A Vero cell-derived whole-virus H5N1 influenza vaccine has been shown to induce neutralizing antibodies directed against the hemagglutinin (HA) protein of diverse H5N1 strains in animal studies and ...clinical trials.However, neuraminidase-inhibiting (NAi) antibodies can reduce viral spread and may be of particular importance in the event of an H5N1 pandemic, where immunity due to HA antibodies is likely absent in the general population. Here we demonstrate the effective induction of NAi antibody titers after H5N1 vaccination in humans. In contrast to the immune response directed toward HA, a single vaccine dose induced a strong NAi response that was not significantly boosted by a second dose, most probably due to priming by previous vaccination or infection with seasonal influenza viruses. After 2 immunizations, seroconversion rates based on antibody titers against HA and NA were similar, indicating the induction of equally strong immune responses against both proteins by this H5N1 vaccine.
Studies evaluating the immunogenicity of two pediatric tick-borne encephalitis virus (TBEV) vaccines have reported contradictory results. These vaccines are based on two different strains of the ...European TBEV subtype: FSME-Immun Junior is based on the Neudörfl (Nd) strain, whereas Encepur Children is based on the Karlsruhe (K23) strain. The antibody (Ab) response induced by these two vaccines might be influenced by antigenic differences in the envelope (E) protein, which is the major target of neutralizing antibodies. We used an established hybrid virus assay platform to compare the levels of induction of neutralizing antibodies against the two vaccine virus strains in children aged 1 to 11 years who received two immunizations with FSME-Immun Junior or Encepur Children. The influence of amino acid differences between the E proteins of the Nd and K23 vaccine strains was investigated by mutational analyses and three-dimensional computer modeling. FSME-Immun Junior induced 100% seropositivity and similar neutralizing antibody titers against hybrid viruses containing the TBEV E protein of the two vaccine strains. Encepur Children induced 100% seropositivity only against the hybrid virus containing the E protein of the homologous K23 vaccine strain. Antibody responses induced by Encepur Children to the hybrid virus containing the E protein of the heterologous Nd strain were substantially and significantly (P < 0.001) lower than those to the K23 vaccine strain hybrid virus. Structure-based mutational analyses of the TBEV E protein indicated that this is due to a mutation in the DI-DII hinge region of the K23 vaccine strain E protein which may have occurred during production of the vaccine seed virus and which is not present in any wild-type TBE viruses.
Our data suggest that there are major differences in the abilities of two European subtype pediatric TBEV vaccines to induce antibodies capable of neutralizing heterologous TBEV strains. This is a result of a mutation in the DI-DII hinge region of the E protein of the K23 vaccine virus strain used to manufacture Encepur Children which is not present in the Nd strain used to manufacture FSME-Immun Junior or in any other known naturally occurring TBEVs.
Highlights ► Vero cell culture-derived whole-virus vaccine is highly immunogenic at low doses. ► High titer HI and virus-neutralizing antibodies induced in mice and guinea pigs. ► Vaccine also ...induces similarly high titers of neuraminidase-inhibiting antibodies. ► Protects against virus replication in the lung after challenge with homologous virus. ► Protects against disease after challenge with highly virulent mouse-adapted virus.
The envelope proteins (E) of flaviviruses form an icosahedral cage-like structure of homodimers that cover completely the surface of mature virions and are responsible for receptor-binding and ...membrane fusion. Fusion is triggered by the acidic pH in endosomes which induces dramatic conformational changes of E that drive the merger of the membranes. We have identified an alternative trigger that induces the first phase of the fusion process only, but then leads to an arrest at an intermediate stage. These data suggest that the early and late stages of flavivirus fusion are differentially controlled by intersubunit and intrasubunit constraints of the fusion protein, respectively. Details of the molecular antigenic structure of the flavivirus E protein were revealed by the use of neutralization escape mutants as well as recombinant expression systems for the generation of virus-like particles. The experimental data provide evidence that each of the three domains contributing to the external face of the E protein can induce and bind neutralizing antibodies. Broadly flavivirus cross-reactive antibodies, however, primarily recognize a site involving residues of the highly conserved fusion peptide loop which is cryptic and largely inaccessible on the surface of native infectious virions.
Young travelers to South-East Asia may be at risk for Japanese encephalitis (JE).
IXIARO® (0.25 ml or 0.5 ml, depending on age) were administrated to 100 travelers aged ≥ 2 months to < 18 years. ...Solicited AEs were collected for 7 days after each injection, unsolicited adverse events (AEs) for a total of 7 months. JE neutralizing antibodies were assessed in 64 subjects.
The most common solicited local AEs were redness (3/12 subjects), induration and tenderness (both 1/12) with 0.25 ml IXIARO®, and tenderness (44/88) and pain (22/88) with 0.5 ml IXIARO®. Common solicited systemic AEs were diarrhea (2/12) and loss of appetite (1/12) with 0.25 ml IXIARO® and muscle pain (27/88) and excessive fatigue (10/88) with 0.5 ml IXIARO®. In total, up to day 56, AEs were reported by 10/12 (83.3%) of subjects who received the 0.25 ml dose and 67/88 (76.1%) of those vaccinated with the 0.5 ml dose.
All subjects (62/62; 100%) developed protective levels of JE neutralizing antibodies by Day 56 and 31/34 (91.2%) retained protective titers at Month 7.
IXIARO® was generally well tolerated in children, with an overall AE profile similar to adults. IXIARO® was highly immunogenic in both dose groups.
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