Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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WHO response to Guinea-Bissau report
- Peter I Folb (8 December 2000)
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BCG vaccination
- M H Moraleda (9 December 2000)
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Re: WHO response to Guinea-Bissau report
- Tedd Koren (9 December 2000)
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Re: Re: WHO response to Guinea-Bissau report
- John P Heptonstall (13 December 2000)
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Response to WHO
- Peter Aaby, Henrik Jensen (13 December 2000)
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Non specific effects of vaccines in wealthy countries
- Michel Odent (14 December 2000)
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Vaccination and child survival in the developing world: lessons from the Guinea Bissau studies
- Kim Mulholland, Mauricio L Barreto (15 December 2000)
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Re: Vaccination and child survival in the developing world: lessons from the Guinea Bissau studies
- John P Heptonstall (17 December 2000)
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Vaccination and autism/bowel problems
- Lisa Blakemore-Brown (20 December 2000)
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Selection bias and lack of information about causes of death make interpretation of study difficult
- Liratsopulos Georgios (21 December 2000)
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Routine vaccinations and child survival
- Lorna Barton (4 January 2001)
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Re: Vaccination and autism/bowel problems
- Zubair Kabir (5 January 2001)
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Cause-effect relationship: a matter of belief or judgment?
- Zubair Kabir (10 January 2001)
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Non-specific effects of vaccinations: lacking gradient, strength, and coherence?
- Peter Aaby, Henrik Jensen (10 January 2001)
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Routine vaccinations and child survival: Authors' response
- Peter Aaby, Henrik Jensen (10 January 2001)
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Vaccination and immune balance
- Alastair Sammon (15 January 2001)
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DTP Vaccine or Poison?
- John Fryer (19 March 2001)
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Routine vaccinations and child survival: effect of gender
- Peter Aaby, Henrik Jensen (13 December 2002)
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Peter I Folb, Professor of Pharmacology at UCT and Director of WHO Collaborating Center for Drug Policy, University of Cape Town, RSA.
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To the Editor, The paper by Kristensen et al. in the December 9 issue of the BMJ (1) challenges the safety of DTP, one of the principal vaccines used by national immunization programmes. The authors shared their study results with the World Health Organization prior to publication and they cooperated in allowing a WHO review of the field sites in Guinea Bissau and of the data bank in Copenhagen. The Global Advisory Committee on Vaccine Safety of the WHO, comprising an independent group of experts in drug safety, vaccine science and epidemiology, which serves in an advisory capacity to the Department of Vaccines and Biologicals of the WHO has given close consideration to the reported findings and conclusions of the Kristensen paper. The members of the committee have concluded that numerous and serious deficiencies in the paper did not allow them to reach the same definitive conclusions reached by the authors. In particular, the reported observations are incomplete and do not tally, no systematic effort has been made to address the likelihood of bias introduced by the data collection method that was applied, and categorical inferences have been drawn from data that are either not statistically significant or are critically dependent on a very small number of results that might equally be explained by chance. As well, the probability of the results being distorted by confounding factors has not been adequately addressed. The analysis was data driven and not based on a priori generation of a hypothesis, which makes interpretation of significance values and confidence limits problematic. The conclusions of this paper need to be given the same level of scrutiny as adverse events mistakenly attributed to DTP vaccine in the past. The Vaccine Safety Advisory Committee is due to meet with the authors on 21st December 2000 at WHO headquarters in Geneva to discuss the committee’s concerns with the study and its conclusions. It is important that the safety and impact of current immunization schedules should be studied, particularly in high-risk situations. WHO is committed to giving support to investigators, including to the authors of the BMJ article, to conduct such work in a robust manner. We emphasize that no change is warranted in current policy with regard to immunization practices including BCG, DTP, oral polio and measles vaccines in national immunization schedules. PI Folb (chair)
Reference 1. Kristensen I, Aaby P, Jensen H. Routine vaccination and child survival: follow up study in Guinea-Bissau, West Africa.. British Medical Journal 2000;321:1435-1439. |
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M H Moraleda, Staff physician Veterans Affairs Medical Center
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BCG supposedly offer some protection against tuberculosis though in a limited way. The problem with BCG vaccination is that BCG vaccinated individuals become positive to tuberculin skin testing and are conveniently grouped with those who are truly exposed to mycobacterium tuberculosis. This becomes a problem in employees health screening and monitoring. |
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Tedd Koren, Private practice Phialdelphia, PA
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To the editor, I have a number of comments on the above referenced paper. The authors write: "Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated...However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines." Am I missing something? These statements appear contradictory. Be that as it may, in a later paragraph we may find another reason why some vaccinated children had decreased mortality - they were better cared for, had higher weights, their mothers could attend to them with fewer distractions and they were born in a cleaner setting: "We examined differences in background factors for vaccinated and unvaccinated children controlling for age and cluster...Vaccinated children had more contact with the health system, their mothers being more likely to have received tetanus vaccination during pregnancy and to have given birth outside the home. Vaccinated children had larger arm circumference and their mothers tended to be younger and have fewer children, to have a latrine in their compound..." This is obvious selecion bias. Another example is given in discussing why the BCG vaccinated children had less death. The larger, presumably stronger babies were vaccinated while the smaller, presumably weaker babies weren't vaccinated: "Since children weighing less than 2500 g are not supposed to receive BCG, unvaccinated children could represent a negatively selected group." A question to the authors: Were the babies vaccinated with Measles also given Vitamin A which is often done in 3rd world countries? I question whether this paper shows improved mortality for vaccinated babies versus unvaccinated babies, if selection bias is accounted for. |
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John P Heptonstall, Director of the Morley Acupuncture Clinic and Complementary Therapy Centre West Yorkshire
