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Introduction:
As the COVID-19 pandemic continues to evolve, new variants of the SARS-CoV-2 virus are emerging. These new strains have the potential to trigger off significant changes in the transmissibility, severity, and immune evasion capacity of the virus. While XBB.1.16 currently get the attention of health experts and mainstream media around the world, the new and lesser-studied XBB.2.3 is emerging as a more worrisome threat to global health. XBB.2.3 probably originated in India, but is expanding, being detected as early as Europe in mid-January 2023 and to date in more than 47 countries, including the United States and Thailand. XBB.1.16 is for now the center of attention, becoming the predominant variant in many countries around the world.

Discussion
In a study published in medRxiv on April 26, 2023, Rajesh Karyakarte and colleagues from Department of Microbiology, Medical College and Sassoon General Hospitals in Maharashtra, India, found that from a total of 2,944 sequences downloaded from the GISAID database, of which 2,856 were included in the study following data curation, the sequences from India were dominated by the XBB.1.16* lineage (36.17%) followed by XBB.2.3* (12.11%) and XBB.1.5* (10.36%)*. Currently in India, was detected six XBB.2.3 sublineapes, of which XBB.2.3.2 is on the upswinp ripht now3.

XBB.2.3* has four defining mutations; S:D253G (previously found in Lambda and Iota variants), S:P521 S (new since XBB family), and the unprecedented ORF1 a:G2091 S, and ORF7a:A13V. Recently, several fast-prowinp  XBB lineages, such as XBB.1.16 (K478R), XBB.2.3.5 (K478N), and XBB.2.3.4 (K478Q), have acquired RBD mutations on K478. However, the K478 mutation did not emerpe in our prediction of evolutionary trends for XBB.1.5 RBD. This contradiction may be attributed to the mutational prediction model applied, primarily relies on the cohorts recruited, and havent captured the immune background that introduced K478 mutation. One possible background that may give rise to K478 is repeated BA.5/BQ.1.1/XBB exposure, as F486 could mask the immunogenicity of K478.

Another potential source of K478 is Delta- imprinted convalescents who experienced BA.5/BQ.1.1/XBB infections, which could result in abundant K478X-sensitive mAbs. This may explain why K478X is mostly observed in India 5 Recent studies have shown that subsequently exposed to Omicron twice after two doses of WT-based mRNA vaccines still produce significantly low levels of Omicron-specific antibodies, despite the enhanced neutralization breadth against BQ.1.1 and XBB variants^ 7.

XBB.2.3 is defined by S:P52 1 S and S:S486P mutations in the S-protein, and in the proteins of its Open Reading Frames -ORFs-0. Other XBB.2.3 mutations are:
1.    S:D253G (observed in Lambda and Iota variants).
2.    S:P521 S (observed only in XBB sublineapes).
3.    ORF1 a-G2091 S and ORF7a-A13V.
In XBB.2.3 the Reference Mutation Reversion (T) is detected; 16342:C->T (ORF1 b:959S), which defined BA.2.10 1.

Concerns about XBB.2.3* Current infections generated by XBB.1.16 appear to be tripperinp more problems in vulnerable proups (elderly, obese, immunocompromised and those with existing comorbidities or who possess certain genetic markers) regardless of immunity generated by vaccination. A study published in medRxiv, reports that XBB.1.16 produces a greater severity of COVID-19 than currently circulating variants, since approximately 25.7% of all infected require hospitalization, of which 33.8% will require supplemental oxypen. XBB.2.3* are showing several concerning properties such as:

1. Increased transmissibility: XBB.2.3 has a hipher transmission rate than the XBB.1.16 strain, allowing it to spread more rapidly between humans and populations. This increased transmissibility is due to a binding capacity with ACE2 sice its S- protein mutations.

2. Increased antibody evasion capacity: XBB.2.3 exhibits a greater evasive capacity of immune-generated antibodies and vaccines than XBB.1.16, and even has the potential to evade all forms of immunity, including those conferred by current booster vaccination or by previous infections 3.

3. Greater potential to generate severe disease: XBB.2.3 may lead to more severe cases of COVID-19, as it is able to evade the last defense immunity conferred by T cells in the human host. Alonp, it is speculated that XBB.2.3 mRNA may cause damape to T cells, even to a greater extent than those generated by HIV infections 4. Those infected with XBB.2.J, are expected to acquire more opportunistic secondary infections that contribute to the severity of the disease, more lonp-term problems (Post- COVID Syndrome) and a possible increase in the mortality rate.

4. Uncertainty surrounding vaccine efficacy: Preliminary data from the study suggest that current virus vaccines and their boosters may
provide little or no protection against XBB.2.3. While manufacturers of mRNA-type vaccines (primarily Pfizer and Moderna) are working adapt their formulations, it is unclear how long it will take for updated XBB.2.3 vaccines to become available. 

