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Rapid Responses: Rapid Responses published:
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Is morbidity or mortality important for childhood vaccine efficacy trials?
- Zubair Kabir (11 May 2003)
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How safe is safe?
- GH Hall (11 May 2003)
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Extent of reduction in Hib response is not the same for all acellular pertussis-containing vaccines
- Nicholas R.E. Kitchin, Jonathan S. Nguyen-Van-Tam (15 May 2003)
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Surveillance should include all Advers Effects
- Michael D Innis (17 May 2003)
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Combination Vaccines
- Pralhad Sadashiv Patki, Suresh S Jadhav, Executive Director,Serum Institute Of India ,Pune, and M A Phadke, Former Director, Medical Education and Research,Govt.Of Maharashtra, Mumbai-400 001 (29 May 2003)
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Value of combination vaccines and explanations for increased incidence of Hib in the UK
- Heinz-Josef Schmitt, Rüdiger von Kries, Helen Kalies, Anette Siedler (2 June 2003)
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Zubair Kabir, Research Fellow CResT Directorate, St. James's Hospital, Dublin 8.
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Sir, Since 1974, the Expanded Programme on Immunization has led to steady reductions in childhood mortality from vaccine-preventable-diseases (VPD). It may also have raised the levels of life expectancy by over four years, particularly in high-mortality populations (1). Millions of children under the age of five die from VPD in the less developed countries annually. In addition, the routine childhood vaccination uptake in the majority of the less-developed countries is poor, unlike the West. The incidence of the common childhood infections may be declining, but there is less significant improvement in overall child mortality rates across the developing countries. Routine vaccines, however, show an interesting immunologic phenomenon, termed ‘non-specific effect’ of vaccines, particularly in high -mortality populations (2). This means that vaccines may protect not only from the morbid conditions of the targeted diseases, but also reduce child mortality substantially from ‘all’ causes. This is more evident in measles and BCG vaccines, which may be attributed to Th1 type immunity (3). Recently, the non-specific ‘beneficial’ effect of measles vaccines on overall child mortality was also confirmed in a relatively low child mortality area with sustained high childhood vaccination uptake (1). These observations may have huge public-health implications across the globe, particularly in high-mortality populations. In addition to possible ‘interactions’, any future combination vaccines can manifest ‘individual’ non-specific effects, which may not be necessarily beneficial (3). It is important that ‘all-cause mortality’ should be considered a useful epidemiological endpoint in future vaccine trials across different population groups, in addition to all the current ‘indirect’ and ‘surrogate’ measures (4). It is also worth considering the ‘culture of eradication’. For example, ‘if measles vaccine does have non-specific beneficial effects, child mortality may increase again should measles vaccine be withdrawn after the eradication of measles’ (5). 1. Kabir Z, Long J, Reddaiah VP, Kevany J, Kapoor SK. Non-specific effect of measles vaccination on overall child mortality in an area of rural India with high vaccination coverage: a population-based case- control study. Bull World Health Organ 2003; 81: 244-50. 2. Shann F. Non-specific effects of vaccines in developing countries. BMJ 2000; 321: 1423-4. 3. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000; 321: 1435-39. 4. Kabir Z. Is all-cause mortality a useful epidemiological endpoint in vaccine trials? An example of BCG. Int J Epidemiol 2003; 32: 161-2. 5. Aaby P, Bhuiya A, Nahar L, Knudsen K, de Francisco A, Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol 2003; 32: 106-15. Competing interests: This eletter is dedicated to my MSc mentor and supervisor, Professor John Kevany, who recently passed away. |
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GH Hall, Retired physician EX1 2HW
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This is not a rhetorical question. If, as stated, “post marketing surveillance is essential”, then it must be concluded that the tests done before release for public use are inadequate in revealing adverse effects. But we are not allowed access to the results of safety testing by the pharmaceutical manufacturers, a situation deplored by such prestigious bodies as the Health Committee of Parliament, the Cochrane Collaboration, and NICE. Openness and honesty are professed by the Department of Health, and its subsidiary the Medicines Control Agency, but not practised. No wonder the public remains sceptical about assertions of safety which cannot be checked by reference to actual results of testing- for “reasons of commercial confidentiality.” Therefore, until an answer is insisted on to the very reasonable question “What threshold of safety is allowed before granting a license for public use?” the cynical experimental testing on unsuspecting populations under the euphemism of “Post marketing surveillance” will continue unchecked. This potential risk can be quantitated. Referral to an elementary statistics table (of the Poisson distribution) will show the chance of missing a positive result depending on the true risk and the numbers studied. For example, if the risk of an adverse effect is 1:1000, then there is approximately a 1:3 chance of finding none in a sample size of 1000. Then see how many people would accept a one in three (or whatever) chance that an adverse effect of this frequency has been missed before using a new substance. It’s high time that the mandarins of public health did something to justify their demands that they be trusted as their dicta can no longer be taken on trust. Competing interests: None declared |
