Ancestral Strain Research Articles

In-silico evaluation of the T-cell based immune response against SARS-CoV-2 omicron variants

During of COVID-19 pandemic, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has continuously evolved, resulting in the emergence of several new variants of concerns (VOCs) with numerous mutations. These VOCs dominate in various regions due to increased transmissibility and antibody evasion, potentially reducing vaccine effectiveness. Nonetheless, it remains uncertain whether the recent SARS-CoV-2 VOCs have the ability to circumvent the T cell immunity elicited by either COVID-19 vaccination or natural infection. To address this, we conducted in-silico analysis to examine the impact of VOC-specific mutations at the epitope level and T cell cross-reactivity with the ancestral SARS-CoV-2. According to the in-silico investigation, T cell responses triggered by immunization or prior infections still recognize the variants in spite of mutations. These variants are expected to either maintain their dominant epitope HLA patterns or bind with new HLAs, unlike the epitopes of the ancestral strain. Our findings indicate that a significant proportion of immuno-dominant CD8 + and CD4 + epitopes are conserved across all the variants, implying that existing vaccines might maintain efficacy against new variations. However, further in-vitro and in-vivo studies are needed to validate the in-silico results and fully elucidate immune sensitivities to VOCs.

Tissue resident memory T cells contribute to protectionagainst heterologousSARS-CoV-2 challenge.

Widespread vaccination and natural infection have resulted in greatly decreased rates of severe disease, hospitalization and death after subsequent infection or reinfection with SARS-CoV-2. New vaccine formulations are based on circulating strains of virus, which have tended to evolve to more readily transmit human to human and to evade the neutralizing antibody response. An assumption of this approach is that ancestral strains of virus will not recur. Recurrence of these strains could be a problem for individuals not previously exposed to ancestral spike protein by vaccination or infection. Here, we addressed this question by infecting mice with recent SARS-CoV-2 variants and then challenging them with a highly pathogenic mouse-adapted virus closely related to the ancestral Wuhan-1 strain (SARS2-N501YMA30). We found that challenged mice were protected from death and substantial weight loss, even though they generally had low or no neutralizing antibody response to SARS2-N501YMA30 at the time of reinfection. T cell depletion from the previously infected mice did not diminish infection against clinical disease, although it did result in delayed kinetics of virus clearance in the nasal turbinate and in some cases, in the lungs. Levels of tissue resident memory T cells were significantly elevated in the nasal turbinate of previously infected mice compared to mice that had no previous exposure to SARS-CoV-2. However, this phenotype was not seen in lung tissues. Together, these results indicate that the immune response to newly circulating variants afforded protection against re-infection with the ancestral virus that was at least in part T cell based.

Antimicrobial Resistance Development in vitro: Adaptive Laboratory Evolution Method (Review)

INTRODUCTION. High rates of emergence and spread of antimicrobial resistance (AMR) necessitate the rapid development of novel antibacterial medicinal products. The assessment of the microbial potential for AMR development under controlled conditions in vitro can save resources during drug development and marketing authorisation and contribute to creating the most effective medicinal products.AIM. The aim was to determine the possibility of the use of the adaptive laboratory evolution (ALE) method to study the development of antimicrobial resistance.DISCUSSION. A variety of methods can be used to investigate the mechanisms of AMR and the influence of medicinal products on the evolution of bacteria towards AMR. One of the options is the ALE method. ALE experiments are conducted under controlled conditions with prolonged exposure of microorganisms to an antibacterial agent. ALE experiments can include serial transfers of microorganisms to fresh liquid media or Petri dishes, as well as continuous cultivation of microorganisms in a chemostat. ALE protocols are used to develop resistance to different antibacterial agents and require meticulous control of the experimental conditions. To obtain reliable results in an experiment, it is necessary to identify parameters that may affect AMR development in microorganisms. These parameters include but are not limited to the concentration of the antibacterial agent, the number of consecutive passages, the duration of incubation.CONCLUSIONS. To achieve the necessary conditions for resistant microorganisms to form, it is essential to adhere strictly to ALE setup requirements, such as using antibacterial agents at subinhibitory or dynamically increasing concentrations (relative to the minimum inhibitory concentrations for the ancestral strain), performing a certain number of passages for ≥20 generations, and incubating cultures until the stationary phase. Despite the fact that ALE experiments are rather lengthy, these studies can reduce the potential waste of resources on developing new compounds that may have to be discontinued at the stage of production because of AMR development.

