Are we prepared for emerging flaviviruses in Europe? Challenges for vaccination.

Tick-borne encephalitis and West Nile fever are endemic flavivirus diseases in Europe. Climate change, virus evolution, and social factors may increase the risk of these flavivirus infections and may lead to the emergence of other flaviviruses in Europe that are endemic in (sub)tropical regions of the world. Control of the spread of flaviviruses is very difficult considering the cycling of flaviviruses between arthropod vectors and animal reservoir hosts. The increasing threat of flavivirus infections emphasizes the necessity of a sustainable vector surveillance system, an active animal health surveillance system and an adequate human surveillance system for early detection of flavivirus infections. Vaccination is the most important approach to prevent flavivirus infections. Effective inactivated whole virus vaccines against tick-borne encephalitis (TBE) infection are available. Implementation of TBE vaccination based on favorable cost-effectiveness estimates per region and per target group can reduce the disease burden of TBE infection. At present, several West Nile virus (WNV) vaccine candidates are in various stages of clinical development. A major challenge for WNV vaccine candidates is to demonstrate efficacy, because of the sporadic nature of unpredictable WNV outbreaks. Universal WNV vaccination is unlikely to be cost-effective, vaccination of high-risk groups will be most appropriate to protect against WNV infections

Routine vaccination against MenB: considerations for implementation

Effective polysaccharide(conjugate) vaccines against Neisseria meningitidis serogroups A, C, W, and Y have been widely used, but serogroup B meningococci remain a major cause of severe invasive meningococcal disease (IMD) worldwide, especially in infants. Recently, a vaccine, 4CMenB (Bexsero(®)), containing three recombinant proteins, and outer membrane vesicles (OMV) derived from a serogroup B meningococcal strain (MenB) has been licensed in Europe and Australia and is indicated for persons aged 2 mo or older. This article discusses what should be considered to enable a successful implementation of a broad coverage MenB vaccine in national immunization programs. Epidemiology data, vaccine characteristics including vaccine coverage, immunogenicity, post-implementation surveillance and costs are relevant aspects that should be taken into account when selecting an appropriate immunization strategy. The potential impact on strain variation and carriage, as well as monitoring vaccine effectiveness, and rare but potentially serious adverse events are points that need to be included in a post-implementation surveillance pla

Past, current and future protocols for combined modality therapy in childhood medulloblastoma

Radiotherapy plays a major role in the management of brain tumors, together with surgical resection and more recently, chemotherapy. Improved efficacy of radiotherapy, ranging from novel techniques of radiotherapy to combination with (new) chemotherapeutic drugs or agents that selectively target tumor cells, are currently being explored and offer some hope for improvement of the prognosis of primary brain tumors. This approach might also enable reducing radiation doses, thereby potentially decreasing the risk of severe late effects in pediatric brain tumor patients. This review will evaluate past, current and future treatment approaches of combined modality therapy in childhood medulloblastoma

Estimation of the infection attack rate of mumps in an outbreak among college students using paired serology

Mumps virus is a highly transmissible pathogen that is effectively controlled in countries with high vaccination coverage. Nevertheless, outbreaks have occurred worldwide over the past decades in vaccinated populations. Here we analyse an outbreak of mumps virus genotype G among college students in the Netherlands over the period 2009–2012 using paired serological data. To identify infections in the presence of preexisting antibodies we compared mumps specific serum IgG concentrations in two consecutive samples (n=746), whereby the first sample was taken when students started their study prior to the outbreaks, and the second sample was taken 2–5 years later. We fit a binary mixture model to the data. The two mixing distributions represent uninfected and infected classes. Throughout we assume that the infection probability increases with the ratio of antibody concentrations of the second to first sample. The estimated infection attack rate in this study is higher than reported earlier (0.095 versus 0.042). The analyses yield probabilistic classifications of participants, which are mostly quite precise owing to the high intraclass correlation of samples in uninfected participants (0.85, 95%CrI: 0.82−0.87). The estimated probability of infection increases with decreasing antibody concentration in the pre-outbreak sample, such that the probability of infection is 0.12 (95%CrI: 0.10−0.13) for the lowest quartile of the pre-outbreak samples and 0.056 (95%CrI: 0.044−0.068) for the highest quartile. We discuss the implications of these insights for the design of booster vaccination strategies

Novel mumps virus epitopes reveal robust cytotoxic T cell responses after natural infection but not after vaccination.

