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Oral Vaccines for Enteric Infections
509
Oral Vaccines for Enteric Infections
protective value of injected antigens was established, vaccine makers, public health officials, and veterinarians have dreamed that one day vaccines for enteric disease might be given by mouth. After the discovery of bacterial phages by Twort and EVER since the
.d’Herelle, between 1914 and 1919, d’Herelle in
particularproposed that bacteriophages active against cholera and shigella should be given by mouth in the hope that they would feed upon and kill the bacteria in the lumen of the intestine and so cure or prevent infection. The results were disappointing. Early claims that killed oral vaccines protected against dysentery and respiratory infections could not be confirmed, and by the 1940s it seemed that oral vaccines had no place in the treatment or prevention of dysentery, typhoid, or cholera. Immunisation has proved very much easier against infections where the pathogen or toxin has to run the gauntlet of circulating antibodies in the bloodstream-e.g., measles and tetanus-than where the agent can gain access directly to a mucous membrane in the nose, throat, or lung or to the lining of the intestine. Lately, genetic manipulation techniques have offered new hope that special laboratory-bred mutant bacteria can be devised which are harmless when swallowed while retaining immunogenicity. Avirulent strains have long been known, but they were usually non-immunogenic; and there was the nightmare of reversion to virulence of a harmless strain. Attenuated live oral poliovirus vaccines have proved effective. Could good oral vaccines now be made to prevent bacterial and viral enteritis? Much work towards the development of bacterial and viral vaccines has been going on, and the greatest success had been achieved with typhoid vaccines. A streptomycin-dependent typhoid strain was shown to be non-reactogenic, immunogenic, and protective in primates, but when lyophilised it gave no clinical protection. A more promising new vaccine was the Ty 21a strain of Salmonella typhi developed by Germanier at the Swiss Serum and Vaccine Institute in Berne.’2 When swallowed, the organism undergoes four or five cell divisions and infects and penetrates the wall of the small intestine; but then it "self-destructs". A controlled trial was conducted in Egyptian children, of whom half received three oral doses of the Ty 21aa strain gal E mutant Ty 21a of Salmonella typhi: a candidate strain for a live, oral typhoid vaccine. J Infect Dis 1975;
1. Germanier R, Furer E Isolation and characterisation of
131: 553-58. 2 Gilman RH, Hornick RB, Woodward WE, DuPont HL, Snyder MJ, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a live oral vaccine. J Infect Dis 1977, 136: 717-23.
and half received placebo. 7 culture-confirmed and 13 probable cases of typhoid were recorded during the first year in the placebo group, whereas there were none in the vaccine group.3 There is no evidence at all of reversion of the vaccine to virulence and no adverse reactions were seen. After three years the annual incidence of typhoid fever in this Egyptian field trial was 4’ 9 cases per 10 000 in the control group and 0’ 2 cases per 10 000 children in the vaccine group (96% efI’iciency).4A major field trial of the vaccine is now underway in Santiago, Chile, where the incidence of typhoid is high. Here the vaccine is being given as a single or double dose in enteric-coated capsules. On p. 523, Dr Sutton and Dr Merson, of the W.H.O. Diarrhoeal Diseases Control Programme, summarise experience with the vaccine. These genetically crippled typhoid bacilli possess plasmids, and some workers are already exploring the possibility of splicing genes specifying other antigens into these plasmids-e.g., the immunising antigen of shigellae or of cholera vibrios. Other avirulent oral vaccines have been tried. Escherichia coli hybrids containing somatic antigens of salmonella or shigella have been used as live oral vaccines in animal protection experiments. So far the results have not been very good, perhaps because the hybrids are rather unsuccessful at colonising the gut. Non-toxigenic isolates of Vibrio cholerae have also been tried. Unfortunately, for the most part, although they have not caused severe adverse reactions, they do not give much protection either. Several new candidates are under development. One, of the El Tor strain Ogawa 3083, has been called Texas Star; it makes a lot of the immunogenic B subunit of cholera enterotoxin but little or none of the A subunit. Both subunits are required to cause cholera. Early results in volunteers were quite encouraging but the frequency of diarrhoea has shown that something better is required. What of human rotaviruses? Now that these have been adapted to tissue culture, attenuated vaccines are a possibility. 6,7 It is also possible that an animal virus (e.g., Nebraska calf diarrhoea virus) could protect human beings. Another notion8 is that the genomic segment specifying the immunogenic protein might be grafted into a bacterial vaccine-e.g., Ty 2 la. The vaccine bacteria might then penetrate the intestinal wall and liberate the immunising virus protein. -Whether this would succeed is anyone’s guess, but it could be done; the technology exists. MH, Serie C, Germanier R, et al. A controlled field trial of live oral typhoid Ty 21a Bull WHO 1980; 58: 469-74 Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live
3. Wahdan
vaccine
4.
Salmonella typhi strain Ty 21a oral vaccine against typhoid: three-year results. J Infect Dis 1982; 145: 292-95. 5. Honda T, Finkelstein RA. Selection and characteristics of a Vibrio cholerae mutant lacking the A (ADP-ribosylating) portion of the cholera enterotoxin Proc Natl Acad Sci USA 1979; 76: 2052-56. 6 Kapikian AZ, Wyatt RG, Greenberg HB, et al. Approaches to immunization of infants and young children against gastroenteritis due to rotavirus. Rev Infect Dis 1980, 2: 459-69. 7. Flewett TH. New prospects for control of virus diarrhoea in children. J Roy Soc Med 1982; 75: 493-94. 8 W.H O. Scientific Working Group on Oral Enteric Vaccines, 1981 (EURO Reports and Studies 63.) Copenhagen: WHO Regional Office for Europe, 1982.
