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  1. Fulltext Role of cytokines in the assessment of clinical outcome and neuroimaging findings in patients with tuberculous meningitis
    Tai, Sharon Mei-Ling, Tan, Hong-Yien, Yong, Yean-Kong, Esaki M. Shankar, Yap, Jun-Fai, Tan, Chong Tin, et al.
    Neurology Asia, 2017;22(3):209-220.
    MyJurnal
    Background: Tuberculous meningitis is a life-threatening manifestation resulting from infection
    by Mycobacterium tuberculosis, especially in the developing countries. The molecular aspects of
    pathogenesis of tuberculous meningitis remain poorly understood. We evaluated the correlation of
    cerebrospinal fluid (CSF) and serum cytokine levels with the clinical outcome of 15 HIV-negative
    patients with tuberculous meningitis. We also assessed the association of CSF and serum cytokines
    with neuroimaging of brain findings in the patients.

    Methods: The prospective longitudinal study was
    conducted at the University Malaya Medical Centre between 2012 and 2014. Neuroimaging of the
    brain was performed and the findings of leptomeningeal enhancement, hydrocephalus, tuberculoma,
    infarcts and vasculopathy were recorded. The CSF and serum specimens were analyzed for IL-1ß,
    IL-8, IL-10, IL-18, IP-10, IFN-γ, MCP-1, TGF-ß, VEGF, TNF- α, IL-18BPa and MMP-9. The clinical
    outcome was graded at 3 months based on Modified Rankin scale (mRS).

    Results: On admission and
    at one month of anti-tuberculosis treatment, the CSF levels of IL-8, IL-1β, IP-10, IFN-γ and VEGF
    were elevated in all of the patients. Serum IP-10, MCP-1, IL-1β and IL-8 levels were increased on
    admission and at one month of anti-tuberculosis treatment. There were statistically significant differences
    between good and poor outcome (mRS at 3 months) for CSF IFN-γ (p=0.033), CSF IL-10 (p=0.033)
    and serum VEGF (p=0.033) at one month of treatment. None of the patients showed any association
    between CSF and serum cytokines on admission and at one month of anti-tuberculosis treatment with
    neuro-radiological findings.

