Non-specific effects of childhood vaccinesBMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5434 (Published 13 October 2016) Cite this as: BMJ 2016;355:i5434
All rapid responses
Cunningham calls for randomised trials of different vaccination schedules, but the omens are not good.
Vaccines are classified as biologicals rather than drugs, so their pre distribution regulatory testing is less structured.
Perhaps because the US vaccine industry has legal immunity to compensation, the industry has further simplified testing and trials.
Another vaccine, or an adjuvant, rather than an inert placebo, is regularly used as an injected control, when safety testing is carried out. (1)
Recording of possible side effects usually extends for a few weeks at most, and the lead investigator decides whether to accept reported ill effects as vaccine related, or not, on the basis of unpublished criteria. (2)
The BMJ has yet to inform its readers of the 30 year failure of the US Department of Health to perform it’s statutory surveillance role of the vaccine industry, (3), which failure may have contributed to some of the above.
Because of the disinclination of the vaccine industry to perform comprehensive testing and trials, the ad hoc reporting of problems after vaccination is effectively left to patients, parents, and the attending physician who may not even be aware of the preceding vaccination.
Under-reporting becomes the norm, and where reports are made they may be dismissed as anecdotes, which too easily becomes an expression of disinterest.
Is this fair?
Goldacre, a well known critic of inadequate trials, wrote: “Amateur critics like to dismiss anecdotes as ‘unscientific’, but this is wrong: anecdotes are weaker evidence than trials, but they are not without value, and are often the first sign of a problem (or an unexpected benefit).” (4)
Once the extent of anecdotal, or uncontrolled observations, concerning vaccine performance and safety is appreciated, vaccine hesitancy begins to appear a very reasonable response.
Miller and Goldman showed that when Infant Mortality Rate (IMR) was compared with the number of vaccines scheduled in the first year of life, in 30 developed countries, divided into five groups, depending on the number of doses given (12-26), the average IMR for each group increased in line with the number of doses. The USA easily topped both lists, for the number of vaccine doses and IMR. (5)
The American Academy of Paediatrics took no action when its official task force reported that Japan’s policy of postponing whole cell and acellular DPT until 24 months of age, caused the disappearance of SIDS as a public health issue, in Japan. (5)
The Japanese, if not the AAP, may have read the comments of Professor Gordon Stewart, a decade before. “This risk [of DPT encephalopathy] far exceeds the present risk of death or permanent damage from whooping-cough, or even, in some parts of the country, from the chance of contracting it .“ (7)
A more recent comment is from a US paediatrician, whose practice income suffered when he chose not to follow CDC vaccination guidelines, advising instead a single dose of MMR at three years of age, when the rapidly developing brain is more resilient, and the immune response is better. He wrote “ I have about a hundred families who have joined my practice after their children became autistic, who have told me that their normally developing one-year-old became severely autistic after the twelve month or eighteen months vaccines, including the MMR. “ (8)
A sad tale of one child may be an anecdote; the same tale about one hundred children, from one paediatrician?
Cunningham is right to call for more trials to test schedules.
Meantime there is an urgent need for our profession to examine the wealth of evidence we already have, and ponder its significance.
1 Richard Moskowitz, Vaccines, a Reappraisal, Skyhorse, 2017. p 29
2 ibid p34
4 Goldacre, B., Bad Pharma, Fourth Estate, 2012, p189
5 Miller, N., and Goldman, G., “ Infant Mortality Rates Regressed against the Number of Vaccine Doses Routinely Given”. Human Experimental Toxicology 30:1420,2011“
6 Cherry, J., et al., “Report of Task Force on Pertussis and Pertussis Immunization,” Supplement, Paediatrics 81:939, 1988.
7 Stewart, G., “ Vaccination against Whooping -Cough: Efficacy vs Risks,” Lancet 309:234, Jan.28, 1977.
8 Paul Thomas, M.D., & Jennifer Margulis, Ph.D. The Vaccine-Friendly Plan. Ballantine Books, 2016 p 190
Competing interests: No competing interests
Frank Shann is no lightweight, and public health authorities should pay attention to his calculations, which suggest a 38% reduction (1,114,200/2,954,000) in mortality among children in poor countries, 1 month to 5 years of age, by modifying the WHO immunization schedule. (Shann, BMJ rr 8/23/18)
The “non-specific effects of childhood vaccines” has been an important subject for at least 23 years. (Aaby, BMJ 1995;311:481) In 2007 Paul Fine and Peter Smith said this: “The dramatic global decreases in frequency of most of the diseases targeted by EPI vaccines (e.g. measles, polio, pertussis, tetanus and diphtheria) are measures of the success of that programme, but mean that any non-specific effects of the vaccines will assume greater relative importance than in the past. As an increasing number of new vaccines is introduced into all populations, the possibility of changing the basic vaccine schedule provides a window of opportunity for making controlled changes that could be designed not only to evaluate the immunologic benefits of different schedules, but also to evaluate possible longer term beneficial or adverse non-specific effects.” (Fine, Trop Med Int Health 2007;12:1) Their proposal has been supported in subsequent articles. (Shann, Arch Dis Child 2010;95:662. Aaby, BMJ 2012;344:e3769)
The “live-vaccine-last” schedule proposed by Shann focuses on poor countries with high childhood mortality, but it also has important implication for high-income countries. (Sorup, JAMA 2014;311:826. Tielemans BMJ 2017;358:j3862) As immunization schedules have expanded, our ignorance of overall risks and benefits has also expanded. (Cunningham, BMJ rr 10/16/16) The relative importance of non-specific effects is likely to have increased, as Fine and Smith suggested in 2007.
