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Safety and immunogenicity of combined rabies and typhoid fever immunization
Short Papers Safety and immunogenicity of combined rabies and typhoid fever immunization Chantal Fritzell*, Pierre E. Rollin *~, Maryvonne Touir*, Pierre Sureau* and Louis Teulieres ~ The prevalence o f rabies and typhoid fever in many developin9 countries poses a serious health hazard to travellers. The development o f a combined immunization schedule would be advantageous. A study was performed on 104 adult volunteers usin9 purified Vero cell rabies vaccine and Typhim Vi, a purified capsular polysaccharide, either separately or in combination. No siynificant difference was observed in immunogenicity or tolerance between the two 9roups. A 3-year follow-up study is planned. Keywords: Rabies ; typhoid fever; combined immunization ; immunogenicity ; side effects
INTRODUCTION Rabies is endemic in most parts of the world, and in tropical areas, where rabies is hyperenzootic in domestic animals, vaccine is often not readily available. In pre-exposure rabies vaccinated individuals exposed to suspected rabid animals, no serotherapy is needed and only two boosters should be given 3 days apart 1. Typhoid fever is a serious disease occurring frequently in many developing countries with inadequate sewage and contaminated water. Earlier vaccines against typhoid fever required several injections with significant sideeffects and giving incomplete protection 2. With the improved and long-term immunogenicity of the new one-shot polysaccharide vaccine Typhim Vi 3'4, it seems feasible to extend the advantages of immunization for travellers to endemic areas. As travellers can be exposed to several diseases 5 and considering the great advantage of vaccinal associations in reducing the number of injections and the time needed to receive all the recommended immunizations, a comparative randomized study was carried out in volunteers to assess the reactogenicity and the immunogenicity of associated a n d / o r combined rabies-typhoid fever vaccines. The study involved a total of 104 healthy volunteers (50 males, 54 females; age range 18-23) from the National Veterinary School of Maison Alfort. They had never previously been immunized against rabies, and typhoid immunization, if any, was done more than 5 years before. Informed consent was obtained from all participants. The purified Vero cell rabies vaccine PVRV 6'7 (Pasteur M~rieux S~rums and Vaccins (PMSV); batch 5125, potency of 2.5 IU per 0.5 ml; lyophilized *Centre Antirabique, HOpital de i'lnstitut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France. ~Pasteur Merieux Serums et Vaccins, BP10, 92430 Marnes la Coquette, France. tTo whom correspondence should be addressed. (Received 15 July 1991; revised 4 November 1991; accepted 7 November 1991) 0264-410X/92/050299~32 © 1992 Butterworth-Heinemann Ltd
vaccine was diluted in 0.5 ml of solvent) and Typhim Vi (purified capsular polysaccharide, PMSV, batch S 1948; 25/~g of Vi polysaccharide/0.5 ml/dose) were used. Both vaccines were intramuscularly injected into the deltoid muscles. On day 0, after blood sampling, volunteers were randomly allocated into two groups : group A : receiving simultaneously in two separate sites the first injection of PVRV and Typhim Vi vaccines; group B: receiving in one site the two vaccines mixed in the same syringe prior to injection, the liquid Typhim Vi being used to reconstitute the lyophilized PVRV. The two groups received the second shot of PVRV 3 weeks later (day 21 ) and were bled on day 48. Tolerance was established on local reactions (redness, induration and pain) and on general reactions (axillar temperature recorded by the subject, malaise and other effects ). Each subject was asked to fill in a form recording any symptoms experienced for 3 consecutive days following each application of the vaccines. The evaluation of rabies antibodies was by an ELISA test (Platelia, Diagnostics Pasteur, ref. 72200). A postvaccination serum titre of 0.5 EU m1-1 was considered as a seroconversion according to the Seventh Report of the WHO Expert Committee on Rabies. Anti-Vi antibody titration was performed by radioimmunoassay (RIA) as previously described 3 and results given in /~gm1-1. A seroconversion or a fourfold
Table
1
Side effects of combined
rabies-typhoid immunization
schedules Vaccination site
Vaccine (in arm)
Redness No. (%)
Induration No. (%)
Tenderness a No. (%)
Rabies (n = 46) Typhoid (n = 46) Rabies+typhoid ( n = 5 1 )
5 (10.9) 6 (13) 3(5.9)
6 (13) 6 (13) 3(5.9)
24 (52.2) 35 (76.1) 41 (80.4)
"Tenderness was only reported as slight or moderate
Vaccine, Vol. 10, Issue 5, 1992
299
Short p a p e r : C. Fritzell et al. Table 2
Immunogenicity of two rabies-typhoid fever immunization schedules Group A Rabies Typhim (two different sites)
No.
