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CANCER AND THE PILL
166 CANCER AND THE PILL power of doctors to treat or even prevent disease derives from the dissemination and application of scientific research. The clinical efficiency and safety of new treatments can, however, only be assessed by controlled trials and by epidemiological surveys which seek to monitor their effects in
S1R,-The ever-increasing
practice. The statistical basis for epidemiological reliability is established as with all scientific tools, distorted data yield wrong conclusions. The skill of the epidemiologist lies in being able to anticipate the relevance of factors which affect the collection of his basic data and in excluding such distortions. There will always be observer errors, and epidemiological studies need to be repeated by different observers and in different locations before the conclusions are allowed to influence clinical practice. On the other hand, the early publication of epidemiological studies is essential if they are to be tested and assessed for relevance. In October, 1983, The Lancet published a paper by Pike et all suggesting a correlation between oral contraceptives and the later development of cancer of the breast. Pike et al and The Lancet editorially warned that the conclusions were tentative and that further studies were necessary. Unfortunately the mass media saw that here was bad news which attracts readers, and another "pill scare" was under way. The basic work has now been repeated, and figures just published by the Centers for Disease Control, Atlanta (A4MWR June 29) would seem to refute the original paper completely. It is to be hoped that the new paper will receive equal publicity with the original.
but,
10 Campden Hill London W8 7LB
Square,
PETER DIGGORY
***Some of the latest figures from the CDC/NICHHD which Mr Diggory refers are given on p 145.-ED. L. 1. Pike
study
to
MC, Henderson BE, Krails MD, Duke A, Roy S. Breast cancer in young women
and the use of oral contraceptives: Possible at use. Lancet 1983; ii: 926-29.
modifying effect of
formulation and age
SIR,-Scientific journals and those who do-the research
cannot
for the way in which the press handles their findings but neither can they ignore the fact that what the public media say has a direct impact upon how people use preventive and curative medicine. The papers and correspondence published in The Lancet on and after Oct 22, 1983, illustrate the problems associated with the publication of epidemiological information on cancer and oral contraceptives. Since the publications by Pike et al and Vessey et al, there have been some specially funded meetings: the National Institutes of Health sponsored at least one meeting, the International Planned Parenthood Federation’s medical committee reviewed the problem, and the Planned Parenthood Federation of America and the Family Planning Association in the UK also looked at it. In short, a lot of money and effort have been put into responding to the original papers. Might it have been possible to do any of these things before rather than after publication?
take
responsibility
Family Health International, Research Triangle Park, North Carolina 27709, USA
MALCOLM POTTS
SAFETY OF VACCINES CONTAINING MENINGOCOCCAL GROUP B POLYSACCHARIDE et all reported that polysialosyl glycoproteins from fetal and infant human brain cross-reacted serologically with Escherichia coli Kl and meningococcal group B capsular polysaccharides, and urged caution in the development of vaccines containing these polysaccharides. The specific concerns mentioned were that use of an artificial vaccine might break the natural tolerance to this polysaccharide and initiate an autoimmune process and that antibodies induced by such a vaccine might cause unexpected adverse effects resulting from interference with the as yet unknown physiological function of the brain polysialosyl structures. Finne et al acknowledged that the development of an effective vaccine against the group B meningococcus is a priority; all the same their warning might seem to apply to all efforts to develop vaccines containing the group B polysaccharide.
SIR,-Finne
derived
We have prepared and tested in human volunteers group B vaccines consisting of the group B capsular polysaccharide noncovalently complexed to outer-membrane proteins.2-7 These studies have shown that, when complexed to the outer-membrane proteins, the group B polysaccharide induces a significant, though often transient, IgM antibody response and also enhances the antigenicity of the proteins.4We concur in the need for caution in the development and use of group B vaccines containing group B polysaccharide that is chemically modified or covalently coupled to a carrier protein in such a way that it might break natural tolerance and induce an IgG response. We believe, however, that the concerns mentioned above are not applicable to the vaccines we have tested, for the following reasons:
’
(1) The group B polysaccharide was not chemically modified or covalently coupled to the outer-membrane proteins, but was in a "natural" hydrophobic complex. (2) A high percentage (80-90%) of adults have serum antibodies to the group B polysaccharide which were presumably acquired through natural exposure to group B meningococci and other organisms, such as E coli K19 and Moraxella nonliquefaciens,1O which carry this antigen. These natural antibodies are nearly all of the IgM class, of relatively low avidity at 3‘7°C,11 and have poor bactericidal activity with human complement.8 There are no known problems associated with having these antibodies. (3) Vaccine-induced antibodies to group B polysaccharide appear to be qualitatively and quantitatively equivalent to naturally occurring antibodies. (4) Group B polysaccharide-serotype protein vaccines have been administered to some 500 Americans of various ages,2-5 to 30 Norwegian
adults, and to over 2000 South African children without ill-effects.
