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Vaccine Detail

Yersinia EV76
Vaccine Information
  • Vaccine Ontology ID: VO_0000828
  • Type: Live attenuated
  • Preparation: The EV76 strain is a pigmentation negative mutant of Y. pestis which was derived from a fully virulent strain. The vaccine has been in use since 1908 and is given as a single dose of 5.8×106 cfu. Findings suggest that immunisation with the EV76 vaccine will provide protection against both bubonic and pneumonic plague in man. However, the safety of this vaccine in man is questionable, because the EV76 strain is not avirulent (Titball et al., 2001).
  • Virulence: A febrile response was reported in 20% of vaccinees, accompanied by headache, weakness, and malaise. Erythema surrounding the site of vaccination, reaching dimensions as large as 15 cm2, was frequently reported. Some severe systemic reactions even required hospitalization. Numerous unsuccessful attempts were made to reduce the incidence of side effects by administering the vaccine by different routes, such as scarification, inhalation, and even intraocularly (Williamson et al., 2005).
  • Description: A live, attenuated vaccine has also been used since 1908 using the avirulent strain of Y pestis, EV76. This strain is not capable of assimilating chromatophores such as Congo Red or haemin from artificial media, and is described as Pigmentation (Pgm) -. Virulent strains of Y. pestis are Pgm+. Although the organisms in the vaccine could multiply following administration, and could therefore theoretically enhance protection, there appeared to be wide variation in the immunogenicity and virulence between different EV76 vaccine preparations. The vaccine caused severe side-effects when used and there was also the danger of reversion to a fully virulent form. A large part of the Vietnamese population was vaccinated with EV76 between 1967 and 1969 (Russell et al., 1995).
Host Response

Human Response

  • Host Strain: Male subjects varying in age (21 to 59 yrs, avg. 39).
  • Vaccination Protocol: 12 male human subjects were inoculated with 1 ml of 1*109 Y. pestis strain EV76.
  • Persistence: On the 28th day, the average MPI was 8.6 and 3 sera yielded an MPI below 5 (Meyer, 1970).
  • Immune Response: An antibody response compatible with some degree of immunity was recorded in 33% of the subjects. The MPI (average 9.2) was within the range charactersitc for human subjects given a single inoculation of killed vaccine suspension containing 3.6*109 Y. pestis. Booster inoculations produced no local or systemic reactions (Meyer, 1970).
  • Side Effects: Systematic reactions included general malaise, aching, and anorexia. At least half of the group was incapacitated for as long as 72 hours; 2 were hospitalized for 48 hours. Local reactions were confined to hot, erythematous, moderately indurated, painful areas. The unpleasant side effects thus discourages mass vaccinations (Meyer, 1970).
  • Description: 28 macaques were inoculated with 1*109 Y. pestis strain EV76. 64% of the vaccinated animals survived a severe subcutaneious challenge infection of 2.3*109 virulent P.pestis strain 195/P. Inoculations of 1 ml of the same suspension used for macaques were made for the human subjects (Meyer, 1970).

Mouse Response

  • Host Strain: Balb/C, Porton outbred, and NIH/S
  • Vaccination Protocol: The median lethal dose (MLD) of a pathogenic strain of Yersinia pestis was established by, three routes of administration (s.c., i.p., i.n.) in three strains of mouse. There was no significant difference in the MLDs in the different strains of mouse. The MLD by the subcutaneous route in Balb/C and an outbred line was approximately I c.fu.; the MLD following the intraperitoneal administration was tenfold higher.
    Y pestis EV76 strain was retrieved from the storage beads. Fresh BAB broth was seeded with an overnight culture and incubated. Neat seeded broth (0.1 ml) was administered as a single injection on day 0. One group received the 28°C cultured bacteria and the other the 37°C culture. The
    mice were then challenged subcutaneously (Russell et al., 1995).
  • Persistence: In all cases, animals showed signs of infection within 24-48 h of challenge with the high doses of Y pestis. The first deaths occurred within 60 h, irrespective of the route and murine strain. The average time-to-death, however, varied according to the administration route.
    Where deaths did occur the mean time to death was ten days in EV76 (37”C-grown)-vaccinated mice and four days in mice vaccinated with EV76 grown at 28°C (Russell et al., 1995).
  • Side Effects: EV76 caused side-effects in nearly all of the mice - some severe - and even one death attributable to the vaccine. Autopsy revealed damage to the spleen, consisting of purulent abscesses over the surface of the organ and apical necrosis. In other animals, the vaccine caused paralysis in the injected limb which did not improve over the total study period. There appeared to be both sensory and motor dysfunction (Russell et al., 1995).
  • Efficacy: EV76 induced protection against a subcutaneous challenge with at least 5 x l0^3 MLD of Y. pestis strain GB. The fatality rate has been reported to be approximately 1% of vaccinees (Russell et al., 1995).

Monkey Response

  • Host Strain: Vervets of three different races or subspecies (Ethiopian race, Kenya race, and Cercopithecus aethiops pygerythrus).
  • Vaccination Protocol: Ethiopian race: 16 vervets were vaccinated with 160 million EV (51f) organisms, 16 million organisms, and 1.6 million organisms, and then challenged on the 41st day after vaccination.
    Kenya race: 20 vervets were vaccinated with 218 million organisms, and then challenged on the 52nd day after vaccination.
    Cercopithecus aethiops pygerythrus: 50 vervets were vaccinated with 100 million and 100,000 organisms, and then challenged with 8,770 organisms of highly virulent strain of P. pestis 166 days after vaccination (Meyer, 1970).
  • Persistence: Deaths occurred within 6-28 days following vaccination (Meyer, 1970).
  • Side Effects: Symptoms included anatomical lesions and bacteriological findings of bubonic-septicaemic plague (Meyer, 1970).
  • Efficacy: Survivors that were challenged showed complete immunity except for 3 of 10 Cercopithecus aethiops pygerythrus (Meyer, 1970).
Meyer, 1970: Meyer KF. Effectiveness of live or killed plague vaccines in man. Bulletin of the World Health Organization. 1970; 42(5); 653-66. [PubMed: 4988692].
Russell et al., 1995: Russell P, Eley SM, Hibbs SE, Manchee RJ, Stagg AJ, Titball RW. A comparison of Plague vaccine, USP and EV76 vaccine induced protection against Yersinia pestis in a murine model. Vaccine. 1995 Nov; 13(16); 1551-6. [PubMed: 8578841].
Titball et al., 2001: Titball RW, Williamson ED. Vaccination against bubonic and pneumonic plague. Vaccine. 2001 Jul 20; 19(30); 4175-84. [PubMed: 11457543].
Williamson et al., 2005: Williamson ED, Flick-Smith HC, Lebutt C, Rowland CA, Jones SM, Waters EL, Gwyther RJ, Miller J, Packer PJ, Irving M. Human immune response to a plague vaccine comprising recombinant F1 and V antigens. Infection and immunity. 2005 Jun; 73(6); 3598-608. [PubMed: 15908389].