The evolution of gene expression plasticity during adaptation to salt in Chlamydomonas reinhardtii.

When environmental change is rapid or unpredictable, phenotypic plasticity can facilitate adaptation to new or stressful environments to promote population persistence long enough for adaptive evolution to occur. However, the underlying genetic mechanisms that contribute to plasticity and its role in adaptive evolution are generally unknown. Two main opposing hypotheses dominate - genetic compensation and genetic assimilation. Here we predominantly find evidence for genetic compensation over assimilation in adapting the freshwater algae Chlamydomonas reinhardtii to 36g/L salt environments over 500 generations. More canalized genes in the high-salt (HS) lines displayed a pattern of genetic compensation (63%) fixing near or at the ancestral native expression level, rather than genetic assimilation of the salt-induced level, suggesting that compensation was more common during adaptation to salt. Network analysis revealed an enrichment of genes involved in energy production and salt-resistance processes in HS lines, while an increase in DNA repair mechanisms was seen in ancestral strains. In addition, whole-transcriptome similarity amongst ancestral and HS lines displayed the evolution of a similar plastic response to salt conditions in independently reared HS lines. We also found more cis-acting regions in the HS lines; however, the expression patterns of most genes did not mimic that of their inherited sequence. Thus, the expression changes induced via plasticity offer temporary relief, but downstream changes are required for a sustainable solution during the evolutionary process.

Humoral and cellular immune responses in vaccinatedandunvaccinated children following SARS-CoV-2 Omicron infection.

The immune response in children elicited by SARS-CoV-2 Omicron infection alone or in combination with COVID-19 vaccination (hybrid immunity) is poorly understood. We examined the humoral and cellular immune response following SARS-CoV-2 Omicron infection in unvaccinated children and children who were previously vaccinated with COVID-19 mRNA vaccine. Participants were recruited as part of a household cohort study conducted during the Omicron predominant wave (Jan to July 2022) in Victoria, Australia. Blood samples were collected at 1, 3, 6 and 12 months following COVID-19 diagnosis. Humoral immune responses to SARS-CoV-2 Spike proteins from Wuhan, Omicron BA.1, BA.4/5 and JN.1, as well as cellular immune responses to Wuhan and BA.1 were assessed. A total of 43 children and 113 samples were included in the analysis. Following Omicron infection, unvaccinated children generated low antibody responses but elicited Spike-specific CD4 and CD8 T-cell responses. In contrast, vaccinated children infected with the Omicron variant mounted robust humoral and cellular immune responses to both ancestral strain and Omicron subvariants. Hybrid immunity persisted for at least 6 months post infection, with cellular immune memory characterised by the generation of Spike-specific polyfunctional CD8 T-cell responses. SARS-CoV-2 hybrid immunity in children is characterised by persisting SARS-CoV-2 antibodies and robust CD4 and CD8 T-cell activation and polyfunctional responses. Our findings contribute to understanding hybrid immunity in children and may have implications regarding COVID-19 vaccination and SARS-CoV-2 re-infections.

Escape of SARS-CoV-2 Variants KP.1.1, LB.1, and KP3.3 From Approved Monoclonal Antibodies.