(5) Animals hyperimmunised with group B meningococci show no ill-effects, despite high antibody levels. The role of human anti-B polysaccharide antibodies in protection against group B disease and the exact nature of the antigenic determinant(s) to which they bind are still unclear. Although they appear to have poor bactericidal activity with human complement, they may be opsonic or act cooperatively with other antibodies in providing protection. 12 These questions should be evaluated before eliminating the B polysaccharide from potential vaccines. Department of Bacterial Diseases, Army Institute of Research, Washington, DC 20307, USA Bacterial Polysaccharides Branch, Office of Biologies Research and Review, National Center for Drugs and Biologics, Food and Drug Administration, Bethesda, Maryland Department of Methodology,
Walter Reed
WENDELL D. ZOLLINGER
JOHN E. BOSLEGO
CARL E. FRASCH
National Institute of Public Health,
Oslo, Norway
L. ODDVAR FROHOLM
J, Leinonen M, Mäkelä PH. Antigenic similarities between brain components and bacteria causing meningitis: Implications for vaccine development and pathogenesis. Lancet 1983; ii: 355-57. 2. Zollinger WD, Mandrell RE, Griffiss JM, Altieri P, Berman S. Complex of meningococcal group B polysaccharide and outer membrane protein immunogenic in man. J Clin Invest 1979; 63: 836-48. 3. Frasch CE, Peppler MS, Cate TR, Zahradnik JM. Immunogenicity and clinical evaluation of group B Neisseria meningitidis outer membrane protein vaccine. In: Robbins JB, Hill JC, Sadoff JC, eds. Seminars in infectious disease: Vol IV, New York: Thieme-Stratton, 1982: 263-67. 4. Zollinger WD, Mandrell RE, Griffiss JM. Enhancement of immunological activity by noncovalent complexing of meningococcal group B polysaccharide and outer membrane proteins. In: Robbins JB, Hill JC, Sadoff JC, eds. Seminars in infectious disease: Vol IV. New York: Thieme-Stratton, 1982: 254-62. 5. Frasch CE. Immunization against Neisseria meningitidis. In: Easman CSF, Jeljaszewicz J, eds Medical microbiology: Vol II. London: Academic Press, 1983: 115-44 6. Froholm LO, Berdal BP, Bovre K, et al. Meningococcal group B vaccine trial in Norway 1981-1982. Natl Inst Publ Hlth Ann (Oslo)1983; 6: 133-38. 7. Frasch CE. Status of a group B Neisseria meningitidis vaccine. WHO Bull(in press) 8. Zollinger WD, Mandrell RE. Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide. Infect Immun 1983; 40: 257-64. 9. Kasper DL, Winkelhake JL, Zollinger WD, Brandt BL, Artenstein MS Immunochemical similarity between polysaccharide antigens of Escherichia coli 07:K1(L7):MN and group B Neisseria meningitidis. J Immunol 1973; 110: 262-68 10. Bovre K, Bryn K, Closs O, Hagen N, Froholm LO. Surface polysaccharide of Moraxella nonliquefaciens identical to Neisseria meningitidis group B polysaccharide Natl Inst Publ Hlth Ann (Oslo) 1983; 6: 66-73. 11. Mandrell RE, Zollinger WD. Measurement of antibodies to meningococcal group B J polysaccharide: low avidity binding and equilibrium binding constants. Immunol 1. Finne
1982; 129: 2172-78. CE, Parkes L, McNelis RM, Gotschlich EC. Protection against group B meningococcal disease I. Comparison of group-specific and type-specific protection in the chick embryo model. J Exp Med 1976; 144: 319-29.