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Editor I, like Tedd Koren, was bemused by the two contradictory passages in the article; how does one reconcile the statement "lower mortality in group vaccinated with any vaccine compared to those unvaccinated" with "DTP and polio vaccines were associated with higher mortality compared with no vaccination"? This ought to gain the attention of any serious reader. I continued to analyse the report and found more apparent inconsistensies. Are these subtle diversions, calculated measures to limit the impact of the real findings, or a naive attempt to put together a meaningful write-up of what appears to have been a very complicated and inconsistent follow-up in complex cohorts? Certainly, the finding that DTP and Polio vaccines are probably killing more children than they are saving should have realised a stronger political response from government health watchdogs, who appear strangely quiet. The report reminds us that the WHO recommends DTP and Polio vaccination in areas of high child mortality to save 1.5% to 2.0% of childrens'lives. Well it appears that they are actually killing these children off more rapidly with said vaccines; in cases where BCG is also provided the familes can now rest assured that their children will be less likely to be killed by DTP and Polio shots, but woe betide those poor kids who don't get their BCG shot - they are more likley to die than if completely unvaccinated! Now what about our children? They do not receive their 'protective' BCG shots until they are young teenagers. They are at the mercy of DTP and Polio shots at an early age. Are they also being killed off more quickly by these vaccines, as many parents believe, or is Guinea-Bissau so far away our kids are untouched by the same findings? Paul Fine's comment that "the findings reported here are not convincing in themselves, though they would be important if true" suggest a man delaying the inevitable. Nowhere does he say that DTP and polio shots should be suspended until further data can be gained to establish the truth, or that proves them to be safe. In light of all the adverse publicity vaccines have received in recent years, particularly DTP with SIDS, epilepsy and other serious ADRs, I would have expected he demand, on behalf of the public, a more precautionary stance. Table 4 suggests that all kids up to 6 months of age who are vaccinated with one dose of DTP, and do not receive a BCG, are more than twice as likley to die than those who refuse vaccination. The WHO's saving of 1.5 to 2% from deaths due to D, T or P, rather pales to insignificance with such figures does it not? Ironically, BCG protection only enhances the survival for children who receive one dose of DTP to the 'unvaccinated without BCG' status (4.7% mortality). So a child might as well have neither BCG or DTP if wishing to have a normal survival chance (4.7% mortality). If the child wishes to have a greater chance of survival, to 5 years old, in Guinea-Bissau the BCG shot seems a good idea, the survival chance jumps to almost double (2.87% mortality). As it is many of these children are being robbed of survival opportunities by being given DTP, without BCG, with resultant 10.5% mortality! (Table 4). A word of caution, if you are between 4 and 6 months old when given the BCG shot you may reduce your survival chance below that of the unvaccinated (mortality drops from 4.8 for BCG vaccinated to 4.3 for unvaccinated children of this age) Table 3. This 'blip' is neatly covered up by a 'Total' which gives the the BCG shot a more 'all round' friendly perspective. According to the authors, their study echoes the findings of the Senegal study where DTP mortality was 1.57, and the Benin study where 74 died after DTP shots (2.20 odds ratio). How many studies does it take before responsible medical people are prepared to call for removal of an obviously dangerous group of vaccines? The study tells us nothing of morbidity, yet from parents worldwide we are hearing of serious adverse reactions to these very vaccines, granted many reports are anecdotal, but these are echoes of a reality that is mirrored in said studies. The report mentions hundreds of children who were 'lost' to follow up as they had died. The increased death rates were obbviously enhanced by DTP and polio shots. There is no information as to which childrens' deaths may have been, through professional dignosis, associated with suspected 'ADRs' to DTP or polio shots. What did the 'lost' children die of, haemorrhage, seizure, SIDS, meningitis, encephalitis? One has a very real cohort through which analysis of data could suggest how and why DTP and polio shots are so dangerous to children. Those having regular shots are said to be more likely to have been subjected to regular medical intervention so death reports should contain useful data for such a study. A 'follow-up' study with this in mind would be most valuable. The most sensible outcome is that DTP and polio shots are withdrawn from public use until a safer alternative can be provided while a follow- up study of the 'death by DTP and polio' children can identify (through autopsy where possible) in what way their deaths were caused by the shots. SIDS deaths are related to DTP shots in figures from the USA Vaccine Adverse Events Reporting System study group as well as in FDA data. Some parents accused of 'Shaken Baby Syndrome' swear their children died of adverse reactions to vaccines; it is often DTP and polio shots that are cited. The main age range for SIDS and SBS are coincident, they are also coincident with the DTP and polio vaccination schedule. One concern for a follow-up study may be that, should analysis of Guinea-Bissau childrens' deaths be performed, the parents of all those whose deaths occurred coincident with brain haemmorrhage, soon after vaccination, could then be accused of murdering these children, as so often seems to be the case in the UK, USA and Australia. Regards John H. |
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Peter Aaby, Bandim Health Project Bissau, Guinea-Bissau, Henrik Jensen
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Our observations in Guinea-Bissau may have far-reaching implications (1), and it is therefore important to see whether they can be replicated by other investigators. Because of this, we have collaborated fully with WHO, and allowed the Organisation full access to the study site in Guinea- Bissau and the original data. A WHO epidemiologist reviewed the study design and statistical analyses in Copenhagen, and concluded that our results were based on sound statistical and epidemiological methods. In addition, WHO appointed three reviewers who visited the study site in Guinea-Bissau - they concluded that the study was well conducted and internally consistent. In view of our cooperation with WHO, we are surprised of Professor Folb's letter and the statement on WHO's website (2,3). These responses seem to reject the findings of WHO's own reviewers and make serious but unsubstantiated criticisms of our study. The accusation that our observations are incomplete and do not tally implies incompetence or fraud. If Professor Folb and the WHO Global Advisory Committee on Vaccine Safety care to publish their critique in the BMJ, we will be pleased to answer the criticisms. Professor Folb criticises our study for having no a priori hypothesis. However, the importance of the non-specific effects of vaccines has been evident since the early 1990s, when it was found that girls given high doses of measles vaccine had a higher mortality than girls given the standard dose (4,5). Further evidence that measles vaccine reduces mortality from diseases other than measles was published in 1995 (6). BCG vaccination was found to be associated with reduced mortality from pneumonia in 1992 (7). The association of diptheria-tetanus -pertussis (DTP) vaccine with increased mortality was reported in 1991 and 1995 (6,8). Our recent studies from Senegal (6) and Guinea-Bissau (1), have found that the non-specific effects of vaccines are stronger in girls than boys - the remarkable consistency of this finding with our previous observations on high-titre vaccines (4,5) increases the probability that vaccines do indeed have important non-specific effects on immunity. As pointed out in our paper (1), trials of the non-specific effects of routine immunizations cannot be conducted. When observations are made that cannot be tested by randomised controlled trials, there are two important considerations. First, is the observation consistent with what is known at the time? Second, can it be replicated by other studies? Our observations are consistent with the previously published studies of the non-specific effects of individual vaccines on total mortality, and Prof Folb provides no information that contradicts these studies (1,4-8). Our finding that DTP may have adverse effects in high mortality areas has worrying implications for the Expanded Programme on Immunisation (EPI). We therefore welcome Prof Folb's assurance that WHO intends to support further studies of the effect of immunisation in high-risk populations. There is an urgent need for such research. Peter Aaby, Henrik Jensen
