896
Postexposure prophylaxis for rabies with antiserum and intradermal vaccination
The Thai Red Cross intradermal postexposure rabies treatment schedule was prospectively assessed in 100 Thai patients severely bitten by proven rabid animals. It consists of 0·1 ml of purified Vero cell rabies vaccine containing more than 2·5 IU of rabies antigen per 0·5 ml of reconstituted vaccine given intradermally at two sites on days 0, 3, and 7, followed by one 0·1 ml injection on days 30 and 90. The commercial vaccine used had an antigen content of 3·17 IU per 0·5 ml ampoule. Purified equine or human rabies immuno-globulin was also given on day 0 to patients with severe exposures. As much of the immunoglobulin as possible was infiltrated around the wounds. All patients were followed for 1 year post exposure. There were no deaths; the efficacy of the regimen was 100%. Antibody titre determination in a randomly selected subgroup showed seroconversion in all 10 patients.
Introduction Canine rabies, which remains endemic in many developing countries of Asia, Africa, and Latin America, is responsible for almost all 5000 000 human postexposure vaccinations worldwide every year.1 Most of these treatments still use nervous tissue rabies vaccines which are less immunogenic than the newer tissue culture products and carry a substantial risk of serious postvaccine central nervous system reactions.’ Efforts to replace these products with tissue culture vaccines in developing countries have not been successful largely because of their prohibitive cost. The production of a new, potent, safe, and effective tissue culture rabies vaccine (purified Vero cell rabies vaccine [PVRV]) on microcarrier cultures is less expensive than human diploid cell rabies vaccine (HDCV).5’6 These new vaccines are, nevertheless, still much more costly than locally made semple or suckling mouse brain vaccines and therefore are unavailable to most people in developing countries. Another approach to the replacement of nervous tissue vaccines is to reduce dose schedules. A regimen proposed by Vodopija5 with the 4-dose intramuscular (2-1-1) schedule represents a 25% reduction in vaccine cost over the conventional 5-dose intramuscular regimens An even more promising approach was the multiple-site, intradermal postexposure schedules proposed by Nicholson, Warrell, and their colleagues.-9 They not only demonstrated vaccine immunogenicity but also, in the case of HDCV, efficacy.8 However, such use of HDCV offers little saving over full intramuscular regimens with PVRV. Phanuphak et al9 therefore modified this intradermal schedule and used PVRV in the Queen Saovabha Memorial Institute postexposure rabies clinic, where about 18 000
Phanuphak,
animal bites are treated annually. Their method resulted in a humoral antibody response equivalent to that of the conventional 5-dose intramuscular schedule and specific cell-mediated immunity detectable by day 7. This regimen (the Thai Red Cross intradermal [TRC-ID] schedule) uses a total of 08 ml PVRV. We have prospectively investigated Thai patients bitten by proven rabid animals to establish the efficacy of this regimen. new
Materials and methods Patient selection 100 patients were selected from the outpatient clinic of the Queen Saovabha Memorial Institute on the basis of the following criteria: (1) bite by an animal proven rabid by fluorescent antibody testing; (2) transdermal injury resulting in active bleeding; (3) delay between exposure and start of treatment of no more than 48 h; (4) patient or close family member had fixed address and regular employment in the Bangkok metropolitan area; (5) patient not on corticosteroids or immunosuppressive drugs, not an alcohol or drug abuser, or had known chronic liver disease; (6) no previous rabies vaccination; and (7) patient or parents agreed to participate in the study, which was explained to them in vernacular language by the
investigators. Vaccine and immunoglobulin All patients received PVRV (Institut Merieux, Lyon, France; lot A0254). The vaccine had an antigen content of 3-17 IU at 4°C per dose when 1 ampoule was reconstituted to 0.55 ml, and was given as two injections of 0 1 ml each at different deltoid area sites intradermally on days 0, 3, and 7, and as one 0-ml injection on days 30 and 90.