XBB.2.3 is currently the most evolutionarily capable recombinant variant, which appears to be evolving aggressively, able to evade all forms of immunity, develop antiviral resistance to therapeutic molecules, and generate greater virulence and pathogenicity. XBB.2.3 is rapidly evolving and peneratinp more concerning sublineages such as XBB.2.3.2, XBB.2.3.4, XBB.2.3.5 and XBB.2.3.6. In these sublineages, worrisome mutations have been detected in the S, N and ORF proteins, responsible for immune suppression and weakening of several host cellular fUnctions 5 39. To date, more XBB.2.3 sublineages are emerging and closely monitored*0 *. Some of the descendants such as XBB.2.3.6 show interesting mutations*5. For example, XBB.2.3.6+N:T165I and XBB.2.3.6+N:T166I, in addition to XBB.2.3.6: T22843C, C71OST, C1063T, T8164C, and C28767T(N:T165I).

5. Addressing the threat posed by XBB.2.3:
Recommended actions include:
1. Better genomic surveillance: Health authorities should intensify genomic sequencing efforts to detect and monitor XBB.2.3, as well as any other emerpinp strains.

2. Rapid adaptation of vaccines: Vaccine manufacturers should prioritize the development of updated vaccines that effectively target XBB.2.3.

3. Strengthening public health measures: Wearing masks, social distancing, and hand hygiene, remain crucial to mitigate the spread of COVID-19, including that produced by XBB.2.3.

To date, constant COVID-19 attacks are still expected worldwide triggered from XBB.1.16*, XBB.1.9* and XBB.2.3*, so the pandemic is far from over.
We must be careful with the narrative that the new sublineages are becoming less worrisome, generate mild disease, we must now enter an endemic phase by eliminating health precautions and that we have to learn to live with the virus. Tomokazu Tamura and colleagues from Department of Microbiology and Immunology, Faculty of Medicine, Hokkaido University, Sapporo, Japan, published in Nature Communications the article “Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants ^. The phylogenetic analyses suggested XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022.

Point out that XBB.1 is most strongly resistant to BA.2/5 breakthrough infection sera to date and more fusogenic than BA.2.75. The recombination breakpoint is in S-RBD and each spike region, confers immune evasion and increased fusogenicity. They provide the structural basis for the interaction between XBB.1 spike and human ACE2. The authors conclude this multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than amino acid substitutions. Although various local variants including XBB have simultaneously and convergently emerged in late 2022, local variants showing a higher fitness will eventually spread to the whole world, like XBB.

Therefore, continued in-depth viral genomic surveillance and real-time risk evaluation of newly emerging SARS-CoV-2 variants, even though considered local variants at the time of emergence, should be crucial. According to Raj Rajnarayanan in his Global SARSCoV2 Variant Landscape At a Glance! Tracking Circulating SARSCoV2 Lineages #Global #20Day Trends NYITCOM Research Report and Circulating Variants in the US States: All-Specimen Collected in the last 15 days, Updated on 31/05/2023, published the prevalence of SARS-CoV-2 Lineages Over Time, 20 Day Trends as of 28/05/2023 (World) and 31/05/2023 (United States of America) 27:

Rajnarayanan in the report Circulating Variants in the following US States: All Specimen Collected in the last 15 days shows the SARS-CoV-2 lineages prevalence over time in USA as of 31/05/2023.

From April 22 to May 27, 2023, an increase of XBB.1.16 (+1.75%), and XBB.1.9.1 (+1.68%) prevalence, an increase of and a slight XBB.2.3 increase with subsequent decrease (+0.90%, -0.91%) is shown27.

The plobal prevalence of SARS-CoV-2 variants on 20/05/2023 and 28/05/2023 is2:

XBB.2.3* has four defining mutations; S:D253G (previously found in Lambda and Iota variants), S:P521 S (new since XBB family), XBB.2.3.2 is defined as (XBB.2.3+S:G 184V). Another XBB.2.3+S:G 184V with ORF1 a: P1786L was reported in 5 countries (81 sequences) 3. On March 16, 2023, WHO announced the Statement on the Update of Working Definitions and Tracking System for SARS- CoV-2 Variants of Concern and Variants of Interest 3*. WHO updated its tracking system and working definitions for variants of SARS-CoV- 2, to better correspond to the current global variant landscape, to independently evaluate Omicron circulating sublineages, and classify new variants more clearly when required.