References 1. Kristensen, I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-1439 2. Folb PI. WHO response to the Guinea-Bissau report. eBMJ-eLetters for Kirstensen I, Aaby P, Jensen H, BMJ 2000;321:1435-39 3. WHO, Routine vaccination and child survival: questions and answers. Available from: URL: http://www.who.int/vaccines- diseases/safety/hottop/routvaccine.htm 4. Aaby P, Knudsen K, Whittle H et al. Long-term survival after Edmonston-Zagreb measles vaccination: increased female mortality. J Pediatr 1993;122:904-8 5. Aaby P, Samb B, Simdonson F et al. Sex specific mortality after high titre measles vaccines in rural Senegal. Bull WHO 1994;72:761-70 6. Aaby P, Samb B, Simondon F et al. Non-specific beneficial effects of measles immunization: analysis of mortality studies from developing countries. BMJ 1995;311:481-485 7. Niobey FML, Duchiade MP, Vasconcelos AGG, de Cavalho ML, Leal MC, Valente JG. Fatores de risco para morte por pneumonia em menores de um ano em uma região metropolitana do sudeste do Brasil. Un estudo tipo caso- controle. Rev Saúde Públ, São Paolo 1992; 26: 229-238=20 8. Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality among users and non-users of primary health care in a rural West African community. Int J Epidemiol 1991;20:474-79 |
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Michel Odent, Director Primal Health Research Centre. London NW3 2NP
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There are striking similarities between the results of the study by I Kristensen and colleagues(1) and the results of our three-step inquiry in wealthy countries, although child survival cannot be used as a criteria of health in Western Europe. We first analysed criteria of health in a population of 446 children (mean age 8 years) who were homogeneous in terms of infant feeding (all of them had been breasfed more than a year and had received only breastmilk during the first 6 months). None of them had received BCG in infancy. In this particular population there were significant differences when classifying the children according to pertussis vaccination(2). When presenting the results we focused on pertussis vaccination (always associated with diphteria and tetanus) as a risk factor for asthma in childhood. In fact there were significant differences when other criteria of health were considered (rates of ear infection, number of days spent in hospitals)(3). In the second and third steps of our inquiry we compared British and French pupils of Rudolf Steiner schools, who share the same "anthroposophical" lifestyle (BCG is routinely given in France, but not in Great Britain). We came to the conclusion that BCG has positive non specific effects on health(4). In particular it appeared that BCG probably protect pertussis-immunised children against asthma. Today it would be ethical to start long term prospective randomised studies of the non specific effects on health of different combinations of vaccines in infancy. References: 1- Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000; 321: 1435-9. 2- Odent MR, Culpin EE, Kimmel T. Pertussis vaccination and asthma: is there a link? JAMA 1994; 272: 592-93. 3- Odent MR. Long term effects of early vaccinations. Primal Health Research Newsletter 1994; 2 (1): 3-7. 4- Odent MR. Future of BCG. Lancet 1999; 354: 2170. |
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Kim Mulholland, Professors Dept. of Paediatrics, Univ. of Melbourne, Australia and Inst. de Saude Coletiva, UFBa, Brazil, Mauricio L Barreto
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Sir, The paper by Kristensen et al. in the current edition of the BMJ (1) describes improved survival in Guinea Bissau infants who received measles or BCG vaccines, but increased mortality in those who received DTP vaccine. At the request of WHO we visited Guinea Bissau between October 8 and 15, 2000 to review this study. We found the methodology for the study to be as it is described in the paper. As data collection is continuing, we were able to accompany the field staff on several visits. We reviewed the data management procedures and found them to be in order. While several potential source of bias could be hypothesised we were not able to identify any one that could invalidate the study. This is a single study, which was not originally designed to address this issue, and there are methodological weaknesses that have been highlighted in the accompanying editorial and commentary. By its characteristics and its surprising findings it should provoke substantial further investigation of the subject. While these result should not be used as a basis for changing national or global vaccination policy, this is a matter for concern demanding an immediate response. The first response it to seek out data from other developing countries that may be used to address this question. It is possible that other studies may not show the same findings in relation to DTP, in which case the particular circumstances of Guinea- Bissau should be considered. In that country, at the time of the study, 25 -30% of all children died before their 5th birthday, most from malaria or pneumonia although this has not been well studied. Of particular interest therefore will be the analysis of data from other high mortality settings with intense malaria transmission. Regardless of the outcome of the ongoing investigations, the work of in Guinea-Bissau highlights the importance of considering the overall impact of vaccines on children's health. In that respect the finding that measles and BCG appear to improve survival beyond what can be attributed to the prevention of those specific diseases is particularly good news that should stimulate similar studies in other areas. There are broader lessons to be learned from the publication of this study. Public health research to support public health interventions is not a luxury, but a necessity. The overall impact of routine childhood vaccines on survival in high mortality settings has not been evaluated systematically. We should learn from this omission and ensure that in the future all public health interventions are underpinned by the appropriate public health experimental and observational research to ensure that they are both safe and efficacious. Dr. Kim Mulholland, Professor, Department of Paediatrics, University of Melbourne, Australia.(email mulhollandek@hotmail.com) Dr. Mauricio L. Barreto, Professor, Instituto de Saude Coletiva, Federal University of Bahia, Salvador-Bahia Brazil (email: mauricio@ufba.br). Reference 1. Kristensen I, Aaby P, Jensen H. Routine vaccination and child survival: follow up study in Guinea-Bissau, West Africa.. British Medical Journal 2000;321:1435-1439. |
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John P Heptonstall, Director of the Morley Acupuncture Clinic and Complementary Therapy Centre West Yorkshire