Equine rabies immunoglobulin (ERIG, Pasteur Vaccins) (40 100 patients on day 0 after skin testing to rule out allergy to the equine product. As much as possible of ERIG was injected around bite wounds, with the remainder given by deep injection into the gluteal region. 4 patients proved to have a positive skin test to ERIG and were given 20 IU/kg human rabies immunoglobulin (National Blood Centre, Thai Red Cross Society).
IU/kg) (lots 5212 and 5659) was given to 96 of the
Follow-up All patients were seen at the clinic for injections and wound care days 0, 3, 7, 30, and 90. They were then visited monthly at home for 1 year. Antibody was measured in 10 randomly selected adults on days 14,90, and 360; serum was frozen at - 40°C until transfer to on
ADDRESSES Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok, Thailand; Viral and Rickettsial Zoonoses Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control, United States Public Health Service, Atlanta, GA, United States (S. Chutivongse, MD, H. Wilde, MD, C Supich, MD, G. M. Baer, DVM, D. B. Fishbein, MD).
Correspondence
to Dr S.
Chutivongse, Queen Saovabha Memorial
Institute, Science Division, Thai Red Cross Society, 1871 Rama IV Road, Bangkok 10330, Thailand.
897
TABLE I-LOCATION OFANIMALBITESAND EXPECTED NUMBER OF DEATHS BASED ON HISTORICAL STUDIES*
noted in 10 patients, and mild fever, malaise, or headache possibly due to vaccine, concurrently administered tetanus toxoid, antibiotics, or traditional treatment were noted in 3. Table II shows antibody responses in 10 patients. 100% seroconversion was seen, with all titres above 0-5 IU/n-il at 14, 90, and 360 days postvaccination. The geometric mean titres were 3 475 IU/ml at day 14, 0-938 IU//ml at day 90, and 0-738 IU/ml 1 year after the first vaccine injection. All titres remained above 0’50 TU/ml 1 year after the first vaccination.
Discussion *Ref 11.
the Centers for Disease Control in Atlanta, Georgia, for measurement by the rapid fluorescent focus inhibition test. 10
Statistical analysis We calculated the expected mortality rates in untreated patients from historical data." 95% confidence intervals (CI) were estimated with the binomial distribution. Statistical significance was based on the null hypothesis that the observed vaccine efficacy was statistically better than 50% efficacy when the expected efficacy was based on historical controls.
Ethics This study was approved by the ethics and human experimentation committee of the science division of the Thai Red Cross Society. Results 61 patients were male and 39 female, mean age 21-8 years
(range 2 months to 60 years). All patients were followed for 1 or longer, and all were alive after completion of this study. 2 patients missed the injection on day 30 but received the day 90 dose, and 2 others did not have their day 90 boosters. Table I shows the location of bites. 18 patients had multiple bites, and 1 elderly man had severe facial bites (exposing bone) that needed suturing. On the basis of historical controls, about 14 patients would have been expected to die if untreated. The efficacy of the regimen was 100% (95% CI, 807%-100%; p < 0-001). year
A mild serum-sickness-like symptom associated with ERIG developed on days 6 and 7 in 3 patients, but treatment with antihistamines and analgesics alleviated the symptoms and no alteration in the treatment schedule was necessary. 1 patient had a mild although delayed serum-sickness-like reaction that worsened after repeat PVRV injections and was thought to be attributable to the vaccine rather than to ERIG. Painless transient regional lymphadenopathy was TABLE II-ANTIBODY TITRES IN SEVERELY EXPOSED THAI PATIENTS TREATED WITH THAI RED CROSS INTRADERMAL POSTEXPOSURE RABIES VACCINE*
*PLirified Vero cell rabies
vaccine.