Rabies GMT
No.
Group B Rabies-Typhim combined injection (one site) Typhoid GMT
No.
Rabies GMT
No.
Typhoid GMT
Day 0
51
0a
51
0.223 + 1.08 ~ (0.06-1.2) c
51
0a
51
0.230 _+ 1.08 (0.1-1.2) ~
Day 48
51
3.91 _+ 1.09 (0.62-13) c
50
1.8 _+ 1.14 ( x 8) ~
51
4.03 _+ 1.1 (0.57 18.2) c
49
2.083 + 1.17 ( x 9) ~
Seroconversion ( % )
100e
84 f
100c
77.6 t
aAII subjects < 0.5 EU m1-1. ~Standard error of the mean. ~Range. ~Mean increase factor. ~>~0.5 EU m1-1. ~Percentage of patients with fourfold increase
increase in serum titre was considered as significant. The differences between the two groups for clinical reactions and seroconversion rate were determined by ~2 and Fisher's exact tests. A few minor side effects at the vaccination site were reported (Table 1 ). The only significant difference was noted between the arm receiving rabies alone and either Typhim alone ()~2 = 5.73, p = 0.016) or Typhim + Rabies ()~2 = 8.71, p = 0.003). No serious side effects occurred, although 2 - 3 % of the subjects noted a slight temperature rise in the two groups and one subject a malaise requiring no treatment in group A. Serological results are showed in Table 2. For rabies, no subject presented specific antibodies on day 0 and seroconversion was observed in 100% at day 48 without any significant difference in the geometric mean titre between the two groups. Typhoid antibodies were noted in some subjects at day 0. Seroconversion or a fourfold increase was observed in 84% (group A) and 77.6% (group B). No significant difference was observed between the two groups (Fisher's exact test). Both the combined and two-site vaccination schedules showed a good immunogenicity and tolerance. Seroconversion rate and geometric mean titres were of the same magnitude as in previous published reports on each separate vaccine3'8'9: 100% seroconversion for rabies, fourfold increase in titre in 77.6% (one site) and 84% (two different sites). The side effects were less than those of whole-cell killed vaccine for typhoid 1° and no serious local or systemic reactions were encountered. A 3-year follow-up will be carried out on these subjects to assess the persistence of antibody. These results should ease the implementation of rabies and typhoid fever immunization for travellers to
300
Vaccine, Vol. 10, I s s u e 5, 1992
developing countries where typhoid fever is endemic and rabies present. REFERENCES 1
Immunization Practices Advisory Committee. Rabies Prevention. Recommendations. Preexposure vaccination and postexposure therapy of previously vaccinated persons. Morbid. Mortal. Week. Rep. 1991, 40, 19 2 Ferenchik, G.S. and Havlichek, D. Clinical reviews of primary prevention and international travel: infections, immunizations and antimicrobial prophylexis. J. Int. Med. 1989, 4, 247 3 Acharya, I.L., Lowe, C.U., Thapa, R. et al. Prevention of Typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N. Engl. J. Med. 1987, 317, 1101 4 Tacket, C.O., Levin, M.M. and Robbins, J.B. Persistence of antibody titres three years after vaccination with Vi polysaccharide vaccine against typhoid fever, Vaccine 1988, 6, 307 5 Cundy, J.M. Precautions against rabies and other hazards of tourism. Br. Med. J. 1981, 283, 724 6 Dureux, B., Canton, P.H., Gerard, A. et al. Rabies vaccine for human use cultivated on Vero cells. Lancet 1986, i, 8498. 7 Fournier, P., Montagnon, B., Vincent-Falquet, J.C., Ajjan, N., Drucker, J. and Roumiantzeff, M. A new vaccine produced from rabies virus cultivated on Vero cells. In: Improvements in Rabies Post-exposure Treatment (Eds Vodopija, I., Nicholson, K.G., Smerdel, S. and Bijok, U.) Institute of Public Health, Zagreb, 1985, pp 115-121 8 Sovjetlicic, M., Vodopija, I., Smerdel, S., Ljbicic, M., Baklaic, Z., Vincent-Falquet, J.C. et al. Compatibility and immunogenicity of Merieux's purified Vero rabies vaccine in healthy subjects. In: Improvements in Rabies Post-exposure Treatment (Eds Vodopija, I., Nicholson, K.G., Smerdel, S., Bijok, U.) Institute of Public Health, Zagreb, 1985, pp 123-127 9 Klietmann, W., Klietmann, B., Cox, J. and Charbonnier, C. Effectiveness and tolerance of pre- and post-exposure treatment with purified inactivated rabies vaccine prepared on a Vero cell line. Vaccine 1988, 6, 39 10 Hornick, R.B. Selective primary health care: strategies for control of disease in the developing world. XX. Typhoid fever. Rev. InL Dis. 1985, 7, 536
