Tick-borne encephalitis in a child with previous history of completed primary vaccination.

We report the case of a 13-year-old girl who presented with fever, headache, nausea and pain behind the right ear. Cerebrospinal fluid (CSF; leukocytes 227/µL), electroencephalogram and cerebral magnetic resonance imaging were indicative of meningoencephalitis. Despite intensive therapy the general condition worsened and the patient was admitted to the intensive care unit. Serological analysis of CSF and serum indicated acute tick-borne encephalitis virus (TBEV) infection (IgG and IgM positive). TBEV infection has been reported after incomplete and complete vaccination. TBEV vaccination breakthrough in childhood has been shown to cause severe disease. It has been suggested that immunized patients develop more severe disease due to altered immune response, but the exact mechanism is unknown. In the presence of typical symptoms and a history of vaccination, possible vaccination breakthrough or missing booster vaccination should be considered.

Invasive pneumococcal serotype 3 infection following pneumococcal vaccination in a hematopoietic stem cell transplant patient: A case report.

Given the high mortality rate of invasive pneumococcal disease (IPD) in hematopoietic stem cell transplant (HSCT) recipients, vaccination is recommended. These recipients respond to most vaccines; however, their immune response is typically weaker during the first months or years after transplantation, compared with that of healthy individuals. Here, we report a case of IPD with serotype 3 pneumonia and empyema in an HSCT recipient who had received three doses of the 13-valent pneumococcal conjugate vaccine (PCV) and one dose of the 23-valent pneumococcal polysaccharide vaccine; furthermore, the recipient had no relapse, graft-versus-host disease, or use of immunosuppressive agents after allogeneic HSCT for acute myeloid leukemia. Moreover, we discussed the characteristics of serotype 3 Streptococcus pneumoniae, a case series of breakthrough infections with S. pneumoniae in HSCT recipients who received pneumococcal vaccines, and the potential implications for the upcoming PCV15 and PCV20 vaccines for serotype 3.

The Impact of Clinical Factors and SARS-CoV-2 Variants on Antibody Production in Vaccinated German Healthcare Professionals Infected Either with the Delta or the Omicron Variant.

BACKGROUND: The aim of the rapid introduction of vaccines during the COVID-19 pandemic was a reduction in SARS-CoV-2 transmission and a less frequent occurrence of severe COVID-19 courses. Thus, we evaluated COVID-19 severity in vaccinated individuals to examine variant-specific symptom characteristics and their clinical impact on the serological immune response. METHODS: A total of 185 individuals previously vaccinated against and infected with the SARS-CoV-2 Delta (B.1.617.2) or Omicron (BA.4 and BA.5) variant, were enrolled for anti-SARS-CoV-2 anti-N- and anti-RBD/S1-Ig level detection. A structured survey regarding medical history was conducted. RESULTS: In 99.5 percent of cases, outpatient treatment was satisfactory. Specific symptoms associated with variants included ageusia and anosmia in patients with Delta infections and throat pain in Omicron infections. Among Delta-infected individuals with specific symptoms, significantly higher levels of anti-N antibodies were observed. CONCLUSION: Our study identified variant-specific differences in the amount of SARS-CoV-2 antibody production and COVID-19 symptoms. Despite this, vaccinated individuals with Omicron or Delta infections generally experienced mild disease courses. Additionally, asymptomatic individuals exhibit lower anti-SARS-CoV-2 antibody levels, indicating a clinical correlation between disease-specific antibodies and distinct symptoms, particularly in the case of the Delta variant. In follow-up studies, exploring post-COVID syndrome and focusing on cognitive symptoms in the acute phase of Omicron infections is crucial as it has the potential to longitudinally impact the lives of those affected.

Assessing the evolution of SARS-CoV-2 lineages and the dynamic associations between nucleotide variations.