The expected number of deaths in a group of patients such as ours would be about 9-18 if untreated. 11,12 The efficacy we show is especially noteworthy in view of the short incubation period of human rabies in Thailand, with 71 % of patients dying of rabies within 1 month and 87% within 3 months of exposure.13 Rabies immunoglobulin must have been partly responsible for the 100% efficacy we observed: experiments in anirnals14,15 and analyses of smaller series of severely exposed human subjects16-18 indicate that mortality rates are high when a large inoculum of virus is introduced and when rabies immunoglobulin is not added to the vaccine. In a previous investigation of Thai patients exposed to rabies and treated only with semple rabies vaccine (without immunoglobulin), no deaths occurred, but no information was recorded on the severity of exposure.12 Previous studies have shown that the TRC-ID regimen resulted in detectable cell-mediated immunoreactivity by day 7 in a substantial number of patients.9 This reactivity might be attributable to the repeated intradermal injections, which are more immunogenic than equivalent single intramuscular injections.7 Several experiments suggest that cell-mediated inmunoreactivity may be an important component of the immune response to rabies virus,19 and the early marshalling of this reactivity in postexposure rabies patients is therefore probably advantageous. The fact that patients are seen on days 0, 3, and 7 assures adequate wound care, early recognition of infection, and of adverse reactions to vaccine, ERIG, or antibiotics. Antibody titres are not reduced by inadvertent subcutaneous injection of one or more of the intradermal injections .20-11 There were only mild adverse effects in our patients, such as mild regional adenopathy, transient fever, and malaise, which did not differ significantly from those we found with the standard intramuscular postexposure schedule.22 The greatest advantage of the intradermal schedule is the much lower vaccine cost. In Thailand the TRC-ID PVRV regimen represents a saving of 68% over an intramuscular 5-dose schedule with the same vaccine, and as a result our institution discontinued the use of all nervous tissue rabies vaccines in 1987. We now treat about 1000 cases monthly with the TRC-ID regimen, which has been given to over 20 000 patients at this institute-75 % of our total number of patients. Only one rabies death has been reported in these patients. A 53-year-old Thai man died after receiving multiple bites on his wrists and fingers; he delayed reporting for treatment for 6 days, was a chronic alcoholic, and had cirrhosis of the liver. 13 Virtually all peripheral health centres in developing countries have staff experienced in intradermal injection techniques, and the intradermal postexposure TRC-ID schedule with PVRV would probably enable others abandon rabies vaccines derived from nervous tissue.
to
898
This study was supported by Institut Merieux, Lyon, France, by the Thai Red Cross Society, and by the Program of Appropriate Technology in Health (DiaTech grant DPE 5935-A-00-5065-00). Mr Sompop Prakongsri, Mrs Aree Sumboonanondha and her nursing staff collected data and did the follow-up studies. Dr Praphan Phanuphak gave much encouragement and provided helpful suggestions. Mrs Duangchand Siwasontiwat prepared the
10. Smith JS, Yager PA, Baer GM. A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO 1973; 48: 535-41. 11. Hattwick MAW, Gregg MB. The disease in man. In: Baer GM, ed. The natural history of rabies. Vol II. New York: Academic Press, 1975: 281-304. 12. Sitthi-Amorn C, Jiratanavattana V, Keoyoo J, Sonpunya N. The
diagnostic properties of laboratory tests for rabies. Int J Epidemiol 1987;
script. REFERENCES
JH. Rabies in the Americas and remarks on global aspects. Rev Infect Dis 1988; 10 (suppl 4): S585-97. 2. Chanthavanich P, Suntharasamai P, Warrell MJ, et al. Antibody response to suckling mouse brain rabies vaccines for post exposure treatment. Trans R Soc Trop Med Hyg 1987; 81: 260-63. 3. Hemachudha T, Phanuphak P, Johnson RT, Griffin DE, Ratanavongsiri J, Siriprasomsup W. Neurologic complications of Semple-type rabies vaccine: clinical and immunologic studies. Neurology 1987; 37: 550-56. 4. Arnason BGW. Neuroimmunology. N Engl J Med 1987; 316: 406-08. 5. Vodopija I. Current issues in human rabies immunization. Rev Infect Dis 1988; 10 (suppl 4): S758-63. 6. Suntharasamai P, Warrell MJ, Warrell DA, et al. New purified Vero-cell vaccine prevents rabies in patients bitten by rabid animals. Lancet 1986; 1. Steele
ii: 129-31. 7. Nicholson KG, Prestage H, Cole PJ, Turner GS, Bauer SP. Multisite intradermal antirabies vaccination: immune responses in man and protection of rabbits against death from street virus by postexposure administration of human diploid-cell-strain rabies vaccine. Lancet 1981; ii: 915-18. 8. 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. 9. Phanuphak P, Khawplod P, Sirivichayakul S, Siriprasomsub W, Ubol S, Thaweepathomwat M. Humoral and cell-mediated immune responses to various economical regimens of purified Vero cell rabies vaccine. Asian Pac J Allergy Immunol 1987; 5: 33-37.
