Successful mucosal immunization of cotton rats in the presence of measles virus-specific antibodies depends on degree of attenuation of vaccine vector and virus dose

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Abstract
After passive transfer of measles virus (MV)-specific antibodies, vaccine-induced seroconversion and subsequent protection is inhibited in cotton rats (Sigmodon hispidus). In this system, an attenuated, recombinant vesicular stomatitis virus expressing the MV haemagglutinin (VSV-H) was found previously to induce neutralizing antibodies and protection against MV challenge after intranasal (i.n.) immunization. Here it is demonstrated that, after i.n. immunization, VSV-H is found in both lung and brain tissue in the absence of clinical signs. Intratracheal inoculation, which does not lead to infection of the brain, proved that immunization via the lung mucosa is sufficient to protect. To reduce or eliminate infection of the brain after i.n. inoculation, stepwise-attenuated VSV-H mutants with truncated cytoplasmic tails of the G protein were tested in cotton rats. A mutant with 9 aa in the G cytoplasmic tail was found at much lower levels in the brain and was protective in the absence or presence of MV-specific antibodies. A more attenuated mutant containing only 1 aa in its tail was not found in brain tissue after inoculation, but it still induced protective antibody to measles in the absence of MV-specific antibody. However, its ability to induce MV-neutralizing antibodies in the presence of passively transferred MV-specific antibodies and its protective capacity was abolished unless higher-dose immunizations were used. This study demonstrates that a lower degree of attenuation is required to be able to immunize in the presence of MV-specific antibodies.