    Conclusion: The CSF cytokine levels were not related to TBM disease severity on admission, and
    changes on MRI/CT scans. CSF levels of IFN-γ and IL-10 at one month of anti-tuberculosis treatment
    were associated with clinical outcome at 3 months. CSF cytokine levels on admission were not
    associated with the clinical outcome.
  2. Fulltext Impact of HIV-1 Subtype on the Time to CD4+ T-Cell Recovery in Combination Antiretroviral Therapy (cART)-Experienced Patients
    Chow WZ, Lim SH, Ong LY, Yong YK, Takebe Y, Kamarulzaman A, et al.
    PLoS One, 2015;10(9):e0137281.
    PMID: 26335136 DOI: 10.1371/journal.pone.0137281
    Human immunodeficiency virus type 1 (HIV-1) subtypes have been shown to differ in the rate of clinical progression. We studied the association between HIV-1 subtypes and the rate of CD4+ T-cell recovery in a longitudinal cohort of patients on combination antiretroviral therapy (cART). We studied 103 patients infected with CRF01_AE (69%) and subtype B (31%) who initiated cART between 2006 and 2013. Demographic data, CD4+ T-cell counts and HIV-1 viral load were abstracted from patient medical charts. Kaplan-Meier was used to estimate the time to CD4+ T-cell count increase to ≥350 between subtypes and effects of covariates were analysed using Cox proportional hazards. An 87% of the study population were male adults (mean age of 38.7 years old). Baseline CD4+ T-cell counts and viral loads, age at cART initiation, sex, ethnicity and co-infection did not differ significantly between subtypes. A shorter median time for CD4+ T-cell count increase to ≥350 cells/μL was observed for CRF01_AE (546 days; 95% confidence interval [CI], 186-906 days; P = .502) compared to subtype B (987 days; 95% CI, 894-1079 days). In multivariate analysis, female sex was significantly associated with a 2.7 times higher chance of achieving CD4+ T-cell recovery (adjusted hazard ratio [HR], 2.75; 95% CI, 1.21-6.22; P = .025) and both baseline CD4+ T-cell count (P = .001) and viral load (P = .001) were important predictors for CD4+ T-cell recovery. Immunological recovery correlated significantly with female sex, baseline CD4+ T-cell counts and viral load but not subtype.
  3. Fulltext Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-An Extempore Game of Misfiring with Defense Arsenals
    Vignesh R, Balakrishnan P, Tan HY, Yong YK, Velu V, Larsson M, et al.
    Pathogens, 2023 Jan 29;12(2).
    PMID: 36839482 DOI: 10.3390/pathogens12020210
    The lethal combination involving TB and HIV, known as "syndemic" diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.
  4. Fulltext Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome
    Tan HY, Yong YK, Shankar EM, Paukovics G, Ellegård R, Larsson M, et al.
    J Immunol, 2016 05 15;196(10):4052-63.
    PMID: 27076678 DOI: 10.4049/jimmunol.1502203
    Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.
  5. Fulltext T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses
    Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, et al.
    Front Immunol, 2018;9:2569.
    PMID: 30473697 DOI: 10.3389/fimmu.2018.02569
    T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
  6. Fulltext Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19
    Yong YK, Wong WF, Vignesh R, Chattopadhyay I, Velu V, Tan HY, et al.
    Front Immunol, 2022;13:889196.
    PMID: 35874775 DOI: 10.3389/fimmu.2022.889196
    The dynamics of host-virus interactions, and impairment of the host's immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue.
  7. Fulltext Chronic viral infection compromises the quality of circulating mucosal-invariant T cells and follicular T helper cells via expression of both activating and inhibitory receptors
    Vimali J, Yong YK, Murugesan A, Tan HY, Zhang Y, Ashwin R, et al.
    Res Sq, 2023 Apr 27.
    PMID: 37163092 DOI: 10.21203/rs.3.rs-2862719/v1
    Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we investigated the role of immune activation and compared the quality of T-cell responses in chronic HBV, HCV, and HIV infections. Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and peripheral CD4+ T cells including circulating Tfh cells, CD8+ T cells, and TCR iVα7.2+ MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-α, IFN-γ) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression. The activation marker CD69 was significantly increased in CD4+ hi T cells, while CD8+ MAIT cells expressing IFN-γ were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-α+CD4+ lo T cells, CD69+CD8+ T cells, CD69+CD4+ MAIT cells, PD-1+CD4+ hi T cells, PD-1+CD8+ T cells, Ki67+CD4+ MAIT cells were independently associated with decelerating the plasma viral load (PVL). TNF-α levels showed a positive correlation with increase in cytokine levels and decrease in PVL. Chronic viral infection negatively impacts the quality of peripheral MAIT cells and TFH cells via expression of both activating and inhibitory receptors.
  8. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome
    Tan HY, Yong YK, Andrade BB, Shankar EM, Ponnampalavanar S, Omar SF, et al.
    AIDS, 2015 Feb 20;29(4):421-31.
    PMID: 25565499 DOI: 10.1097/QAD.0000000000000557
    Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin-18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS.
  9. Tuberculosis (TB)-associated immune reconstitution inflammatory syndrome in TB-HIV co-infected patients in Malaysia: prevalence, risk factors, and treatment outcomes
    Tan HY, Yong YK, Lim SH, Ponnampalavanar S, Omar SF, Pang YK, et al.
    Sex Health, 2014 Dec;11(6):532-9.
    PMID: 25200957 DOI: 10.1071/SH14093
    Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication of antiretroviral therapy (ART) in countries with high rates of endemic TB, but data from South-East Asia are incomplete. Identification of prevalence, risk factors and treatment outcomes of TB-IRIS in Malaysia was sought.

    METHODS: A 3-year retrospective study was conducted among TB-HIV co-infected patients treated at the University of Malaya Medical Centre. Simple and adjusted logistic regressions were used to identify the predictors for TB-IRIS while Cox regression was used to assess the influence of TB-IRIS on long-term CD4 T-cell recovery.

