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Vaccine trials

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Abstract

This article reviews some of the issues involved in evaluating vaccines in humans. Vaccine trials are required for licensure and are essential for demonsrating a vaccine’s safety and protective efficacy. The formal framework of phase I, II, and III trials is described, with particular emphasis on the choice of hypotheses, trial design, and biases that arise in the context of vaccine trials. However, some aspects of a vaccine’s performance cannot be evaluated in clinical trials owing to their relatively small size. Thus, vaccine evaluation must continue after licensure, for example, to evaluate the vaccine with respect to rare reactions, duration of protection, and ecological effects. The article reviews some of the methods commonly used for post-licensure studies of vaccine efficacy and safety.

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References

  1. Anon (1997) World Medical Association Declaration of Helsinki. JAMA 277, 925,926.

  2. Pocock, S. J. (1993) Statistical and ethical issues in monitoring clinical trials. Statistics in Med. 12, 1459–1469.

    Article  CAS  Google Scholar 

  3. Bellanti, J. A., Zeligs, B. J., Vetro, S., Pung, Y.-H., Luccioli, S., Malvasic, M. J., Hook, A. M., Ubertini, T. R., Vanni, R., and Nencioni, L. (1993) Studies of safety, infectivity and immunogenicity of a new temperature-sensitive (ts) 51-1 strain of Salmonella typhi as a new live oral typhoid fever vaccine candidate. Vaccine 11, 587–590.

    Article  PubMed  CAS  Google Scholar 

  4. Costantino, P., Viti, S., Audino, P., Velmonte, M. A., Nencioni, L., and Rappuoli, R. (1992) Development and phase I clinical testing of a conjugate vaccine against meningococcus A and C. Vaccine 10, 691–698.

    Article  PubMed  CAS  Google Scholar 

  5. Gold, R., Leplow, M. L., Goldchneider, I., Draper, T. F., and Gotschlich, E. (1979) Kinetics of antibody production to group A and C meningococcal polysaccharide vaccines administered during the first six years of life: prospects for routine immunisation of infants and children. J. Infect. Dis. 140, 690–697.

    PubMed  CAS  Google Scholar 

  6. Rutter, D. A., Ashworth, L. A. E., Day, A., Funnell, S., Lovell, F., and Robinson, A. (1988) Trial of a new acellular pertussis vaccine in healthy adult volunteers. Vaccine 6, 29–32.

    Article  PubMed  CAS  Google Scholar 

  7. Bock, H. L., Klockmann, U., Jungst, C., Schindel-Kunzel, F., Theobald, K., and Zerban, R. (1990) A new vaccine against tick-borne encephalitis: initial trial in man including a dose-response study. Vaccine 8, 22–24.

    Article  PubMed  CAS  Google Scholar 

  8. Richmond, P., Goldblatt, D., Fusco, P. C., and others. (2000) Safety and immunogenicity of a new Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine in healthy adults. Vaccine 18, 641–646.

    Article  Google Scholar 

  9. Picard, O., Giral, P., Defer, M. C., Fouchard, M., Morel, M., Meyohas, M. C., et al. (1990) AIDS vaccine therapy: phase I trial (letter). Lancet 336, 179.

    Article  PubMed  CAS  Google Scholar 

  10. Miller, E., Richmond, P., Borrow, R., Kaczmarski, E., Cartwright, K., Morris, R., et al. (1998) UK strategy for the introduction of meningococcal C conjugate vaccines. Eleventh International Pathogenic Neisseria Conference (abstract p 57). Paris.

  11. Goldschneider, I., Gotschlich, E. C., Artenstein, M. S. (1969) Human immunity to the meningococcus. I. The role of humoral antibodies. J. Exp. Med. 129, 1307–1326.

    Article  PubMed  CAS  Google Scholar 

  12. Tappero, J. W., Lagos, R., Ballesteros, A. M., and others. (1999) Immunogenicity of 2 serogroup B outer membrane protein meningococcal vaccines. JAMA 281, 1520–1527.

    Article  PubMed  CAS  Google Scholar 

  13. Scheifele, D., Bjornson, G., Barreto, L., Meekison, W., and Guasparini, R. (1992) Controlled trial of Haemophilus influenzae type b diphtheria toxoid conjugate combined with diphtheria, tetanus and pertussis vaccines, in 18-month old children, including comparison of arm versus thigh injection. Vaccine 10, 455–460.

    Article  PubMed  CAS  Google Scholar 

  14. Miller, E., Ashworth, L. A., Robinson, A., Waight, P. A., and Irons, L. I. (1991) Phase II trial of whole-cell pertussis vaccine versus an acellular vaccine. Lancet 337, 70–73.