16: 602-05. 13. Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies postexposure treatment in Thailand. Vaccine 1989; 7: 49-52. 14. Koprowski H, Van der Scheer CE, Black J. Use of hyperimmune antirabies serum concentrates in experimental rabies. Am J Med 1950; 8: 412-30. 15. Habel K. Antiserum in the prophylaxis of rabies. Bull WHO 1954; 10: 781-88. 16. Baltazard M, Bahmanyar M. Essai pratique du serum antirabique chez les mordus par loups enrages. Bull WHO 1955; 13: 747-72. 17. Selimov M, Boltucij L, Semenova E, Kobrinskij G, Zmusko L. Anwendung Des Antirabies-GAMA-Globulins Bei Menschen, Die Von Tollwutigen Wolfen Oder Anderen Tieren Schwer Gebissen Wurden. J Hyg Epidemiol Microbiol Immunol 1959; 3: 168-80. 18. Lin FT, Chen SB, Wang YZ, Sun CZ, Zeng FZ, Wang GF. Use of serum and vaccine in combination for prophylaxis following exposure to rabies. Rev Infect Dis 1988; 10 (suppl 4): S766-70. 19. Hemachuda T. Rabies. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Amsterdam: Elsevier 1989: 383-404. 20. Fishbein DB, Pacer RE, Holmes DF, Ley AB, Yager P, Tong TC. Rabies preexposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis 1987; 156: 50-55. 21. Phanuphak P, Khawplod P, Benjavongkulchai M, et al. What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously? Bull WHO (in press). 22. Chutivongse S, Supich C, Wilde H. Acceptability and efficacy of purified vero-cell rabies vaccine in Thai children exposed to rabies. Asia Pac J Public Hlth 1988; 2: 179-84.
MODERN VACCINES Pneumococcus and influenza
Pneumococcus
bacteraemia in 15-19/100 000 persons per year, and meningitis in 1-2/100 000 persons per year.! By 3 years of age, over 20% of children have had one or more episodes of pneumococcal otitis media. Morbidity and mortality are even higher in developing countries; for example, pneumococcal pneumonia causes over 1 million deaths each year in children under 5 years old, and the US Institute of Medicine’s 1985 review of new vaccines for developing countries gave the highest priority to development of a pneumococcal vaccine effective in infants.2 Antibiotic therapy alone will not be a satisfactory way to control pneumococcal infection. First, antibiotic therapy does not reduce mortality in the first three days of treatment; second, developing countries are unlikely to be able to deliver antibiotics effectively in remote rural areas where a substantial proportion of the deaths occur; and, third,
In the United States pneumococci cause 10-25% of all pneumonias with an estimated 40 000 deaths per year,
ADDRESS: Intensive Care Unit, Royal Children’s Hospital, Parkville, Victoria 3052, Australia (Dr F Shann, FRACP).
By different mechanisms Streptococcus pneumoniae and influenza virus make a large contribution to morbidity and mortality from respiratory tract infection in man. Although pneumococci come in many serotypes, the antigenic structure of each capsular polysaccharide is stable, and most important infections are caused by just a few serotypes; the nasopharynx is often colonised without symptomatic infection, and a given serotype rarely causes invasive disease on more than one occasion. Influenza virus, on the other hand, causes symptomatic infection in a high proportion of the community in a short time and then fades from the scene, only to reappear a year later with a different antigenic structure-so that it often causes symptomatic infection in the
same
individual many times.
