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Economical use of rabies vaccine
THE LANCET 4
5
Warrell MJ, Nicholson KG, Warrell DA, et al. Economical multiple site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985; i: 1059–62. Chutivongse S, Wilde H, Supich C, et al. Post-exposure prophylaxis for rabies with antiserum and intradermal vaccination. Lancet 1990; 335: 896–98.
SIR—Hasbahceci and colleagues1 conclude that a four-dose schedule of human diploid-cell rabies vaccine (HDCV) does not compromise protection, but substantially reduces the cost. I recommend caution lest someone should give inadequate prophylaxis under the pretext of reducing cost. There are three cell-culture rabies vaccines—namely, HDCV (Pasteur-Mérieux, France), Vero cell vaccine (Verorab, Pasteur Mérieux), and purified chick embryo cell culture vaccine (PCEC, Rabipur, Behringwerke AG, Germany). All three meet the WHO standards of potency and are equally safe and effective. However, their prices differ; in India their retail prices per dose are Rupees 756 for HDCV, 258 for Vero cell vaccine, and 238 for PCEC. If cost is an issue, the obvious choice is either PCEC or Vero cell vaccine and not HDCV even in a four-dose schedule. The more important difficulty is in defining adequate prophylaxis. Hasbahceci and colleagues gave vaccine doses on days 0, 3, 7, 14, and 30, and obtained blood 16 days after dose four and 45 days after dose five. Four doses elicited protective levels of antibody in all vaccinees. Indeed there have been several studies showing that on day 14 all people (given any cell culture vaccine on days 0, 3, and 7) do have protective levels of virus-neutralising antibodies.2–4 Yet, why has no one recommended a three-dose schedule? The answer lies in the study itself: by day 45 antibody levels had dropped (p<0·01) despite a fifth dose of vaccine; it is reasonable to assume that the levels would have been much lower without this dose. Therefore, the role of the fifth dose is to sustain protective antibody levels for the incubation period of rabies, which might be 6 months or more. If a four-dose schedule is wanted, there is one already approved by the WHO expert committee on rabies: it is two doses on day 0, and one dose each on days 7 and 21.5 This 2-1-1 schedule is especially suitable in case passive immunisation is not given after the bite of a rabid animal,5 as was the case with the 23 individuals reported by Hasbahceci. The standard post-exposure prophylaxis after the bite of a proven or presumed rabid animal is passive immunisation plus active immunisation with five doses of a cell culture rabies vaccine. To mitigate against the inhibitory effect of passive immunisation on the sustained antibody levels induced by active immunisation, a sixth dose on day 90 is recommended by many experts. When rabies immunoglobulin (or antiserum) is not available, a 2-1-1 schedule must be followed, since it induces antibody response earlier than the regular five-dose schedule.5 T Jacob John Christian Medical College Hospital, Vellore, 632 004, Tamil Nadu, India
1
2
3
4 5
Hasbahceci M, Kiyan M, Eyol E, Ewatt LC, Lodmell DL. Human diploid-cell rabies vaccine: efficacy of four doses. Lancet 1996; 347: 976–77. Natarajan M, Mukundan P, John TJ. Immune response to purified chick embryo cell culture rabies vaccine manufactured in India. Ind J Med Res 1992; 95: 51–53. Selvakumar R, John TJ. Immune response to purified chick embryo cell culture rabies vaccine (Rabipur) in dog-bite victims. Ind J Med Res 1989; 89: 217–20. Barth B, Bijok U, Gruschkau H, et al. Purified chick embryo cell rabies vaccine for human use. Lancet 1983; i: 700. WHO Expert Committee on Rabies. Tech Rep Ser 824. Geneva: World Health Organization, 1992: 21–26.
Vol 348 • August 31, 1996
Author’s reply SIR—I thank Warrell and Warrell for their interest in our report of rabies vaccination. First, I point out that none of our cases had received rabies immunoglobulin since immunisation was used prophylactically, not for treatment.1 Our results showed that maximum antibody concentration could be obtained with the fourth dose of prophylactic rabies vaccine administration, which was not immediately intensified by the fifth dose (in fact there was a substantial decrease in antibody titre after the fifth dose compared with the fourth). As far as I am aware, the comparison of the antibody titration after the fourth and fifth doses of standard regimen2 for post-exposure rabies has not been studied. Therefore, I question the value of the fifth dose. Since antibody titre was decreased after the fifth dose, we suggested that for the post-exposure immunisation the fifth dose may not be required. On the basis of our experience, it is not possible to evaluate the efficacy of multisite intradermal regimens. Vero cell and PCEC vaccines are cheaper than HDCV but they are not popular in Turkey, and the WHO four-dose schedule was not suitable for our study. John seems to misunderstand the sample timings (16 and 45 days after the fourth and fifth doses, respectively). *Mustafa Hasbahceci Hacettepe University Faculty of Medicine, Department of Surgery, 06100 Ankara, Turkey
1 2
World Health Organization. Expert Committee on Rabies. WHO Tech Ser 1992; no 824: 1–84. Report of a WHO Consultation on Intradermal Application of Human Rabies Vaccines. WHO/Rab. Res./95.47.1995.
