1542
Recombinant vaccines SIR,-In our Science article’ the aim was not to discredit recombinant vaccines. We fully agree with the requirements suggested by Ada.2 Our experiments on the murine lymphocytic choriomeningitis (LCM) model yielded the surprising result that vaccination with whole virus conferred protection whereas vaccination with a recombinant vaccinia virus vaccine sometimes caused increased susceptibility to a T-cell-mediated triggered by a subsequent challenge infection. immunopathology The recombinant vaccine may not have met the requirements a vaccine should meet to confer optimal protection. Although it included the entire nucleoprotein or the entire glycoprotein (that also carries the neutralising determinants), it provided a limited number of T-cell epitopes, which can only be presented by selected MHC antigens. A second factor influencing the equilibrium between protection and immunopathology may be the quality and the kinetics of T-cell memory about which we know very little, especially in respect of viral infections, including recombinant vaccinia virus. As stated in your editorial (April 6) neutralising antibody titres are very often the most important factor in protective immunity by vaccination. The LCM model is special, in that the virus is non-cytopathic and immunosuppressive and that its clearance by the host depends largely on cytotoxic CD8 + T cells. Neutralising antibodies are generated very late, 30-50 days after infection, and in studies with a recombinant vaccinia virus expressing LCM virus nucleoprotein such antibodies are unlikely to have influenced the result. Since a vaccine must meet high safety standards any limitations of efficacy or unwanted complications that are demonstrated in models must be taken into account. We have all seen the ups and downs of "new" vaccines, especially subunit vaccines. In the early 1980s, peptide vaccines were thought to solve many problems;z’ some of these ideas were theoretical and in some instances great practical success followed. Recombinant vaccines are promising; hepatitis B recombinant vaccine comprising the correct neutralising determinants is a good example. Recombinant vaccines based on vaccinia virus, adenovirus, or bacteria are encouraging developments too. But we have also learned that the best vaccines are often attenuated or inactivated whole virus vaccines or cocktails of recombinant vaccines that reconstruct the whole virus. Careful experiments need to be done on the ability of a virus, recombinant virus, or antigens to induce a strong protective immune response, on the requirements for long-lasting T memory response, on the nature of immunological memory, and on antigen persistence. Nonetheless is it not interesting-and worth reporting with all due reservations-if, in a model, vaccine causes rather than prevents disease? Almost every virus has its own pathogenic mechanisms, and may therefore influence the virus-host equilibrium differently. There have, after all, been complications with earlier vaccines, against measles or respiratory syncytial viruss,6 that caused adverse effects still not fully understood; T cells and/or antibodies have been
implicated.7,8 Although LCM may be a special
case, many other viruses and bacteria may fall into this category of poorly to non-cytopathic infectious agents; HIV is another possible example. Considerable efforts are being made to develop subunit vaccines expressing only selected HIV antigens-for example, glycoprotein (gpl60, gp120) in vaccinia recombinants or other fonns.9,1O Although HIV is assumed by many to act via cytopathic effects, immunopathological damage accumulating over time may well be responsible for immunosuppression. If so, an improved triggering of a CD8 and exacerbate immunopathology might response immunosuppression in certain circumstances, as in the LCM model. This may happen even if the vaccine also induces
neutralising antibody responses. Department of Experimental Pathology, Universitatsspital Zurich, CH-8091 Zurich, Switzerland 1. Oehen
STEPHAN OEHEN HANS HENGARTNER ROLF ZINKERNAGEL
S, Hengartner H, Zinkernagel RM. Vaccination for disease. Science 1991; 251:
195-98.