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Editor Drs Mulholland and Barreto's comments are reassuring inasmuch as the authors' work was reviewed and found to be accurate and valid. I'm not sure what to make of the way the 'WHO reviewing team' appear to readily dispose of the drastic news about DTP and polio vaccines whilst referring to results from BCG and measles 'good news'. I would have preferred to see a more balanced reference DTP and polio results as 'bad news'; their apparently qualifying ramble about 'high mortality' and '25- 30% deaths before 5 yrs old through possibly malaria or pneumonia' seemed out of place in reference to DTP and polio results - was this expected to somehow modify the DTP/polio results? How about something like.. ..."measles and BCG appear to improve survival beyond what can be attributed to the prevention of those specifying diseases, this is good news" ..."DTP and polio appear to reduce survival beyond what can be attributed to the effects of those specifying diseases is bad news, this is bad news" I'm astounded at the media hush surrounding bad news that appears consistent with many parents' fears about DTP, and polio vaccines, especially in relation to SIDs and SBS, let alone epilepsy, asthma and other serious known ADRs. Regards John H. |
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Lisa Blakemore-Brown, UK Psychologist Independent
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For many years I have trawled through vast amounts of data on each and every child assessment I undertake. It took very little time before I realised that a small percentage of children had been affected by vaccine. In some cases the effect was dramatic and immediate. In others a gradual falling away of communication skills and an emergence, in some cases, of bowel problems. In a few startling cases video evidence showed a perfectly normal child the day before the vaccination - never to return. If a child swallows a noxious substance and then falls over or is sick, we would not dismiss the most obvious event which had just occurred as being possibly linked with the child's behaviour. In the children with autism who appear to have regressed and /or developed allergies and bowel problems after the vaccination, it was also clear that those children had been medically vulnerable children before the vaccine and /or children with allergies, say, to dairy products. There has been a vast increase in numbers of children with such presenting problems since the MMR, in particular, was introduced, but it is likely that these children are few in number compared to the whole child population who have been vaccinated, my heightened awareness more likely given that I specialise in autism. An open an honest approach by the Government would be far less likely to jeopardise the vaccination programme than ignoring what is a very real and increasingly obvious problem for many desperate families who have `lost ` their children to autism after vaccine. Recognising which children are vulnerable, whether the triple vaccine is actually viable and whether it is necessary to have 3 shots which could compromise the immune system just at the point in time when a child is developing a complex tapestry of cognitive skills, are surely reasonable questions to raise in a civilised society? |
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Liratsopulos Georgios, SpR in Public Health Medicine Dept of Public Health, Wigan and Bolton Health Authority, Bryan House, 61 Standishgate, Wigan, WN1
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Editor-In Guinea-Bissau, Kristensen et al.(1) followed up young children to determine rates of mortality associated with administration of BCG, DTP, polio and measles vaccines. A combined analysis for any vaccine, or BCG or measles vaccine was associated with lower mortality, compared with children not given these vaccinations. However, DTP or polio vaccines were found to increase mortality. Out of 10298 (see extended e-bmj version) children born alive, 686 children had died by the time that the field visits took place and so were not included in the study. This means that 6.6% of the total cohort of children (accounting for 49% of the total of 1438 deaths observed) were excluded from the analysis. As BCG, polio and DTP vaccines are scheduled to be given from birth and up to the age of 14 weeks, some (but not all) of these 686 children would have had at least one of these vaccinations. Not accounting for the likely differential effect of the vaccination status of these 686 children introduces selection bias and makes it difficult to reach firm conclusions from this study. Furthermore, no information is provided about the cause of death in children who died during the follow up period. This information can help to substantiate or refute the hypothesis that administration of, for example, DTP is associated with increased mortality. Although definitive diagnoses are unlikely to have been possible in the setting of the study, a syndromic categorisation of death causes (for example, "diarrhoeal" or "febrile illness", "acute respiratory infection") with which primary health care workers in developing countries are familiar would have been possible. This is particularly the case since the investigators are experienced with the "verbal autopsy" technique, which they used to ascertain cause of mortality of maternal deaths among the same cohort of mother-child pairs(2). We argue that the methodological problems we have raised make the correct interpretation of the study findings problematic but would welcome future robust research about the likely non-specific effects of vaccination. Georgios Liratsopulos, SpR in Public Health Medicine Roger Harrison, NHS Research Fellow Marian O'Donnell M, SpR in Public Health Medicine Robert Aston, Consultant in Communicable Disease Control Dept. of Public Health Medicine, Wigan and Bolton Health Authority, Bryan House, 61 Standishgate, Wigan, WN1 1AH 1. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow-up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-1438. 2. Hoj L, Stensaballe J, Aaby P. Maternal mortality in Guineal- Bissau: the use of verbal autopsy in a multi-ethnic population. |
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Lorna Barton, Medical Student Medical School, University Of Newcastle Upon Tyne
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Editor, Kristensen et al.’s (1) prospective cohort study of the effect of childhood vaccinations on survival could have significant implications on future immunisation programmes in developing countries. The conclusion that "recipients of one dose of DTP or polio vaccines have higher mortality than children who receive none of the vaccines" appears alarming but should be approached with caution. We concur with the comments already made on the lack of comparability of the study groups, (2) the complexity of the methodology (3) and the small numbers involved in some groups. (4) We noticed a significant discrepancy in the number of women recruited for the study, which is stated as 10,000 in the introduction and methods and 15,351 in the abstract and results. Further contradiction lies in the two statements:"…there was no loss to follow up because it was always possible to get information on all children from relatives…" and "…information was unavailable for children who moved, died, or were travelling…". Such lack of clarity leads to further doubt over the actual numbers involved in the study. The causes of death are never discussed, as touched upon by Liratsopulos, G. (3). This is presumably due to such information being unavailable in Guinea-Bissau. Knowledge of this would add further dimension to results already drawn. Congenital diseases and accidents, for example, could be completely unrelated to the unspecific effects of vaccines. Despite issues raised here and by others, the study’s objectives were both original and worthwhile and its conclusions open doors for further research. Lorna Barton
Stage 3 medical students
(1) Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-9. (2) Fine P. Commentary: an unexpected finding that needs confirmation or rejection. BMJ 2000; 321:1439. (3) Liratsopulos, G. Selection bias and lack of information about causes of death make interpretation of study difficult. http://www.BMJ.com. (4) Folb, P. WHO response to Guinea-Bissau report. http://www.BMJ.com. |
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Zubair Kabir, RESEARCH OFFICER RESEARCH & EDUCATION INSTITUTE, CREST DIRECTORATE, ST JAMES'S HOSPITAL, DUBLIN 8, IRELAND