First-generation anti-SARS-CoV-2 monoclonal antibodies (mAbs) used for prophylaxis or therapeutic purposes in immunocompromised patients have been withdrawn because of the emergence of resistant Omicron variants. In 2024, 2 novel mAbs, VYD222/Pemivibart and AZD3152/Sipavibart, were approved by health authorities, but their activity against contemporary JN.1 sublineages is poorly characterized. We isolated authentic JN.1.1, KP.1.1, LB.1, and KP.3.3 viruses and evaluated their sensitivity to neutralization by these mAbs in 2 target cell lines. Compared to ancestral strains, VYD222/Pemivibart remained moderately active against JN.1 subvariants, with a strong increase of 50% Inhibitory Concentration (IC50), reaching up to 3 to 15 µg/mL for KP3.3. AZD3152/Sipavibart neutralized JN.1.1 but lost antiviral efficacy against KP.1.1, LB.1, and KP3.3. Our results highlight the need for a close clinical monitoring of VYD222/Pemivibart and raise concerns about the clinical efficacy of AZD3152/Sipavibart.

SARS-CoV-2-Specific T-Cell as a Potent Therapeutic Strategy against Immune Evasion of Emerging COVID-19 Variants.

Despite advances in vaccination and therapies for coronavirus disease, challenges remain due to reduced antibody longevity and the emergence of virulent variants like Omicron (BA.1) and its subvariants (BA.1.1, BA.2, BA.3, and BA.5). This study explored the potential of adoptive immunotherapy and harnessing the protective abilities using virus-specific T cells (VSTs). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VSTs were generated by stimulating donor-derived peripheral blood mononuclear cells with spike, nucleocapsid, and membrane protein peptide mixtures. Phenotypic characterization, including T-cell receptor (TCR) vβ and pentamer analyses, was performed on the ex vivo-expanded cells. We infected human leukocyte antigen (HLA)-partially matched human Calu-3 cells with various authentic SARS-CoV-2 strains in a Biosafety Level 3 facility and co-cultured them with VSTs. VSTs exhibited a diverse TCR vβ repertoire, confirming their ability to target a broad range of SARS-CoV-2 antigens from both the ancestral and mutant strains, including Omicron BA.1 and BA.5. These ex vivo-expanded cells exhibited robust cytotoxicity and low alloreactivity against HLA-partially matched SARS-CoV-2-infected cells. Their cytotoxic effects were consistent across variants, targeting conserved spike and nucleocapsid epitopes. Our findings suggest that third-party partial HLA-matching VSTs could counter immune-escape mechanisms posed by emerging variants of concern.

The Platform Trial In COVID-19 Priming and BOOsting (PICOBOO): The immunogenicity, reactogenicity, and safety of different COVID-19 vaccinations administered as a second booster (fourth dose) in AZD1222 primed individuals aged 50-

PICOBOO is a randomised, adaptive trial evaluating the immunogenicity, reactogenicity, and safety of COVID-19 booster strategies. We report data for second boosters among individuals 50-<70 years old primed with AZD1222 (50-<70y-AZD1222) until Day 84. Immunocompetent adults who received any first booster ≥three months prior were eligible. Participants were randomly allocated to BNT162b2, mRNA-1273 or NVX-CoV2373 1:1:1. The concentrations of ancestral anti-spike immunoglobulin were summarised as the geometric mean concentrations (GMC). Reactogenicity and safety outcomes were captured. Additional analyses including neutralising antibodies were performed on a subset. ACTRN12622000238774. Between Mar 2022 and Aug 2023, 743 participants were recruited and had D28 samples; 155 belonged to the 50-<70y-AZD1222 stratum. The mean adjusted GMCs (95% credible intervals) were 20,690 (17 555-23 883), 23,867 (20 144-27 604) and 8654 (7267-9962) U/mL at D28 following boosting with BNT162b2, mRNA-1273 and NVX-CoV2372, respectively, and 10,976 (8826-13 196), 15,779 (12 512-19 070) and 6559 (5220-7937) U/mL by D84. IgG against Omicron BA.5 was 2.7-2.9 times lower than the ancestral strain. Limited neutralisation against Omicron subvariants was found following all vaccines. Severe reactogenicity events were <4%. All vaccines were immunogenic with more rapid waning after mRNA vaccines. These data support boosting with vaccines with greater specificity for circulating Omicron subvariants.

