Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques (original) (raw)
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Journal of Infectious …, 1999
Measles remains a major cause of childhood mortality, with questions about virus virulence and pathogenesis still requiring answers. Rhesus macaques were infected with 5 different culture-adapted strains of measles virus, including 2 from patients with progressive vaccineinduced disease, and a sixth nonculture-adapted strain, Bilthoven. All caused infection detectable by reverse transcriptase-polymerase chain reaction and induction of antibody. Chicago-1 and Bilthoven induced viremias detectable by leukocyte cocultivation. Bilthoven induced Koplik's spots, conjunctivitis, and rash. Lymphopenia and depressed interleukin (IL)-2 production were followed by monocytosis and eosinophilia. All monkeys, including 41 involved in a primate facility outbreak, showed suppressed responses to phytohemagglutinin. As the rash resolved production of IL-2, IL-1b, tumor necrosis factor-a, IL-6, and IL-5 mRNA increased. Monkeys are useful for studies of measles immunopathogenesis, but virus strains must be carefully chosen. Increased virulence of vaccine strains isolated from immunocompromised infants with fatal infections was not evident.
Journal of General Virology, 2007
Both rhesus and cynomolgus macaques have been used as animal models for measles vaccination and immunopathogenesis studies. A number of studies have suggested that experimental measles virus (MV) infection induces more-characteristic clinical features in rhesus than in cynomolgus monkeys. In the present study, both macaque species were infected with two different wild-type MV strains and clinical, virological and immunological parameters were compared. The viruses used were a genotype C2 virus isolated in The Netherlands in 1991 (MV-Bil) and a genotype B3 virus isolated from a severe measles case in Sudan in 1997 (MV-Sudan). Following infection, all rhesus monkeys developed a skin rash and conjunctivitis, which were less obvious in cynomolgus monkeys. Fever was either mild or absent in both species. Virus reisolation profiles from peripheral blood mononuclear cells and broncho-alveolar lavage cells and the kinetics of MV-specific IgM and IgG responses were largely identical in the t...
Journal of Virology, 2013
DNA vaccines formulated with the cationic lipid-based adjuvant Vaxfectin induce protective immunity in macaques after intradermal (i.d.) or intramuscular (i.m.) delivery of 0.5 to 1 mg of codon-optimized DNA encoding the hemagglutinin (H) and fusion (F) proteins of measles virus (MeV). To characterize the effect of Vaxfectin at lower doses of H؉F DNA, rhesus macaques were vaccinated twice with 20 g of DNA plus Vaxfectin i.d., 100 g of DNA plus Vaxfectin i.d., 100 g of DNA plus Vaxfectin i.m. or 100 g of DNA plus phosphate-buffered saline (PBS) i.m. using a needleless Biojector device. The levels of neutralizing (P ؍ 0.036) and binding (P ؍ 0.0001) antibodies were higher after 20 or 100 g of DNA plus Vaxfectin than after 100 g of DNA plus PBS. Gamma interferon (IFN-␥)-producing T cells were induced more rapidly than antibody, but were not improved with Vaxfectin. At 18 months after vaccination, monkeys were challenged with wild-type MeV. None developed rash or viremia, but all showed evidence of infection. Antibody levels increased, and IFN-␥-and interleukin-17-producing T cells, including cells specific for the nucleoprotein absent from the vaccine, were induced. At 3 months after challenge, MeV RNA was detected in the leukocytes of two monkeys. The levels of antibody peaked 2 to 4 weeks after challenge and then declined in vaccinated animals reflecting low numbers of bone marrow-resident plasma cells. Therefore, Vaxfectin was dose sparing and substantially improved the antibody response to the H؉F DNA vaccine. This immune response led to protection from disease (rash/viremia) but not from infection. Antibody responses after challenge were more transient in vaccinated animals than in an unvaccinated animal.
Vaccine, 2002
Although the currently used live attenuated measles vaccines are safe and effective, they are dependent on cold chain maintenance and are often ineffective in young infants due to interference by maternal antibody. Therefore, besides vector-based vaccines, different new generation non-replicating candidate measles vaccines are being considered, including nucleic acid vaccines. We have vaccinated cynomolgus macaques transdermally with DNA plasmids encoding measles virus (MV) proteins. Following two vaccinations, low serum antibody responses were detected. Wild-type measles virus challenge 1 year after vaccination showed reduced viraemia in some animals. However, accelerated humoral-and cellular-immune responses were observed in all vaccinated macaques, demonstrating successful priming by the DNA vaccines.
