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EDITORIALS: Paul E M Fine Non-specific "non-effects" of vaccination BMJ 2004; 329: 1297-1298 [Full text]

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Vaccines do have nonspecific (heterologous) effects

Frank Shann   (5 December 2004)

Sex-differential ”non-effects” of vaccination

Peter Aaby, Christine Stabell Benn, Ida Maria Lisse, and Henrik Jensen   (21 December 2004)

Diphtheria-tetanus-pertussis vaccination in low-income countries: improved child survival or survival bias?

Henrik Jensen, Christine S. Benn, Jens Nielsen, Ida M. Lisse, Amabelia Rodrigues, and Peter Aaby   (16 February 2005)

Vaccines do have nonspecific (heterologous) effects 5 December 2004
Frank Shann, Director of Intensive Care Royal Children's Hospital, Melbourne 3052, Australia Send response to journal: Re: Vaccines do have nonspecific (heterologous) effects	I strongly support Professor Fine’s plea that we review the optimal immunisation schedule in developing countries using evidence from controlled trials rather than observational data (1). It is of great concern that there are almost no controlled trials of the effect on mortality from all causes for any of the vaccines in the WHO schedule. The title of Professor Fine’s editorial claims that literature does not support nonspecific effects of vaccines – this is incorrect. First, as Professor Fine points out, BCG protects against leprosy, and it is also the treatment of choice for some types of bladder carcinoma (2); these are clearly nonspecific effects. Second, there is now strong experimental evidence that an individual’s history of previous infection or immunisation may influence the response to subsequent infections, and much is now known about the immunology of this phenomenon – which immunologists call heterologous immunity, rather than nonspecific immunity (3). Third, the evidence that vaccines have nonspecific effects is not all from "observational studies comparing non-comparable populations". I have recently summarised the evidence from randomised controlled trials and twin studies that vaccines alter mortality from non-target diseases in girls (4). Professor Fine points out that it is important to be clear about what is meant by the hypothesis that vaccines have heterologous (nonspecific) effects. Let me state the hypothesis: [1] in communities where many children die from infections, vaccines may affect mortality from diseases other than the target disease (for example, measles vaccine may reduce mortality from infectious diseases other than measles); [2] these effects are much stronger in girls than boys; [3] they are strongest in the first 3-6 months after immunisation; and [4] they are largely determined by the most recent vaccine received. The discovery of heterologous immunity is potentially a major medical advance that could save many thousands of children. It is very important that epidemiologists consult with immunologists who are working on the molecular biology of heterologous immunity, and then design controlled trials to determine the optimal immunisation schedule for children in developing countries. 1. Fine PEM. Non-specific “non-effects” of vaccination: literature does not support either beneficial or detrimental effects. BMJ 2004;329:1297-8. 2. Parfitt K. Martindale: the complete drug reference. 32nd ed. London: Pharmaceutical Press, 1999:1504-6. 3. Welsh RM, Selin LK. No one is naïve: the significance of heterologous T-cell immunity. Nat Rev Immunol 2002;2:417-46. 4. Shann F. Heterologous immunity and the nonspecific effects of vaccines: a major medical advance? Pediatr Infect Dis J 2004;23:555-8. Competing interests: None declared
Sex-differential ”non-effects” of vaccination 21 December 2004
Peter Aaby, professor Bandim Health Project, Statens Serum Institut, Apartado 861, Bissau, Guinea-Bissau, Christine Stabell Benn, Ida Maria Lisse, and Henrik Jensen Send response to journal: Re: Sex-differential ”non-effects” of vaccination	We welcome professor Fine´s plea for more data from randomised studies of the routine immunizations programmes in low-income countries (1). However, WHO Task Force has recently claimed such studies to be unethical (2). If we at the same time completely dismiss observational studies, we might be left with no way of evaluating the impact of routine immunizations. We will argue that observational studies can be an important source of new information. Obviously, using problematic data with selective misclassification hardly provides assurance of no association between vaccine and increased mortality in