Time-course analysis of antibody and cytokine response after the third SARS-CoV-2 vaccine dose

The widespread administration of an additional dose of the SARS-CoV-2 vaccine has been promoted across adult populations, demonstrating a robust immune response against COVID-19. Longitudinal studies provide crucial data on the durability of immune response after the third vaccination. This study aims to explore the antibody response, neutralizing activity, and cytokine response against the SARS-CoV-2 ancestral strain (wild-type) and its variants during the timeline before and after the administration of the third vaccine dose. Anti-spike antibody titers and neutralizing antibodies blocking ACE2 binding to spike antigens were measured in 62 study participants at baseline, and on days 7, 21, and 180 post-vaccination. Cytokine levels were assessed at the same points except for day 180, with an additional measurement on day 3 post-vaccination. The analysis revealed no substantial variation in anti-spike antibody titer against the SARS-CoV-2 ancestral strain between the pre-vaccination phase and three days following the third dose. However, a significant nine-fold increase in these titers was observed by day 7, maintained until day 21. Although a decrease was observed by day 180, all participants still had detectable antibody levels. A similar trend was noted for neutralizing antibodies, with a four-fold rise by day 7 post-vaccination. At day 180, a diminution of neutralizing antibody titers was evident for both wild-type and all variants, including Omicron subvariant. A transient increase in cytokine activity, notably involving components of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, such as CXCL10 and IL-10, was observed within three days after the third dose. This study underscores a distinct amplification of humoral immune response seven days following the third SARS-CoV-2 vaccine dose and observes a decline in neutralizing antibody titers 180 days following the third dose, thus indicating the temporal humoral effectiveness of booster vaccination. A short-term cytokine surge, notably involving the JAK/STAT pathway, highlights the dynamic immune modulation post-vaccination.

Methotrexate and Tumor Necrosis Factor Inhibitors Independently Decrease Neutralizing Antibodies after SARS-CoV-2 Vaccination: Updated Results from the SUCCEED Study.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied the effects of methotrexate and tumor necrosis factor inhibitor (TNFi) on neutralization responses after COVID-19 vaccination in immune-mediated inflammatory disease (IMID). Methods: Prospective data and sera of adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and systemic lupus (SLE) were collected at six academic centers in Alberta, Manitoba, Ontario, and Quebec between 2022 and 2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between five laboratories, and each lab's results were analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for the effects of methotrexate and TNFi were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID-19 vaccinations (number/type), and infections in the 6 months prior to sampling. The adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for the ancestral strains and the Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) were RA, and the remainder were PsA, SpA, and SLE. The mean age was 57 (62.2% female). For both the individual labs and the meta-analyses, the adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval (CI) 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

CircRNA based multivalent neuraminidase vaccine induces broad protection against influenza viruses in mice

Developing broad-spectrum influenza vaccines is crucial for influenza control and potential pandemic preparedness. Here, we reported a novel vaccine design utilizing circular RNA (circRNA) as a delivery platform for multi-subtype neuraminidases (NA) (influenza A N1, N2, and influenza B Victoria lineage NA) immunogens. Individual NA circRNA lipid nanoparticles (LNP) elicited robust NA-specific antibody responses with neuraminidase inhibition activity (NAI), preventing the virus from egressing and infecting neighboring cells. Additionally, the administration of circRNA LNP induced cellular immunity in mice. To achieve a universal influenza vaccine, we combined all three subtypes of NA circRNA-LNPs to generate a trivalent circRNA vaccine. The trivalent vaccine elicited a balanced antibody response against all three NA subtypes and a Th1-biased immune response in mice. Moreover, it protected mice against the lethal challenge of matched and mismatched H1N1, H3N2, and influenza B viruses, encompassing circulating and ancestral influenza virus strains. This study highlights the potential of delivering multiple NA antigens through circRNA-LNPs as a promising strategy for effectively developing a universal influenza vaccine against diverse influenza viruses.