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Nicholas R.E. Kitchin, Head of Clinical Affairs and Pharmacovigilance Mallards Reach, Bridge Avenue, Maidenhead, Berkshire, SL6 1QP., Jonathan S. Nguyen-Van-Tam
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Elliman and Bedford draw attention to the fact that combination vaccines have an invaluable role to play in maximising vaccination coverage, but that they are also complicated and sometimes difficult to develop. One example they cite is the recent rise in Haemophilus influenzae type b (Hib) disease in the United Kingdom. This has been attributed in part to the use of a diphtheria, tetanus, acellular pertussis, Hib (DTaP/Hib) combination vaccine containing three-component acellular pertussis (Infanrix™ Hib: GlaxoSmithKline) [1]. They make the point that “lower concentrations of Hib PRP antibodies have been observed” with DTaP/Hib combinations. Whilst this is true when compared with whole cell pertussis-containing combinations, the extent of the reduction is not the same for all DTaP/Hib combinations. DTaP/Hib combinations containing five-component acellular pertussis appear to show little, if any, such reduction [2]. Elliman and Bedford also highlight that particular difficulties may arise with vaccines that have conjugates in common (e.g. Hib, meningococcal group C and pneumococcal conjugates), whether administered in combination or simultaneously. Recent data with the five-component acellular pertussis DTaP/Hib/IPV combination Pediacel® (Aventis Pasteur MSD), given concomitantly with meningococcal group C conjugate vaccine, have demonstrated differential effects on both Hib and meningococcal group C antibody levels [3]. Despite these, the Hib response with this vaccine was substantially higher than that observed with the three-component acellular pertussis DTaP/Hib combination used in similar conditions. In addition, the meningococcal group C antibody levels were well above those considered protective. Thus, it is important that health professionals and regulatory authorities judge each vaccine on its merits. 1. McVernon J, Andrews N, Slack MPE, Ramsay ME. Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis. Lancet 2003; 361: 1521-23. 2. Lee CY, Thipphawong J, Huang LM et al. An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b- tetanus toxoid conjugate vaccine (PRP-T) in Taiwanese infants. Pediatrics 1999; 103(1): 25-30. 3. Miller E, Southern J, Kitchin N, et al. Interaction between different meningococcal C conjugate vaccines and the Hib component of concomitantly administered diphtheria/tetanus/pertussis/Hib vaccines with either whole cell or acellular pertussis antigens. Poster presentation at 21st European Society for Paediatric Infectious Diseases Meeting, Sicily, 9-11th April 2003. Competing interests: Both authors are employees of Aventis Pasteur MSD, which supplies vaccines used in the UK childhood immunisation programme. |
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Michael D Innis, Director Medisets International Home 4575
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Editor, “Studies on human subjects have reported decreased levels of vitamin C in plasma, leukocytes, and in urine during various infections, including pneumonia, which suggests that infections affect vitamin C metabolism”[1]. This being so there is every reason to be believe that other forms of antigenic stimulation such as the administration of vaccines are also capable of decreasing levels of Vitamin C even to the extent of causing an adverse reaction[2]. Hopefully in their “ post-marketing surveillance”, which they consider essential, Dr Elliman and Dr Bedford will include surveillance of adverse reactions to the vaccines especially those occurring within 3 weeks of administration. Among the adverse reactions they could, or rather should,include evidence of Acute Vitamin C deficiency: 1.Anorexia, vomiting and diarrhoea. 2.Weight loss 3.Irritability 4.Seizure 5.Apparent Life Threatening Event (Apnoea followed by gagging, cyanosis, muscle weakness and limpness) 6.“Fractured ribs” reported by Radiologists who label any rib callus (healing subperiosteal haemorrhage from any cause including Vitamin C deficiency) a “fracture”. 7.Haemorrhage anywhere including Intracranial, Intraspinal, Pulmonary and Subcutaneous. 8.Death Some Pathologists could no longer say “beyond reasonable doubt” that “fractured ribs” were evidence of child abuse but could offer no alternative explanation. g.rayner@dailymail.co.uk Perhaps the Pathologists, and for that matter the whole Medical Profession, should consider Barlow’s Disease (Vitamin C deficiency in Infants) a reasonable explanation of these “fractures” Michael D. Innis FRCPath; FRCPA Reference: 1.Hemila H. Vitamin C and SARS eBMJ 16th May 2003 2.Kalokerinos A. Every Second Child. Foreword by Linus Pauling. Thomas Nelson (Australia) Limited 1981 Keats Publishing Inc Competing interests: Advising accused. |
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Pralhad Sadashiv Patki, Deputy Director(Medical) Serum institute of india Pune-411 028, Suresh S Jadhav, Executive Director,Serum Institute Of India ,Pune, and M A Phadke, Former Director, Medical Education and Research,Govt.Of Maharashtra, Mumbai-400 001