Mumps is nowadays re-emerging despite vaccination. The contribution of T cell immunity to protection against mumps has not been clearly defined. Previously, we described a set of 41 peptides that were eluted from human leukocyte antigen (HLA) class I molecules of mumps virus (MuV)-infected cells. Here, we confirmed immunogenicity of five novel HLA-B*07:02- and HLA-A*01:01-restricted MuV T cell epitopes from this set of peptides. High frequencies of T cells against these five MuV epitopes could be detected ex vivo in all tested mumps patients. Moreover, these epitope-specific T cells derived from mumps patients displayed strong cytotoxic activity. In contrast, only marginal T cell responses against these novel MuV epitopes could be detected in recently vaccinated persons, corroborating earlier findings. Identifying which MuV epitopes are dominantly targeted in the mumps-specific CD8+ T- response is an important step towards better understanding in the discrepancies between natural infection or vaccination-induced cell-mediated immune protection

Development of an IFNγ ELISPOT for the analysis of the human T cell response against mumps virus

AbstractIn the last decade, mumps virus (MuV) causes outbreaks in highly vaccinated populations. Sub-optimal T cell immunity may play a role in the susceptibility to mumps in vaccinated individuals. T cell responses to mumps virus have been demonstrated, yet the quality of the MuV-specific T cell response has not been analyzed using single cell immunological techniques. Here we developed an IFNγ ELISPOT assay to assess MuV-specific T cell responses in peripheral blood mononuclear cells (PBMC) of healthy (vaccinated) donors and mumps patients. Various in vitro MuV-specific stimulation methods of PBMC were compared, using either live or inactivated MuV alone or MuV-infected autologous antigen presenting cells, i.e. Epstein Barr Virus-transformed B lymphoblastoid cell lines (EBV-BLCL) or (mitogen pre-activated) PBMC, for their ability to recall IFNγ-producing responder cells measured by ELISPOT. For the detection of MuV-specific T cell responses, direct exposure (24h) to live MuV was the preferred stimulation method when assay sensitivity and practical reasons were considered. Notably, flowcytometric confirmation of data revealed that primarily T cells and NK cells produce IFNγ upon live MuV stimulation. Depleting PBMC from CD56+ NK cells prior to stimulation with live MuV led to the enumeration of MuV-specific T cell responses by ELISPOT. Our assay constitutes a tool to evaluate memory MuV-specific T cell responses in MuV vaccinated or infected persons. Furthermore, this study provides evidence that live MuV not only induces IFNγ production by T cells, but also by NK cells

SARS-CoV-2 Omicron BA.4/BA.5 Mutations in Spike Leading to T Cell Escape in Recently Vaccinated Individuals.

SARS-CoV-2 Omicron (B.1.1.529) lineages rapidly became dominant in various countries reflecting its enhanced transmissibility and ability to escape neutralizing antibodies. Although T cells induced by ancestral SARS-CoV-2-based vaccines also recognize Omicron variants, we showed in our previous study that there was a marked loss of T cell cross-reactivity to spike epitopes harboring Omicron BA.1 mutations. The emerging BA.4/BA.5 subvariants carry other spike mutations than the BA.1 variant. The present study aims to investigate the impact of BA.4/BA.5 spike mutations on T cell cross-reactivity at the epitope level. Here, we focused on universal T-helper epitopes predicted to be presented by multiple common HLA class II molecules for broad population coverage. Fifteen universal T-helper epitopes of ancestral spike, which contain mutations in the Omicron BA.4/BA.5 variants, were identified utilizing a bioinformatic tool. T cells isolated from 10 subjects, who were recently vaccinated with mRNA-based BNT162b2, were tested for functional cross-reactivity between epitopes of ancestral SARS-CoV-2 spike and the Omicron BA.4/BA.5 spike counterparts. Reduced T cell cross-reactivity in one or more vaccinees was observed against 87% of the tested 15 non-conserved CD4+ T cell epitopes. These results should be considered for vaccine boosting strategies to protect against Omicron BA.4/BA.5 and future SARS-CoV-2 variants

SARS-CoV-2 Omicron BA.4/BA.5 Mutations in Spike Leading to T Cell Escape in Recently Vaccinated Individuals

SARS-CoV-2 Omicron (B.1.1.529) lineages rapidly became dominant in various countries reflecting its enhanced transmissibility and ability to escape neutralizing antibodies. Although T cells induced by ancestral SARS-CoV-2-based vaccines also recognize Omicron variants, we showed in our previous study that there was a marked loss of T cell cross-reactivity to spike epitopes harboring Omicron BA.1 mutations. The emerging BA.4/BA.5 subvariants carry other spike mutations than the BA.1 variant. The present study aims to investigate the impact of BA.4/BA.5 spike mutations on T cell cross-reactivity at the epitope level. Here, we focused on universal T-helper epitopes predicted to be presented by multiple common HLA class II molecules for broad population coverage. Fifteen universal T-helper epitopes of ancestral spike, which contain mutations in the Omicron BA.4/BA.5 variants, were identified utilizing a bioinformatic tool. T cells isolated from 10 subjects, who were recently vaccinated with mRNA-based BNT162b2, were tested for functional cross-reactivity between epitopes of ancestral SARS-CoV-2 spike and the Omicron BA.4/BA.5 spike counterparts. Reduced T cell cross-reactivity in one or more vaccinees was observed against 87% of the tested 15 non-conserved CD4+ T cell epitopes. These results should be considered for vaccine boosting strategies to protect against Omicron BA.4/BA.5 and future SARS-CoV-2 variants