    Article  PubMed  CAS  Google Scholar 

  15. Pichichero, M. E., Marsocci, S. M., Francis, A. B., Green, J. L., Disney, F. A., Rennels, M. B., Lewis, E. D., Sugarman, L., Losonsky, G. A., Zito, E., and Davidson, B. L. (1993) A comparative evaluation of the safety and immunogenicity of a single dose of unbuffered oral rhesus rotavirus serotype 3, rhesus/human reassortant serotypes 1, 2 and 4 and combined (tetravalent) vaccines in healthy infants. Vaccine 11, 747–753.

    Article  PubMed  CAS  Google Scholar 

  16. Lachin, J. M. (1981) Introduction to sample size determination and power analysis for clinical trials. Controlled Clinical Trials 2, 93–113.

    Article  PubMed  CAS  Google Scholar 

  17. Machin, D., and Campbell, M. J. (1987) Statistical Tables for the Design of Clinical Trials, Blackwell Scientific, Oxford.

    Google Scholar 

  18. Strauss, S. E., Corey, L., Burke, R. L., Savarese, B., Barnum, G., Krause, P. R., Kost, R. G., Meir, J. L., Sekulovitch, R., Adair, S. F., and Dekker, C. L. (1994) Placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes. Lancet 343, 1460–1463.

    Article  Google Scholar 

  19. Valero, M. V., Amador, L. R., Galindo, C., Figueroa, J., Bello, M. S., Murillo, L. A., et al. (1993) Vaccination with SPf66, a chemically synthesised vaccine against Plasmodium falciparum malaria in Colombia. Lancet 341, 705–710.

    Article  PubMed  CAS  Google Scholar 

  20. Sempertegui, F., Estrella, B., Moscoso, J., Piedrahita, L., Hernandez, D., Gaybor, J., et al. (1994) Safety, immunogenicity and protective effect of the SPf66 malaria synthetic vaccine against Plasmodium falciparum infection in a randomized double-blind placebo-controlled field trial in an endemic area of Ecuador. Vaccine 12, 337–342.

    Article  PubMed  CAS  Google Scholar 

  21. Hall, A. J. and Aaby, P. (1990) Tropical trials and tribulations. Int. J. Epidemiol. 19, 777–781.

    Article  PubMed  CAS  Google Scholar 

  22. Fine, P. E. M. and Clarkson, J. A. (1987) Reflections on the efficacy of pertussis vaccines. Rev. Infect. Dis. 9, 866–883.

    PubMed  CAS  Google Scholar 

  23. Vesikari, T. (1993) Clinical trials of live oral rotavirus vaccines: the Finnish experience. Vaccine 11, 255–261.

    Article  PubMed  CAS  Google Scholar 

  24. Bjune, G., Holby, E. A., Gronesby, J. K., and others. (1991) Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 338, 1093–1096.

    Article  PubMed  CAS  Google Scholar 

  25. Simanjuntak, C. H., Paleologo, F., Punjabi, N. H., Darmowigoto, R., Soeprawoto, Totosuderjo, H., Haryanto, P., Suprijanto, E., Witham, N. D., and Hoffman, S. L. (1991) Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 338, 1055–1059.

    Article  PubMed  CAS  Google Scholar 

  26. Medical Research Council (1951) The prevention of whooping-cough by vaccination: a Medical Research Council investigation. Br. Med. J. June 30, 1463–1471.

    Google Scholar 

  27. Farrington, C. P. (1990) Quantifying misclassification bias in cohort studies of vaccine efficacy. Stat. Med. 9, 1327–1337.

    Article  PubMed  CAS  Google Scholar 

  28. PHLS Epidemiological Research Laboratory and 21 Area Health Authorities (1982) Efficacy of pertussis vaccination in England. Br. Med. J. 285, 357–359.

    Google Scholar 

  29. Storsaeter, J., Hallander, H., Farrington, C. P., Olin, P., Mollby, R., and Miller, E. (1990) Secondary analyses of the efficacy of two acellular pertussis vaccines evaluated in a Swedish phase III trial. Vaccine 8, 457–461.

    Article  PubMed  CAS  Google Scholar 

  30. Ad-Hoc Group for the Study of Pertussis Vaccines (1988) Placebo-controlled trial of two acellular pertussis vaccines in Sweden: protective efficacy and adverse events. Lancet April 30, 955–960.

    Google Scholar 

  31. Gustafsson, L., Hallander, H., Olin, P., Reizenstein, E., and Storsaeter, J. (1995) Efficacy trial of acellular pertussis vaccines. Swedish Institute for Infectious Disease Control. Technical report Trial I.

