Alexander Strubel

Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies (nmAbs) from the plasmablasts of a ZIKV-infected patient-SMZAb1, SMZAb2, and SMZAb5-directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fcγ receptor binding, thus eliminating potential therapy-mediated antibody-dependent enhancement. We administered a cocktail of these three nmAbs to nonhuman primates 1 day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum after challenge. Given that numerous antibodies have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses.

Zika virus (ZIKV) shares a high degree of homology with dengue virus (DENV), suggesting that preexisting immunity to DENV could affect immune responses to ZIKV. We have tracked the evolution of ZIKV-induced B cell responses in three DENV-experienced donors. The acute antibody (plasmablast) responses were characterized by relatively high somatic hypermutation and a bias toward DENV binding and neutralization, implying the early activation of DENV clones. A DENV-naïve donor in contrast showed a classical primary plasmablast response. Five months after infection, the DENV-experienced donors developed potent type-specific ZIKV neutralizing antibody responses in addition to DENV cross-reactive responses. Because cross-reactive responses were poorly neutralizing and associated with enhanced ZIKV infection in vitro, preexisting DENV immunity could negatively affect protective antibody responses to ZIKV. The observed effects are epitope-dependent, suggesting that a ZIKV vaccine should be carefully designed for DENV-seropositive populations.

The impact of interferon-gamma (IFN) treatment of tumor cells on non-adaptive and adaptive immune defense and its reflection by metastatic spread were evaluated using a weakly metastasizing variant of B16 melanoma (B16-FI). Treatment of B16-FI with IFN resulted in a decrease in binding structures for NK cells and concomitantly in augmented metastasizing capacity. In line with this, activation of NK cells and Mo, which led to reduction of metastatic nodes, was less efficient with IFN-treated B16-FI, while after elimination of non-adaptive immune defense, the number of metastases increased significantly, but irrespective of IFN treatment. On the other hand, IFN-treated B16-FI cells become more prone to killing by cytotoxic T-cells (CTL). This was due to increased lysability by CTL and to increased immunogenicity; i.e., a higher frequency of B16-specific CTL was observed after immunization with IFN-treated than with untreated B16-FI. The reverse phenomenon was observed with anomalous and/or lymphokine-activated killer cells (AK/LAK). The common cause of increased antigenicity and immunogenicity may reside in increased expression of class-I and de novo expression of class-II MHC antigens after IFN treatment. Increased antigenicity and immunogenicity of IFN-treated B16-FI was reflected by significant reduction of metastatic nodes, prolonged survival and increased TD100 in animals immunized with IFN-treated vs. untreated melanoma cells. Comparison of the divergent effects of IFN treatment on B16-FI melanoma cells showed that the benefit of increased antigenicity/immunogenicity clearly outweighed the disadvantage of reduced susceptibility to non-adaptive immune defense.

Post-infectious sequelea such as Guillain Barré syndrome (GBS), reactive arthritis (RA), and inflammatory bowel disease (IBD) may arise as a consequence of acute Campylobacter-enteritis (AE). However, reliable seroprevalence data of Campylobacter-associated sequelae has not been established. The objectives of this study were, first, to identify the most specific and sensitive test antigen in an optimized ELISA assay for diagnosing a previous Campylobacter-infection and, second, to compare the prevalence of anti-Campylobacter antibodies in cohorts of healthy blood donors (BD), AE, GBS, RA, and IBD patients with antibodies against known GBS, RA and IBD triggering pathogens. Optimized ELISAs of single and combined Campylobacter-proteins OMP18 and P39 as antigens were prepared and sera from AE, GBS, RA and IBD patients and BD were tested for Campylobcter-specific IgA and IgG antibodies. The results were compared with MIKROGEN™-recomLine Campylobacter IgA/IgG and whole cell lysate-immunoblot. Antibodies specific for Helicobacter pylori, Mycoplasma pneumoniae, Yersinia enterocolitica, and Borrelia afzelii were tested with commercial immunoblots. ROC plot analysis revealed AUC maxima in the combination of OMP18 and P39 for IgA and in the P39-antigen for IgG. As a result, 34-49 % GBS cases, 44-62 % RA cases and 23-40 % IBD cases were associated with Campylobacter-infection. These data show that Campylobcater-seropositivity in these patient groups is significantly higher than other triggering pathogens suggesting that it plays an important role in development of GBS and RA, and supports the hypothesis that recurrent acute campylobacteriosis triggers IBD.