Despite seminal advances towards understanding the infection mechanism of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), it continues to cause significant morbidity and mortality worldwide. Though mass immunization programmes have been implemented in several countries, the viral transmission cycle has shown a continuous progression in the form of multiple waves. A constant change in the frequencies of dominant viral lineages, arising from the accumulation of nucleotide variations (NVs) through favourable selection, is understandably expected to be a major determinant of disease severity and possible vaccine escape. Indeed, worldwide efforts have been initiated to identify specific virus lineage(s) and/or NVs that may cause a severe clinical presentation or facilitate vaccination breakthrough. Since host genetics is expected to play a major role in shaping virus evolution, it is imperative to study the role of genome-wide SARS-CoV-2 NVs across various populations. In the current study, we analysed the whole genome sequence of 3543 SARS-CoV-2-infected samples obtained from the state of Telangana, India (including 210 from our previous study), collected over an extended period from April 2020 to October 2021. We present a unique perspective on the evolution of prevalent virus lineages and NVs during this period. We also highlight the presence of specific NVs likely to be associated favourably with samples classified as vaccination breakthroughs. Finally, we report genome-wide intra-host variations at novel genomic positions. The results presented here provide critical insights into virus evolution over an extended period and pave the way to rigorously investigate the role of specific NVs in vaccination breakthroughs.

High neutralizing antibody mismatch as a possible reason for vaccine failure in two children with severe tick-borne encephalitis.

We describe two adolescents (13 and 16 years old) with severe tick-borne encephalitis (TBE) and vaccination breakthrough (VBT). Both suffer from severe persistent neurologic sequelae. Both patients had high TBE-IgG-titers after vaccination at the beginning of the infection and a low or missing TBE-IgM response (Type 2 vaccine failure). Neutralization tests show low titers against the respective infecting TBE virus strain and higher titers against the vaccine strain at the beginning of the infection implying an individual weak or impaired immune response to the respective virus as possible cause of TBE vaccine failure. We do not know of any similar observation or explanation for the phenomenon and at the moment can only speculate of a severe course correlated to highly mismatched IgG. This constellation of high TBE IgGs, the lack of immune response and a severe course strongly resembles the severe TBE courses that occurred in the past after TBE immunoglobulin administration. To our knowledge differentiation between structural and functional antibodies by neutralization tests with a) the affecting TBE virus strain and b) the vaccine virus strain in TBE vaccine failures has never been described before. We conclude (1) to consider a TBE virus infection also in vaccinated children presenting with meningoencephalitis, (2) to perform a broad immunological work-up in severe TBE especially after VBT, (3) to further study if high mismatch IgG's are a possible reason for vaccine failure.

Heterologous Vector-mRNA Based SARS-CoV-2 Vaccination Strategy Appears Superior to a Homologous Vector-Based Vaccination Scheme in German Healthcare Workers Regarding Humoral SARS-CoV-2 Response Indicating a High Boosting Effect by mRNA Vaccines.

BACKGROUND: Longitudinal humoral SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) immunity for up to 15 months due to vaccination, the efficacy of vaccination strategies (homologous, vector-vector versus heterologous, vector-mRNA), the influence of vaccination side effects, and the infection rate in German healthcare workers need to be investigated. METHODS: In this study, 103 individuals vaccinated against SARS-CoV-2 were enrolled to examine their anti-SARS-CoV-2 anti-N- and anti-RBD/S1-Ig levels. A total of 415 blood samples in lithium heparin tubes were prospectively obtained, and a structured survey regarding medical history, type of vaccine, and vaccination reactions was conducted. RESULTS: All participants demonstrated a humoral immune response, among whom no values decreased below the positivity cutoff. Five to six months after the third vaccination, three participants showed anti-RBD/S1 antibodies of less than 1000 U/mL. We observed higher levels for heterologous mRNA-/vector-based combinations compared to pure vector-based vaccination after the second vaccination, which is harmonized after a third vaccination with the mRNA-vaccine only in both cohorts. The incidence of vaccine breakthrough in a highly exposed cohort was 60.3%. CONCLUSION: Sustained long-term humoral immunity was observed, indicating the superiority of a heterologous mRNA-/vector-based combination compared to pure vector-based vaccination. There was longevity of anti-RBD/S1 antibodies of at least 4 and up to 7 months without external stimulus. Regarding vaccination reactogenity, the occurrence of local symptoms as pain at the injection site was increased after the first mRNA application compared to the vector-vector cohort with a general decrease in adverse events at later vaccination time points. Overall, a correlation between the humoral vaccination response and vaccination side effects was not observed. Despite the high prevalence of vaccine breakthroughs, these only occurred in the later course of the study when more infectious variants, which are, however, associated with milder courses, were present. These results provide insights into vaccine-related serologic responses, and the study should be expanded using additional vaccine doses and novel variants in the future.