Current status and clinical outcomes of pharmacotherapies according to SARS-CoV-2 mutations in patients with mild-to-moderate COVID-19: a retrospective single center study

BackgroundDuring the pandemic period, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutated, leading to changes in the disease’s severity and the therapeutic effect of drugs accordingly. This study aimed to present the actual use of therapeutics and clinical outcomes based on the prevalence of each variant using real-world data.MethodsWe analyzed the electronic medical records of adult patients admitted to Busan Medical Center after confirming coronavirus disease 2019 (COVID-19) from February 1, 2020, to June 30, 2022. Patients with mild-to-moderate COVID-19 who were at a high risk of disease progression were selected as study subjects, and the time period was classified according to the variants as ancestral strain, Delta variant, or Omicron variant. We compared drug use status and clinical outcomes by time period.ResultsAmong all 3,091 patients, corticosteroids were the most commonly used therapy (56.0%), being used most frequently in the Delta variant (93.0%), followed by the Omicron variant (42.9%) and ancestral strain (21.2%). Regdanvimab accounted for the majority of therapeutic use in the Delta variant (82.9%) and ancestral strain (76.8%), whereas remdesivir was most frequently used during the Omicron variant period (68.9%). The composite outcomes of death or disease aggravation were ranked in the order of the Delta variant, Omicron variant, and ancestral strain (14.5, 11.9, and 6.0%, respectively, P < 0.001).ConclusionRegdanvimab was primarily used during the ancestral strain period, regdanvimab plus corticosteroids during the Delta variant period, and remdesivir during the Omicron variant period. The rate of death or disease aggravation was highest in the Delta variant, followed by the Omicron variant and the ancestral strain.

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial

Most individuals show immunity to SARS-CoV-2 from vaccination or infection, or both. We aimed to determine the safety and immunogenicity of an omicron-containing COVID-19 vaccine (mRNA-1273.222) in vaccine-naive adolescents who were SARS-CoV-2 positive. Part 3 of the phase 2/3 TeenCOVE trial was a phase 3, open-label, single-arm part done in the USA and the Dominican Republic that enrolled healthy, vaccine-naive adolescents (aged 12-17 years) to receive two 50 μg doses of mRNA-1273.222 (ancestral strain Wuhan-Hu-1 and omicron subvariants BA.4 and BA.5), 6 months apart. Primary reactogenicity and safety outcomes included assessment of solicited local or systemic adverse reactions 7 days after vaccination, and unsolicited and prespecified adverse events throughout study participation. Inferred effectiveness (primary immunogenicity outcome) was established by comparing neutralising antibody responses 28 days after dose 1 of mRNA-1273.222 in SARS-CoV-2-positive adolescents with responses 28 days after dose 2 of mRNA-1273 100 μg primary series in SARS-CoV-2-negative young adults (aged 18-25 years) from the COVE trial. This study is registered with ClinicalTrials.gov (NCT04649151). Between Dec 21, 2022, and June 5, 2023, 379 adolescents (378 of whom were SARS-CoV-2 positive) received at least one mRNA-1273.222 dose and were included in the safety analysis set. The reactogenicity profile was favourable compared with the mRNA-1273 primary series, with no new safety concerns identified. Unsolicited adverse events were reported in 49 (13%) of 379 participants; no deaths or adverse events leading to study discontinuation were reported. The immunogenicity set included 245 adolescents from the per-protocol immunogenicity subset who were SARS-CoV-2 positive at baseline and 296 young adults who were SARS-CoV-2 negative. Compared with the mRNA-1273 primary series in SARS-CoV-2-negative young adults, a single dose of mRNA-1273.222 induced superior (geometric mean ratio [GMR] 95% CI lower bound >1) neutralising antibody responses against omicron BA.4 and BA.5 (GMR 48·95 [95% CI 44·21-54·21]) and non-inferior (GMR 95% CI lower bound >0·667) neutralising antibody responses against ancestral SARS-CoV-2 (GMR 4·25 [95% CI 3·69-4·88]) in SARS-CoV-2-positive adolescents. In vaccine-naive, SARS-CoV-2-positive adolescents, single-dose mRNA-1273.222 was effective against COVID-19 based on successful immunobridging to the two-dose mRNA-1273 primary series in young adults. The findings support a simplified single-dose vaccination schedule with variant-containing mRNA vaccines, regardless of previous vaccination status. Moderna.