12. Frasch
S1R,-The ever-increasing
practice. The statistical basis for epidemiological reliability is established as with all scientific tools, distorted data yield wrong conclusions. The skill of the epidemiologist lies in being able to anticipate the relevance of factors which affect the collection of his basic data and in excluding such distortions. There will always be observer errors, and epidemiological studies need to be repeated by different observers and in different locations before the conclusions are allowed to influence clinical practice. On the other hand, the early publication of epidemiological studies is essential if they are to be tested and assessed for relevance. In October, 1983, The Lancet published a paper by Pike et all suggesting a correlation between oral contraceptives and the later development of cancer of the breast. Pike et al and The Lancet editorially warned that the conclusions were tentative and that further studies were necessary. Unfortunately the mass media saw that here was bad news which attracts readers, and another "pill scare" was under way. The basic work has now been repeated, and figures just published by the Centers for Disease Control, Atlanta (A4MWR June 29) would seem to refute the original paper completely. It is to be hoped that the new paper will receive equal publicity with the original.
but,
10 Campden Hill London W8 7LB
Square,
PETER DIGGORY
***Some of the latest figures from the CDC/NICHHD which Mr Diggory refers are given on p 145.-ED. L. 1. Pike
study
to
MC, Henderson BE, Krails MD, Duke A, Roy S. Breast cancer in young women
and the use of oral contraceptives: Possible at use. Lancet 1983; ii: 926-29.
modifying effect of
formulation and age
SIR,-Scientific journals and those who do-the research
cannot
for the way in which the press handles their findings but neither can they ignore the fact that what the public media say has a direct impact upon how people use preventive and curative medicine. The papers and correspondence published in The Lancet on and after Oct 22, 1983, illustrate the problems associated with the publication of epidemiological information on cancer and oral contraceptives. Since the publications by Pike et al and Vessey et al, there have been some specially funded meetings: the National Institutes of Health sponsored at least one meeting, the International Planned Parenthood Federation’s medical committee reviewed the problem, and the Planned Parenthood Federation of America and the Family Planning Association in the UK also looked at it. In short, a lot of money and effort have been put into responding to the original papers. Might it have been possible to do any of these things before rather than after publication?
take
responsibility
Family Health International, Research Triangle Park, North Carolina 27709, USA
MALCOLM POTTS
SAFETY OF VACCINES CONTAINING MENINGOCOCCAL GROUP B POLYSACCHARIDE et all reported that polysialosyl glycoproteins from fetal and infant human brain cross-reacted serologically with Escherichia coli Kl and meningococcal group B capsular polysaccharides, and urged caution in the development of vaccines containing these polysaccharides. The specific concerns mentioned were that use of an artificial vaccine might break the natural tolerance to this polysaccharide and initiate an autoimmune process and that antibodies induced by such a vaccine might cause unexpected adverse effects resulting from interference with the as yet unknown physiological function of the brain polysialosyl structures. Finne et al acknowledged that the development of an effective vaccine against the group B meningococcus is a priority; all the same their warning might seem to apply to all efforts to develop vaccines containing the group B polysaccharide.
SIR,-Finne
derived
We have prepared and tested in human volunteers group B vaccines consisting of the group B capsular polysaccharide noncovalently complexed to outer-membrane proteins.2-7 These studies have shown that, when complexed to the outer-membrane proteins, the group B polysaccharide induces a significant, though often transient, IgM antibody response and also enhances the antigenicity of the proteins.4We concur in the need for caution in the development and use of group B vaccines containing group B polysaccharide that is chemically modified or covalently coupled to a carrier protein in such a way that it might break natural tolerance and induce an IgG response. We believe, however, that the concerns mentioned above are not applicable to the vaccines we have tested, for the following reasons:
’
(1) The group B polysaccharide was not chemically modified or covalently coupled to the outer-membrane proteins, but was in a "natural" hydrophobic complex. (2) A high percentage (80-90%) of adults have serum antibodies to the group B polysaccharide which were presumably acquired through natural exposure to group B meningococci and other organisms, such as E coli K19 and Moraxella nonliquefaciens,1O which carry this antigen. These natural antibodies are nearly all of the IgM class, of relatively low avidity at 3‘7°C,11 and have poor bactericidal activity with human complement.8 There are no known problems associated with having these antibodies. (3) Vaccine-induced antibodies to group B polysaccharide appear to be qualitatively and quantitatively equivalent to naturally occurring antibodies. (4) Group B polysaccharide-serotype protein vaccines have been administered to some 500 Americans of various ages,2-5 to 30 Norwegian
adults, and to over 2000 South African children without ill-effects.