Clinico-Genomic Analysis Reiterates Mild Symptoms Post-vaccination Breakthrough: Should We Focus on Low-Frequency Mutations?

Vaccine development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been of primary importance to contain the ongoing global pandemic. However, studies have demonstrated that vaccine effectiveness is reduced and the immune response is evaded by variants of concern (VOCs), which include Alpha, Beta, Delta, and, the most recent, Omicron. Subsequently, several vaccine breakthrough (VBT) infections have been reported among healthcare workers (HCWs) due to their prolonged exposure to viruses at healthcare facilities. We conducted a clinico-genomic study of ChAdOx1 (Covishield) VBT cases in HCWs after complete vaccination. Based on the clinical data analysis, most of the cases were categorized as mild, with minimal healthcare support requirements. These patients were divided into two sub-phenotypes based on symptoms: mild and mild plus. Statistical analysis showed a significant correlation of specific clinical parameters with VBT sub-phenotypes. Viral genomic sequence analysis of VBT cases revealed a spectrum of high- and low-frequency mutations. More in-depth analysis revealed the presence of low-frequency mutations within the functionally important regions of SARS-CoV-2 genomes. Emphasizing the potential benefits of surveillance, low-frequency mutations, D144H in the N gene and D138Y in the S gene, were observed to potentially alter the protein secondary structure with possible influence on viral characteristics. Substantiated by the literature, our study highlights the importance of integrative analysis of pathogen genomic and clinical data to offer insights into low-frequency mutations that could be a modulator of VBT infections.

Transcriptomic study reveals lncRNA-mediated downregulation of innate immune and inflammatory response in the SARS-CoV-2 vaccination breakthrough infections.

Introduction: The emergence of multiple variants of concerns (VOCs) with higher number of Spike mutations have led to enhanced immune escape by the SARS-CoV-2. With the increasing number of vaccination breakthrough (VBT) infections, it is important to understand the possible reason/s of the breakthrough infections. Methods: We performed transcriptome sequencing of 57 VBT and unvaccinated COVID-19 patients, followed by differential expression and co-expression analysis of the lncRNAs and the mRNAs. The regulatory mechanism was highlighted by analysis towards repeat element distribution within the co-expressed lncRNAs, followed by repeats driven homologous interaction between the lncRNAs and the promoter regions of genes from the same topologically associated domains (TAD). Results: We identified 727 differentially expressed lncRNAs (153 upregulated and 574 downregulated) and 338 mRNAs (34 up- and 334 downregulated) in the VBT patients. This includes LUCAT1, MALAT1, ROR1-AS1, UGDH-AS1 and LINC00273 mediated modulation of immune response, whereas MALAT1, NEAT1 and GAS5 regulated inflammatory response in the VBT. LncRNA-mRNA co-expression analysis highlighted 34 lncRNAs interacting with 267 mRNAs. We also observed a higher abundance of Alu, LINE1 and LTRs within the interacting lncRNAs of the VBT patients. These interacting lncRNAs have higher interaction with the promoter region of the genes from the same TAD, compared to the non-interacting lncRNAs with the enrichment of Alu and LINE1 in the gene promoter. Discussion: Significant downregulation and GSEA of the TAD gene suggest Alu and LINE1 driven homologous interaction between the lncRNAs and the TAD genes as a possible mechanism of lncRNA-mediated suppression of innate immune/inflammatory responses and activation of adaptive immune response. The lncRNA-mediated suppression of innate immune/inflammatory responses and activation of adaptive immune response might explain the SARS-CoV-2 breakthrough infections with milder symptoms in the VBT. Besides, the study also highlights repeat element mediated regulation of genes in 3D as another possible way of lncRNA-mediated immune-regulation modulating vaccination breakthroughs milder disease phenotype and shorter hospital stay.