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Dear Editor I fully agree with Lisa (1) regarding the side-effects of vaccines such as autism occurring to a negligible proportions of children compared to the whole of child population vaccinated. This reminds me of the article published two years ago in the Lancet, which suggested that the MMR vaccine was linked to autism.(2) The same article was "blamed" for reducing the uptake in the United Kingdom from 90.4% to 87.6% as reported earlier.(3) The Irish National Disease Surveillance Centre today (the 4th of Jan) in its webpage said that 1597 cases of measles have been reported till 23rd of December 2000.(4) The Centre cannot say, however, whether the MMR vaccine uptake rate in Ireland has been influenced by the Lancet article. Nevertheless, parents in Ireland have been influenced by the "Best" case. The Supreme Court found in 1992 that Kenneth Best, a severely brain damaged adult, was affected by being given a dose from a toxic batch of pertussis vaccine. As a public health specialist, I believe that articles published such as Kristensen et al(5) should be interpreted with caution to reinforce faith in the general public. Further studies examining cause-effect relationship and measuring the strength of associations such as population attributable risk percent between vaccination and child survival in the populations are necessary before drawing such conclusions. Regards,
References 1. Brown L. Vaccination and autism/bowel problems. http://www. BMJ.com 2. Wakefield AJ, Murch SH, Anthony A et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet 1998; 351: 637-41. 3. Report on Measles. National Disease Surveillance Centre Ireland. http://www.ndsc.ie. 4. Payne D. Ireland's measles outbreak kills two. BMJ 2000; 321: 197. 5. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000; 321: 1435-9. No competing interests. |
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Zubair Kabir, Research Officer Research & Education Institute, Crest Directorate, St James's Hospital, Dublin 8, Ireland
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Dear Editor, To my mind, Paul Fine's (1) comment of "not convincing" at the findings of Kristensen et al is not in good taste in epidemiologic parlance. Nonetheless, he tried to analyze the validity of the associations examined in the article as well as commented at the "causality" of such associations.Making judgments about causality from epidemiologic data involves a chain of logic. The "classic" attributes of causality cited by Fine are mere "guidelines". In epidemiologic research, causation must always remain a matter of belief or judgment based on those guidelines. Such a judgment can only be made in the context of all evidence "available at that moment". Since what is considered "bilogically plausible" at any given time depends on the current state of knowledge, the lack of a known or postulated biologic mechanism as pointed out by Fine does not necessarily mean that a particular relationship is not causal. Examples may be cited to demonstrate that epidemiologic observations have sometimes preceded biologic knowledge as most of the epidemiologists of today are aware of. Thus, there must often come a point at which it becomes prudent to act on the premise that a causal relationship exists rather than await further evidence, which necessarily does not happen. In fact, acting on the judgment of proof beyond a reasonable doubt in a cause-effect relationship may well precede by years a complete understanding of the disease or its biologic mechanism. To conclude, Bradford Hill, who cautioned: "All scientific work is incomplete- whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. This does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time. Who knows, asked Robert Browning, but that the world may end tonight? True, but on available evidence most of us make ready to commute on the 8.30 next day." (2) Regards, Zubair Kabir References: 1. Fine P. Commentary: an unexpected finding that needs confirmation or rejection. BMJ 2000; 321: 1439. 2. Hill AB. The environment and disease: Association or causation? Proc. R. Soc. Med. 58: 295, 1965. No competing interests |
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Peter Aaby Bandim Health Project, Henrik Jensen
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In our study in Bissau, we found that different vaccines had opposite effects on mortality: BCG and measles vaccines reduced mortality, and diphtheria-tetanus-pertussis (DTP) and polio vaccines increased mortality. It would not have been ethical for us to randomise children to receive vaccine or placebo, so we had to perform a cohort study rather than a controlled trial. Hence, as we stated in the Discussion section of the paper, it is not possible to give precise estimates of the effect of the individual vaccines on mortality. We were therefore surprised that Professor Fine concluded that our study lacked the classical attributes of causality: gradient, strength, and coherence (2). As should be evident from the conclusion of the Abstract, we did not claim that our study had these attributes for each vaccine - our main conclusion was that the observed effects of the vaccines are unlikely to have been caused by confounding because selection bias should not produce opposite mortality trends for different vaccines. The strength of these trends should be the subject of future studies. Prof Fine gives several reasons for claiming lack of gradient, strength, and coherence. Firstly, the estimates only just reach conventional statistical significance. However, significance for each vaccine was not the focus of the paper. The important finding was that the trends in mortality were in opposite directions for BCG on the one hand, and DTP-polio on the other (see Table 3 in reference 1) - with the difference in trends being significant (p=0.005). Secondly, Prof Fine suggests that the association of BCG and measles vaccines with reduced mortality was surprising, and that it may have occurred because the mothers of vaccinated children make greater use of health services. He also suggested that the association of DTP with increased mortality could be due to DTP coverage being higher in the children of young mothers (who have increased mortality). In fact, Prof Fine should not have been surprised at these findings, as they have all been reported before: numerous studies have found that measles vaccine reduces mortality from diseases other than measles (3), BCG was found to be associated with reduced mortality from pneumonia in 1992 (4), and the association of DTP with increased mortality was reported in 1991 and 1995 (3,5). As stated in the paper, adjustment for the background factors listed in Table 2 had minimal effect on the estimates for the effect of the vaccines (1). Given the low prevalence of young mothers (Table 2), it is not surprising that the small increase in DTP coverage in the children of young mothers has only a trivial effect: the mortality rate ratio estimates for BCG, one dose of DTP, and two or more doses of DTP presented in the paper were 0.55 (0.36 to 0.85), 1.84 (1.10 to 3.10), and 1.38 (0.73 to 2.61), respectively; adjustment for mother's age gave estimates of 0.54 (0.35 to 0.84), 1.82 (1.08 to 3.07), and 1.37 (0.72 to 2.59), respectively. Thirdly, Prof Fine considers that the results are anomalous because mortality declines with age in BCG unvaccinated children, but increases with age among vaccinated children. This is true in Table 3, which compares BCG vaccinated and unvaccinated children, but not in Table 5, where mortality is declining with age for both measles-vaccinated and unvaccinated children (1). These findings are understandable if exposure to DTP does increase mortality. As seen in Table A, among children who survived to the second visit, exposure time to DTP and the number of DTP doses increased markedly with age in the BCG vaccinated group, whereas there was little change in the exposure time to DTP or number of DTP doses for children who had not received BCG prior to the first visit. The explanation for these patterns is presumably that children who have reached several months of age without receiving BCG are less likely to have contact with the health system, and are therefore less likely to receive additional doses of DTP during follow-up. On the other hand, when children have received BCG vaccine, the older they become, the longer they have had to be exposed to DTP.
