Studies Warn That Mexican SAR-CoV-2 Variant B.1.1.519 Causes Increased Risk Of Hospitalization, Disease Severity and Death. WHO Still Not Reacting!

B.1.1.519 Variant Researchers are warning that the Mexican variant B.1.1.519 which has been ravaging Mexico for a few months now not only causes an increased risk of hospitalization and disease severity but also increased the risk of mortality. Further just like the Delta and Mu variants, it is spawning sub-variants that are of concern.

 
Two studies have already been published by Mexican researchers, one by detailing the emergence of the variant and the other describing its evolutionary landscape and its clinical impact in Mexico City.
 
https://link.springer.com/article/10.1007/s00705-021-05208-6
 
https://www.medrxiv.org/content/10.1101/2021.09.07.21262911v2
 
In the first study, the research team reported the identification of a potential variant of interest, harboring the mutations T478K, P681H, and T732A in the spike protein, within the newly named lineage B.1.1.519 that rapidly outcompeted the preexisting variants in Mexico and has been the dominant virus in the country during the first trimester of 2021.
 
The overall genome analysis of the viruses in the B.1.1.519 lineage showed the presence of 20 mutations in total, compared to the Wuhan-Hu-1 reference genome sequence (NCBI accession number MN908947). Eleven of these mutations are non-synonymous, and four of them are present in the spike protein. https://link.springer.com/article/10.1007/s00705-021-05208-6/tables/1
 
The B.1.1.519 variant is grouped in an independent clade derived from the clade 20B NextClade classification according to phylogenetic analysis. The B.1.1.519 variant is characterized by nine mutations, four of which are ORF1 substitutions and three spike substitutions.
 
Notably, a T478K mutation is present in the receptor binding domain (RBD), where mutations have been shown to reduce the activity of some monoclonal antibodies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053237/
 
The B.1.1.519 lineage, represented by the vast majority of the reported Mexican sequences, was first identified as a B.1.1.222 lineage. However, the presence of the mutations T478K, P681H, and T732A clearly differentiated it from this lineage, which does not contain these mutations, giving rise to the B.1.1.519 lineage. 
 
An in silico analysis using different potent structures of related strains suggested that the position of the T478K mutation in the S protein is involved in antibody recognition and the receptor binding site. In a deep mutational scanning of the SARS-CoV-2 receptor binding domain, the T478K mutation did not have a significant effect on folding or binding to human angiotensin-converting enzyme 2 (ACE2) . https://pubmed.ncbi.nlm.nih.gov/32841599/
 
It is however speculated that this mutation may be involved in immune evasion, particularly escape from antibody neutralization. https://pubmed.n cbi.nlm.nih.gov/33535027/
 
The P681H mutation is one of the mutations also found in the B.1.1.7 variant detected in the UK. It has been found to increase spike cleavage by furin-like proteases and some speculate that it might increase transmissibility.
 
The T732A mutation and the 69-70 deletion were also found in the in the spike protein. Both are believed to play roles in immune evasion.
 
In the second study, the research team found that the B.1.1.519 Mexican variant with the P681H, T478K, and T732A mutations was responsible for 90% of cases detected in February 2021 in Mexico City.
 
The team reported the effective reproduction number of B.1.1.519 and presents its geographical origin based on phylogenetic analysis. Also investigated was this variants evolution through haplotype analysis, and the most recent haplotypes were identified. The team also examined the clinical impact of patients infected with variant B.1.1.519 compared to individuals infected with non-B.1.1.519 SARS-CoV-2.
 
According to the study, the first patient infected with the B.1.1.519 variant in Mexico City was identified on November 3, 2020, only the second case recorded worldwide.
 
However within Mexico City, the variant frequency increased from 16% to 90% in February 2021 but decreased to 51% in May 2021.
 
It was found that of sequences generated from SARS-CoV-2 infections, variant B.1.1.519 represented 74.3% from November 2020 to May 2021 in Mexico City. The B.1.1.519 variant was detected in 31 countries, making up 55% of cases in Mexico.
 
In order to determine the transmissibility of variant B.1.1.519, the research team studied the effective reproduction number (Rt), which was defined as the average number of secondary cases per primary case at a given time within the year. It was observed that there was a sharp increase in the Rt for the B.1.1.519 variant, up to a value of 2.9 in the second week of December 2020, which corresponded with the increased detection. However, the Rt value began to stabilize in the following months, between 0.5 and 1.
 
Importantly the B.1.1.519 variant was the second most frequently detected in Mexico City. The Rt value for variant B.1.1.519 fluctuated strongly in the months following December, which may have been influenced by the small number of cases associated with this variant. This strong fluctuation differs from other variants detected in that region as other variants stabilized or disappeared as the year progressed.
 
The detailed maximum phylogeny was calculated, which included all SARS-CoV-2 genomes of interest to examine the geographic origin of variant B.1.1.519 and its evolutionary relationship to the B.1.1.222 variant. There are three defined clusters shown in the phylogenetic tree. Two only correspond to the B.1.1.519 and B.1.1.222 variants, with clear separation and a mixed cluster, displaying undefined separation among lineages. This demonstrates that the evolution of this SARS-CoV-2 variant lineage remains unclear, although the mixed cluster formed by variant B.1.1.519 sequences is most closely related to variant B.1.1.222 sequences.
 
The research team studied the clinical impact of the B.1.1.519 variant by analyzing associations between the variant and the number of clinical traits. The only sequences considered for the analyses were those with complete sets of clinical data (N=600).
 
Alarmingly evaluation of the data revealed that patients infected with the B.1.1.519 variant displayed a significant increase in the likelihood of developing symptoms affecting the respiratory tract relative to non-B.1.1.519 variants.
 
Detailed logistic regression models adjusted for viral cycle threshold, number of comorbidities, age, and sex revealed that B.1.1.519 variant was associated with a 1.786-fold increase in shortness of breath, a 1.489-fold increase in chest pain, and a 3.655-fold increase in cyanosis. Also, variant B.1.1.519 was associated with a higher fraction of patients developing serious illness or death.
 
The study team observed that the B.1.1.519 SAR-CoV-2 variant was significantly associated with hospitalization, severe disease, and death. Patients infected with variant B.1.1.519 also appeared to show a higher prevalence of symptoms such as shortness of breath, chest pains, and cyanosis.
 
It should be noted that the more severe outcomes associated with variant B.1.1.519 are similar to those shown with the delta variant. Recent research has shown that infections with the delta variant put patients at a higher risk of severe disease leading to hospitalization.
 
Despite reports sent to the WHO, the rather slow and complacent international health agency still has not elevated the B.1.1.519 variant to that of a Variant of Concern or VOC!
 
Mexican researchers are warning that the variant is still spreading globally and worse, new sub-variants of the B.1.1.591 with unique mutations and deletions are being found and some are worrying the research teams.
 
Both study teams warn that sustained genomic surveillance is critical to identify newly emerging variants. Any significant clinical associations could be of great importance to attempt to contain the pandemic.
 
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