Postexposure prophylaxis for rabies with antiserum and intradermal vaccination
The Thai Red Cross intradermal postexposure rabies treatment schedule was prospectively assessed in 100 Thai patients severely bitten by proven rabid animals. It consists of 0·1 ml of purified Vero cell rabies vaccine containing more than 2·5 IU of rabies antigen per 0·5 ml of reconstituted vaccine given intradermally at two sites on days 0, 3, and 7, followed by one 0·1 ml injection on days 30 and 90. The commercial vaccine used had an antigen content of 3·17 IU per 0·5 ml ampoule. Purified equine or human rabies immuno-globulin was also given on day 0 to patients with severe exposures. As much of the immunoglobulin as possible was infiltrated around the wounds. All patients were followed for 1 year post exposure. There were no deaths; the efficacy of the regimen was 100%. Antibody titre determination in a randomly selected subgroup showed seroconversion in all 10 patients.
Introduction Canine rabies, which remains endemic in many developing countries of Asia, Africa, and Latin America, is responsible for almost all 5000 000 human postexposure vaccinations worldwide every year.1 Most of these treatments still use nervous tissue rabies vaccines which are less immunogenic than the newer tissue culture products and carry a substantial risk of serious postvaccine central nervous system reactions.’ Efforts to replace these products with tissue culture vaccines in developing countries have not been successful largely because of their prohibitive cost. The production of a new, potent, safe, and effective tissue culture rabies vaccine (purified Vero cell rabies vaccine [PVRV]) on microcarrier cultures is less expensive than human diploid cell rabies vaccine (HDCV).5’6 These new vaccines are, nevertheless, still much more costly than locally made semple or suckling mouse brain vaccines and therefore are unavailable to most people in developing countries. Another approach to the replacement of nervous tissue vaccines is to reduce dose schedules. A regimen proposed by Vodopija5 with the 4-dose intramuscular (2-1-1) schedule represents a 25% reduction in vaccine cost over the conventional 5-dose intramuscular regimens An even more promising approach was the multiple-site, intradermal postexposure schedules proposed by Nicholson, Warrell, and their colleagues.-9 They not only demonstrated vaccine immunogenicity but also, in the case of HDCV, efficacy.8 However, such use of HDCV offers little saving over full intramuscular regimens with PVRV. Phanuphak et al9 therefore modified this intradermal schedule and used PVRV in the Queen Saovabha Memorial Institute postexposure rabies clinic, where about 18 000
Phanuphak,
animal bites are treated annually. Their method resulted in a humoral antibody response equivalent to that of the conventional 5-dose intramuscular schedule and specific cell-mediated immunity detectable by day 7. This regimen (the Thai Red Cross intradermal [TRC-ID] schedule) uses a total of 08 ml PVRV. We have prospectively investigated Thai patients bitten by proven rabid animals to establish the efficacy of this regimen. new
Materials and methods Patient selection 100 patients were selected from the outpatient clinic of the Queen Saovabha Memorial Institute on the basis of the following criteria: (1) bite by an animal proven rabid by fluorescent antibody testing; (2) transdermal injury resulting in active bleeding; (3) delay between exposure and start of treatment of no more than 48 h; (4) patient or close family member had fixed address and regular employment in the Bangkok metropolitan area; (5) patient not on corticosteroids or immunosuppressive drugs, not an alcohol or drug abuser, or had known chronic liver disease; (6) no previous rabies vaccination; and (7) patient or parents agreed to participate in the study, which was explained to them in vernacular language by the
investigators. Vaccine and immunoglobulin All patients received PVRV (Institut Merieux, Lyon, France; lot A0254). The vaccine had an antigen content of 3-17 IU at 4°C per dose when 1 ampoule was reconstituted to 0.55 ml, and was given as two injections of 0 1 ml each at different deltoid area sites intradermally on days 0, 3, and 7, and as one 0-ml injection on days 30 and 90.
