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Vaccine Detail

Chloroform-methanol residue (CMR)
Vaccine Information
  • Vaccine Name: Chloroform-methanol residue (CMR)
  • Target Pathogen: Coxiella burnetii
  • Target Disease: Q fever
  • Vaccine Ontology ID: VO_0004132
  • Type: chloroform-methanol residue vaccine
  • Preparation: The CMR vaccine is prepared from chloroform-methanol residue of Formalin-killed whole cells of C. burnetii. C. burnetii whole cells are lyophilized and refluxed with CM azeotrope of 4:1. 150 mg of whole cells are then added to 100 ml of CM, which is then refluxed for 6 to 8 hours. Cellular material is separated by filtration and the residue on filter is mixed with 100 ml of CM. After three repetitions, the filtrate (extractable component) is the CME and the residue (particulate material) is the CMR (Williams and Cantrell, 1982).
  • Description: The CMR vaccine consists of chloroform-methanol residues from killed whole cells of C. burnetii.
Host Response

Monkey Response

  • Host Strain: Adult cynomolgus monkeys
  • Vaccination Protocol: Two groups of 10 monkeys (2.0 to 6.0 kg in weight) were immunized with 30 μg of CMR subcutaneously. Single groups were immunized with 30 μg of Q-Vax, or 100 μg of CMR, or placebo subcutaneously.The group initially given 30 μg of CMR was given a booster of another 30 μg of CMR after twenty-eight days (Waag et al., 2002).
  • Persistence: The antibody responses at single 100 μg dose of CMR and two 30 μg doses of CMR were short-lived. Anti-phases I and II antibody levels dropped to baseline levels at the 17th week after immunization (Waag et al., 2002).
  • Immune Response: A single 30 μg dose of CMR and a single 30 μg dose of Q-Vax resulted in similar antibody responses. The 100 μg single CMR dose and the two 30 μg doses of CMR increased the immunogenicity of the vaccine, but the antibody responses were short-lived. Anti-phases I and II antibody responses rose at equal magnitude and antibody titers leveled off 2 weeks after challenge for the vaccinated monkeys. In contrast, control monkeys had a higher anti-phase II response than anti-phase I response. Within three weeks, monkeys in control group had anti-phase II response that was greater than that in the vaccinated monkeys (Waag et al., 2002).
  • Side Effects: Monkeys challenged six months after vaccination showed signs of illness. However, the illnesses were less severe and/or of shorter duration for the vaccinated monkeys than for the control monkeys. A majority of the control monkeys had increases in interstitial and bronchial opacity (as opposed to only a minority of vaccinated monkeys showing those changes). A drop in hemaglobin and hematocrit was observed in all groups. All monkeys, besides groups vaccinated with single dose 100 μg CMR or two 30 μg doses of CMR, were bacteremic, which correlated with fever (Waag et al., 2002).
  • Challenge Protocol: After six months of initial immunization, the monkeys were challenged with approximately 105 virulent phase I Henzerling strian C. burnetii administered using aerosol (Waag et al., 2002).
  • Efficacy: The study showed that CMR and Q-Vax were equally efficacious and immunogenic in monkeys challenged by aerosol (Waag et al., 2002).
  • Description: This study investigated the vaccine efficacy of CMR and Q-Vax in monkeys challenged by aerosol, which resembles the route of human infection (Waag et al., 2002).

Guinea pig Response

  • Host Strain: Hartley guinea pigs
  • Vaccination Protocol: Groups of seven 250-300 g Hartley guinea pigs were vaccinated subcutaneously with 0.5 ml of 0.003, 0.03, 0.3, 3, or 30 μg of CMR. Guinea pigs in control groups were given USP saline (Waag et al., 1997).
  • Immune Response: None reported
  • Side Effects: None reported
  • Challenge Protocol: Six weeks from vaccination, the guinea pigs were challenged with10-fold 50% infection dose of phase I Henzerling strain C. burnetii administered in a small particle aerosol (Waag et al., 1997)
  • Efficacy: 0.003 and 0.03 μg dose did not effectively protect the pigs from infection. Guinea pigs vaccinated with 0.3, 3.0, or 30.0 μg CMR were significantly protected compared to the groups injected with USP saline (Waag et al., 1997).

Mouse Response

  • Host Strain: A/J
  • Vaccination Protocol: Groups of ten six-week-old A/J strain female mice were immunized with 0.5 ml of 0.01, 0.1, or 1.0 μg of CMR. Mice in control groups were given USP saline (Waag et al., 1997).
  • Immune Response: None reported
  • Side Effects: None reported
  • Challenge Protocol: Six weeks from vaccination, the mice were challenged with10-fold 50% infection dose of phase I Henzerling strain C. burnetii administered in a small particle aerosol (Waag et al., 1997).
  • Efficacy: Mice vaccinated with 0.01 or 0.1 μg of CMR were not protected. However, the 1.0 μg dose of CMR were effective in protecting the mice from infection (Waag et al., 1997).