  32. Olin, P., Gustafsson Rasmussen, F., Hallander H., Heijbel, H., and Gottfarb, P. (1997) Efficacy trial of acellular pertussis vaccines. Swedish Institute for Infectious Disease Control. Technical report Trial II.

  33. Francis, T., Korns, R. F., Voight, T., Boisen, M., Hemphill, F. M., Napier, J. A., and Tolchinsky, E. (1955) An evaluation of the 1954 poliomyelitis vaccine trials. Am. J. Public Health Part 2, 45, 1–63.

    Google Scholar 

  34. Wahdan, M. H., Rizk, F., El-Akkad, A. M., and others. (1973) A controlled field trial of a serogroup A meningococcal polysaccharide vaccine. WHO Bulletin 48, 667–673.

    CAS  Google Scholar 

  35. Farrington, C. P. and Manning, G. (1990) Test statistics and sample size formulae for comparative binomial trials with null hypotheses of non-zero risk difference or non-unity relative risk. Stat. Med. 9, 1447–1454.

    Article  PubMed  CAS  Google Scholar 

  36. Pocock, S. J. (1983) Clinical Trials: A Practical Approach. Wiley, Chichester.

    Google Scholar 

  37. Halloran, M. E., Haber, M., Longini, I. M., and Struchiner, C. J. (1991) Direct and indirect effects in vaccine efficacy and effectiveness. Am. J. Epidemiol. 133, 323–331.

    PubMed  CAS  Google Scholar 

  38. Sierra, G. V. G., Campa, H. C., Varcael, N. M., and others. (1991) Vaccine against group B Neisseria meningitidis: Protection trial and mass vaccination results in Cuba. NIPH Annals 14, 187–192.

    Google Scholar 

  39. Devine, L. F., Pierce, W. E., Floyd, T. M., et al. (1970) Evaluation of group C meningococcal polysaccharide vaccine in marine recruits, San Diego, California. Am. J. Epidemiol. 92, 25–32.

    PubMed  CAS  Google Scholar 

  40. Peltola, H., Makela, P. H., Kayhty, H., and others. (1977) Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age. N. Engl. J. Med. 297, 686–691.

    Article  PubMed  CAS  Google Scholar 

  41. Gambian Hepatitis Study Group (1987) The Gambia hepatitis intervention study. Cancer Research 47, 5782–5787.

    Google Scholar 

  42. Hayes, R. J. and Bennett, S. (1999) Simple sample size calculation for cluster-randomized trials. Int. J. Epidemiol. 28, 319–326.

    Article  PubMed  CAS  Google Scholar 

  43. Storsaeter, J., Olin, P., Renemar, B., Lagergard, T., Norberg, R., Romanus, V., Tiru, M. et al. (1988) Mortality and morbidity from invasive bacterial infections during a clinical trial of acellular pertussis vaccines in Sweden. Pediatr. Infect. Dis. J. 7, 637–645.

    Article  PubMed  CAS  Google Scholar 

  44. Garenne, M., Leroy, O., Beau, J.-P., and Sene, I. (1991) Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet 338, 903–907.

    Article  PubMed  CAS  Google Scholar 

  45. Farrington, C. P. (1992) The measurement and interpretation of age-specific vaccine efficacy. Int. J. Epidemiol. 21, 1014–1020.

    Article  PubMed  CAS  Google Scholar 

  46. Kanaan, M. N. and Farrington, C. P. (2000) Definition and estimation of age-specific vaccine efficacy. Preprint, Open University Department of Statistics (2000).

  47. Datta, S., Halloran, M. E., and Longini, I. M. (1999) Efficiency of estimating vaccine efficacy for susceptibility and infectiousness: randomization by individual versus household. Biometrics 55, 792–798.

    Article  PubMed  CAS  Google Scholar 

  48. Longini, I. R., Sagatelian, K., Rida, W. N., and Halloran, M. E. (1998) Optimal vaccine trial design when estimating vaccine efficacy for susceptibility and infectiousness from multiple populations. Statistics in Medicine 17, 1121–1136.

    Article  PubMed  Google Scholar 

  49. Medical Research Council Whooping Cough Immunisation Committee (1956) Vaccination against whooping cough: relation bertween protection and results of laboratory tests. Br. Med. J. 2, 454–462.

    Article  Google Scholar 

  50. Newell, D. J. (1992) Intention-to-treat analysis: implications for quantitative and qualitative research. Int. J. Epidemiol. 21, 837–841.

