This is in contrast to a recent OMV immunization study, demonstrating that LPS is the major protective antigen of a V. cholerae vaccine candidate based on OMVs and that no crossserogroup protection can be achieved by just using OMVs derived from one V. cholerae serogroup in the immunization mixture. One explanation might be that the LOS of NTHi strains is much shorter compared to the V. cholerae LPS with relatively long and variable O-antigens, which might act as spacers between the surface antigens associated with the OM and the respective antibodies. Like any other animal model, the NTHi mouse model cannot reflect all parts of the human infection. A limitation is the lack of a chronic pulmonary colonization due to rapid clearing of the bacteria in the respiratory tract. Nevertheless, the mouse model is well established in the field and has been used in the past to study several NTHi vaccine candidates. This study should be seen as a first Gomisin-D report characterizing a new vaccine candidate based on OMVs, which induces cross-protection against heterologous NTHi strains. Future work has to investigate, if the initial results of the present study using the mouse model also hold true in the human system. Noteworthy, in the case of otitis media caused by NTHi, several studies suggest a correlation between the presence of serum antibodies against NTHi and protection. In summary, this study has confirmed that NTHi strains release OMVs and has shown that these OMVs have a high potential to act as vaccine against NTHi infections. We have demonstrated that already an intranasal immunization with OMVs derived from one NTHi strain results in a robust and complex humoral, mucosal, and protective immune response against homologous and heterologous NTHi strains, even without the use of a mucosal adjuvant. Obviously, OMVs naturally Albaspidin-AA contain a balanced mixture of immunogenic, protective antigens and adjuvants. OMVs can be isolated from different donor strains and easily combined in OMV mixtures. Based on the data of this study, the use of an OMV mixture is not necessary, but also has no disadvantage for 
the induction of a protective immune response against NTHi strains. It can be speculated that the use of a heterogeneous OMV mixture might be advantageous by inducing a more complex immune response against different antigens of NTHi strains. Additionally, one could extend this idea and create a combined vaccine candidate against several Gram-negative pathogens by combining OMVs derived from different donor species. Thus, the increased antigenic diversity of an OMV mixture could further stimulate the induction of cross-reacting antibodies, which in turn may help to develop a broad-spectrum vaccine not only against heterologous NTHi strains, but also against other Gram-negative pathogens of interest. Parkinson disease involves the degeneration of dopamine neurons in the substantia nigra and a subsequent DA depletion in the striatum. Pharmacological replacement with L-3,4-dihydroxyphenylalanine is the gold standard treatment for PD. However, long-term administration of L-DOPA induces abnormal involuntary movements known as L-DOPAinduced dyskinesia in the majority of PD patients. These motor complications are potentially disabling, and affect up to 40% of PD patients within 5 years of treatment. Although the specific mechanisms underlying LID are poorly understood there is vast consensus that it results from dysregulated DA neurotransmission depending on both presynaptic alterations and postsynaptic dopamine receptor supersensitivity. Altered glutamatergic transmission within the basal ganglia may also be involved since changes in NMDA and metabotropic glutamate receptors have been reported. The basal ganglia form a highly organized network and the subthalamic nucleus occupies a prominent position in the indirect pathway.