Equine rabies immunoglobulin (ERIG, Pasteur Vaccins) (40 100 patients on day 0 after skin testing to rule out allergy to the equine product. As much as possible of ERIG was injected around bite wounds, with the remainder given by deep injection into the gluteal region. 4 patients proved to have a positive skin test to ERIG and were given 20 IU/kg human rabies immunoglobulin (National Blood Centre, Thai Red Cross Society).
IU/kg) (lots 5212 and 5659) was given to 96 of the
Follow-up All patients were seen at the clinic for injections and wound care days 0, 3, 7, 30, and 90. They were then visited monthly at home for 1 year. Antibody was measured in 10 randomly selected adults on days 14,90, and 360; serum was frozen at - 40°C until transfer to on
ADDRESSES Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok, Thailand; Viral and Rickettsial Zoonoses Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control, United States Public Health Service, Atlanta, GA, United States (S. Chutivongse, MD, H. Wilde, MD, C Supich, MD, G. M. Baer, DVM, D. B. Fishbein, MD).
Correspondence
to Dr S.
Chutivongse, Queen Saovabha Memorial
Institute, Science Division, Thai Red Cross Society, 1871 Rama IV Road, Bangkok 10330, Thailand.
897
TABLE I-LOCATION OFANIMALBITESAND EXPECTED NUMBER OF DEATHS BASED ON HISTORICAL STUDIES*
noted in 10 patients, and mild fever, malaise, or headache possibly due to vaccine, concurrently administered tetanus toxoid, antibiotics, or traditional treatment were noted in 3. Table II shows antibody responses in 10 patients. 100% seroconversion was seen, with all titres above 0-5 IU/n-il at 14, 90, and 360 days postvaccination. The geometric mean titres were 3 475 IU/ml at day 14, 0-938 IU//ml at day 90, and 0-738 IU/ml 1 year after the first vaccine injection. All titres remained above 0’50 TU/ml 1 year after the first vaccination.
Discussion *Ref 11.
the Centers for Disease Control in Atlanta, Georgia, for measurement by the rapid fluorescent focus inhibition test. 10
Statistical analysis We calculated the expected mortality rates in untreated patients from historical data." 95% confidence intervals (CI) were estimated with the binomial distribution. Statistical significance was based on the null hypothesis that the observed vaccine efficacy was statistically better than 50% efficacy when the expected efficacy was based on historical controls.
Ethics This study was approved by the ethics and human experimentation committee of the science division of the Thai Red Cross Society. Results 61 patients were male and 39 female, mean age 21-8 years
(range 2 months to 60 years). All patients were followed for 1 or longer, and all were alive after completion of this study. 2 patients missed the injection on day 30 but received the day 90 dose, and 2 others did not have their day 90 boosters. Table I shows the location of bites. 18 patients had multiple bites, and 1 elderly man had severe facial bites (exposing bone) that needed suturing. On the basis of historical controls, about 14 patients would have been expected to die if untreated. The efficacy of the regimen was 100% (95% CI, 807%-100%; p < 0-001). year
A mild serum-sickness-like symptom associated with ERIG developed on days 6 and 7 in 3 patients, but treatment with antihistamines and analgesics alleviated the symptoms and no alteration in the treatment schedule was necessary. 1 patient had a mild although delayed serum-sickness-like reaction that worsened after repeat PVRV injections and was thought to be attributable to the vaccine rather than to ERIG. Painless transient regional lymphadenopathy was TABLE II-ANTIBODY TITRES IN SEVERELY EXPOSED THAI PATIENTS TREATED WITH THAI RED CROSS INTRADERMAL POSTEXPOSURE RABIES VACCINE*
*PLirified Vero cell rabies
vaccine.