infants (1,3). However, well performed observational studies which control the bias inherent in observational studies and utilise the occasional unplanned experiments as when a new vaccine is introduced (4,5), there is shortage of a vaccine (6), no vaccination during a war (7), or when vaccines are given out of sequence (8) can provide important information and generate new intriguing hypotheses. In the process of conducting such observational studies, we found that live vaccines may be more beneficial for girls than for boys in areas with high-mortality whereas the opposite seems to be the case for inactivated aluminium-based vaccines (4,5,7-10). Hypotheses may be cheap to manufacture but difficult to test, as emphasized by Fine (1), and we have therefore used the last couple of years to test this idea in very different settings: during a war (7), among female-male twin pairs (9), at paediatric ward (10), and at the introduction of a new vaccine (5). These studies all supported that vaccines have sex-differential effects. Furthermore, these observations generated a new interpretation of the increased female mortality in the high-titre measles vaccine (HTMV) trials. HTMV had been given early at 4-5 months of age and DTP and IPV administered after HTMV were associated with increased female mortality (8). The advantage of focusing on sex-differential effects of vaccinations in countries with similar age and coverage of vaccination for boys and girls is that these effects cannot be dismissed as likely due to the confounding effect of parental education, occupation, economic status and the like. This is particularly so if different vaccines have opposite effects for boys and girls. There is no indication of strong sex- differences in mortality in infancy in the pre-vaccination era (9). Hence, if vaccines have strong sex-differential effects, beneficial or detrimental non-specific effects of vaccines must be important. Whether these effects are beneficial or detrimental they should obviously be examined by the public health community in controlled studies to take advantage of a beneficial effect or limit a negative impact. Peter Aaby, Christine Stabell Benn, Ida Maria Lisse, Henrik Jensen Bandim Health Project, Danish Epidemiology Science Centre/Statens Serum Institute, Apartado 861, Bissau, Guinea-Bissau; psb@mail.gtelecom.gw References 1. Fine P. Non-specific “non-effects” of vaccination. BMJ 2004;329:1297-8. 2. WHO Task Force on Routine Infant Vaccination and Child Survival. Report of a meeting to review evidence for a deleterious effect of DTP vaccination on child survival. London, 2004. www.who.int/vaccine_safety/topics/dtp/en/taskforce_report.pdf (accessed 20 Dec 2004) 3. Vaugelade J, Pinchinat S, Guielle G, Elguero E, Simondon F. Lower mortality in vaccinated children: follow up study in Burkina Faso. BMJ, doi.:10.1136/bmj.38261.496366.82 (published 18 November 2004) 4. Aaby P, Jensen H, Gomes J, Fernandes M, Lisse IM. The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea- Bissau: An observational study. Int J Epidemiol 2004,33:374-80 5. Garly ML, Jensen H, Martins CL, Balé C, Balde MA, Lisse IM, Aaby P Hepatitis-B vaccination may be associated with an increased female mortality in Guinea-Bissau: An observational study. Pediatr Inf Dis J (in press) 6. Aaby P, Rodrigues A, Biai S, Martins C, Veirum JE, Benn CS, Jensen H. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine 2004;22:3014-7 7. Aaby P, Garly ML, Balé C, Martins C, Lisse I, Jensen H. Routine vaccinations and child survival in war situation with high mortality: effect of gender. Vaccine 2002;21:15-20 8. Aaby P,Jensen H, Samb B, Cisse B, Sodeman M, Jakobsen M, Poulsen A, Rodrigues A, Lisse IM, Simondon F, Whittle H. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: a re-analysis of the West African studies. Lancet 2003;361: 2183-88 9. Aaby P, Jensen H, Rodrigues A, Garly ML, Benn CS, Lisse IM, Simondon F. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol 2004;33:367-73 10. Veirum JE, Sodemann M, Biai S, Jakobsen M, Hedegaard K, Jensen H, Aaby P. Diphtheria-tetanus-pertussis and measles vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine (in press) Competing interests: None declared
Diphtheria-tetanus-pertussis vaccination in low-income countries: improved child survival or survival bias? 16 February 2005