Oral Vaccines for Enteric Infections
protective value of injected antigens was established, vaccine makers, public health officials, and veterinarians have dreamed that one day vaccines for enteric disease might be given by mouth. After the discovery of bacterial phages by Twort and EVER since the
.d’Herelle, between 1914 and 1919, d’Herelle in
particularproposed that bacteriophages active against cholera and shigella should be given by mouth in the hope that they would feed upon and kill the bacteria in the lumen of the intestine and so cure or prevent infection. The results were disappointing. Early claims that killed oral vaccines protected against dysentery and respiratory infections could not be confirmed, and by the 1940s it seemed that oral vaccines had no place in the treatment or prevention of dysentery, typhoid, or cholera. Immunisation has proved very much easier against infections where the pathogen or toxin has to run the gauntlet of circulating antibodies in the bloodstream-e.g., measles and tetanus-than where the agent can gain access directly to a mucous membrane in the nose, throat, or lung or to the lining of the intestine. Lately, genetic manipulation techniques have offered new hope that special laboratory-bred mutant bacteria can be devised which are harmless when swallowed while retaining immunogenicity. Avirulent strains have long been known, but they were usually non-immunogenic; and there was the nightmare of reversion to virulence of a harmless strain. Attenuated live oral poliovirus vaccines have proved effective. Could good oral vaccines now be made to prevent bacterial and viral enteritis? Much work towards the development of bacterial and viral vaccines has been going on, and the greatest success had been achieved with typhoid vaccines. A streptomycin-dependent typhoid strain was shown to be non-reactogenic, immunogenic, and protective in primates, but when lyophilised it gave no clinical protection. A more promising new vaccine was the Ty 21a strain of Salmonella typhi developed by Germanier at the Swiss Serum and Vaccine Institute in Berne.’2 When swallowed, the organism undergoes four or five cell divisions and infects and penetrates the wall of the small intestine; but then it "self-destructs". A controlled trial was conducted in Egyptian children, of whom half received three oral doses of the Ty 21aa strain gal E mutant Ty 21a of Salmonella typhi: a candidate strain for a live, oral typhoid vaccine. J Infect Dis 1975;
1. Germanier R, Furer E Isolation and characterisation of
131: 553-58. 2 Gilman RH, Hornick RB, Woodward WE, DuPont HL, Snyder MJ, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a live oral vaccine. J Infect Dis 1977, 136: 717-23.
and half received placebo. 7 culture-confirmed and 13 probable cases of typhoid were recorded during the first year in the placebo group, whereas there were none in the vaccine group.3 There is no evidence at all of reversion of the vaccine to virulence and no adverse reactions were seen. After three years the annual incidence of typhoid fever in this Egyptian field trial was 4’ 9 cases per 10 000 in the control group and 0’ 2 cases per 10 000 children in the vaccine group (96% efI’iciency).4A major field trial of the vaccine is now underway in Santiago, Chile, where the incidence of typhoid is high. Here the vaccine is being given as a single or double dose in enteric-coated capsules. On p. 523, Dr Sutton and Dr Merson, of the W.H.O. Diarrhoeal Diseases Control Programme, summarise experience with the vaccine. These genetically crippled typhoid bacilli possess plasmids, and some workers are already exploring the possibility of splicing genes specifying other antigens into these plasmids-e.g., the immunising antigen of shigellae or of cholera vibrios. Other avirulent oral vaccines have been tried. Escherichia coli hybrids containing somatic antigens of salmonella or shigella have been used as live oral vaccines in animal protection experiments. So far the results have not been very good, perhaps because the hybrids are rather unsuccessful at colonising the gut. Non-toxigenic isolates of Vibrio cholerae have also been tried. Unfortunately, for the most part, although they have not caused severe adverse reactions, they do not give much protection either. Several new candidates are under development. One, of the El Tor strain Ogawa 3083, has been called Texas Star; it makes a lot of the immunogenic B subunit of cholera enterotoxin but little or none of the A subunit. Both subunits are required to cause cholera. Early results in volunteers were quite encouraging but the frequency of diarrhoea has shown that something better is required. What of human rotaviruses? Now that these have been adapted to tissue culture, attenuated vaccines are a possibility. 6,7 It is also possible that an animal virus (e.g., Nebraska calf diarrhoea virus) could protect human beings. Another notion8 is that the genomic segment specifying the immunogenic protein might be grafted into a bacterial vaccine-e.g., Ty 2 la. The vaccine bacteria might then penetrate the intestinal wall and liberate the immunising virus protein. -Whether this would succeed is anyone’s guess, but it could be done; the technology exists. MH, Serie C, Germanier R, et al. A controlled field trial of live oral typhoid Ty 21a Bull WHO 1980; 58: 469-74 Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live
3. Wahdan
vaccine
4.
Salmonella typhi strain Ty 21a oral vaccine against typhoid: three-year results. J Infect Dis 1982; 145: 292-95. 5. Honda T, Finkelstein RA. Selection and characteristics of a Vibrio cholerae mutant lacking the A (ADP-ribosylating) portion of the cholera enterotoxin Proc Natl Acad Sci USA 1979; 76: 2052-56. 6 Kapikian AZ, Wyatt RG, Greenberg HB, et al. Approaches to immunization of infants and young children against gastroenteritis due to rotavirus. Rev Infect Dis 1980, 2: 459-69. 7. Flewett TH. New prospects for control of virus diarrhoea in children. J Roy Soc Med 1982; 75: 493-94. 8 W.H O. Scientific Working Group on Oral Enteric Vaccines, 1981 (EURO Reports and Studies 63.) Copenhagen: WHO Regional Office for Europe, 1982.