(5) Animals hyperimmunised with group B meningococci show no ill-effects, despite high antibody levels. The role of human anti-B polysaccharide antibodies in protection against group B disease and the exact nature of the antigenic determinant(s) to which they bind are still unclear. Although they appear to have poor bactericidal activity with human complement, they may be opsonic or act cooperatively with other antibodies in providing protection. 12 These questions should be evaluated before eliminating the B polysaccharide from potential vaccines. Department of Bacterial Diseases, Army Institute of Research, Washington, DC 20307, USA Bacterial Polysaccharides Branch, Office of Biologies Research and Review, National Center for Drugs and Biologics, Food and Drug Administration, Bethesda, Maryland Department of Methodology,
Walter Reed
WENDELL D. ZOLLINGER
JOHN E. BOSLEGO
CARL E. FRASCH
National Institute of Public Health,
Oslo, Norway
L. ODDVAR FROHOLM
J, Leinonen M, Mäkelä PH. Antigenic similarities between brain components and bacteria causing meningitis: Implications for vaccine development and pathogenesis. Lancet 1983; ii: 355-57. 2. Zollinger WD, Mandrell RE, Griffiss JM, Altieri P, Berman S. Complex of meningococcal group B polysaccharide and outer membrane protein immunogenic in man. J Clin Invest 1979; 63: 836-48. 3. Frasch CE, Peppler MS, Cate TR, Zahradnik JM. Immunogenicity and clinical evaluation of group B Neisseria meningitidis outer membrane protein vaccine. In: Robbins JB, Hill JC, Sadoff JC, eds. Seminars in infectious disease: Vol IV, New York: Thieme-Stratton, 1982: 263-67. 4. Zollinger WD, Mandrell RE, Griffiss JM. Enhancement of immunological activity by noncovalent complexing of meningococcal group B polysaccharide and outer membrane proteins. In: Robbins JB, Hill JC, Sadoff JC, eds. Seminars in infectious disease: Vol IV. New York: Thieme-Stratton, 1982: 254-62. 5. Frasch CE. Immunization against Neisseria meningitidis. In: Easman CSF, Jeljaszewicz J, eds Medical microbiology: Vol II. London: Academic Press, 1983: 115-44 6. Froholm LO, Berdal BP, Bovre K, et al. Meningococcal group B vaccine trial in Norway 1981-1982. Natl Inst Publ Hlth Ann (Oslo)1983; 6: 133-38. 7. Frasch CE. Status of a group B Neisseria meningitidis vaccine. WHO Bull(in press) 8. Zollinger WD, Mandrell RE. Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide. Infect Immun 1983; 40: 257-64. 9. Kasper DL, Winkelhake JL, Zollinger WD, Brandt BL, Artenstein MS Immunochemical similarity between polysaccharide antigens of Escherichia coli 07:K1(L7):MN and group B Neisseria meningitidis. J Immunol 1973; 110: 262-68 10. Bovre K, Bryn K, Closs O, Hagen N, Froholm LO. Surface polysaccharide of Moraxella nonliquefaciens identical to Neisseria meningitidis group B polysaccharide Natl Inst Publ Hlth Ann (Oslo) 1983; 6: 66-73. 11. Mandrell RE, Zollinger WD. Measurement of antibodies to meningococcal group B J polysaccharide: low avidity binding and equilibrium binding constants. Immunol 1. Finne
1982; 129: 2172-78. CE, Parkes L, McNelis RM, Gotschlich EC. Protection against group B meningococcal disease I. Comparison of group-specific and type-specific protection in the chick embryo model. J Exp Med 1976; 144: 319-29.
12. Frasch