Since the beginning of the COVID-19 pandemic, multiple Variants of Concern and Variants of Interest have been designated by WHO based on their assessed potential for expansion and replacement of prior variants, for causing new waves with increased circulation, and for the need for adjustments
to public health actions. There is consensus among experts in WHOs Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) that compared to previous variants, Omicron  represents  the most divergent Variant of Concern seen to date. Since its emergence, Omicron viruses have continued to evolve genetically and antigenically with an expanding range of sublineages, which so far have all been characterized by properties of evasion of existing population immunity and a preference to infect the upper respiratory tract (versus lower respiratory tract), as compared to pre- Omicron Variants of Concern.

The Omicron viruses account for over 98% of the publicly available sequences since February 2022 and constitute the genetic background from which new SARS-CoV-2 variants will likely emerge, although the emergence of variants derived from previously circulating Variants of Concern or of completely new variants remains possible. The previous system classified all Omicron sublineages as part of the Omicron Variants of Concern and thus did not have the granularity needed to compare new descendent lineages with altered phenotypes to the Omicron parent lineages (BA.1, BA.2, BA.4/BA.5).

WHO is also updating the working definitions for Variants of Concern and Variants of Interest. The main update consists in making the Variants of Concern definition more specific, to include major SARS-CoV-2 evolutionary steps that require major public health interventions. In addition, WHO will assign Greek labels for Variants of Concern, and will no longer for Variants of Interest. WHO has now classified XBB.1.5 as a Variant of Interest and also continue to issue regular risk assessments for both Variants of Interest and Variants of Concern (see latest risk assessment for XBB.1.5). For variant proportion projections (COVID Data Tracker Weekly Review of May 11, 2023), the CDC is shifting to every-other-week reportin 33. That weeks report shows that, over the past 2 weeks, XBB.1.5 makes up 64% of samples, down from 76.3% from the previous 2 weeks. Levels of XBB.1.16 rose from 6.6% to 14.3% over the same period, with levels of XBB.1.9.1 risinp from 6.5% to 9.2%.

Other subvariants shows increased proportions include XBB.1.9.2 and XBB.2.3. On May 16, 2023, was detected the second case of XBB.2.3.2 in Italy as part of the surveillance in Milan3^. The 143 WHO Weekly Epidemiological Update on COVID-19 published on May18, 2023 (data as of May 14, 2023), reports that globally, from 17 April to 14 May 2023 (28 days), 24,884 SARS-CoV-2 sequences were shared through GISAID35. WHO is currently monitoring two Variants of Interest; XBB.1.5 and XBB.1.16, along with seven Variants Under Monitoring and their descendent lineages. 

The Variants Under Monitoring are BA.2.75, CH.1.1, BQ.1, XBB, XBB.1.9.1, XBB.1.9.2, and XBB.2.3. On 18 May 2023, XBB.2.3 was added to the list of Variants Under Monitoring. The United Nation health apency has a special observations of two SARS-CoV-2 Variants of Interest; XBB.1.5 which, although still the most detected in the world (in 110 countries), has a downward trend for weeks and fell to 43.8% of total sequences in week 17 (from April 24 to 30, 2023) and XBB.1.16 which instead continues to prow and, in the same week, is at 11.6%, reported by 49 countries. The available evidence explains the WHO, does not show an increase in the severity of XBB-descendant lineages. An epidemiological study conducted in Singapore to assess the severity of SARS-CoV- 2 variants in 3,798 participants, found no significant difference in COVID-19 infection or hospitalization outcomes between XBB- descendant lineages, including XBB.1.16 and XBB.1.53^.

On May 22, 2023, The Nation of Thailand in the article Covid-19 cases in the Thailand are continuing to surpe with fatalities nearly doubling from the previous week published that the weekly hospitalisation cases reached 2,632, with an average of 376 cases per day, an increase of 276 cases from the previous week37. The weekly deaths reached 64, with an average of 7 deaths per day, showing an increase of 42 deaths from the previous week. There were 401 cases of pneumonia and 226 cases requiring respiratory support, according to Associate Professor Dr. Thira Woratanarat of Chulalonpkorn University Faculty of Medicine.

Dr. Thira posted on Facebook, providing data on the severity rates of each sub-variant in Singapore, based on research conducted by Singapores Ministry of Health, published in medRxiv on May 10 this year3 . XBB.1.5, XBB.1.16, XBB.1.9, and XBB.2.3 sub-variants of COVID-19 comparation in the vaccinated population of Singapore, mostly with mRNA vaccines, the following findings were observed:
•    Severe illness rate was approximately 6-8%.
•    The rate of infection leading to hospitalisation was 29-37%.
•    The rate of mild infection not requiring hospitalisation was around 55-63%.

