Since the first case of SARS-CoV-2 in March 2020, India has witnessed three pandemic waves. Delta (B.1.617.2) and its sublineages caused the second wave, and Omicron (B.1.1.529) and its sublineages (BA.1 and BA.2) are driving the third wave. After the waning of the third wave, India saw a surge in COVID-19 cases from May 2022. On sequencing, these variants were characterised as BA.2 by Pangolin. However, the predominance of BA.2 after the waning of the third COVID wave was unexplainable. Subsequently, the Indian isolates of BA.2 were further classified into sub-lineages BA.2.74, BA.2.75 and BA.2.76.
Since their designation, these new sub-lineages have already spread to over 40 countries. They have acquired additional mutations in their spike protein compared to BA.2. These added mutations, over and above those of the parental BA.2 variant, have raised concerns about their impact on viral pathogenicity, transmissibility, and immune evasion properties of the new variants.
We have been the coordinating laboratory for the surveillance of the SARS-CoV-2 virus in the community in Maharashtra. We receive samples from its attached hospital and various RT-PCR testing laboratories across the State for whole genome sequencing. During our study, a total of 990 RT-PCR positive SARS-CoV-2 samples, with a cycle threshold value (Ct) of less than 25, were processed for whole genome sequencing between June 3 and August 7, 2022. A set of individual-level data was obtained corresponding to the samples. Additional information on the presence of any symptoms, hospitalisation, treatment, comorbidities and vaccination status was collected via a telephonic interview with each patient.
Out of 990 samples sequenced, BA.2.75 (23.03%) was the predominant Omicron sublineage, followed by BA.2.38 (21.01%), BA.5 (9.70%), BA.2 (9.09%), BA.2.74 (8.89%) and BA.2.76 (5.56%). One of the most characteristic features of the SARS-CoV-2 virus has been its rapid evolution during the pandemic. New variants have emerged from time to time with selective advantages, replacing the previously circulating variants and achieving global dominance. When the world was experiencing the latest global outbreak driven by the BA.4 and BA.5 Omicron lineages, India did not see an exponential increase in cases due to these two lineages. This probably could be as both Delta and BA.4/BA.5 share the L452R mutation on the receptor-binding domain (RBD) of spike protein, the convalescent sera from Delta infection may contain L452R-specific neutralising antibodies, which could have impaired the BA.4/BA.5 transmission in India.
Also, BA.2.75 has shown 57-fold higher binding affinity to ACE2 receptors when compared with BA.5, accounting for its higher transmissibility. Another study in a small sample of plasma from post-vaccination Delta infection shows that BA.2.75 is more immune evasive than the BA.4/BA.5 lineages in the Delta-stimulated immune background, which explains why BA.2.75 has a growth advantage over BA.4/BA.5 in India.
The current study indicates that these newly designated BA.2 sublineages caused mild disease with reduced need for hospital admission. Out of 228 cases of BA.2.74, BA.2.75 and BA.2.76 contacted by telephone, 94.30% were symptomatic with mild symptoms, and 5.70% had no symptoms. Around 85.53% cases recovered at home, and 14.47% cases were institutionally quarantined. Recovery with conservative treatment was seen in 92.98% of cases, while 4.83% required additional oxygen therapy.
Only 1.32% cases had poor outcomes resulting in death, and the remaining 98.68% had a good outcome. In animal models, BA.2.75 replicated more efficiently in the lungs of hamsters than other Omicron variants causing focal pneumonia characterised by patchy inflammation in alveolar regions. This finding suggests that the Omicron subvariant, BA.2.75, can cause severe respiratory disease and may affect the clinical outcome in infected humans. The fact that subvariant BA.2.75 contains mutations greater than BA.2 and BA.4/BA.5 raise concern regarding the possibility of reduced sensitivity to therapeutic monoclonal antibodies and antibodies developed by vaccination/natural infection. Among the 228 cases studied, 96.05% cases were vaccinated with at least one dose of COVID-19 vaccine; of these 72.60% had received both doses, 26.03% had also received the precautionary booster dose, while 1.37% had received one dose.
Various studies on the evasion of neutralising antibodies have found that BA.2.75 is 1.8 and 1.1 times more resistant to sera from vaccinated individuals than BA.2 and BA.2.12.1, respectively. Due to presence of mutations G446S and R460K in its spike protein, it has increased resistance to class 1 and 3 monoclonal antibodies but is sensitive to Class 2 monoclonal antibodies. It is also 3.7 times more resistant to Bebtelovimab, the only monoclonal antibody potent against all Omicron subvariants. Also, BA.2.75 has higher resistance to BA.5 induced immunity. This property may make BA.2.75 variant spread efficiently in areas where BA.5 has been widely circulating.
These second-generation variants have the potential to be successfully transmitted across several countries due to the presence of critical mutations and significant growth advantages. It is, however, unclear as to what extent the intrinsic virulence of the virus and the immunity due to vaccination or previous infections could have contributed to mild disease in India. The ability of the SARS-CoV-2 virus to evolve continuously and achieve increased transmission and immune evasion reinforces the importance of vaccination and sustained epidemiological surveillance to detect the emerging variants.
(The authors are from the Department of Microbiology, Byramjee Jeejeebhoy Government Medical College (BJGMC), Pune)
