Is the timing of recommended childhood vaccines evidence based?BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i867 (Published 23 February 2016) Cite this as: BMJ 2016;352:i867
All rapid responses
The questions raised by Dr Havinga (29 Feb) and by me (4 March) in rapid responses remain unanswered. The manufacturers are silent. Dr Roberts and others in the higher reaches of the UK governments are silent. Shocked into silence? Or, turning a blind eye?
Competing interests: No competing interests
We thank all those who responded for their interest in our writings (1). Despite the very many good points raised, timing of childhood vaccination schedules remains evidence-free, if by evidence we mean the results of comparative studies (randomised or not) comparing childhood schedule A vs B or C. That is why we inserted no bibliographical references in our brief. Lack of evidence is not really surprising as “new vaccine creep” is now a fact of life. Over a decade ago as the pharmaceutical industry’s progressive involvement in vaccines became clear, we advocated the introduction of vaccination registers (2). These would have data-linked all children’s exposure to possible outcomes taking into account the non-exposure periods, generating data which could have informed decisions on common and rare outcomes. Our suggestions were dismissed with the same tone as that used by Roberts in his response (3). Nowadays the non-exposure windows are virtually nil, so the time for any meaningful evidence generation has passed.
We have a suggestion for the editor of the BMJ. She may consider passing it on for debate to the International Committee of Medical Journals Editors. Looking at some disclosures made in debate, it occurred to us that there are two levels of conflicts: personal and institutional. Readers need to know what is influencing what people write at personal and institutional levels.
As Edwards et al have done, anyone writing of behalf of an institution (public or private) should declare their conflicts and those of their parent body, including all sources of funding.
(1) Jefferson T, Demicheli V. Is the timing of recommended childhood vaccines evidence based? NO. BMJ 2016;352:i867.
(2) Jefferson TO, Price D, Demicheli V, Bianco E. Unintended Events following immunisation with MMR: a systematic review. Vaccine 2003; 21(25-26):3954-60.
(3) Roberts R. What constitutes evidence? http://www.bmj.com/content/352/bmj.i867/rr-1
Competing interests: TJ and VD are both former coordinators of the Cochrane vaccines field. TJ was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for preventing and treating influenza. In addition TJ receives royalties from his books. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in a litigation case related to oseltamivir and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013) and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In 2014-15 TJ was a member of two advisory boards for Boerhinger and is in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. He is a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial. VD is employed by the Italian National Health Service and provides advice on vaccination policies both at regional and national level.
The "Head to Head" confined itself to timing only. However, others as well as I have raised more fundamental questions. Questions which have not been answered. Neither by the government appointed public health "Czars" in the UK, nor by the manufacturers, nor by academics, nor by the medical ethicists.
They must have collectively decided that plebs (such as I) can be ignored. The patricians decide. And pronounce.
A few points-
1. Why does the UK Govt not institute a reporting system, based on payment to the reporting doctor, of reactions assisted with the adminstration of a vaccine?
2. If the Exchequer money is tight, why do not the manufacturers pay the reporting doctor?
3. What arrangements has the Govt made to arrange a study of the relationship between imm and vac and later onset of illnesses of immune disturbances or of unknown origin? Dr Havinga's comments are worth considering.
4. Is it morally (shall I say, ethically) justified to bring in to use a vaccine which was developed or co-developed by a scientist who also participated in the decision to authorise the use of such vaccine?
5. In the case of the Ministry of Defence, there is (or at least was) a ban on "revolving door" employment. You could not retire/resign from the civil,service and join a weapon manufacturer or dealer. Q. Can HMG assure us that the same restrictions apply and have always applied in the Dept of Health and its predecessor, the DHSS.?
6. From Italy, the BMJ reported that a public health doctor - Dr Demicelli - was being gagged by legal threats.
Can the professional organisations representing the public health consultants registered with the General Medical Council please assure us the public, that:
a) these consultants are FREE to voice their reservations or disagreements?
b) these consultants are required to answer the questions raised by a member of the public or the press, in their patch, instead of simply citing the D o H?
Competing interests: Member of the public. Formerly responsible for immunisation in tne areas served by me in old public health, community medicine, public health medicine.
Jefferson and Demicheli argue that evidence about vaccination schedules is limited. Here we would like to add that: 1) decisions about vaccination schedules are based on considerations other than trials exploring the efficacy and safety of vaccines; 2) quality of non-experimental data and their relative importance in the decision-making process are often ambiguous, and 3) members of national expert advisory groups might largely disagree in interpreting and accepting arguments in relation to vaccine schedules, even within the same country or jurisdiction. Thus vaccination schedules are highly disputable.