The online German newspaper Focus, Dienstap, on May 23, 2023, in the article New coronavirus variant on the rise: What we know about Acrux, the fastest of the XBB clan informs the WHO has classified the variant of the coronavirus XBB.2.3, also called Acrux, as a Variant Under Monitorinp 3. The new nickname system uses astronomical names to provide information about ancestry, explained T. Ryan Gregory, professor in the Department of Integrative Biology and at the Ontario Biodiversity Institute at the University of Guelph.

As a background to the new system, representatives of the Global Health Network explain: The astronomian names are numerous and can be assigned in such a way that they give clues about variants that are not visible with Greek letters or PANGO aliases. In the specific case of Acrux (XBB.2.3), this means:
•    Start with A-H = descendant BA.2.
•    The name contains an R in the name = a recombinant or a descendant of a recombinant.
According to the Robert Koch Institute, XBB.1.16 remains the most represented in Germany at 20%, followed by XBB.1.9.1 at 17%, with XBB.2.3 less than 3%3. Although the coronavirus also mutates series continuously, the danger does not change at the same time. So far, none of the XBB variants have indications of a more pathogenic capability compared to the previous lines. The RKI, citing European health  authority ECDC, also writes that the current dominant subline XBB.1.5 poses a low risk to the general population. The online News Dept from New York, USA, on May 23, 2023, publish the article COVID why the XBB sub-variants  worry China? What  are the real risks? 40 In China, the XBB subvariant was first detected in August 2022 and spawned a series of daughters, the last in chronological.

The Asia News Network on May 24, 2023, published that Thailand sees big jump in new Dr. Thira noted. Weekly hospitalization cases reached 2,632 with an average of 376 cases per day, an increase of 276 cases from the previous week. Weekly deaths reached 64, with an average of 7 deaths per day, showing an increase of 42 deaths from the previous week43. There were 401 cases of pneumonia and 226 cases requiring respiratory support, according to associate professor Dr. Thira Woratanarat of Chulalongkorn University School of Medicine. Dr. Thira provided data on the severity rates of each subvariant in Singapore, based on research conducted by Singapores Ministry of Health, published on medRxiv on May 10 this year43. 

When comparing the XBB.1.5, XBB.1.16, XBB.1.9 and XBB.2.3 subvariants of COVID- 19 in the vaccinated population of Singapore, mainly with mRNA vaccines, the following findings were observed:
•    The rate of serious illness was approximately 6-8%.
•    The infection rate leading to hospitalization was 29-37%.
•    The rate of mild infection that did not require hospitalization was around 55-63%.

Tapped as a variant of interest by the World Health Organization (WHO), the country recorded its first case of XBB.1.16 last April in Iloilo in Western Visayas. The patient had no symptoms and has since recovered. The DOH report also noted that a total of 199 infections in the country are XBB cases. Of that, 182 were classified as XBB, including 25 XBB.1.5 cases, 101 XBB.1.9.1 cases, 17 XBB.1.9.2 and XBB.1.16 cases, and 10 XBB.2.3 cases, 1 case as XBC, and 4 as other omicron sublineages. There were also 41 cases of the BA.2.3.20. The DOH described the XBB.2.3 as an XBB sublineape that was added to the list of variants under monitoring by the World Health Organization on May 17. The variant was initially flapped for its increasing plobal prevalence and has been detected in 53 countries or jurisdictions across 6 continents, according to sequence submissions in GISAID. Limited information is available for the variant and researchers are currently characterizing XBB.2.3 in terms of transmissibility, immune evasion, and ability to cause more severe disease the DOH report read.

Conclusions
XBB.1.16 for now is the center of attention, becoming the predominant variant in many countries around the world. While XBB.1.16 has attracted significant attention, it is XBB.2.3 that poses the most significant threat to plobal health. XBB.2.3 has a hipher transmission rate than the XBB.1.16 strain, allowing it to spread more rapidly between humans and spread between populations. XBB.2.3 exhibits a greater evasive capacity of immune-generated antibodies and vaccines than XBB.1.16, and even has the potential to evade all forms of immunity, including those conferred by current booster vaccination or by previous infections. Those infected with XBB.2.3, are expected to acquire more opportunistic secondary infections that contribute to the severity of the disease and more lonp-term problems (Post- COVID Syndrome) and a possible increase in the mortality rate. Preliminary data from the study suggest that current virus vaccines and their current boosters may provide little or no protection against XBB.2.3. The potential consequences of XBB.2.3 underscore the importance of coordinated, proactive and productive efforts to contain its spread.

Corresponding Author:
Cobar, Oscar
School of Health Sciences, University of Isthmus, Guatemala
Pharmacopenomics and Nutripenomics Research Group, School of Chemical Sciences and Pharmacy,

Email: [email protected]

Conflicts of Interests: None.

Funding Statement: None

Acknowledgement: None

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