It is taboo to suggest that vaccines might account for some of the increase in frequency of our “mystery diseases” (SIDS, Kawasaki disease, autism), but in the absence of properly controlled long-term trials we can neither confirm nor dismiss a causal role for vaccines. (Cunningham, BMJ rr 3/29/18)
This is the background for “vaccine hesitancy” in Europe and North America. Shann and others believe there is an urgent need for controlled trials of different vaccine schedules in poor countries. There is a similar need in high-income countries.
Allan S. Cunningham
Competing interests: No competing interests
Dr Yung claims that the evidence that vaccines have *any* “off target” effects is weak and vulnerable to biases. This is incorrect. BCG has a strong off-target effect against carcinoma of the bladder, and two randomised trials of BCG-Denmark in low birth weight infants were classified as having low risk of bias in the WHO-sponsored systematic review of vaccines by Higgins and colleagues (Higgins Review). A third randomised trial has been published since, and the three trials combined show that BCG-Denmark reduces all-cause neonatal mortality by 38% (95% CI, 17% to 54%), a spectacular reduction.
Dr Yung claims that it is beyond debate that diphtheria, tetanus and pertussis (DTP) vaccine is safe, and yet the Higgins Review found that DTP is associated with a 38% (-8% to 108%) increase in mortality – and with a 53% (2% to 130%) increase in mortality if the Papua New Guinea study with extreme survival and/or frailty bias is excluded, as recommended by 2 of the 3 peer reviewers. This finding cannot be dismissed as being due to bias: first the main sources of bias in vaccine cohort studies, survival bias and frailty bias, make DTP look less harmful; second, bias *cannot* explain why mortality is reduced by BCG at birth, then increased by DTP at 2-4 months, then reduced again by measles vaccine at 9 months within individual studies where there are the similar biases for all three vaccines (Higgins Review, Figure 8). Dr Yung points out that there are no randomised trials of the effect of DTP on all-cause mortality, which is precisely why a trial is urgently needed to demonstrate that DTP is safe (or not) – this could be done by randomising children to receive or not receive the booster dose of DTP in the second year of life, which many countries do not give even though it is recommended by WHO.
The findings of the WHO-sponsored Higgins Review are consistent with the hypothesis that, until a different vaccine is given, live vaccines (such as BCG and measles vaccine) *reduce* mortality from diseases other than the target disease, but that non-live vaccines (such as DTP) *increase* mortality from diseases other than the target disease. The Figure shows a simplified version of the current WHO-recommended immunisation schedule (Schedule A), and a “live vaccine last” schedule modified so that a child’s most recent immunisation is with a live vaccine for as long as possible (Schedule B). The Higgins Review (Figure 5) suggests that giving BCG with DTP at 14 weeks (as in Schedule B) reduces mortality by 48% (100% - 52%) compared to giving DTP after BCG (as in the WHO-recommended Schedule A), and giving MV after DTP (as in Schedule B) reduces mortality by 62% (100% - 100%/2.66) compared to giving DTP after MV (as in the WHO-recommended Schedule A) .
Worldwide, excluding North America and Western Europe, in 2016 there were 2.641 million neonatal deaths, 1.672 million post-neonatal infant deaths (34,623 each week of age from 28 days to 366 days), and 1.282 million post-infant under-5 deaths (26,705 each month of age from 12 to 59.99 months). If all children were immunised on schedule, compared to Schedule A (WHO-recommended), Schedule B (live-vaccine-last) would have 34,623 x 0.48 x 25.2 = 418,800 fewer deaths per year among children aged 14wk to 8.99mo (25.2wk), and 26,705 x 0.62 x 42 = 695,400 fewer deaths per year among children aged 18-59.99mo (42mo); 418,800 + 695,400 = 1,114,200 fewer deaths per year. Schedule B gives a second dose of BCG with the third priming dose of DTP at 14w of age, and omits the DTP booster at 18m of age – and would have approximately 1.1 million fewer under-5 deaths per year compared to the WHO-recommended Schedule A.
Figure. A simplified version of the immunisation schedule recommended by WHO (Schedule A) and a “live-vaccine-last” schedule where a child's most recent immunisation is with a live vaccine for as long as possible (Schedule B).
SCHEDULE A: 0wk BCG; 6wk, 10wk, 14wk DTP; 9mo MV; 18mo DTP + MV
SCHEDULE B: 0wk BCG; 6,10wk DTP; 14wk DTP+BCG; 9mo MV; 18mo MV
BCG = BCG-Denmark + OPV; DTP = DTP-containing vaccines; MV = EZ MV (or MMR ± YF).
1 Higgins JPT, Soares-Weiser K, López-López JA, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016;355:i5170.
2 Biering-Sørensen S, Aaby P, Lund N, et al. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis 2017;65:1183–90. doi:10.1093/cid/cix525
3 Higgins J. Re: Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ Published Online First: 27 February 2017. http://www.bmj.com/content/355/bmj.i5170/rr-7 (accessed 23 Aug 2018).
4 Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Non-Specific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J 2016;35:1247–57.
5 Shann F. The heterologous (non-specific) effects of vaccines: implications for policy in high-mortality countries. Trans R Soc Trop Med Hyg 2015;109:5–8. doi:10.1093/trstmh/tru161
6 UNICEF. The State of the World’s Children 2017. UNICEF. 2017.https://www.unicef.org/sowc2017/ (accessed 23 Aug 2018).
Competing interests: No competing interests