    RESULTS: One hundred and fifty-three TB-HIV patients were enrolled, of whom 106 had received both anti-TB treatment (ATT) and ART. The median (IQR) baseline CD4 T-cell count was 52 cells μL(-1) (13-130 cells μL(-1)). Nine of 96 patients (9.4%) developed paradoxical TB-IRIS and eight developed unmasking TB-IRIS, at a median (IQR) time of 27 (12-64) and 19 (14-65) days, respectively. In adjusted logistic regression analysis, only disseminated TB was predictive of TB-IRIS [OR: 10.7 (95% CI: 1.2-94.3), P=0.032]. Mortality rates were similar for TB-IRIS (n=1, 5.9%) and non-TB-IRIS (n=5, 5.7%) patients and CD4 T-cell recovery post-ART was not different between the two groups (P=0.363).

    CONCLUSION: Disseminated TB was a strong independent predictor of TB-IRIS in Malaysian HIV-TB patients after commencing ART. This finding underscores the role of a high pathogen load in the pathogenesis of TB-IRIS; so interventions that reduce pathogen load before ART may benefit HIV patients with disseminated TB.

  10. Identification of a novel second-generation circulating recombinant form (CRF48_01B) in Malaysia: a descendant of the previously identified CRF33_01B
    Li Y, Tee KK, Liao H, Hase S, Uenishi R, Li XJ, et al.
    J Acquir Immune Defic Syndr, 2010 Jun;54(2):129-36.
    PMID: 20386110 DOI: 10.1097/QAI.0b013e3181d82ce5
    A molecular epidemiological investigation conducted among injecting drug users in eastern Peninsular Malaysia in 2007 identified a cluster of sequences (n = 3) located outside any known HIV-1 genotype. Analyses of near full-length nucleotide sequences of these strains from individuals with no recognizable linkage revealed that they have an identical subtype structure comprised of CRF01_AE and subtype B', distinct from any known circulating recombinant forms (CRFs). This novel CRF, designated CRF48_01B, is closely related to CRF33_01B, previously identified in Kuala Lumpur. Phylogenetic analysis of multiple CRF48_01B genome regions showed that CRF48_01B forms a monophyletic cluster within CRF33_01B, suggesting that this new recombinant is very likely a descendant of CRF33_01B. CRF48_01B thus represents one of the first examples of a "second-generation" CRF, generated by additional crossover with pre-existing CRFs. Corroborating these results, Bayesian molecular clock analyses indicated that CRF48_01B emerged in approximately 2001, approximately approximately 8 years after the emergence of CRF33_01B.
  11. Chronic inflammation involves CCL11 and IL-13 to facilitate the development of liver cirrhosis and fibrosis in chronic hepatitis B virus infection
    Wong SW, Ting YW, Yong YK, Tan HY, Barathan M, Riazalhosseini B, et al.
    Scand J Clin Lab Invest, 2021 Apr;81(2):147-159.
    PMID: 33528280 DOI: 10.1080/00365513.2021.1876245
    The pathogenesis involving non-alcoholic fatty liver disease (NAFLD) in the context of chronic HBV (CHB) virus infection requires to be understood for developing improved modalities of diagnosis and treatment. We retrospectively investigated the association between NAFLD and CHB virus infection in the context of liver fibrosis. Among the 522 consecutive CHB patients who underwent transient elastography between years 2013 and 2016, we studied 455 subjects in the current investigation. