Measles Vaccination of Nonhuman Primates Provides Partial Protection against Infection with Canine Distemper Virus

Abstract

Measles virus (MV) is being considered for global eradication, which would likely reduce compliance with MV vaccination. As a result, children will grow up without MV-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (CDV). Natural CDV infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that CDV can cause disease in primates. We studied the virulence and tropism of recombinant CDV expressing enhanced green fluorescent protein in naive and measles-vaccinated cynomolgus macaques. In naive animals CDV caused viremia and fever and predominantly infected CD150 ؉ lymphocytes and dendritic cells. Virus was reisolated from the upper and lower respiratory tracts, but infection of epithelial or neuronal cells was not detectable at the time points examined, and the infections were self-limiting. This demonstrates that CDV readily infects nonhuman primates but suggests that additional mutations are necessary to achieve full virulence in nonnatural hosts. Partial protection against CDV was observed in measles-vaccinated macaques, as demonstrated by accelerated control of virus replication and limited shedding from the upper respiratory tract. While neither CDV infection nor MV vaccination induced detectable cross-reactive neutralizing antibodies, MV-specific neutralizing antibody levels of MV-vaccinated macaques were boosted by CDV challenge infection, suggesting that cross-reactive VN epitopes exist. Rapid increases in white blood cell counts in MV-vaccinated macaques following CDV challenge suggested that cross-reactive cellular immune responses were also present. This study demonstrates that zoonotic morbillivirus infections can be controlled by measles vaccination. IMPORTANCEThroughout history viral zoonoses have had a substantial impact on human health. Given the drive toward global eradication of measles, it is essential to understand the zoonotic potential of animal morbilliviruses. Morbilliviruses are thought to have evolved from a common ancestral virus that jumped species and adapted to new hosts. Recently, canine distemper virus (CDV), a morbillivirus normally restricted to carnivores, caused disease outbreaks in nonhuman primates. Here, we report that experimental CDV infection of monkeys resulted in fever and leukopenia. The virus replicated to high levels in lymphocytes but did not spread to epithelial cells or the central nervous system. Importantly, like measles virus in macaques, the infections were selflimiting. In measles-vaccinated macaques CDV was cleared more rapidly, resulting in limited virus shedding from the upper respiratory tract. These studies demonstrate that although CDV can readily infect primates, measles immunity is protective, and CDV infection is self-limiting.

Pathogenesis of canine distemper virus in experimentally infected raccoon dogs, foxes, and minks

“…3 and 5). These findings are similar to the results of experimental infections in ferrets, seals and Cynomolgus macaques with either CDV or MV, in which a higher tropism was demonstrated for lymphatic tissues von Messling et al, 2004;de Swart et al, 2007;de Vries et al, 2014). In a previous study, SLAM is markedly up-regulated in lymphoid cells of infected tissues after CDV infection, indicating a possible virus strategy to increase amplification in the host (Wenzlow et al, 2007).…”

“…Previous field epidemiology and observational studies in China suggested that CDV infection was more common and more relevant clinically in raccoon dogs and foxes than in minks (Zhao et al, 2010a;Wang et al, 2009). Accordingly, it is possible to assume that raccoon dogs or foxes are more susceptible than minks to CDV, although virus-related factors should be also considered when assessing CDV pathogenesis (Nielsen et al, 2009;Jensen et al, 2015;de Vries et al, 2014). For this reason, the differences in susceptibility between these species required thorough investigation using experimental infections.…”

Live-Attenuated Measles Virus Vaccine Targets Dendritic Cells and Macrophages in Muscle of Nonhuman Primates

“…The rationale for insertion after the P gene was that the N and P proteins are predicted to be required in large amounts, while this location can retain balanced levels of envelope associated M, F, and H proteins. Insertion after the H gene has been successful in previous morbillivirus studies (26,29,30). We designed the constructs so that the ATUs were identical in rMV EZ EGFP(3) and rMV EZ EGFP(6).…”

“…The overattenuation of rMV EZ EGFP(6) was a surprise, given that equivalent viruses are apparently unperturbed in other systems (26,29,30). Also, in a previous study where IFN-␣/␤ receptor knockout mice expressing human CD46 were injected intraperitoneally with 5 ϫ 10 6 TCID 50 of Schwarz-based rMVs containing an ATU, the position 3 and 6 viruses induced equivalent immune responses at 28 d.p.i.…”

Advances in peste des petits ruminants vaccines

“…When two independently developed PPRV vaccine strains (Nigeria/75 and Sungri/96) along with a virulent strain of PPRV were used to inoculate cattle, a cross protection against virulent RPV was observed only when virulent PPRV was inoculated in cattle (Holzer et al, 2016a), a finding which is in accordance with very early studies where crude material from animals suffering from PPR was shown to protect cattle from rinderpest (Mornet et al, 1956a). Increased disease outbreaks due to CDV in primates (de Vries et al, 2014) suggests that the presence of measles virus in human population would have prevented disease caused by CDV.…”