Immune responses against measles virus in cynomolgus monkeys
Comparative Immunology, Microbiology and Infectious Diseases, 2008
Measles virus (MV) induces profound suppression of the immune response during and for weeks after acute infection. On the other hand, virus-specific immune responses that mediate viral clearance and confer long-lasting immunity are efficiently generated. To investigate this paradox, we studied the immune responses to MV using a monkey model of acute measles. Cynomolgus monkeys were experimentally infected with wild-type MV (MV-HL) and showed marked leukopenia associated with a steady reduction in CD4+ T cell numbers for 18 days post-inoculation. Transient expression of interferon and IL-6 were observed in the serum between 4 and 6 days post-inoculation, and IL-10 levels increased after 11 days postinoculation. Interestingly, IL-8 showed a three-peak increase that correlated with an increase
Journal of Virology, 2000
Recombinant modified vaccinia virus Ankara (MVA), encoding the measles virus (MV) fusion (F) and hemagglutinin (H) (MVA-FH) glycoproteins, was evaluated in an MV vaccination-challenge model with macaques. Animals were vaccinated twice in the absence or presence of passively transferred MV-neutralizing macaque antibodies and challenged 1 year later intratracheally with wild-type MV. After the second vaccination with MVA-FH, all the animals developed MV-neutralizing antibodies and MV-specific T-cell responses. Although MVA-FH was slightly less effective in inducing MV-neutralizing antibodies in the absence of passively transferred antibodies than the currently used live attenuated vaccine, it proved to be more effective in the presence of such antibodies. All vaccinated animals were effectively protected from the challenge infection. These data suggest that MVA-FH should be further tested as an alternative to the current vaccine for infants with maternally acquired MV-neutralizing antibodies and for adults with waning vaccine-induced immunity.
Experimental Measles. I. Pathogenesis in the Normal and the Immunized Host
Virology, 1997
An animal model to study measles pathogenesis and the correlates of protective immunity was established using rhesus monkeys. A measles isolate, obtained during an epidemic of measles in the primate colony at the University of California, Davis, was passaged through rhesus monkeys and amplified in rhesus mononuclear cells to create a pathogenic virus stock. Sequence analysis of the nucleoprotein and hemagglutinin genes of this isolate revealed strong homology with the Chicago 89 strain of measles virus. Conjunctival/intranasal inoculation of juvenile rhesus monkeys with this virus resulted in skin rash, pneumonia, and systemic infection with dissemination to other mucosal sites and to the lymphoid tissues. Inflammation and necrosis occurred in the lungs and lymphoid tissues and many cell types were infected with measles virus on Day 7 postinoculation (p.i.). The most commonly infected cell type was the B lymphocyte in lymphoid follicles. Measles antigen was found in follicular dendritic cells on Day 14 p.i. In contrast to naive monkeys infected with measles virus, animals vaccinated with the attenuated Moraten strain did not develop clinical or pathologic signs of measles after challenge. However, moderate to marked hyperplasia occurred in the lymph nodes and spleen of a vaccinated animal on Day 7 after pathogenic virus challenge, suggesting that an effective measles vaccine limits but does not prevent infection with wild-type measles virus.
Evolution of T Cell Responses during Measles Virus Infection and RNA Clearance
Scientific Reports
Measles is an acute viral disease associated both with immune suppression and development of lifelong immunity. Clearance of measles virus (MeV) involves rapid elimination of infectious virus during the rash followed by slow elimination of viral RNA. To characterize cellular immune responses during recovery, we analyzed the appearance, specificity and function of MeV-specific T cells for 6 months after respiratory infection of rhesus macaques with wild type MeV. IFN-γ and IL-17-producing cells specific for the hemagglutinin and nucleocapsid proteins appeared in circulation in multiple waves approximately 2-3, 8 and 18-24 weeks after infection. IFN-γ-secreting cells were most abundant early and IL-17secreting cells late. Both CD4 + and CD8 + T cells were sources of IFN-γ and IL-17, and IL-17-producing cells expressed RORγt. Therefore, the cellular immune response evolves during MeV clearance to produce functionally distinct subsets of MeV-specific CD4 + and CD8 + T cells at different times after infection.