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) scores were generally higher in patients with steatosis and fibrosis or cirrhosis. Antiviral treatment had significantly reduced the hepatitis B virus (HBV) viral load. Other liver function markers showed a significant positive correlation with both CAP and LSM scores. Plasma IL-13 was independently associated with increased CAP score where every increase of 1 unit of IL-13 was associated with an increase in CAP score by 0.98 unit. CCL11 was independently associated with LSM with every increase of CCL11 by a unit that, in turn, was associated with an increase of LSM score. We found that there was a high concurrence of NAFLD among patients with CHB virus infection. The presence of metabolic syndrome and chronic inflammation in CHB virus-infected patients were two independent factors that led to the progression of liver cirrhosis, with IL-13 playing the key role in linking the metabolic with the inflammatory components.
  12. Fulltext Plasma interleukin-7 correlation with human immunodeficiency virus RNA and CD4+ T cell counts, and interleukin-5 with circulating hepatitis B virus DNA may have implications in viral control
    Vimali J, Yong YK, Murugesan A, Vishnupriya K, Ashwin R, Daniel EA, et al.
    Front Med (Lausanne), 2022;9:1019230.
    PMID: 36405584 DOI: 10.3389/fmed.2022.1019230
    Chronic viral infections represent a leading cause of global morbidity and mortality. Chronic HBV, HCV, and HIV infections result in cytokine perturbations that may hold key implications in understanding the complex disease mechanisms driving virus persistence and/or resolution. Here, we determined the levels of various plasma cytokines using a commercial Bio-Plex Luminex cytokine array in chronic HBV (n = 30), HCV (n = 15), and HIV (n = 40) infections and correlated with corresponding plasma viral loads (PVLs) and liver parameters. We observed differential perturbations in cytokine profiles among the study groups. The cytokines levels positively correlated with PVL and liver transaminases. The monocyte-derived cytokines viz., MIP-1β, IL-8, and TNF-α, and Th2 cytokines like IL-4, IL-5, and IL-13 showed a better correlation with liver enzymes as compared to their corresponding PVLs. Our investigation also identified two cytokines viz., IL-5 and IL-7 that inversely correlated with HBV DNA and HIV PVLs, respectively. Regression analysis adjusted for age showed that every increase of IL-5 by one unit was associated with a reduction in HBV PVL by log10 0.4, whereas, every elevation by a unit of IL-7 was associated with decreased HIV PVL by log10 2.5. We also found that IL-7 levels correlated positively with absolute CD4+ T cell counts in HIV-infected patients. We concluded that plasma IL-5 and IL-7 may likely have a key role on viral control in HBV and HIV infections, respectively. A noteworthy increase in cytokines appears to bear protective and pathological significance, and indeed is reflective of the host's versatile immune armory against viral persistence.
  13. Fulltext Factors Associated With the Decay of Anti-SARS-CoV-2 S1 IgG Antibodies Among Recipients of an Adenoviral Vector-Based AZD1222 and a Whole-Virion Inactivated BBV152 Vaccine
    Selvavinayagam ST, Yong YK, Tan HY, Zhang Y, Subramanian G, Rajeshkumar M, et al.
    Front Med (Lausanne), 2022;9:887974.
    PMID: 35770011 DOI: 10.3389/fmed.2022.887974
    BACKGROUND: The magnitude of protection conferred following recovery from COVID-19 or by vaccine administration, and the duration of protective immunity developed, remains ambiguous.