Fourthly, Professor Fine finds it strange that the effect associated with one dose of DTP is not significant for two or three doses. Because fewer children received two or more doses of DTP, it is not surprising that the effect is not significant in these children. However, Prof Fine is presumably emphasising that the estimate of 1.84 (1.10 to 3.10) for one dose of DTP declined to 1.38 (0.73 to 2.61) for two or more doses of DTP - but the difference between these two estimates is not statistically significant (p=0.250). We did not discuss this issue because the main point of the paper was that BCG and measles vaccines on the one hand, and DTP-polio on the other hand, have opposite effects on mortality. However, we did mention in the Discussion that the mortality estimates were conservative due to interference from subsequent vaccinations during the period of follow-up (1). The children who received two or more doses of DTP were much more likely to receive measles vaccine before or during follow-up (51% - among children who survived to the second visit) than children who received only one dose of DTP (28%) or no DTP (13%). If follow-up is censored at 9 months of age to minimize the effect of interference from subsequent measles vaccinations, there is minimal difference between the estimates for one dose of DTP (mortality ratio 1.81, 95% CI 1.00-3.26) versus two or more doses of DTP (mortality ratio 1.75, 95% CI 0.86-3.59). Although we did not claim this in the paper, the non-specific effects of DTP-polio vaccination may well have had gradient, strength, and coherence in our study (1). As pointed out by Prof Fine, the DTP-polio effect was mainly measured among children who had already received BCG - this is to be expected in a developing country, where virtually all children get BCG as their first vaccine. We readily agree that a single study is not convincing, and that further studies of the non-specific effects of vaccines are needed - and this point was emphasized in the paper (1). It will be particularly important to see what happens when DTP- polio is used among children who have not received BCG. Peter Aaby, Henrik Jensen
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 -1438 2. Fine P. Commentary: an unexpected finding that needs confirmation or rejection. BMJ 2000, 321; 1439 3. Aaby P, Samb B, Simondon F et al. Non-specific beneficial effects of measles immunization: analysis of mortality studies from developing countries. BMJ 1995;311:481-485 4. Niobey FML, Duchiade MP, Vasconcelos AGG, de Cavalho ML, Leal MC, Valente JG. Fatores de risco para morte por pneumonia em menores de um ano em uma região metropolitana do sudeste do Brasil. Un estudo tipo caso- controle. Rev Saúde Públ, São Paolo 1992; 26: 229-238 5. Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality among users and non-users of primary health care in a rural West African community. Int J Epidemiol 1991;20:474-79 |
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Peter Aaby , Henrik Jensen
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Both Tedd Koren and John P. Heptonstall did not understand our statements that "Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated…However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines". Note that we wrote "none of these vaccines" rather than "no vaccine". Because virtually all children having received diphtheria, tetanus, pertussis and polio vaccines had already received BCG (see Table 4), the statement implies that among children who had received BCG, those who had been vaccinated with diphtheria, tetanus, pertussis and polio vaccines had a higher mortality than those who had received only BCG. The trend was the same among the few children who had received diphtheria, tetanus, and pertussis and polio vaccines but not BCG. However, the main effect was among children who had already received BCG as also pointed out in Paul Fine's commentary. Both Tedd Koren and the paper emphasised the possible selection biases which may have influenced the mortality ratios between vaccinated and unvaccinated children: these include better contact with the health care system, and restriction of BCG vaccination to children with normal birth weight. However, it is difficult to understand how selection bias would work differently for different vaccines. If one believes that mothers complying with the vaccination programme have children with lower mortality, the beneficial effect of BCG and measles may have been overestimated whereas the harmful effect of diphtheria, tetanus, pertussis and polio vaccines would have been underestimated. Conversely, if one believes that sick children are more likely to be vaccinated when their mothers bring them to a health centre, the beneficial effect of BCG and measles would have been underestimated and the harmful effect of diphtheria, tetanus, and pertussis and polio vaccines overestimated. While we discussed the likelihood of these interpretations in the paper, the main point was that the estimated effects of different vaccines went in different directions, and that the non-specific effects of the vaccines are therefore likely to be important. Only further research can clarify the relative importance of the different vaccines. Children were not given vitamin A at the time they were immunised against measles. Vitamin A has not been used for general supplementation in Guinea-Bissau until the recent war in 1998-1999 (1). John Heptonstall, Liratsopulos Georgios et al, and Lorna Barton et al. raised questions about the causes of deaths. Virtually all the children died from infectious disease, which presented with fever, malaria, convulsions, diarrhoea, oedema, inflammation, malnutrition, vomiting, cough, respiratory problems, tetanus, measles, or contaminated maternal milk (that is the mother had broken the taboo against having sexual relations while breastfeeding). Only one death may have been due to an accident (burns). However, it should be recognised that the vast majority were recorded only as having fever, so the precise cause of death is unclear in most cases. As pointed out by Dr. Georgios et al, we have done verbal autopsies for women of fertile age (2). It is, however, quite a different matter to do verbal autopsies for child deaths in an animistic culture, where many child deaths will be ascribed to malevolent spirits. It is impolite to recall the death of a child in the presence of the mother. It might have been possible to obtain better retrospective information on the sequence of events leading to a child's death using a medically qualified interviewer. However, such a study would be offensive to the mothers, and would not provide definitive information about the causes of death. The study was large and complex and many potential details have not been adequately covered even in the long version of the paper. Several readers raised questions about the follow up, including John Heptonstall and