As the introduction of vaccines in the National Immunisation Plan have important public health implications, a number of key variables needs to be carefully evaluated by the policy makers [1,2]. This is even more relevant when considering vaccinations for diseases with low incidence and high mortality or vice versa.
Governmental immunisation technical advisory panels advise regional and national authorities on decisions to introduce new vaccines or to adjust existing immunisation strategies considering direct and indirect consequences of the immunisation programme and answering different questions regarding the vaccination (e.g., vaccine efficacy, overall effectiveness, benefits and harms, resources consumption, expected compliance and possible interferences within the immunisation schedule in place). These authorities are usually commissioned to perform their own analyses (e.g., effectiveness or economic) based on existing studies that are not fully generalisable to local contexts due to differences such as disease epidemiology, vaccine-specific issues (e.g., distribution and replacement of serotypes), local immunisation strategies, effective coverage, budgets and vaccination policies.
The panels are likely to face difficulty re-adapting or re-interpreting data pertaining to relevant vaccine dimensions and criteria, which may introduce several problems and lower the quality of their recommendations. This is why policy makers must often support recommendations on the introduction of new vaccines without a transparent, structured and independent assessment process, in situations characterised by considerable external pressure from the media and those with commercial interests.
We believe that transparent, unbiased and comprehensive frameworks built on evidence-based criteria are promising tools to guide decision-making on vaccine adoption. Therefore we recently developed a multi-dimensional framework  structured around six dimensions and conceived from the DECIDE - Evidence to decision Framework, which is a general framework based on evidence-based criteria to guide decision-making on intervention adoption .
We then proceeded to validate our framework by conducting a real data and evidence set collection on varicella vaccination and tested it with a multidisciplinary panel group (e.g., policy makers, paediatricians, experts in communicable diseases, other stakeholders) .
There were disagreements about the best schedule. The question of vaccine schedule is secondary to questions about the overall efficacy and safety of the varicella vaccine. Only 60% of health professionals and regulators supported the adoption of the varicella vaccine as part of the National Immunization Program, assuming that benefits far outweigh risks. This percentage becomes larger (more in favor of the vaccine) if we consider who recommended the introduction with restrictions (9%). A half (50%) favored the monovalent vaccine while the other half chose the tetravalent vaccine. About 90% of responders found information in the EtD framework comprehensive, easy to understand, and presented in a way that helped make decisions.
We cannot say which dimensions of the framework may have affected the final choice, or played a key role in disagreements. Nevertheless we can argue that more is the load and clearness of information more the relevance and validity of the final choice.
1. Ahmed F, Temte JL, Campos-Outcalt D, Schunemann HJ. Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine. 2011;29(49): 9171–6.
2. World Health Organization. Vaccine Introduction Guidelines Adding a vaccine to a national immunization programme: decision and implementation. WHO; 2005. Available: http://www.who.int/immunization/hpv/plan/vaccine_introduction_guidelines....
3. González-Lorenzo M, Piatti A, Coppola L, Gramegna M, Demicheli V, Melegaro A, et al. Conceptual frameworks and key dimensions to support coverage decisions for vaccines. Vaccine. 2015; 33(9):1206-17.
4. Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice Based on Evidence. Available: http://www.decide-collaboration.eu/key-decide-tools.
5. González-Lorenzo M, Tirani M, Piatti A, Coppola L, Gramegna M, Ruggiero F, et al. Modello decisionale per l’adozione del vaccino antivaricella: una sfida di fattibilità. Recenti Progressi in Medicina. 2016; 107(2): 84-107.
Competing interests: No competing interests
I would put a spotlight on some points that were not addressed in this head to head or that have been addressed inadequately.
A global historic overview of infectious diseases shows that since the epidemiologic transition  took place in developed countries most infectious diseases have decreased dramatically specially pneumoniae  and their lethality, for those that are lethal, has adopted a U shape ( invasive penumococcal disease) or a J shape (invasive meningococcal disease), being maximal in extreme ages among the most vulnerable people that is young infants, often those with constitutional impairments or premature infants, and mostly in the perinatal period, and also in old people with degenerative chronic diseases.
There is such a close relationship between the share of infectious diseases in morbidity and mortality in a country and its development level that It could be says that this share is a good indicator of this development level.