Mouse Response

  • Host Strain: C57BL/10ScN mice
  • Vaccination Protocol: Endotoxin nonresponder male mice (C57BL/10ScN, 8 to 10 weeks old) in experimental groups of 5 to 10 were given a single injection of 30 or 300 μg of killed cells, CMR, or CME (Williams and Cantrell, 1982).
  • Immune Response: High titers of phase II antibodies were detected with mice immunized with CMR.Similar detection was found for killed cells treated mice. However, there was a lower level of phase I antibodies for CMR treated mice than killed whole cells treated mice. Neither phase I nor phase II antibodies was found for mice immunized with CME (Williams and Cantrell, 1982).
  • Side Effects: No side effects of splenomegaly, hepatomegaly, or liver necrosis were observed for mice treated with CMR or CME. However, the mice group treated with killed whole cells showed severe, life-threatening side effects (Williams and Cantrell, 1982).
  • Challenge Protocol: Fourteen or thirty days after vaccination, the mice were challenged with 7 x 1010 PFU of viable organisms of phase I C. burnetii Ohio strain (Williams and Cantrell, 1982).
  • Efficacy: Mice immunized with 30 μg of CMR resulted in higher protection (70% to 90%) than mice inoculated with killed whole cells (which was 50%). However, mice immunized with 300 μg CME had only 10% survival rate (Williams and Cantrell, 1982).

Human Response

  • Host Strain: Volunteers without cardiovascular, pulmonary, hepatitis, renal, or immunologic disease or without hepatitis B virus or HIV type 1 infection or without receiving any immunosuppressive medication
  • Vaccination Protocol: Human subjects were randomly assigned to receive either vaccine or placebo in a ratio of 5:2. Groups of five subjects were immunized with 30, 60, or 120 μg of CMR at one-week intervals. Twenty subjects then received 240 μg of CMR. Each group had corresponding placebo recipients in the 5:2 ratio. Subjects’ temperatures were checked on days 1, 2, 3, 7, 15, and 30 with blood specimens obtained 15, 30, 90, and 180 days after immunization. Vaccine immunogenicity were assayed with kinetic enyzme-linked immunosorbent assay (KELISA) (Fries et al., 1993).
  • Immune Response: CMR induced the greatest IgM responses. IgM responses to phase I antigen were similar while the IgM responses to phase II antigen were less frequent. IgG responses were less common to CMR, phase I, and phase II antigens (Fries et al., 1993).
  • Side Effects: CMR at 30 and 60 μg caused minimal side effects. Higher doses of CMR caused reactions similar to those cause by 30 μg of whole-cell vaccines. 120 μg and 240 μg dose induced local erythema in 5 (out of 15) and 8 (out of 10) recipients and subcutaneous induration in 4 (out of 15) and 7 (out of 10) recipients, respectively (Fries et al., 1993).
  • Challenge Protocol: Subjects were not challenged (Fries et al., 1993).
  • Description: CMR vaccine could be safely administered to human subjects unscreened for prior C. burnetii immunity with acceptable local reactions at 30 to 120 μg doses (Fries et al., 1993).
  • Host IgM (partial) response
    • Description: CMR induced the greatest serum IgM responses. IgM responses to phase I antigen were similar while the IgM responses to phase II antigen were less frequent. The group receiving 240 micrograms had significantly higher responses than the placebo group at all post immunization time points. The 120-microgram dose group approached significant difference from placebo recipients at days 30, 90, and180 post immunization ( (Fries et al., 1993).
    • Detailed Gene Information: Click Here.
Fries et al., 1993: Fries LF, Waag DM, Williams JC. Safety and immunogenicity in human volunteers of a chloroform-methanol residue vaccine for Q fever. Infection and immunity. 1993; 61(4); 1251-1258. [PubMed: 8454328 ].
Waag et al., 1997: Waag DM, England MJ, Pitt ML. Comparative efficacy of a Coxiella burnetii chloroform:methanol residue (CMR) vaccine and a licensed cellular vaccine (Q-Vax) in rodents challenged by aerosol. Vaccine. 1997; 15(16); 1779-1783. [PubMed: 9364683 ].
Waag et al., 2002: Waag DM, England MJ, Tammariello RF, Byrne WR, Gibbs P, Banfield CM, Pitt ML. Comparative efficacy and immunogenicity of Q fever chloroform:methanol residue (CMR) and phase I cellular (Q-Vax) vaccines in cynomolgus monkeys challenged by aerosol. Vaccine. 2002; 20(19-20); 2623-2634. [PubMed: 12057622 ].
Williams and Cantrell, 1982: Williams JC, Cantrell JL. Biological and immunological properties of Coxiella burnetii vaccines in C57BL/10ScN endotoxin-nonresponder mice. Infection and immunity. 1982; 35(3); 1091-1102. [PubMed: 7068212].