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The Editorial by David Elliman and Helen Bedford (1) on Safety and Efficacy of Combination vaccines has brought out interesting facts for discussion. With entry of a number of vaccines in the immunisation programme, Combination vaccines have become a necessity. Despite unparalleled success in improving the health of children, the immunisation programme faces challenges of unsubstantiated adverse events that could threaten the continued successful control of vaccine preventable diseases. (2).When suspicion about a vaccine begin to spread, there may be dangerous consequences for the public health.In this context, it is very pertinent to note that good post-marketing surveillance(PMS) studies are conducted to reassure the public about the safety and efficacy of vaccines, specially so with MMR vaccine since this combination vaccine draws a lot of current concerns. Surveillance is extremely important and must continue in a very active manner. Several evaluation and surveillance activities related to the vaccination campaigns have been implemented; this includes surveillance of vaccine-associated adverse events. We carried out a PMS study of MMR vaccine between 1998 and 2000 in which 93,547 children (15 months to 10 years) were vaccinated and followed up atleast for a period of one month in India. The study indicated that Fever (n=66,0.1%) seen within 8-12 days and subsided with antipyretics, parotitis (0.01%) and rash (0.01%) were the commonly observed adverse events. Joint pain occurred in 0.001% of vaccine recipients. Lymphadenopathy, aseptic meningitis did not occur in any of the vaccine recipients. Concerns that combination vaccinations might overwhelm the immune system don't appear to be justified. (3).Vaccines are among the safest of pharmaceuticals. The effect of giving multiple vaccines to prevent a large number of diseases must be continuously evaluated to ensure that we can document and understand any level of harm that is introduced and that overall benefit is measurable and substantial (4). References. 1.David Elliman and Helen Bedford. Safety and efficacy of combination vaccines.BMJ 2003;326:995-996. 2.Offit PA,Hackett CJ. Addressing parents concerns: do vaccines cause allergic or autoimmune disease?. Pediatrics 2003;111:653-659. 3.Neal A. Halsey. Safety of combination vaccines: perception versus reality.Pediatr Infect Dis J 2001;20:S 40-44. 4.Robert F.Breiman.Vaccines as tools for advancing more than public health:Perspective of a former Director Of the National vaccine program office. Clinical Infectious Diseases 2001;32:283-288. Competing interests: Pralhad S Patki and Suresh S Jadhav are employed by Serum Institute Of India, Pune, which manufactures vaccines. |
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Heinz-Josef Schmitt, Professor of Pediatrics and Specialist in Microbiolgy and Infectious Diseases Department of Pediatrics, Johannes Gutenberg University, Mainz D-55101 Germany, Rüdiger von Kries, Helen Kalies, Anette Siedler
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Safety and efficacy of combination vaccines: Value of combination vaccines and explanations for increased incidence of Hib in UK EDITOR— We share Elliman and Bedford’s view that combination vaccines are a huge win for children. We would like to add that although diphtheria-tetanus toxoid- acellular pertussis/H. influenzae type b (DTaP/Hib) or diphtheria-tetanus toxoid-acellular pertussis (-inactivated poliovirus)/H. influenzae type b (DTaP-IPV/Hib) combination vaccines resulted in lower Hib titres, in Germany these lowered levels were not associated with a reduced effectiveness against invasive Hib diseases.(1) Our five year ongoing surveillance through 2002 has not indicated waning protection rates (unpublished data). Elliman and Bedford point out the increase in Hib cases in fully immunised children in the UK, and its possible association with a combined vaccine. We suggest that problems in the UK with this increase in cases may be due to one of several different causes. Most notably, in the past, no booster dose was given to infants in the UK after the third dose of Hib in a combination vaccine at 4 months. To address this problem, in April 2003, a catch-up program was started to give all children ages 1-5 an Hib booster.(2) Another possible explanation for the increased Hib numbers may be the concomitant administration of MenC vaccine. The vaccination schedule of the UK is different from that of Germany since vaccination in the UK is begun when a child is 6 weeks old. In Germany, the recommended vaccination age starts at 8 weeks, but most vaccinations are not given on schedule, rather after age 8 weeks.(3) The German experience with DTaP containing Hib vaccines over more than 6 years suggests that these vaccines are highly effective if given in a vaccination protocol which is different from that applied in the UK. The importance of ongoing surveillance is imperative. Competing interests: none References: 1. Schmitt HJ, von Kries R, Hassenpflug B, Hermann M, Siedler A, Niessing W, Clemens R, Weil J (2001). Haemophilus influenzae type b disease: impact and effectiveness of diphtheria-tetanus toxoids-acellular pertussis (- inactivated poliovirus)/H. influenzae type b combination vaccines. PIDJ 8:767-774 2. www.immunisation.co.uk (National Health Service) 3. Laubereau B, Hermann M, Schmitt HJ, Weil J, von Kries R (2002). Detection of delayed vaccination: a new approach to visualize vaccine uptake. Epidemiol. Infect. 128, 185-192. Competing interests: None declared |
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