When recent vaccines were introduced, the diseases they targeted had already being declining for a long time. The number of cases of severe forms of infections with bacteria that are otherwise widespread in the population (healthy carriers and mild infections) such as haemophilus b, streptococcus pneumonia, or meningococcus are between 0,1 in 100 000 and 10 in 100 000 roughly. For a country that has a population of 60 millions people that means 60 to 6000 cases every year.
If trials enroll “tens of thousands” of children, this is because trials are trying to highlight very rare benefits, and this needs very large samples.
Few studies have been done to estimate the real burden of diseases targeted by vaccines. An investigation conducted in pediatric French ICU about deaths from community invasive infections in children 10 days to 18 years old, during two years, in 1998 and 1999, with 60% of responders, showed that 70 in 100 deaths found (mean: 50 per year) were in infants under 1 year and the third under 2 months. 26 of the total 100 deaths of children from 10 days to 18 years were due to pneumococcal disease (that is 13 per year, non completed data) and 16 from all types meningococcal disease . That was before pneumococcal and meningococcal vaccines were recommended for current children immunization.
Vaccines assessment by regulation agencies is not a purely scientific process based on irremovable rules. It is rather the result of a negotiation between the agency and the pharmaceutical company representatives. This was the case for Merck’s HPV vaccine. In November 2001 there was a discussion of possible outcomes concerning the papillomavirus vaccinte trial at the FDA. Merck wanted to assess the vaccine only for HPV infections, a common condition, whereas the FDA would have liked to assess it for cancer which it considered “the most relevant endpoint” in order to claim cancer prevention. The final endpoint was the result of a trade off.
For the HPV vaccine, the transition to a two doses schedules was based on unclear reasons. It was based mainly on short term studies assessing the effectiveness of the vaccine on warts and condyloma . At the same moment an Australian study showed that the effectiveness of the vaccine on high grade dysplasia was much lower with a two dose schedule than with a three dose schedule.
Hepatits B is a non lethal disease which incidence was spontaneously declining in late eighties in developed european countries . Hepatits B, as is known, is exceptionally found in children in developed countries and more than 80% of incident acute hepatitis B cases (roughly 1500 cases a year in France) are found in adults born abroad. What would then be the point of vaccinating infants like in most European countries?
With the current shortage of vaccines, the hexavalent vaccine containing hepatits b is the only vaccine available for infants immunization in France. The price with the complete three doses schedule with a trivalent vaccine against diphtheria tetanus and polio would be 24 euros, while the price of a complete hexavalent vaccine schedule is 120 euros ie five times more.
The introduction of combined vaccines resulted in the loss of any flexibility in timing since vaccines are all injected at the same time. This lack of flexibility has worsened in Europe with the current shortage of vaccines that are manufactured by two pharmaceutical companies Sanofi Pasteur MSD and GSK.
These are some examples that show that the timing of vaccines is anything but scientific.
Competing interests: No competing interests
The evidence base is purely based on the limited research that has been done (1), however vital vaccine safety research is missing in several important areas.
Has, due to vaccination, the overall burden of disease increased from (acute) infectious diseases to a greater burden of disease due to (chronic) non-communicable diseases?
The apparent success of vaccines coincides with overcoming poverty: malnutrition, poor hygiene, unclean drinking water, overcrowding and stress. These are the morbidity and mortality risk factors in relation to infectious diseases.
The following 11 areas need to be covered with systematic research to make sure that immunisations do no harm.
The ISAAC studies (International Studies on Asthma and Allergies in Childhood) show that in highly vaccinated affluent countries the incidence of non-communicable diseases (NCD) like asthma and allergies, is high. However, these studies do not mention vaccines as an environmental factor.
Studies are needed that check the prevalence of NCD like asthma and allergies in affluent highly vaccinated countries, between vaccinated and non-vaccinated children.
Furthermore, the immune system in the newborn might be primed in the first few months to react in an allergic fashion. This needs to be researched and could be done with a cohort of children who receive vaccines after the maturation of the immune system of the infant, rather than within the first few months of life. (2)
Vaccines have changed the microbiome. However, vaccines are again consistently ignored in articles discussing the effects of the microbiome. Vaccines are not mentioned in articles on the gut-brain axis, even though rates have soared in childhood anxiety, depression, ASD, ADHD.
Bacteria and viruses are of vital importance for human health. Guidelines are now produced to curb antibiotic prescribing. Never the less, the "infections are bad" paradigm still prevails. But hardly any research is done to check for benefits from these infectious diseases.