Liratsopulos Georgios et al. It is noted that 686 children had died before the first visit, and that these deaths constitute such a large proportion of the deaths in the study that the conclusions of the paper are questionable. We have probably assumed too much familiarity with mortality patterns in developing countries. We had indicated that there were 437 stillbirths in the cohort, and one would normally expect a similar number of neonatal deaths in a developing country. In the present study there were 525 neonatal deaths few of which could have been affected by immunisations, since most neonatal deaths occur on the day of birth. The remaining 161 infant deaths occurred before we visited the village. Using a Cox proportional hazard model and adjusting for cluster as in the paper, the mortality rate ratio between 1 and 6 months of age was 0.88 (0.69-1.12) for children not yet visited for the first time compared with mortality following the first visit. Liratsopulos Georgios et al are saying "Not accounting for the likely differential effect of the vaccination status of these 686 children introduces selection bias.." It is not clear to us what differential effect there would be, and how it would introduce a selection bias. It may be appropriate to look at the study in the following way: Since all pregnancies were registered, we have been able to report on total perinatal mortality in the cohort. However, for immunization status we could only use the information collected at the 6-monthly visits. The visits can be seen as randomly distributed semi- annual events where we recruited the children alive at the visit. By the nature of this design, we would lose around 50% of the follow up time for children between 1 and 6 months of age, and it is therefore not surprising that many deaths occurred before we visited the village. For this procedure to introduce a bias, there should be differential mortality of vaccinated and unvaccinated children prior to the visit where the children were recruited for the vaccine analysis, e.g. that frail children died more quickly in the unvaccinated group, producing a higher proportion of frail children in the vaccinated group. A similar pattern could have produced higher mortality in the diphtheria, tetanus, pertussis vaccinated group. If that were the case in the present analysis, the difference between vaccinated and unvaccinated children should increase with age at recruitment, as the selection process had had longer time to produce an effect. The trend was actually in the opposite direction as can be seen from Table 4 in the paper. Furthermore, we are unable to understand how a selection bias related to inclusion-non-inclusion of certain children could produce a beneficial effect for BCG but a negative effect for diptheria, tetatnus, pertussis and polio vaccines. Lorna Barton et al emphasise that we stated that the study initially recruited 10,000 women, but that 15,351 were included in the analysis. As explained in greater detail elsewhere (2), at each 6-monthly visit we included young girls as they reached fertile age, as well as women moving to the compound. There is no contradiction between the statements on "no loss to follow up" and "information was unavailable", as "no loss to follow up" refers to information about survival status, whereas "information was unavailable" refers to vaccinations received between the first and the second visits for children who had died, or moved or were not present at the second visit. John Heptonstall suggests that we may have made "subtle diversions, calculated measures to limit the impact of the real findings". That was certainly not intended. As all totally unexpected observations, the study was not planned to prevent the major sources of potential bias. Therefore, a single study cannot be conclusive. The important test of unexpected observations is to see whether they are repeatable in subsequent studies - and that is certainly the case with our findings. Peter Aaby,
Henrik Jensen
(1) Aaby P, Gomes J, Fernandes M, Djana Q, Lisse I, Jensen H. Nutritional status and mortality of refugees and residents in a non-camp setting during conflict: follow up study. BMJ 1999;319:878-81 (2) Høj L, Stensballe J, Aaby P. Maternal mortality in Guinea-Bissau: the use of verbal autopsy in a multi-ethnic population. Int J Epidemiol 1999;28:70-76 |
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Alastair Sammon
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Dear Sir - The findings of Kristensen et al’s study(1) fall into place if there is a preexisting Th1 weakness / Th2 predominance of immune response in the community. That there is such a pre-existing condition in many parts of Africa is supported by the remarkable susceptibility to tuberculosis, measles, and HIV infection, all of which depend on a good Th1 response for successful resistance. BCG and measles vaccine, by stimulating a swing toward Th1 response, may in fact be returning the immune system to a relatively normal balance; diphtheria, pertussis, tetanus and polio vaccination stimulate a Th2 response, and may swing the immune system further away from the ideal balance, and inhibit a good Th1 response. Dietary reasons why this preconditioning may exist have been put forward. In an otherwise deficient diet, heavy dependence on maize geographically parallels high incidence of diseases which should be resisted by the cellular immune response. A maize dependent diet is weighted so strongly with n-6 fatty acids that an excessive output of Prostaglandin E2 will occur unless there is also an adequate intake of other fats. Prostaglandin E2 is a suppressor of Th1 function (2). Children with kwashiorkor, an extreme example of what is usually a maize- diet malnutrition, have been described as having a "nutritional thymectomy"(3), and may have no demonstrable cellular immune response to tuberculin during the acute phase of their illness. Our understanding of potential control of the immune response is accumulating, and Kristensen et al's paper has taken us a tentative step forward. Alastair Sammon, 1 Kristensen I, Aaby P, Jensen H Routine vaccinations and child survival: follow-up study in Guinea-Bissau, West Africa. BMJ 2000;1435-8. (9 December) 2 Sammon AM Dietary linoleic acid, immune inhibition and disease. Postgrad. Med. J. 1999;75:129-32 3 Purtilo DT, ConnorDH, Fatal infections in protein-calorie malnourished children with thymolymphatic atrophy. Arch Dis Child 1975; 50: 149-52 |
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John Fryer, Retired Scientist Home