2. Ada G. The immunological principles of vaccination. Lancet 1990, 335: 523-26. 3. Beale J Synthetic peptides as the basis for future vaccines. Nature 1982; 298: 14-15. 4. Zanetti M, Sarcarz E, Salk J. The immunology of new generation vaccines Immunol Today 1987; 8: 18-25 5. Fulginiti VA, Eller JJ, Downie AW, Kempe CH. Atypical measles in children previously immunized with inactivated measles virus vaccine, altered reactivity to measles virus JAMA 1967; 202: 1075-80 6. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE An
epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969; 89: 405-21. 7. Cannon MJ, Openshaw PJ, Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 1988; 168: 1163-68 8. Prince GA, Jenson
AB, Hemming VG, et al. Enhancement of respiratory syncytial pulmonary pathology in cotton rats by pnor intramuscular inoculation of formalin-inactivated virus. J Virol 1986; 57: 721-28. 9. Orentas RJ, Hildreth JEK, Obah E, et al. Induction of CD4 + human cytolytic T cells specific for HIV-infected cells by a gp160 subunit vaccine Science 1990; 248: virus
1234-37. 10. Berman PW, Gregory T, Riddle L, et al. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gpl20 but not gpl60. Nature 1990; 345: 622-25.
Ticlopidine SiR,—In your recent editorial (Feb 23, p 459) your comment that the administration of
ticlopidine to patients with peripheral arterial supported by the results of the Swedish Ticlopidine Multicentre Studyl that showed a 39% reduction in fatal and non-fatal cardiovascular events over five years. In addition, ticlopidine improves walking ability: In a double-blind placebo controlled multicentre trial of 151 patients with intermittent claudication2 coordinated by one of us (S. C.), an early and significant improvement in pain-free and absolute walking distances of patients treated with ticlopidine for 12 months was found. Furthermore, the number of patients able to walk on a treadmill for 500 m or more at any given follow-up point was consistently greater in the ticlopidine group. No major side-effects were observed. We also found that ticlopidine reduced fibrinogen and blood viscosity in manThis effect may be not only a mechanism for improving walking ability but also a treatment for the "chronic haematological stress reaction" present in atherothrombotic vascular disease.4 Ticlopidine treatment seems especially suitable in stage II peripheral arterial disease. disease is
Department of Angiology and Blood Coagulation, University Hospital of Sant’Orsola, 40135 Bologna, Italy 1.
SERGIO COCCHERI GUALTIERO PALARETI GIANCARLO FORTUNATO
Janzon L, Bergquist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990; 227:
301-08. 2. Balsamo F, Cocchen S, Libretti A, et al. Ticlopidine in the treatment of intermittent claudication: a 21-month double blind trial. J Lab Clin Med 1989; 114: 84-91. 3. Palareti G, Poggi M, Torricelli P, Balestra V, Coccheri S. Long-term effects of ticlopidine on fibrinogen and haemorheology in patients with intermittent claudication. Thromb Res 1988; 52: 621-29. 4 Stuart J. The acute-phase reaction and haematological stress syndrome in vascular disease. Int J Microcirc Clin Exp 1984, 3: 115-29.