Frank Ryan in his book Virolution makes the case that evolution was made possible due to viruses changing our DNA.
Are infections needed for a healthy maturation of the body? For example are infections a protective factor against cancers? Do viral infections have epigenetic effects, for example can the mumps virus protect against testicular cancer?
In general with reference to childhood fevers, considering that: "Evidence indicates that survival benefits are accorded to individuals who achieve an increase in body temperature (i.e. fever) following infection" (3), could childhood fevers be an important protection against cancer over a life time?
Therefore, research is needed into the epigenetic effects of infections and the positive effects of childhood fevers in view of the upward cancer incidence trend. (4)
And considering the upward trend in autoimmune diseases, are for example gastro-intestinal commensals and infections (like rotavirus) also needed to protect the body from developing chronic inflammatory bowel diseases?
Public health has now started to vaccinate for economic reasons, but are birth cohorts in place comparing vaccinated with unvaccinated children to check whether this shift in vaccination reasoning is benefiting or harming the child? (5)
In the developing world there is a big push to vaccinate children but are any birth cohorts in place to check whether the balance in burden of disease shifts from acute to chronic diseases (NCD)?
As vaccines are given to everyone in society, scrutinising safety should be paramount to make sure that the overall burden of disease is not increased by vaccination, by having proper ongoing research in the 11 aforementioned areas in place.
1) Edwards KM, Maldonado Y, Byington CL, Jefferson T, Demicheli V. Is the timing of recommended childhood vaccines evidence based? BMJ 2016;352:i867 http://www.bmj.com/content/352/bmj.i867
2) Havinga W. Risk of asthma. Lancet. 2001 Jan 27;357(9252):313-4 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2805%2971...
3) Repasky EA, Evans SS, Dewhirst MW. Temperature Matters! And Why it Should Matter to Tumor Immunologists. Cancer immunology research. 2013;1(4):210-216. http://cancerimmunolres.aacrjournals.org/content/1/4/210
5) Havinga W. Vaccinating for economic reasons. Acceptable? BMJ rr 15 May 2013 http://www.bmj.com/content/346/bmj.f2792/rr/645591
Competing interests: No competing interests
In the ‘yes’ argument of this article, Edwards, Maldonado and Byington refer to “the introduction of maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination to reduce pertussis among infants in the US and many European countries”. The inference is that maternal Tdap vaccination is reducing pertussis in infants, and the ‘evidence’ they provide is a single reference to an observational study published in The Lancet in 2014, currently behind the paywall. I suggest this is a very poor example of ‘evidence’. At this stage we have no idea of the long term consequences of Tdap vaccination of pregnant women.
Edwards et al do not allude to the emerging problems with pertussis vaccination i.e. that the apparently defective acellular pertussis vaccine may actually be causing new strains of the disease to develop, and spreading the disease via vaccinated individuals.
The response to the emerging problems with acellular pertussis vaccination has been to recommend ‘boosters’, e.g. A/Professor Ruiting Lan of the University of New South Wales says: “We need to look at changes to the vaccine itself or increase the number of boosters.”
The question is, how does increasing the number of ‘boosters’ of the current acellular pertussis vaccine protect against new strains?
Repeated revaccination with the apparently defective acellular vaccine is now being foisted upon the community. I question whether it is ethical to (a) not properly inform citizens about the uncertainties surrounding pertussis revaccination, and (b) to implement vaccination laws (as in Australia for instance) which coerce parents to have their children repeatedly revaccinated with the questionable diphtheria, tetanus and acellular pertussis vaccine product (DTPa).
In Australia the National Immunisation Program Schedule now stipulates that children be vaccinated six times with the aluminium-adjuvanted combination diphtheria, tetanus and acellular pertussis vaccine product, i.e. primary vaccination at two months, four months and six months, then so-called boosters i.e. revaccination at 18 months, four years, and again between 10-15 years.
And it doesn’t stop there… As well as pregnant women, household contacts of infants and healthcare workers are also being urged to be revaccinated again and again with the diphtheria, tetanus and acellular pertussis vaccine, in other words lifelong revaccination with this vaccine product.
What is the point of imposing more and more so called ‘boosters’ with an apparently defective acellular pertussis vaccine product which may be causing new strains of the disease to develop, and spreading the disease via vaccinated individuals? What sort of science is this? The so-called vaccination experts seem to be making this up as they go along, and using the community as guinea pigs, without informed consent.