Henrik Jensen, Statistician Danish Epidemiology Science Centre, DK-2300 Copenhagen S, Christine S. Benn, Jens Nielsen, Ida M. Lisse, Amabelia Rodrigues, and Peter Aaby Send response to journal: Re: Diphtheria-tetanus-pertussis vaccination in low-income countries: improved child survival or survival bias?	We suggested that BCG and measles vaccine have non-specific beneficial effects whereas diphtheria-tetanus-pertussis (DTP) vaccination might have no beneficial effect1. In response, WHO commissioned several studies2-4. A WHO expert Task Force found substantial evidence against a deleterious effect of DTP, all studies showing DTP to be associated with reduced mortality. A negative DTP effect was only found in Guinea-Bissau and was suggested to be due to a country-specific issue or a peculiarity of the data5.   In our survival analysis1, vaccination status was a time-fixed variable, held constant from the initial visit to the next; without perfect information for all children, vaccinations during follow-up could not be accounted for, and is a potential source of bias. In the WHO-sponsored analyses, vaccination status was a time-varying variable changing status at the date of vaccination based on information achieved at a subsequent visit2-5. We re-analysed our data1 using this approach (Table). The distribution of deaths was similar. Using time-varying variables, person-years decreased for the unvaccinated and BCG groups, and mortality went up. Person-years increased for the DTP groups and mortality decreased. Hence, DTP was associated with reductions in mortality (Table) similar to results from WHO-sponsored studies2-4.    Why this difference? Information on vaccinations is typically collected through periodic home visits. When a child dies, the vaccination card is usually thrown away; hence vaccination information is collected conditionally on survival to the subsequent visit. If an unvaccinated child was vaccinated and died before the next visit the death would be classified as unvaccinated, in an analysis using time-varying variables. If a vaccinated child survived, its follow-up time as vaccinated would be moved to the new vaccination. This survival time is risk-free – that is, we only know that the child was vaccinated because it survived. Such survival bias may turn a negative estimate into a positive one: our original 84% increase in mortality for one dose of DTP1 became a 32% reduction (Table).   Survival bias can only be avoided if all vaccinations are provided by the researchers, or perfect vaccination information is obtained from all children. There is nothing to indicate that these conditions were met in the WHO-commissioned studies2-4 . In contrast to our study 1, none of the WHO studies documented which children were unvaccinated; they do not distinguish between “unvaccinated” and “no information”. In conclusion, the contradiction between our study1 and the WHO-sponsored studies might be due to methodological differences and not peculiarity of the data.   References 1)      Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-8 2)      Lehmann D, Vail J, Firth MJ, de Klerk NH, Alpers MP. Benefits of routine immunisations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea. Int J Epidemiol 2005;34:138-148. 3)      Breiman RF, Streatfield PK, Phelan M, Shifa N, Rashi M, Yunus M. Effect of infant immunization on childhood mortality in rural Bangladesh: analysis of health and demographic surveillance data. Lancet 2004; 364:2204-11 4)     Vaugelade J, Pinchinat S, Guielle G, Elguero E, Simondon F. Lower mortality in vaccinated children: follow up study in Burkina Faso . BMJ 2004;329:1309-11. 5)      Global Advisory Committee on Vaccine Safety. Weekly Epidemiological Record 2004; 79:269-72.   Table: Deaths and person-years according to vaccination group using vaccination status as time-fixed or time-varying variable.  Bissau 1990-1996.   Vaccination status Vaccination status as time-fixed variable Vaccination dates as time-varying variables Deaths PYRS* Rate** Deaths PYRS Rate No BCG DTP 1 dose 2 9.0 222 2 16.3 123 No BCG DTP 2 doses 0 4.5 0 0 3.5 0 No BCG DTP 3 doses 0 1.4 0 0 4.2 0 BCG No DTP 33 537.6 61 33 334.4 99 BCG DTP 1 dose 59 595.5 99 60 679.5 88 BCG DTP 2 doses  21 266.6 79 20 443.4 45 BCG DTP 3 doses 12 119.6 100 15 425.0 35 Vaccinated 127 1534.2 83 130 1906.3 68 Unvaccinated 95 875.1 109 92 503.0 183 All 222 2409.3 92 222 2409.3 92 Mortality ratios     Unvaccinated vs. vaccinated 1.35 (0.97-1.89) 2.96 (2.15-4.08) BCG vs. BCG-unvaccinated 0.55 (0.36-0.85) 0.62 (0.41-0.92) DTP 1 vs. DTP-unvaccinated 1.84 (1.10-3.10) 0.68 (0.44-1.04) DTP 2 vs. DTP-unvaccinated   1.38 (0.73-2.61) 0.26 (0.15-0.47) DTP 3 vs. DTP-unvaccinated 0.16 (0.08-0.32)                                                 * Person years at risk     ** Mortality rate per 1000 person years. Competing interests: None declared