Constraint on boric acid resistance and tolerance evolvability in Candida albicans.

Boric acid is a broad-spectrum antimicrobial used to treat vulvovaginal candidiasis when patients relapse on the primary azole drug fluconazole. Candida albicans is the most common cause of vulvovaginal candidiasis, colloquially referred to as a "vaginal yeast infection". Little is known about the propensity of C. albicans to develop BA resistance or tolerance (the ability of a subpopulation to grow slowly in high levels of drug). We evolved 96 replicates from eight diverse C. albicans strains to increasing BA concentrations to test the evolvability of BA resistance and tolerance. Replicate growth was individually assessed daily, with replicates passaged when they had reached an optical density consistent with exponential growth. Many replicates went extinct quickly. Although some replicates could grow in much higher levels of BA than the ancestral strains, evolved populations isolated from the highest terminal BA levels (after 11 weeks of passages) surprisingly showed only modest growth improvements and only at low levels of BA. No large increases in resistance or tolerance were observed in the evolved replicates. Overall, our findings illustrate that there may be evolutionary constraints limiting the emergence of BA resistance and tolerance, which could explain why it remains an effective treatment for recurrent yeast infections.

SARS-CoV-2 infection results in a unique lung proteome long after virus resolution in the hamster

Long COVID or post-acute sequelae of COVID-19 (PASC) remains an ongoing public health issue that causes impairment for those afflicted and diminishes their ability to contribute to society. To address the host response underpinning respiratory PASC, we used the Golden Syrian hamster model infected with ancestral SARS-CoV-2 and examined its lung proteome in a longitudinal experiment. We infected young 6-week old male and female hamsters with 105 TCID50 of virus via the intranasal route and sampled the lung at 1, 3, 5, and 31 days post infection (dpi). We compared the infected lung proteome to that of uninfected sex-matched controls. We found almost no differences in protein levels at 1 dpi, with hundreds at 3 dpi, and thousands at 5 dpi. Many overlapping differential protein levels and pathways were seen in both sexes at 3 and 5 dpi including the Coagulation and Complement cascades. Notably, we found differences between the sexes at 31 dpi which included many targets with decreased levels of protein in the males. We also noted an increase in 7 proteins in both sexes at 31 dpi including proteins responsible for airway mucosal layer integrity such as Mucin 5B and Calcium-activated chloride channel regulator 1. Longitudinally, 38 proteins were changed in levels across more than one timepoint in the males but only three proteins were in the females, Secretoglobin family 1 A member 1, Poly [ADP-ribose] polymerase, and Apolipoprotein D. Overall, we show that there are changes to the lung proteome at 31 dpi, a time when no SARS-CoV-2 remains, and that there are sex differences in that proteome after infection with the ancestral strain. We conclude that biological sex should be examined as a variable when testing medical countermeasures for PASC in the Golden Syrian hamster due to host differences between the sexes.

Repeated Omicron exposures redirect SARS-CoV-2-specific memory B cell evolution toward the latest variants.