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The research by Ines Kristensen and Peter Aaby and Henrik Jensen is both very important and deeply disturbing. The use of DTP vaccine to prevent the corresponding illnesses is essential. The cost of losing 84% extra lives to achieve this is totally unacceptable. The introduction of the earlier use of DTP vaccine was precisely to save lives. This is clearly not happening. The study coincides with the use of the accelerated scheme which dates back to May 1990 in the UK and presumably is the same for this country? The death of 4% of a nations children due to the use of a vaccine to save life is nothing short of a major catastrophe. The only other case which immediately comes to mind is the 2% deformity rate due to the use of thalidomide back in circa 1961. An immediate connection then comes to mind. In the thalidomide case and in respect of tetanus, (also diphtheria) a toxic compound is at the heart of the problem. The solution here is easier, however - we need to look at the purity of the vaccine, the age of infant, the amount used, the strength, be more careful about possible adverse reactions, where it is administered (can it enter the bloodstream rather than beneath the skin and with what result) and so on. The use of the DTP vaccine could also by analogy easily explain the daily death rate put down to cot death in the UK? The amount of tetanus toxin to cause death is microscopically small compared to the 0.5 gram injection commonly used. The time to cause death is never immediate and may be 5 hours or as long as three or four days. the link is therefore denied. Because we assume or accept Cot Death or put mothers in jail for murder are we missing a similar response to UK DTP vaccination? The same vaccine used on teenage children in the UK caused over 90% adverse reactions with systemic symptoms including difficulty in getting breath, when administered in the 1990s. This research again answers the simple question: are toxic chemicals toxic to life. The answer is clear: Toxic chemicals are indeed clearly toxic. When will we realise this and take appropriate care and control? John Fryer |
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Peter Aaby, Head Bandim Health Project, Guinea-Bissau, Henrik Jensen
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Routine
vaccinations and child survival: effect of gender
WHO’s Global Advisory Committee on Vaccine Safety (GACVS) has recently reviewed our paper on the non-specific effect of routine vaccinations (1). According to GACVS, this paper suggested “a nonspecific effect of routine vaccination that might influence survival in infants, either negatively or positively, depending on the vaccine. Increased mortality was reported in children vaccinated with DTP in the 6 months following vaccination. Female gender was suggested as a modifier of the outcome” (2). The GACVS has sponsored reanalyses of existing data sets from Bangladesh, Burkina Faso, Indonesia, and Papua New Guinea. Based on the four as yet unpublished studies, it is concluded that the WHO-sponsored studies “showed no negative effect of DTP vaccination and no difference between males and females” (2). Our paper (1) made no reference to gender. Since GACVS has emphasised the gender
aspect, we report the mortality data (1) by vaccination status and gender in
the table. In the present study of 100 clusters of 100 women and their children
in Guinea-Bissau (1), children aged 0-6 months had their vaccination status
assessed during a home visit and the survival status at a second visit around
six months later. The survival analysis controlled for length of follow-up, age,
cluster, and other vaccinations and followed the
children for 6 months from the day of the home visit when the vaccination
status was assessed – not from the date of vaccination (2). Vaccines given
between the two visits were not taken into consideration, as information would
only be obtained for surviving children seen at the second visit and would have
introduced a survival bias if they had been included in the analysis. For all
children whose vaccination card was examined or who had no card and were
considered unvaccinated (1), the table shows the mortality depending on BCG and
DTP (1 dose) vaccination status. The mortality ratio (MR) for BCG versus no BCG
was 0.56 (0.37-0.84) and for DTP1 1.74 (1.10-2.75)) compared with DTP
unvaccinated children (1). Girls who had received BCG had a mortality ratio (MR) of 0.45
(0.23-0.86) and boys a MR of 0.63 (0.38-1.04) compared with children who had
not received BCG. Girls having received DTP had a MR of 2.31 (1.16-4.59) and
boys had a MR of 1.45 (0.81-2.59) compared to children who had not received
DTP. The divergence in the MR estimates for BCG and DTP-vaccinated children was
significant for girls (p=0.009) but not
for boys (p=0.089), suggesting that DTP may have a relatively worse effect for
girls than for boys. The trends were similar if all three doses of DTP were
included in the analysis (data not shown). In the pre-vaccination era in West Africa, there
was no sex-difference in post-neonatal child mortality (3). However, vaccines
do have non-specific effects and these may be gender-specific. Several studies
have suggested that standard-titre measles vaccine may be associated with lower
female mortality (3-5), whereas high-titre measles vaccine was associated with
two-fold increased female mortality (4). Since there was no difference in
vaccine efficacy in the high-titre trials, the increased mortality was clearly
a non-specific effect, and the specific increase in female mortality would
therefore be an indicator of gender-specific non-targeted effects of vaccines. Three other studies from West African (4,6,7) have suggested slightly higher mortality for children
having received DTP compared with DTP-unvaccinated children; none have reported
lower mortality. Only one study has reported data by gender. During the recent
war in Guinea-Bissau, the health system broke down and the female-male
mortality ratio was 3.08 (1.11-8.56) for
children who had received DTP just before the war (but not measles vaccine)
whereas the ratio was 0.63 (0.28-1.40) for children
who had received measles vaccine (test of homogeneity, p=0.013) (7). There may
be no absolute differential effect on survival by gender if different vaccines
have opposite effects. However, if different vaccines were changing the
female-male mortality ratio at different ages this would suggest important
non-targeted effects of our routine vaccinations. Peter Aaby Henrik Jensen Bandim Health Project, Danish Epidemiology Science Centre, Apartado 861, Bissau, Guinea-Bissau References
Table. Mortality during six months of follow-up according to BCG and
diptheria, tetanus, pertussis (DTP) vaccination status, age at initial visit,
and sex, Guinea-Bissau, 1990-6
Notes: Information on sex was missing for one child who died. Furthermore, the present analysis includes all children aged 0-6 months, and the estimate for DTP1 is therefore slightly different from the estimate previously presented from an analysis of all children aged 1½-6 months (1). The mortality estimates adjusted for length of follow-up, age, and cluster. Competing interests: None declared |
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