Brucella melitensis can be transmitted sexually SIR—Mantur and colleagues (June 22, p 1763)1 report sexual transmission of Brucella melitensis in a young Indian couple. As long ago as 1905, Captain J C Kennedy, RAMC, infected two monkeys with cottonwool soaked in urine containing B melitensis by wrapping it around the glans of one for 30 s and by slight friction of the glans of the other.2 Kennedy, a member of the Mediterranean Fever Commission in Malta, had noticed that “by far the larger proportion of those who developed Malta fever after admission to hospital were venereal cases”. He therefore “began going around all the brothels under the escort of the Superintendent of Police. These places were as a rule in an indescribably filthy condition and one would think that it would be possible to contract any disease in existence by patronising these establishments”. He isolated this bacterium from the urine of four of the women and from vaginal swabs of two.2 He also isolated the bacteria from vaginal swabs, milk, and urine of a married woman one week after her discharge as convalescent from the Military Families Hospital, Valletta.2 However, he did not isolate bacteria from 32 samples of saliva from four severe cases.3 He received a gold medal for his thesis, but his work seems to have been forgotten. H V Wyatt School of Healthcare Studies, University of Leeds, Leeds LS2 9HD, UK
1 2
3
Mantur BG, Mangalgi SS, Mulimani M. Brucella melitensis—a sexually transmitted agent? Lancet 1996; 347: 1763. Kennedy JC. Malta fever. University of Edinburgh, MD thesis, 1907 (also published in the Reports of the Commission for the Investigation of Mediterranean Fever I–VII. London: Harrison, 1905–1907). Kennedy JC. χ-bacteriological examinations of cases of Mediterranean fever. Rep Commiss Invest Mediterranean Fever 1906; iv: 92–95.
615
5
Warrell MJ, Nicholson KG, Warrell DA, et al. Economical multiple site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985; i: 1059–62. Chutivongse S, Wilde H, Supich C, et al. Post-exposure prophylaxis for rabies with antiserum and intradermal vaccination. Lancet 1990; 335: 896–98.
SIR—Hasbahceci and colleagues1 conclude that a four-dose schedule of human diploid-cell rabies vaccine (HDCV) does not compromise protection, but substantially reduces the cost. I recommend caution lest someone should give inadequate prophylaxis under the pretext of reducing cost. There are three cell-culture rabies vaccines—namely, HDCV (Pasteur-Mérieux, France), Vero cell vaccine (Verorab, Pasteur Mérieux), and purified chick embryo cell culture vaccine (PCEC, Rabipur, Behringwerke AG, Germany). All three meet the WHO standards of potency and are equally safe and effective. However, their prices differ; in India their retail prices per dose are Rupees 756 for HDCV, 258 for Vero cell vaccine, and 238 for PCEC. If cost is an issue, the obvious choice is either PCEC or Vero cell vaccine and not HDCV even in a four-dose schedule. The more important difficulty is in defining adequate prophylaxis. Hasbahceci and colleagues gave vaccine doses on days 0, 3, 7, 14, and 30, and obtained blood 16 days after dose four and 45 days after dose five. Four doses elicited protective levels of antibody in all vaccinees. Indeed there have been several studies showing that on day 14 all people (given any cell culture vaccine on days 0, 3, and 7) do have protective levels of virus-neutralising antibodies.2–4 Yet, why has no one recommended a three-dose schedule? The answer lies in the study itself: by day 45 antibody levels had dropped (p<0·01) despite a fifth dose of vaccine; it is reasonable to assume that the levels would have been much lower without this dose. Therefore, the role of the fifth dose is to sustain protective antibody levels for the incubation period of rabies, which might be 6 months or more. If a four-dose schedule is wanted, there is one already approved by the WHO expert committee on rabies: it is two doses on day 0, and one dose each on days 7 and 21.5 This 2-1-1 schedule is especially suitable in case passive immunisation is not given after the bite of a rabid animal,5 as was the case with the 23 individuals reported by Hasbahceci. The standard post-exposure prophylaxis after the bite of a proven or presumed rabid animal is passive immunisation plus active immunisation with five doses of a cell culture rabies vaccine. To mitigate against the inhibitory effect of passive immunisation on the sustained antibody levels induced by active immunisation, a sixth dose on day 90 is recommended by many experts. When rabies immunoglobulin (or antiserum) is not available, a 2-1-1 schedule must be followed, since it induces antibody response earlier than the regular five-dose schedule.5 T Jacob John Christian Medical College Hospital, Vellore, 632 004, Tamil Nadu, India
1
2
3
4 5
Hasbahceci M, Kiyan M, Eyol E, Ewatt LC, Lodmell DL. Human diploid-cell rabies vaccine: efficacy of four doses. Lancet 1996; 347: 976–77. Natarajan M, Mukundan P, John TJ. Immune response to purified chick embryo cell culture rabies vaccine manufactured in India. Ind J Med Res 1992; 95: 51–53. Selvakumar R, John TJ. Immune response to purified chick embryo cell culture rabies vaccine (Rabipur) in dog-bite victims. Ind J Med Res 1989; 89: 217–20. Barth B, Bijok U, Gruschkau H, et al. Purified chick embryo cell rabies vaccine for human use. Lancet 1983; i: 700. WHO Expert Committee on Rabies. Tech Rep Ser 824. Geneva: World Health Organization, 1992: 21–26.
