions ins643:PMA
and ins791P.
These alterations sit in regions previously linked to both receptor engagement and antibody recognition. Branch length on public trees is already substantial and is systematically underestimated when insertions are excluded from distance calculations. Internal diversity within the lineage is consistent with prolonged intra-host evolution inside one or a small number of chronically infected individuals followed by limited onward community transmission. Although absolute case numbers remain low, the steady accumulation of wastewater hits across multiple U.S. jurisdictions indicates that PJ.2.1 is no longer confined to its Canadian origin and continues to seed new locations.
PQ.16.1.1 and the Rapidly Diversifying SV Sub-lineages
PQ.16.1.1 sits within the expanding PQ series that descends from XDV.1.5.1.1.8-related branches of the broader JN.1 family. Genomic trackers first noted accelerated growth that appears to radiate outward from mainland China.
Sequences have subsequently been deposited from Liaoning and Shanxi provinces, Singapore, Hong Kong, Taiwan, Queensland and New South Wales in Australia, and scattered sites in North America. Several sub-lineages have already received formal Pango designations under the SV prefix. SV.1 is defined by Orf3a:A23S and has produced further branches that additionally carry S:K679R together with N:G243C. SV.2 is marked by ORF1a:A687T (nucleotide G2324A) and has generated a vigorous Singapore-centered sub-cluster SV.2.1 that also harbors S:I1216V; more than one hundred sequences of this single sub-branch have already been recorded.
SV.4 is characterized by ORF1a:T1001I (C3267T) together with a larger constellation of changes that include S:S256L. Other spike mutations recurring on PQ.16.1.1 branches include S:R190K, S:S680F, S:A222V, S:H445N, S:R214C and S:K444T. These substitutions are concentrated in the N-terminal domain and receptor-binding domain, regions repeatedly shown to influence both transmissibility and antigenic properties. The density of successive spike changes within a relatively short time window is characteristic of lineages that later achieve wider success.
Comparative Evolutionary Strategies and Early Growth Indicators
The three lineages illustrate distinct evolutionary modes operating simultaneously. RF.5 exemplifies progressive community transmission accompanied by incremental mutational refinement along a well-established JN.1-derived backbone. PJ.2.1 represents the classic long-branch saltation pathway that can suddenly inject a highly altered genome into the circulating pool after prolonged intra-host evolution. PQ.16.1.1 and its SV offspring demonstrate rapid regional diversification accompanied by successive waves of additional spike substitutions. Wastewater surveillance, traveler screening and routine clinical sequencing all register rising detection rates across Asia, North America and Oceania through the first half of 2026. Absolute numbers remain modest relative to earlier pandemic peaks, yet the concurrent geographic expansion of multiple antigenically evolving sub-lineages creates favorable conditions for a synchronized upswing once residual population immunity and seasonal factors align.
The density of novel spike changes, particularly the rare substitutions and insertions in PJ.2.1 and the successive SV markers in PQ.16.1.1, underscores the value of ongoing antigenic characterization and the potential need for updated therapeutics.
Public-health laboratories emphasize that high-resolution genomic surveillance remains the primary early-warning system. Platforms such as GISAID, Nextstrain and specialized wastewater dashboards continue to supply the real-time data required to track these lineages. Individuals are advised to maintain basic respiratory hygiene and seek testing promptly when symptoms appear, especially if they belong to higher-risk groups.
The simultaneous rise of RF.5 across South and Southeast Asia, the spread of the highly mutated PJ.2.1 from its Canadian origin into multiple American states, and the China-centered expansion of PQ.16.1.1 with its proliferating SV sub-lineages collectively demonstrate that SARS-CoV-2 retains substantial evolutionary capacity. Their concurrent appearance at a time of relatively low background circulation strongly suggests that the early phase of a potential global increase is already under way, reinforcing the continued importance of vigilant surveillance, transparent data sharing and sustained preparedness measures across public-health systems worldwide.
References:
https://github.com/cov-lineages/pango-designation/issues/3238
https://github.com/cov-lineages/pango-designation/issues/3237
https://github.com/sars-cov-2-variants/lineage-proposals/issues/3386
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