Immunological imprinting by ancestral SARS-CoV-2 strains is thought to impede the robust induction of Omicron-specific humoral responses by Omicron-based booster vaccines. Here, we analyzed the specificity and neutralization activity of memory B (Bmem) cells after repeated BA.5 exposure in individuals previously imprinted by ancestral strain-based mRNA vaccines. After a second BA.5 exposure, Bmem cells with BA.5 spike protein-skewed reactivity were promptly elicited, correlating with preexisting antibody titers. Clonal lineage analysis identified BA.5-skewed Bmem cells that had redirected their specificity from the ancestral strain to BA.5 through somatic hypermutations. Moreover, Bmem cells with redirected BA.5 specificity exhibited accelerated development compared with de novo Bmem cells derived from naïve repertoires. This redirected BA.5 specificity demonstrated greater resilience to viral point mutation and adaptation to recent Omicron variants HK.3 and JN.1, months after the second BA.5 exposure, suggesting that existing Bmem cells elicited by older vaccines can redirect their specificity toward newly evolving variants.

Characterization of the SARS-CoV-2 antibody landscape in Norway in the late summer of 2022: high seroprevalence in all age groups with patterns of primary Omicron infection in children and hybrid immunity in adults

BackgroundAccording to Norwegian registries, 91% of individuals ≥ 16 years had received ≥ 1 dose of COVID-19 vaccine by mid-July 2022, whereas less than 2% of children < 12 years were vaccinated. Confirmed COVID-19 was reported for 27% of the population, but relaxation of testing lead to substantial underreporting. We have characterized the humoral immunity to SARS-CoV-2 in Norway in the late summer of 2022 by estimating the seroprevalence and identifying antibody profiles based on reactivity to Wuhan or Omicron-like viruses in a nationwide cross-sectional collection of residual sera, and validated our findings using cohort sera.Methods1,914 anonymized convenience sera and 243 NorFlu-cohort sera previously collected from the Oslo-area with reported infection and vaccination status were analyzed for antibodies against spike, the receptor-binding domain (RBD) of the ancestral Wuhan strain and Omicron BA.2 RBD, and nucleocapsid (N). Samples were also tested for antibodies inhibiting RBD-ACE2 interaction. Neutralization assays were performed on subsets of residual sera against B.1, BA.2, XBB.1.5 and BQ.1.1.ResultsThe national seroprevalence estimate from vaccination and/or infection was 99.1% (95% CrI 97.0-100.0%) based on Wuhan (spike_W and RBD_W) and RBD_BA2 antibodies. Sera from children < 12 years had 2.2 times higher levels of antibodies against RBD_BA2 than RBD_W and their seroprevalence estimate showed a 14.4 percentage points increase when also including anti-RBD_BA2 antibodies compared to Wuhan-antibodies alone. 50.3% (95% CI 45.0-55.5%) of residual sera from children and 38.1% (95% CI 36.0-40.4%) of all residual sera were positive for anti-N-antibodies. By combining measurements of binding- and ACE2-RBD-interaction-inhibiting antibodies, reactivity profiles indicative of infection and vaccination history were identified and validated using cohort sera. Residual sera with a profile indicative of hybrid immunity were able to neutralize newer Omicron variants XBB.1.5 and BQ.1.1.ConclusionsBy late summer of 2022, most of the Norwegian population had antibodies to SARS-CoV-2, and almost all children had been infected. Antibody profiles indicated that children mostly had experienced a primary Omicron infection, while hybrid immunity was common among adults. The finding that sera displaying hybrid immunity could neutralize newer Omicron variants indicates that Wuhan-like priming of the immune response did not have a harmful imprinting effect and that infections induce cross-reacting antibodies against future variants.

Genomic Characterization of Three Canadian Mumps Outbreaks Demonstrates Endemic Transmission in Canada.