The expected number of deaths in a group of patients such as ours would be about 9-18 if untreated. 11,12 The efficacy we show is especially noteworthy in view of the short incubation period of human rabies in Thailand, with 71 % of patients dying of rabies within 1 month and 87% within 3 months of exposure.13 Rabies immunoglobulin must have been partly responsible for the 100% efficacy we observed: experiments in anirnals14,15 and analyses of smaller series of severely exposed human subjects16-18 indicate that mortality rates are high when a large inoculum of virus is introduced and when rabies immunoglobulin is not added to the vaccine. In a previous investigation of Thai patients exposed to rabies and treated only with semple rabies vaccine (without immunoglobulin), no deaths occurred, but no information was recorded on the severity of exposure.12 Previous studies have shown that the TRC-ID regimen resulted in detectable cell-mediated immunoreactivity by day 7 in a substantial number of patients.9 This reactivity might be attributable to the repeated intradermal injections, which are more immunogenic than equivalent single intramuscular injections.7 Several experiments suggest that cell-mediated inmunoreactivity may be an important component of the immune response to rabies virus,19 and the early marshalling of this reactivity in postexposure rabies patients is therefore probably advantageous. The fact that patients are seen on days 0, 3, and 7 assures adequate wound care, early recognition of infection, and of adverse reactions to vaccine, ERIG, or antibiotics. Antibody titres are not reduced by inadvertent subcutaneous injection of one or more of the intradermal injections .20-11 There were only mild adverse effects in our patients, such as mild regional adenopathy, transient fever, and malaise, which did not differ significantly from those we found with the standard intramuscular postexposure schedule.22 The greatest advantage of the intradermal schedule is the much lower vaccine cost. In Thailand the TRC-ID PVRV regimen represents a saving of 68% over an intramuscular 5-dose schedule with the same vaccine, and as a result our institution discontinued the use of all nervous tissue rabies vaccines in 1987. We now treat about 1000 cases monthly with the TRC-ID regimen, which has been given to over 20 000 patients at this institute-75 % of our total number of patients. Only one rabies death has been reported in these patients. A 53-year-old Thai man died after receiving multiple bites on his wrists and fingers; he delayed reporting for treatment for 6 days, was a chronic alcoholic, and had cirrhosis of the liver. 13 Virtually all peripheral health centres in developing countries have staff experienced in intradermal injection techniques, and the intradermal postexposure TRC-ID schedule with PVRV would probably enable others abandon rabies vaccines derived from nervous tissue.
to
898
This study was supported by Institut Merieux, Lyon, France, by the Thai Red Cross Society, and by the Program of Appropriate Technology in Health (DiaTech grant DPE 5935-A-00-5065-00). Mr Sompop Prakongsri, Mrs Aree Sumboonanondha and her nursing staff collected data and did the follow-up studies. Dr Praphan Phanuphak gave much encouragement and provided helpful suggestions. Mrs Duangchand Siwasontiwat prepared the
10. Smith JS, Yager PA, Baer GM. A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO 1973; 48: 535-41. 11. Hattwick MAW, Gregg MB. The disease in man. In: Baer GM, ed. The natural history of rabies. Vol II. New York: Academic Press, 1975: 281-304. 12. Sitthi-Amorn C, Jiratanavattana V, Keoyoo J, Sonpunya N. The
diagnostic properties of laboratory tests for rabies. Int J Epidemiol 1987;
script. REFERENCES
JH. Rabies in the Americas and remarks on global aspects. Rev Infect Dis 1988; 10 (suppl 4): S585-97. 2. Chanthavanich P, Suntharasamai P, Warrell MJ, et al. Antibody response to suckling mouse brain rabies vaccines for post exposure treatment. Trans R Soc Trop Med Hyg 1987; 81: 260-63. 3. Hemachudha T, Phanuphak P, Johnson RT, Griffin DE, Ratanavongsiri J, Siriprasomsup W. Neurologic complications of Semple-type rabies vaccine: clinical and immunologic studies. Neurology 1987; 37: 550-56. 4. Arnason BGW. Neuroimmunology. N Engl J Med 1987; 316: 406-08. 5. Vodopija I. Current issues in human rabies immunization. Rev Infect Dis 1988; 10 (suppl 4): S758-63. 6. Suntharasamai P, Warrell MJ, Warrell DA, et al. New purified Vero-cell vaccine prevents rabies in patients bitten by rabid animals. Lancet 1986; 1. Steele
ii: 129-31. 7. Nicholson KG, Prestage H, Cole PJ, Turner GS, Bauer SP. Multisite intradermal antirabies vaccination: immune responses in man and protection of rabbits against death from street virus by postexposure administration of human diploid-cell-strain rabies vaccine. Lancet 1981; ii: 915-18. 8. 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. 9. Phanuphak P, Khawplod P, Sirivichayakul S, Siriprasomsub W, Ubol S, Thaweepathomwat M. Humoral and cell-mediated immune responses to various economical regimens of purified Vero cell rabies vaccine. Asian Pac J Allergy Immunol 1987; 5: 33-37.
