SARS-CoV-2 BA.3 Variant Returns in South Africa but This Time with More Than 57 New Mutations!

Medical News: A Shocking Resurgence
In a development that has stunned virologists and public health experts worldwide, the BA.3 variant of SARS-CoV-2 - a once-diminished member of the Omicron family - has re-emerged in South Africa, now boasting an astonishing 57 mutations in its spike protein alone, alongside 120 nucleotide substitutions compared to the original Wuhan strain. First identified during the early Omicron wave in late 2021, BA.3 had faded into obscurity as newer subvariants dominated.


SARS-CoV-2 BA.3 Variant Returns in South Africa but This Time with More Than 57 New Mutations!
Image: AI-Generated
 
However, routine surveillance by South African virologists between November 2024 and January 2025 has uncovered three highly divergent sequences of this variant, detected in two distinct regions of the country. This unexpected comeback signals a potential new chapter in the ever-evolving saga of COVID-19, raising alarms about the virus’s capacity for dramatic evolutionary leaps.
 
The re-emergence of BA.3 is not just a surprising plot twist - it’s a stark reminder of SARS-CoV-2’s relentless adaptability. With over 57 amino acid changes in its spike protein, this hyper-mutated strain could pose significant challenges to the immunity conferred by vaccines and prior infections. While it’s not currently spreading rapidly, its presence in multiple regions suggests a capacity for transmission that could escalate under the right conditions. South Africa, long a sentinel for viral variants since detecting the original Omicron in November 2021, once again finds itself at the forefront of this global health mystery, prompting urgent questions about what drove this transformation and what it might mean for the world.
 
A Three-Year Evolution in Hiding
Scientists suspect that this BA.3 variant’s dramatic mutation profile stems from nearly three years of intrahost evolution within a chronically infected individual - likely someone with a weakened immune system. As many past Medical News reports have shown, South Africa has a huge population of individuals with HIV, many them immunocompromised.
 
Chronic infections provide a unique environment where SARS-CoV-2 can accumulate mutations over time, experimenting with genetic changes that might otherwise be weeded out in a broader population. This “saltation” event, where the virus undergoes a sudden evolutionary jump, mirrors patterns seen in other highly divergent variants, such as BA.2.87.1, and suggests that chronic infections could serve as hidden reservoirs for future viral threats.
 
South Africa’s robust genomic surveillance, bolstered by a network of labs established in 2020 with support from the World Health Organization (WHO) and the Africa CDC, has been crucial in catching this early signal. A December 2024 WHO call for enhanced genomic surveillance across Africa, following the emergence of new variants with higher transmissibility, aligns perfectly with this discovery, underscoring the continent&am p;rsquo;s critical role in global pandemic monitoring.
 
Yet, the question lingers: Why BA.3, and why now? Researchers are racing to unravel whether these mutations enhance transmissibility, immune evasion, or disease severity, drawing on South Africa’s history of identifying variants like 501Y.V2 (B.1.351), which quickly dominated in 2021 due to its advantageous mutations.
 
Mutations That Could Redefine the Threat
The BA.3 variant’s mutation tally - 57 amino acid changes and 120 nucleotide substitutions - is staggering, particularly in the spike protein, which SARS-CoV-2 uses to invade human cells. These mutations cluster in regions critical for immune recognition and cell entry, potentially allowing the virus to dodge antibodies generated by vaccines or previous infections.
 
There have been specific changes, such as the elimination of the N-terminal domain (NTD) disulfide bond (via P9L and ∆136-147), the addition of new glycans at N101, N185, N354, and N529, and the loss of ORF7ab and ORF8 genes through an over-800-nucleotide deletion - similar to patterns seen in late-XBB variants like GW.5.1.1.
https://github.com/cov-lineages/pango-designation/issues/2909
 
This genetic streamlining, coupled with the retention of the N17 glycan (lost in many Omicron subvariants but regained here due to the absence of T19I), suggests evolutionary pressures favoring a more agile, immune-evasive virus. The variant’s resemblance to a 2023 New York BA.1 sequence, which also featured S:A852K and other shared mutations, hints at convergent evolution in chronic infections, a phenomenon researchers are now scrutinizing for clues about viral adaptation. While the full impact on vaccine efficacy and disease severity remains unclear, the potential for BA.3 to challenge existing defenses cannot be ignored, especially given its parallels with past variants that outcompeted their predecessors.
 
A Global Wake-Up Call
As of March 12, 2025, the reappearance of BA.3 in South Africa serves as a sobering wake-up call for the global community. After a relatively mild COVID-19 winter wave in 2025, the emergence of this novel variant underscores the virus’s ongoing evolution, even as case numbers decline worldwide. A January 2025 WHO report warned of emerging variants despite falling global infections, positioning BA.3 as a potential wildcard in the pandemic’s next phase. If this strain acquires transmission-enhancing mutations - like BA.2.86 did to become JN.1 - it could spark a new wave, especially in a landscape where JN.1 variants may have weakened over time, forced to adopt infectivity-reducing changes to evade broadening immunity.
 
For now, BA.3’s slow spread offers a window for action. The Africa CDC and international partners are likely to intensify sequencing and monitoring, leveraging South Africa’s lab network to track its trajectory. Public health measures like vaccination, masking, and distancing remain vital, as emphasized by WHO’s Dr. Matshidiso Moeti in 2024, even against new variants.
 
Some view the new BA.3 emergence as a testament to the virus’s cunning, while others see it as a call for renewed vigilance.
 
Whether this hyper-mutated BA.3 fades away like BA.2.87.1 or surges to global prominence, its emergence highlights the need for sustained surveillance and international cooperation. South Africa’s role as an early warning system, combined with the virus’s unpredictable nature, reminds us that the fight against COVID-19 is far from over - requiring agility, science, and solidarity to meet whatever challenges lie ahead.
 
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