Despite the provision of a mumps vaccination program in Canada for over three decades, mumps has not reached elimination. Instead, a re-emergence has been observed in vaccinated populations, particularly in young adults. These outbreaks have been almost exclusively due to genotype G infections, a trend that has been seen in other countries with high mumps vaccination rates. To characterize mumps outbreaks in Canada, genomes from samples from Manitoba (n = 209), Newfoundland (n = 25), and Nova Scotia (n = 48) were sequenced and analysed by Bayesian inference. Whole genome sequencing was shown to be highly discriminatory for outbreak investigations compared to traditional Sanger sequencing. The results showed that mumps virus genotype G most likely circulated endemically in Canada and between Canada and the US. Overall, this Canadian outbreak data from different provinces and ancestral strains demonstrates the benefits of molecular genomic data to better characterize mumps outbreaks, but also suggests genomics could further our understanding of the reasons for potential immune escape of mumps genotype G and evolution in highly vaccinated populations. With a possible endemic circulation of mumps genotype G and the remaining risk of new imported cases, increased surveillance and alternative vaccination strategies may be required for Canada to reach the current target for mumps or a future elimination status.

Vancomycin-resistant Staphylococcus aureus (VRSA) can overcome the cost of antibiotic resistance and may threaten vancomycin's clinical durability.

Vancomycin has proven remarkably durable to resistance evolution by Staphylococcus aureus despite widespread treatment with vancomycin in the clinic. Only 16 cases of vancomycin-resistant S. aureus (VRSA) have been documented in the United States. It is thought that the failure of VRSA to spread is partly due to the fitness cost imposed by the vanA operon, which is the only known means of high-level resistance. Here, we show that the fitness cost of vanA-mediated resistance can be overcome through laboratory evolution of VRSA in the presence of vancomycin. Adaptation to vancomycin imposed a tradeoff such that fitness in the presence of vancomycin increased, while fitness in its absence decreased in evolved lineages. Comparing the genomes of vancomycin-exposed and vancomycin-unexposed lineages pinpointed the D-alanine:D-alanine ligase gene (ddl) as the target of loss-of-function mutations, which were associated with the observed fitness tradeoff. Vancomycin-exposed lineages exhibited vancomycin dependence and abnormal colony morphology in the absence of drug, which were associated with mutations in ddl. However, further evolution of vancomycin-exposed lineages in the absence of vancomycin enabled some evolved lineages to escape this fitness tradeoff. Many vancomycin-exposed lineages maintained resistance in the absence of vancomycin, unlike their ancestral VRSA strains. These results indicate that VRSA might be able to compensate for the fitness deficit associated with vanA-mediated resistance, which may pose a threat to the prolonged durability of vancomycin in the clinic. Our results also suggest vancomycin treatment should be immediately discontinued in patients after VRSA is identified to mitigate potential adaptations.

The impact of vaccine type and booster dose on the magnitude and breadth of SARS-CoV-2-specific systemic and mucosal antibodies among COVID-19 vaccine recipients

The COVID-19 pandemic has had a major impact on global health and economy, which was significantly mitigated by the availability of COVID-19 vaccines. The levels of systemic and mucosal antibodies against SARS-CoV-2 correlated with protection. However, there is limited data on how vaccine type and booster doses affect mucosal antibody response, and how the breadth of mucosal and systemic antibodies compares. In this cross-sectional study, we compared the magnitude and breadth of mucosal and systemic antibodies in 108 individuals who received either the BNT162b2 (Pfizer) or CoronaVac (SinoVac) vaccine. We found that BNT162b2 (vs CoronaVac) or booster doses (vs two doses) were significantly associated with higher serum IgG levels, but were not significantly associated with salivary IgA levels, regardless of prior infection status. Among non-infected individuals, serum IgG, serum IgA and salivary IgG levels were significantly higher against the ancestral strain than the Omicron BA.2 sublineage, but salivary IgA levels did not differ between the strains. Salivary IgA had the weakest correlation with serum IgG (r = 0.34) compared with salivary IgG (r = 0.63) and serum IgA (r = 0.60). Our findings suggest that intramuscular COVID-19 vaccines elicit a distinct mucosal IgA response that differs from the systemic IgG response. As mucosal IgA independently correlates with protection, vaccine trials should include mucosal IgA as an outcome measure.