In humans, maternal antibodies inhibit successful immunization against measles, because they interfere with vaccine-induced seroconversion. We have investigated this problem using the cotton rat model (Sigmodon hispidus). As in humans, passively transferred antibodies inhibit the induction of measles virus (MV)-neutralizing antibodies and protection after immunization with MV. In contrast, a recombinant vesicular stomatitis virus (VSV) expressing the MV hemagglutinin (VSV-H) induces high titers of neutralizing antibodies to MV in the presence of MV-specific antibodies. The induction of neutralizing antibodies increased with increasing virus dose, and all doses gave good protection from subsequent challenge with MV. Induction of antibodies by VSV-H was observed in the presence of passively transferred human or cotton rat antibodies, which were used as the models of maternal antibodies. Because MV hemagglutinin is not a functional part of the VSV-H envelope, MV-specific antibodies only slightly inhibit VSV-H replication in vitro. This dissociation of function and antigenicity is probably key to the induction of a neutralizing antibody in the presence of a maternal antibody.Measles virus (MV) is the single most important cause of infant mortality worldwide. Vaccination with an attenuated live virus vaccine has proven to induce protective immunity in seronegative individuals, and even low titers of neutralizing antibodies seem to be protective (4, 12). In developing countries with a high level of infection, infants below the age of 12 months are at high risk for MV infection. In this age group passively transferred maternal immunoglobulins (Ig) pose a problem because declining maternal antibodies interfere with vaccine-induced seroconversion but do not protect against infection with wild-type MV (13, 15). To induce immunity in the presence of maternal antibodies, high-titer vaccines (Ͼ10 4.7 PFU) were administered to infants at the age of 4 to 6 months (1, 17). These infants showed good serological responses and protection against measles. However, especially in female children, an increased mortality due to infections other than measles was observed after immunization with high-titer vaccines (2, 7), and the use of this vaccine was therefore discontinued.In order to develop vaccine alternatives which induce MVneutralizing antibodies in the presence of maternal antibodies, we have used MV infection in the cotton rat model (Sigmodon hispidus, inbred strain Cotton NIco) (9). Cotton rats are the only rodents in which MV replicates in the respiratory tract (18). Here we demonstrate that the passive transfer of human serum containing MV-specific antibodies inhibits vaccine-induced seroconversion and abolishes protection against MV. To induce neutralizing antibodies in the presence of MV-specific antibodies, we tested a recombinant vesicular stomatitis virus (VSV) expressing the MV hemagglutinin (VSV-H) (14). VSV is known for the rapid induction of neutralizing antibodies against its surface protein G, and VSV recombinant...
Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( Identifier: NCT02243787).
Plasmids that expressed the nucleocapsid, haemagglutinin and fusion proteins of measles virus (MV) were used to immunize cotton rats (Sigmodon hispidus) against intranasal MV infection. After immunization with all three plasmids, T cell responses and MV-specific antibodies were induced. A reduction in virus titre was observed in lung tissue from animals immunized with plasmids expressing the viral glycoproteins. Histologically, however, a moderate peribronchitis was observed after immunization with the plasmid expressing the fusion protein whereas, after immunization with plasmids expressing haemagglutinin or both glycoproteins, only mild or focal peribronchitis was seen. Immunization with the nucleocapsid did not reduce virus titres, probably because of the failure to induce neutralizing antibodies. A disadvantage of plasmid immunization was its inefficacy in the presence of MV-specific ' maternal' antibodies. This indicates that genetic immunization has to be improved to be a useful alternative vaccine against measles.Measles is still one of the most serious infectious diseases worldwide. Although a live-attenuated vaccine virus exists, roughly one million children die of measles virus (MV) infection every year, mostly in developing countries (Katz, 1995). Immunization at an early age is necessary in order to protect infants against infection. However, because of maternal antibodies, vaccine-induced seroconversion is often inhibited (Griffin, 1995). In addition, because of the immaturity of the neonatal immune system, early immunization in the absence of maternal antibodies results in inadequate levels of immune protection. As the WHO has set the eradication of MV as a public health goal, alternative vaccine candidates are needed (Wild, 1999).
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