Vol 348 • August 31, 1996
Author’s reply SIR—I thank Warrell and Warrell for their interest in our report of rabies vaccination. First, I point out that none of our cases had received rabies immunoglobulin since immunisation was used prophylactically, not for treatment.1 Our results showed that maximum antibody concentration could be obtained with the fourth dose of prophylactic rabies vaccine administration, which was not immediately intensified by the fifth dose (in fact there was a substantial decrease in antibody titre after the fifth dose compared with the fourth). As far as I am aware, the comparison of the antibody titration after the fourth and fifth doses of standard regimen2 for post-exposure rabies has not been studied. Therefore, I question the value of the fifth dose. Since antibody titre was decreased after the fifth dose, we suggested that for the post-exposure immunisation the fifth dose may not be required. On the basis of our experience, it is not possible to evaluate the efficacy of multisite intradermal regimens. Vero cell and PCEC vaccines are cheaper than HDCV but they are not popular in Turkey, and the WHO four-dose schedule was not suitable for our study. John seems to misunderstand the sample timings (16 and 45 days after the fourth and fifth doses, respectively). *Mustafa Hasbahceci Hacettepe University Faculty of Medicine, Department of Surgery, 06100 Ankara, Turkey
1 2
World Health Organization. Expert Committee on Rabies. WHO Tech Ser 1992; no 824: 1–84. Report of a WHO Consultation on Intradermal Application of Human Rabies Vaccines. WHO/Rab. Res./95.47.1995.
Brucella melitensis can be transmitted sexually SIR—Mantur and colleagues (June 22, p 1763)1 report sexual transmission of Brucella melitensis in a young Indian couple. As long ago as 1905, Captain J C Kennedy, RAMC, infected two monkeys with cottonwool soaked in urine containing B melitensis by wrapping it around the glans of one for 30 s and by slight friction of the glans of the other.2 Kennedy, a member of the Mediterranean Fever Commission in Malta, had noticed that “by far the larger proportion of those who developed Malta fever after admission to hospital were venereal cases”. He therefore “began going around all the brothels under the escort of the Superintendent of Police. These places were as a rule in an indescribably filthy condition and one would think that it would be possible to contract any disease in existence by patronising these establishments”. He isolated this bacterium from the urine of four of the women and from vaginal swabs of two.2 He also isolated the bacteria from vaginal swabs, milk, and urine of a married woman one week after her discharge as convalescent from the Military Families Hospital, Valletta.2 However, he did not isolate bacteria from 32 samples of saliva from four severe cases.3 He received a gold medal for his thesis, but his work seems to have been forgotten. H V Wyatt School of Healthcare Studies, University of Leeds, Leeds LS2 9HD, UK
1 2
3
Mantur BG, Mangalgi SS, Mulimani M. Brucella melitensis—a sexually transmitted agent? Lancet 1996; 347: 1763. Kennedy JC. Malta fever. University of Edinburgh, MD thesis, 1907 (also published in the Reports of the Commission for the Investigation of Mediterranean Fever I–VII. London: Harrison, 1905–1907). Kennedy JC. χ-bacteriological examinations of cases of Mediterranean fever. Rep Commiss Invest Mediterranean Fever 1906; iv: 92–95.
615