    Article  PubMed  CAS  Google Scholar 

  51. Farrington, C. P. (1993) Intention-to-treat analysis: implications for quantitative and qualitative research (letter). Int. J. Epidemiol. 22, 566.

    Article  PubMed  CAS  Google Scholar 

  52. Cornfield, J. (1978) Randomization by group: a formal analysis. Am. J. Epidemiol. 108, 100–102.

    PubMed  CAS  Google Scholar 

  53. Begg, N. and Miller, E. (1990) Role of epidemiology in vaccine policy. Vaccine 8, 180–189.

    Article  PubMed  CAS  Google Scholar 

  54. Orenstein, W. A., Bernier, R. H., Dondero, T. J., and others. (1985) Field evaluation of vaccine efficacy. WHO Bulletin 63, 1055–1068.

    CAS  Google Scholar 

  55. Rodrigues, L. C. and Smith, P. G. (1999) Use of the case-control approach in vaccine evaluation: efficacy and adverse effects. Epidemiological Reviews 21, 56–72.

    CAS  Google Scholar 

  56. Farrington, C. P. (1993) Estimation of vaccine effectiveness using the screening method. Int. J. Epidemiol. 22, 742–746.

    Article  PubMed  CAS  Google Scholar 

  57. Fine, P. E. M. and Chen, R. T. (1992) Confounding in studies of adverse reactions to vaccines. Am. J. Epidemiol. 136, 121–135.

    PubMed  CAS  Google Scholar 

  58. Farrington, C. P. (1995) Relative incidence estimation from case series for vaccine safety evaluation. Biometrics 51, 228–235.

    Article  PubMed  CAS  Google Scholar 

  59. Farrington, C. P., Nash, J., and Miller, E. (1996) Case series analysis of adverse reactions to vaccines: a comparative evaluation. Am. J. Epidemiol. 143, 1165–1173.

    PubMed  CAS  Google Scholar 

  60. Miller, E., Waight, P., and Farrington, P. (1998) Safety assessment post-licensure. Developments in Biological Standardisation 95, 235–243.

    CAS  Google Scholar 

  61. Centers for Disease Control and Prevention (1999) Intussusception among recipients of rotavirus vaccine — United States, 1998–1999. MMWR 48, 577–81.

    Google Scholar 

  62. Miller, E., Goldacre, M., Pugh, S., Colville, A., Farrington, P., Flower, A., Nash, J., MacFarlane, L., and Tettmar, R. (1993) Risk of aseptic meningitis after measles mumps and rubella vaccine in UK children. Lancet 341, 979–982.

    Article  PubMed  CAS  Google Scholar 

  63. Farrington, P., Pugh, S., Colville, A., Flower, A., Nash, J., Morgan-Capner, P. et al. (1995) A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 345, 567–569.

    Article  PubMed  CAS  Google Scholar 

  64. Fine, P. E. M. (1993) Herd immunity: History, theory, practice. Epidemiologic Reviews 15, 265–302.

    PubMed  CAS  Google Scholar 

  65. PHLS Whooping-Cough Committee and Working Party (1973) Efficacy of whooping-cough vaccines used in the United Kingdom before 1968. Br. Med. J. Feb 3, 259–262.

    Google Scholar 

  66. Gold, R. and Artenstein, M. S. (1971) Meningococcal Infections 2: Field trial of group C meningococcal polysaccharide vaccine in 1969–70. Bull. World Health Org. 45, 279–282.

    PubMed  CAS  Google Scholar 

  67. Maiden, M. C. J. and Spratt, B. G. (1999) Meningococcal conjugate vaccines: new opportunities and new challenges. Lancet 354, 615–616.

    Article  PubMed  CAS  Google Scholar 

  68. Byar, D. P., Schoenfeld, D. A., Green, S. B., Amato, D. A., DAvis, R., DeGruttola, V., et al. (1990) Design considerations for AIDS trials. N. Engl. J. Med. 323, 1343–1348.

    Article  PubMed  CAS  Google Scholar 

  69. Datta, S., Halloran, M. E., and Longini, I. M. (1998) Augmented HIV vaccine trial design for estimating reduction in infectiousness and protective efficacy. Statistics in Medicine 17, 185–200.

    Article  PubMed  CAS  Google Scholar 

  70. Fine, P. E. M. (1995) Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346, 1339–1345.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Statistics, The Open University, Walton Hall, MK7 6AA, Milton Keynes, England

    C. P. Farrington

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Correspondence to C. P. Farrington.

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Farrington, C.P., Miller, E. Vaccine trials. Mol Biotechnol 17, 43–58 (2001). https://doi.org/10.1385/MB:17:1:43

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