INTRODUCTION Rabies is endemic in most parts of the world, and in tropical areas, where rabies is hyperenzootic in domestic animals, vaccine is often not readily available. In pre-exposure rabies vaccinated individuals exposed to suspected rabid animals, no serotherapy is needed and only two boosters should be given 3 days apart 1. Typhoid fever is a serious disease occurring frequently in many developing countries with inadequate sewage and contaminated water. Earlier vaccines against typhoid fever required several injections with significant sideeffects and giving incomplete protection 2. With the improved and long-term immunogenicity of the new one-shot polysaccharide vaccine Typhim Vi 3'4, it seems feasible to extend the advantages of immunization for travellers to endemic areas. As travellers can be exposed to several diseases 5 and considering the great advantage of vaccinal associations in reducing the number of injections and the time needed to receive all the recommended immunizations, a comparative randomized study was carried out in volunteers to assess the reactogenicity and the immunogenicity of associated a n d / o r combined rabies-typhoid fever vaccines. The study involved a total of 104 healthy volunteers (50 males, 54 females; age range 18-23) from the National Veterinary School of Maison Alfort. They had never previously been immunized against rabies, and typhoid immunization, if any, was done more than 5 years before. Informed consent was obtained from all participants. The purified Vero cell rabies vaccine PVRV 6'7 (Pasteur M~rieux S~rums and Vaccins (PMSV); batch 5125, potency of 2.5 IU per 0.5 ml; lyophilized *Centre Antirabique, HOpital de i'lnstitut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France. ~Pasteur Merieux Serums et Vaccins, BP10, 92430 Marnes la Coquette, France. tTo whom correspondence should be addressed. (Received 15 July 1991; revised 4 November 1991; accepted 7 November 1991) 0264-410X/92/050299~32 © 1992 Butterworth-Heinemann Ltd
vaccine was diluted in 0.5 ml of solvent) and Typhim Vi (purified capsular polysaccharide, PMSV, batch S 1948; 25/~g of Vi polysaccharide/0.5 ml/dose) were used. Both vaccines were intramuscularly injected into the deltoid muscles. On day 0, after blood sampling, volunteers were randomly allocated into two groups : group A : receiving simultaneously in two separate sites the first injection of PVRV and Typhim Vi vaccines; group B: receiving in one site the two vaccines mixed in the same syringe prior to injection, the liquid Typhim Vi being used to reconstitute the lyophilized PVRV. The two groups received the second shot of PVRV 3 weeks later (day 21 ) and were bled on day 48. Tolerance was established on local reactions (redness, induration and pain) and on general reactions (axillar temperature recorded by the subject, malaise and other effects ). Each subject was asked to fill in a form recording any symptoms experienced for 3 consecutive days following each application of the vaccines. The evaluation of rabies antibodies was by an ELISA test (Platelia, Diagnostics Pasteur, ref. 72200). A postvaccination serum titre of 0.5 EU m1-1 was considered as a seroconversion according to the Seventh Report of the WHO Expert Committee on Rabies. Anti-Vi antibody titration was performed by radioimmunoassay (RIA) as previously described 3 and results given in /~gm1-1. A seroconversion or a fourfold
Table
1
Side effects of combined
rabies-typhoid immunization
schedules Vaccination site
Vaccine (in arm)
Redness No. (%)
Induration No. (%)
Tenderness a No. (%)
Rabies (n = 46) Typhoid (n = 46) Rabies+typhoid ( n = 5 1 )
5 (10.9) 6 (13) 3(5.9)
6 (13) 6 (13) 3(5.9)
24 (52.2) 35 (76.1) 41 (80.4)
"Tenderness was only reported as slight or moderate
Vaccine, Vol. 10, Issue 5, 1992
299
Short p a p e r : C. Fritzell et al. Table 2
Immunogenicity of two rabies-typhoid fever immunization schedules Group A Rabies Typhim (two different sites)
No.
Rabies GMT
No.
Group B Rabies-Typhim combined injection (one site) Typhoid GMT
No.
Rabies GMT
No.