Isolation of novel
microorganism from gastric biopsy specimen
SIR,-We report here the recovery of a novel bacterium (UA768)
gastric biopsy of a 53-year-old man who had erosive oesophagitis, hiatus hernia, and antral gastritis accompanied by Helicobacter pylori for the past two years, for which he had been given ranitidine. This bacterium was culturable on H pylori medial under conditions similar to those used to isolate H pylori. It was spiral in shape and resembled Campylobacterjejuni (see figure) but differed greatly in its biochemical properties. UA768 was oxidase, urease, and catalase negative, negative for hippurate hydrolysis, indoxyl acetate, and nitrate, and positive for hydrogen sulphide (TSI) and for succinate production; growth was - at 25°C, + at 37’C, and ± at at
42°C; the G + C content was 34%. The organism resembled organisms of the Wollinella spp but differed in its G + C content and showed no DNA homology with this genus. It did not resemble "Gastrospirillum hominis"2,3 or Cjejuni ss doylei, which have also been recovered from gastric biopsy specimens.’5 DNA homology
Recombinant vaccines SIR,-In our Science article’ the aim was not to discredit recombinant vaccines. We fully agree with the requirements suggested by Ada.2 Our experiments on the murine lymphocytic choriomeningitis (LCM) model yielded the surprising result that vaccination with whole virus conferred protection whereas vaccination with a recombinant vaccinia virus vaccine sometimes caused increased susceptibility to a T-cell-mediated triggered by a subsequent challenge infection. immunopathology The recombinant vaccine may not have met the requirements a vaccine should meet to confer optimal protection. Although it included the entire nucleoprotein or the entire glycoprotein (that also carries the neutralising determinants), it provided a limited number of T-cell epitopes, which can only be presented by selected MHC antigens. A second factor influencing the equilibrium between protection and immunopathology may be the quality and the kinetics of T-cell memory about which we know very little, especially in respect of viral infections, including recombinant vaccinia virus. As stated in your editorial (April 6) neutralising antibody titres are very often the most important factor in protective immunity by vaccination. The LCM model is special, in that the virus is non-cytopathic and immunosuppressive and that its clearance by the host depends largely on cytotoxic CD8 + T cells. Neutralising antibodies are generated very late, 30-50 days after infection, and in studies with a recombinant vaccinia virus expressing LCM virus nucleoprotein such antibodies are unlikely to have influenced the result. Since a vaccine must meet high safety standards any limitations of efficacy or unwanted complications that are demonstrated in models must be taken into account. We have all seen the ups and downs of "new" vaccines, especially subunit vaccines. In the early 1980s, peptide vaccines were thought to solve many problems;z’ some of these ideas were theoretical and in some instances great practical success followed. Recombinant vaccines are promising; hepatitis B recombinant vaccine comprising the correct neutralising determinants is a good example. Recombinant vaccines based on vaccinia virus, adenovirus, or bacteria are encouraging developments too. But we have also learned that the best vaccines are often attenuated or inactivated whole virus vaccines or cocktails of recombinant vaccines that reconstruct the whole virus. Careful experiments need to be done on the ability of a virus, recombinant virus, or antigens to induce a strong protective immune response, on the requirements for long-lasting T memory response, on the nature of immunological memory, and on antigen persistence. Nonetheless is it not interesting-and worth reporting with all due reservations-if, in a model, vaccine causes rather than prevents disease? Almost every virus has its own pathogenic mechanisms, and may therefore influence the virus-host equilibrium differently. There have, after all, been complications with earlier vaccines, against measles or respiratory syncytial viruss,6 that caused adverse effects still not fully understood; T cells and/or antibodies have been
implicated.7,8 Although LCM may be a special
case, many other viruses and bacteria may fall into this category of poorly to non-cytopathic infectious agents; HIV is another possible example. Considerable efforts are being made to develop subunit vaccines expressing only selected HIV antigens-for example, glycoprotein (gpl60, gp120) in vaccinia recombinants or other fonns.9,1O Although HIV is assumed by many to act via cytopathic effects, immunopathological damage accumulating over time may well be responsible for immunosuppression. If so, an improved triggering of a CD8 and exacerbate immunopathology might response immunosuppression in certain circumstances, as in the LCM model. This may happen even if the vaccine also induces
neutralising antibody responses. Department of Experimental Pathology, Universitatsspital Zurich, CH-8091 Zurich, Switzerland 1. Oehen
STEPHAN OEHEN HANS HENGARTNER ROLF ZINKERNAGEL
S, Hengartner H, Zinkernagel RM. Vaccination for disease. Science 1991; 251:
195-98.