    METHODS: We investigated the factors associated with anti-SARS-CoV-2 S1 IgG decay in 519 individuals who recovered from COVID-19 illness or received COVID-19 vaccination with two commercial vaccines, viz., an adenoviral vector-based (AZD1222) and a whole-virion-based inactivated (BBV152) vaccine in Chennai, India from March to December 2021. Blood samples collected during regular follow-up post-infection/-vaccination were examined for anti-SARS-CoV-2 S1 IgG by a commercial automated chemiluminescent immunoassay (CLIA).

    RESULTS: Age and underlying comorbidities were the two variables that were independently associated with the development of a breakthrough infection. Individuals who were >60 years of age with underlying comorbid conditions (viz., hypertension, diabetes mellitus and cardiovascular disease) had a ~15 times and ~10 times greater odds for developing a breakthrough infection and hospitalization, respectively. The time elapsed since the first booster dose was associated with attrition in anti-SARS-CoV-2 IgG, where each month passed was associated with an ebb in the anti-SARS-CoV-2 IgG antibody levels by a coefficient of -6 units.

    CONCLUSIONS: Our findings advocate that the elderly with underlying comorbidities be administered with appropriate number of booster doses with AZD1222 and BBV152 against COVID-19.

  14. Fulltext Molecular diversity of HIV-1 among people who inject drugs in Kuala Lumpur, Malaysia: massive expansion of circulating recombinant form (CRF) 33_01B and emergence of multiple unique recombinant clusters
    Chow WZ, Ong LY, Razak SH, Lee YM, Ng KT, Yong YK, et al.
    PLoS One, 2013;8(5):e62560.
    PMID: 23667490 DOI: 10.1371/journal.pone.0062560
    Since the discovery of HIV-1 circulating recombinant form (CRF) 33_01B in Malaysia in the early 2000 s, continuous genetic diversification and active recombination involving CRF33_01B and other circulating genotypes in the region including CRF01_AE and subtype B' of Thai origin, have led to the emergence of novel CRFs and unique recombinant forms. The history and magnitude of CRF33_01B transmission among various risk groups including people who inject drugs (PWID) however have not been investigated despite the high epidemiological impact of CRF33_01B in the region. We update the most recent molecular epidemiology of HIV-1 among PWIDs recruited in Malaysia between 2010 and 2011 by population sequencing and phylogenetic analysis of 128 gag-pol sequences. HIV-1 CRF33_01B was circulating among 71% of PWIDs whilst a lower prevalence of other previously dominant HIV-1 genotypes [subtype B' (11%) and CRF01_AE (5%)] and CRF01_AE/B' unique recombinants (13%) were detected, indicating a significant shift in genotype replacement in this population. Three clusters of CRF01_AE/B' recombinants displaying divergent yet phylogenetically-related mosaic genomes to CRF33_01B were identified and characterized, suggestive of an abrupt emergence of multiple novel CRF clades. Using rigorous maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of CRF33_01Bpol sequences to elucidate the past population dynamics, we found that the founder lineages of CRF33_01B were likely to have first emerged among PWIDs in the early 1990 s before spreading exponentially to various high and low-risk populations (including children who acquired infections from their mothers) and later on became endemic around the early 2000 s. Taken together, our findings provide notable genetic evidence indicating the widespread expansion of CRF33_01B among PWIDs and into the general population. The emergence of numerous previously unknown recombinant clades highlights the escalating genetic complexity of HIV-1 in the Southeast Asian region.
  15. Fulltext Low SARS-CoV-2 viral load among vaccinated individuals infected with Delta B.1.617.2 and Omicron BA.1.1.529 but not with Omicron BA.1.1 and BA.2 variants
    Selvavinayagam ST, Yong YK, Joseph N, Hemashree K, Tan HY, Zhang Y, et al.
    Front Public Health, 2022;10:1018399.
    PMID: 36211690 DOI: 10.3389/fpubh.2022.1018399
    The rapid spread of SARS-CoV-2 variants in the global population is indicative of the development of selective advantages in emerging virus strains. Here, we performed a case-control investigation of the clinical and demographic characteristics, clinical history, and virological markers to predict disease progression in hospitalized adults for COVID-19 between December 2021 and January 2022 in Chennai, India. COVID-19 diagnosis was made by a commercial TaqPath COVID-19 RT-PCR, and WGS was performed with the Ion Torrent Next Generation Sequencing System. High-quality (<5% of N) complete sequences of 73 Omicron B.1.1.529 variants were randomly selected for phylogenetic analysis. SARS-CoV-2 viral load, number of comorbidities, and severe disease presentation were independently associated with a shorter time-to-death. Strikingly, this was observed among individuals infected with Omicron BA.2 but not among those with the BA.1.1.529, BA.1.1, or the Delta B.1.617.2 variants. Phylogenetic analysis revealed severe cases predominantly clustering under the BA.2 lineage. Sequence analyses showed 30 mutation sites in BA.1.1.529 and 33 in BA.1.1. The mutations unique to BA.2 were T19I, L24S, P25del, P26del, A27S, V213G, T376A, D405N and R408S. Low SARS-CoV-2 viral load among vaccinated individuals infected with Delta B.1.617.2 and the Omicron BA.1.1.529 variant but not with Omicron BA.1.1 or BA.2 suggests that the newer strains are largely immune escape variants. The number of vaccine doses received was independently associated with increased odds of developing asymptomatic disease or recovery. We propose that the novel mutations reported herein could likely bear a significant impact on the clinical characteristics, disease progression, and epidemiological aspects of COVID-19. Surging rates of mutations and the emergence of eclectic variants of SARS-CoV-2 appear to impact disease dynamics.
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