Dynamics and Extent of Non-Structural Protein 1-Antibody Responses in Tick-Borne Encephalitis Vaccination Breakthroughs and Unvaccinated Patients.

Tick-borne encephalitis (TBE) has a substantial impact on human public health in many parts of Europe and Asia. Effective inactivated purified whole-virus vaccines are in widespread use in TBE-endemic countries. Nevertheless, vaccination breakthroughs (VBTs) with manifest clinical disease do occur, and their specific serodiagnosis was shown to be facilitated by the detection of antibodies to a non-structural protein (NS1) that is produced during virus replication. However, recent data have shown that NS1 is also present in the current inactivated vaccines, with the potential of inducing corresponding antibodies and obscuring a proper interpretation of NS1-antibody assays for diagnosing VBTs. In our study, we quantified anti-virion and anti-NS1 antibody responses after vaccination as well as after natural infection in TBE patients, both without and with a history of previous TBE vaccination (VBTs). We did not find significant levels of NS1-specific antibodies in serum samples from 48 vaccinees with a completed vaccination schedule. In contrast, all TBE patients mounted an anti-NS1 antibody response, irrespective of whether they were vaccinated or not. Neither the dynamics nor the extent of NS1-antibody formation differed significantly between the two cohorts, arguing against substantial NS1-specific priming and an anamnestic NS1-antibody response in VBTs.

Tick-borne encephalitis virus vaccination breakthrough infections in Germany: a retrospective analysis from 2001 to 2018.

OBJECTIVES: There are few data available regarding the clinical course of tick-borne encephalitis virus (TBEV) vaccination breakthrough infections. The published studies suggest that vaccination breakthrough infections may have a more severe course than native TBEV infection in unvaccinated individuals-potentially due to antibody-dependent enhancement. Here we report a large analysis of vaccination breakthrough infections. METHODS: This retrospective analysis was based on a national surveillance dataset spanning the years 2001-2018. Variables reflecting disease severity, such as 'CNS symptoms', 'myelitis', 'fatal outcome' and 'hospitalization' were analysed as well as general epidemiological variables. Cases were categorized as 'unvaccinated' or 'ever vaccinated', the latter category including cases with at least one dose of a TBEV vaccine. RESULTS: A total of 6073 notified TBEV infection cases were included in our analysis. Sufficient data on vaccination status were available for 95.1% of patients (5777/6073); of these, 5298 presented with a native infection. A total of (334/5777) cases developed an infection despite having been vaccinated at least once. Comparing unvaccinated patients with those with at least one vaccination, we find an odds ratio (OR) 2.73, (95% confidence interval (CI) 0.79-9.50) regarding the variable fatal outcome that did not reach statistical significance. Analysing the clinical variables 'CNS symptoms' and 'myelitis', there is no difference between these groups (OR 0.86, 95% CI 0.68-1.08; and OR 1.30, 95% CI 0.74-2.27 respectively). Patients who were vaccinated and had an assumed protection at symptom onset (n = 100) had a higher risk for the development of myelitic symptoms (OR 2.21, 95% CI 1.01-4.86]) than unvaccinated patients. CONCLUSION: Our findings could neither verify that vaccination breakthrough infections might cause a more severe disease than native infections nor prove a clear antibody-dependent enhancement phenomenon. It remains unclear whether the increased myelitis risk in a subgroup of vaccinated patients is a true effect or confounded.