2. Ada G. The immunological principles of vaccination. Lancet 1990, 335: 523-26. 3. Beale J Synthetic peptides as the basis for future vaccines. Nature 1982; 298: 14-15. 4. Zanetti M, Sarcarz E, Salk J. The immunology of new generation vaccines Immunol Today 1987; 8: 18-25 5. Fulginiti VA, Eller JJ, Downie AW, Kempe CH. Atypical measles in children previously immunized with inactivated measles virus vaccine, altered reactivity to measles virus JAMA 1967; 202: 1075-80 6. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE An
epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969; 89: 405-21. 7. Cannon MJ, Openshaw PJ, Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 1988; 168: 1163-68 8. Prince GA, Jenson
AB, Hemming VG, et al. Enhancement of respiratory syncytial pulmonary pathology in cotton rats by pnor intramuscular inoculation of formalin-inactivated virus. J Virol 1986; 57: 721-28. 9. Orentas RJ, Hildreth JEK, Obah E, et al. Induction of CD4 + human cytolytic T cells specific for HIV-infected cells by a gp160 subunit vaccine Science 1990; 248: virus
1234-37. 10. Berman PW, Gregory T, Riddle L, et al. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gpl20 but not gpl60. Nature 1990; 345: 622-25.
Ticlopidine SiR,—In your recent editorial (Feb 23, p 459) your comment that the administration of
ticlopidine to patients with peripheral arterial supported by the results of the Swedish Ticlopidine Multicentre Studyl that showed a 39% reduction in fatal and non-fatal cardiovascular events over five years. In addition, ticlopidine improves walking ability: In a double-blind placebo controlled multicentre trial of 151 patients with intermittent claudication2 coordinated by one of us (S. C.), an early and significant improvement in pain-free and absolute walking distances of patients treated with ticlopidine for 12 months was found. Furthermore, the number of patients able to walk on a treadmill for 500 m or more at any given follow-up point was consistently greater in the ticlopidine group. No major side-effects were observed. We also found that ticlopidine reduced fibrinogen and blood viscosity in manThis effect may be not only a mechanism for improving walking ability but also a treatment for the "chronic haematological stress reaction" present in atherothrombotic vascular disease.4 Ticlopidine treatment seems especially suitable in stage II peripheral arterial disease. disease is
Department of Angiology and Blood Coagulation, University Hospital of Sant’Orsola, 40135 Bologna, Italy 1.
SERGIO COCCHERI GUALTIERO PALARETI GIANCARLO FORTUNATO
Janzon L, Bergquist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990; 227:
301-08. 2. Balsamo F, Cocchen S, Libretti A, et al. Ticlopidine in the treatment of intermittent claudication: a 21-month double blind trial. J Lab Clin Med 1989; 114: 84-91. 3. Palareti G, Poggi M, Torricelli P, Balestra V, Coccheri S. Long-term effects of ticlopidine on fibrinogen and haemorheology in patients with intermittent claudication. Thromb Res 1988; 52: 621-29. 4 Stuart J. The acute-phase reaction and haematological stress syndrome in vascular disease. Int J Microcirc Clin Exp 1984, 3: 115-29.
Isolation of novel
microorganism from gastric biopsy specimen
SIR,-We report here the recovery of a novel bacterium (UA768)
gastric biopsy of a 53-year-old man who had erosive oesophagitis, hiatus hernia, and antral gastritis accompanied by Helicobacter pylori for the past two years, for which he had been given ranitidine. This bacterium was culturable on H pylori medial under conditions similar to those used to isolate H pylori. It was spiral in shape and resembled Campylobacterjejuni (see figure) but differed greatly in its biochemical properties. UA768 was oxidase, urease, and catalase negative, negative for hippurate hydrolysis, indoxyl acetate, and nitrate, and positive for hydrogen sulphide (TSI) and for succinate production; growth was - at 25°C, + at 37’C, and ± at at
42°C; the G + C content was 34%. The organism resembled organisms of the Wollinella spp but differed in its G + C content and showed no DNA homology with this genus. It did not resemble "Gastrospirillum hominis"2,3 or Cjejuni ss doylei, which have also been recovered from gastric biopsy specimens.’5 DNA homology