16: 602-05. 13. Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies postexposure treatment in Thailand. Vaccine 1989; 7: 49-52. 14. Koprowski H, Van der Scheer CE, Black J. Use of hyperimmune antirabies serum concentrates in experimental rabies. Am J Med 1950; 8: 412-30. 15. Habel K. Antiserum in the prophylaxis of rabies. Bull WHO 1954; 10: 781-88. 16. Baltazard M, Bahmanyar M. Essai pratique du serum antirabique chez les mordus par loups enrages. Bull WHO 1955; 13: 747-72. 17. Selimov M, Boltucij L, Semenova E, Kobrinskij G, Zmusko L. Anwendung Des Antirabies-GAMA-Globulins Bei Menschen, Die Von Tollwutigen Wolfen Oder Anderen Tieren Schwer Gebissen Wurden. J Hyg Epidemiol Microbiol Immunol 1959; 3: 168-80. 18. Lin FT, Chen SB, Wang YZ, Sun CZ, Zeng FZ, Wang GF. Use of serum and vaccine in combination for prophylaxis following exposure to rabies. Rev Infect Dis 1988; 10 (suppl 4): S766-70. 19. Hemachuda T. Rabies. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Amsterdam: Elsevier 1989: 383-404. 20. Fishbein DB, Pacer RE, Holmes DF, Ley AB, Yager P, Tong TC. Rabies preexposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis 1987; 156: 50-55. 21. Phanuphak P, Khawplod P, Benjavongkulchai M, et al. What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously? Bull WHO (in press). 22. Chutivongse S, Supich C, Wilde H. Acceptability and efficacy of purified vero-cell rabies vaccine in Thai children exposed to rabies. Asia Pac J Public Hlth 1988; 2: 179-84.
MODERN VACCINES Pneumococcus and influenza
Pneumococcus
bacteraemia in 15-19/100 000 persons per year, and meningitis in 1-2/100 000 persons per year.! By 3 years of age, over 20% of children have had one or more episodes of pneumococcal otitis media. Morbidity and mortality are even higher in developing countries; for example, pneumococcal pneumonia causes over 1 million deaths each year in children under 5 years old, and the US Institute of Medicine’s 1985 review of new vaccines for developing countries gave the highest priority to development of a pneumococcal vaccine effective in infants.2 Antibiotic therapy alone will not be a satisfactory way to control pneumococcal infection. First, antibiotic therapy does not reduce mortality in the first three days of treatment; second, developing countries are unlikely to be able to deliver antibiotics effectively in remote rural areas where a substantial proportion of the deaths occur; and, third,
In the United States pneumococci cause 10-25% of all pneumonias with an estimated 40 000 deaths per year,
ADDRESS: Intensive Care Unit, Royal Children’s Hospital, Parkville, Victoria 3052, Australia (Dr F Shann, FRACP).
By different mechanisms Streptococcus pneumoniae and influenza virus make a large contribution to morbidity and mortality from respiratory tract infection in man. Although pneumococci come in many serotypes, the antigenic structure of each capsular polysaccharide is stable, and most important infections are caused by just a few serotypes; the nasopharynx is often colonised without symptomatic infection, and a given serotype rarely causes invasive disease on more than one occasion. Influenza virus, on the other hand, causes symptomatic infection in a high proportion of the community in a short time and then fades from the scene, only to reappear a year later with a different antigenic structure-so that it often causes symptomatic infection in the
same
individual many times.