Typhoid GMT
Day 0
51
0a
51
0.223 + 1.08 ~ (0.06-1.2) c
51
0a
51
0.230 _+ 1.08 (0.1-1.2) ~
Day 48
51
3.91 _+ 1.09 (0.62-13) c
50
1.8 _+ 1.14 ( x 8) ~
51
4.03 _+ 1.1 (0.57 18.2) c
49
2.083 + 1.17 ( x 9) ~
Seroconversion ( % )
100e
84 f
100c
77.6 t
aAII subjects < 0.5 EU m1-1. ~Standard error of the mean. ~Range. ~Mean increase factor. ~>~0.5 EU m1-1. ~Percentage of patients with fourfold increase
increase in serum titre was considered as significant. The differences between the two groups for clinical reactions and seroconversion rate were determined by ~2 and Fisher's exact tests. A few minor side effects at the vaccination site were reported (Table 1 ). The only significant difference was noted between the arm receiving rabies alone and either Typhim alone ()~2 = 5.73, p = 0.016) or Typhim + Rabies ()~2 = 8.71, p = 0.003). No serious side effects occurred, although 2 - 3 % of the subjects noted a slight temperature rise in the two groups and one subject a malaise requiring no treatment in group A. Serological results are showed in Table 2. For rabies, no subject presented specific antibodies on day 0 and seroconversion was observed in 100% at day 48 without any significant difference in the geometric mean titre between the two groups. Typhoid antibodies were noted in some subjects at day 0. Seroconversion or a fourfold increase was observed in 84% (group A) and 77.6% (group B). No significant difference was observed between the two groups (Fisher's exact test). Both the combined and two-site vaccination schedules showed a good immunogenicity and tolerance. Seroconversion rate and geometric mean titres were of the same magnitude as in previous published reports on each separate vaccine3'8'9: 100% seroconversion for rabies, fourfold increase in titre in 77.6% (one site) and 84% (two different sites). The side effects were less than those of whole-cell killed vaccine for typhoid 1° and no serious local or systemic reactions were encountered. A 3-year follow-up will be carried out on these subjects to assess the persistence of antibody. These results should ease the implementation of rabies and typhoid fever immunization for travellers to
300
Vaccine, Vol. 10, I s s u e 5, 1992
developing countries where typhoid fever is endemic and rabies present. REFERENCES 1
Immunization Practices Advisory Committee. Rabies Prevention. Recommendations. Preexposure vaccination and postexposure therapy of previously vaccinated persons. Morbid. Mortal. Week. Rep. 1991, 40, 19 2 Ferenchik, G.S. and Havlichek, D. Clinical reviews of primary prevention and international travel: infections, immunizations and antimicrobial prophylexis. J. Int. Med. 1989, 4, 247 3 Acharya, I.L., Lowe, C.U., Thapa, R. et al. Prevention of Typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N. Engl. J. Med. 1987, 317, 1101 4 Tacket, C.O., Levin, M.M. and Robbins, J.B. Persistence of antibody titres three years after vaccination with Vi polysaccharide vaccine against typhoid fever, Vaccine 1988, 6, 307 5 Cundy, J.M. Precautions against rabies and other hazards of tourism. Br. Med. J. 1981, 283, 724 6 Dureux, B., Canton, P.H., Gerard, A. et al. Rabies vaccine for human use cultivated on Vero cells. Lancet 1986, i, 8498. 7 Fournier, P., Montagnon, B., Vincent-Falquet, J.C., Ajjan, N., Drucker, J. and Roumiantzeff, M. A new vaccine produced from rabies virus cultivated on Vero cells. In: Improvements in Rabies Post-exposure Treatment (Eds Vodopija, I., Nicholson, K.G., Smerdel, S. and Bijok, U.) Institute of Public Health, Zagreb, 1985, pp 115-121 8 Sovjetlicic, M., Vodopija, I., Smerdel, S., Ljbicic, M., Baklaic, Z., Vincent-Falquet, J.C. et al. Compatibility and immunogenicity of Merieux's purified Vero rabies vaccine in healthy subjects. In: Improvements in Rabies Post-exposure Treatment (Eds Vodopija, I., Nicholson, K.G., Smerdel, S., Bijok, U.) Institute of Public Health, Zagreb, 1985, pp 123-127 9 Klietmann, W., Klietmann, B., Cox, J. and Charbonnier, C. Effectiveness and tolerance of pre- and post-exposure treatment with purified inactivated rabies vaccine prepared on a Vero cell line. Vaccine 1988, 6, 39 10 Hornick, R.B. Selective primary health care: strategies for control of disease in the developing world. XX. Typhoid fever. Rev. InL Dis. 1985, 7, 536