Certainly repeated revaccinations/’boosters’ must be a very lucrative profit centre for vaccine manufacturers.
 See for example: Sharp rise in cases of new strain of whooping cough. UNSW Newsroom. 21 March 2012: http://newsroom.unsw.edu.au/news/health/sharp-rise-cases-new-strain-whoo...
 See for example: FDA study helps provide an understanding of rising rates of whooping cough and response to vaccination. FDA News Release, 27 November 2013: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376937.htm and Jason M Warfel et al. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. PNAS, 22 October 2013: http://www.pnas.org/content/111/2/787.full.pdf
 No Jab, No Pay – New Immunisation Requirements for Family Assistance Payments. Australian Government Department of Health. Fact sheet for vaccination providers. November 2015: http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Conte...$File/No-Jab-No-Pay.pdf
 Australian National Immunisation Program Schedule (From February 2016): http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Conte...$File/NIP-schedule2016.pdf
 4.12.7 Recommendations. Pertussis. The Australian Immunisation Handbook, 10th edition: http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Conte...
Competing interests: No competing interests
Rather than asking whether there is evidence that the timing of the vaccination programme prevents the targeted diseases, the question should be whether the timing of the programme optimises the impact of vaccines on child health.
That evidence base is insufficient. In low-income countries, where the burden of child mortality lies, the vaccines at the core of the Expanded Programme on Immunization (EPI) were not evaluated for their effect on child mortality before being introduced. An accumulating number of studies have now shown that the four core vaccines of the EPI, the Bacillus Calmette-Guerin vaccine (BCG, against tuberculosis), the diphtheria-tetanus-pertussis vaccine (DTP), the oral polio vaccine (OPV) and the measles vaccine (MV) all have effects on child health beyond their effect due to specific disease protection; i.e., the vaccines have non-specific effects (NSEs). These effects are strongest as long as a given vaccine is the most recent vaccine.
The studies have mostly been observational, since it is difficult to conduct randomised trials of already recommended vaccines. However, where feasible, randomised trials have supported the conclusions from observational studies by showing that the live attenuated vaccines BCG vaccine[2 3], OPV and MV[5 6] are associated with lower mortality than predicted by the prevention of the target infections, i.e. these vaccines have beneficial NSEs. In contrast, DTP vaccine is associated with increased female mortality, in spite of protecting against the target infections.
These NSEs, however, have not been taken into consideration in the timing of vaccinations. For instance, all available data show that a policy of providing an additional early dose of MV shortly after DTP, to abrogate the negative mortality effect of DTP, would reduce mortality. Also, in countries which use booster-DTP, a revaccination with BCG one month after booster-DTP may be very beneficial.
Both the “yes” and “no” side state that the time for randomised trials has passed, as it is not ethical to deprive children of a vaccine which is part of the recommended schedule. The Strategic Advisory Group of Experts on Immunization (SAGE) recently reviewed the evidence for the NSEs of BCG, DTP and MV on all-cause child mortality. Based on a literature review which found evidence of a beneficial effect of BCG and MV, but not for DTP (“the majority of the studies indicating a detrimental effect”), SAGE has recommended further research and where possible randomised trials.
With the limited evidence behind the current timing, and an increasing amount of evidence documenting that changes to the current schedule may improve child health, there should be equipoise for studies evaluating alternatives to the current timing.
1. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends in immunology 2013;34(9):431-9 doi: 10.1016/j.it.2013.04.004.
2. Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204(2):245-52 doi: 10.1093/infdis/jir240.
3. Biering-Sorensen S, Aaby P, Napirna BM, et al. Small Randomized Trial Among Low-birth-weight Children Receiving Bacillus Calmette-Gueerin Vaccination at First Health Center Contact. Pediatr Infect Dis J 2012;31(3):306-8 doi: 10.1097/INF.0b013e3182458289.
4. Lund N, Andersen A, Hansen AS, et al. The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2015;61(10):1504-11 doi: 10.1093/cid/civ617.
5. Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 2010;341:c6495 doi: 10.1136/bmj.c6495.
6. Aaby P, Garly ML, Bale C, et al. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J 2003;22(9):798-805 doi: 10.1097/01.inf.0000083821.33187.b5.
7. Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ open 2012;2(3):e000707 doi: 10.1136/bmjopen-2011-000707.
8. Roth AE, Benn CS, Ravn H, et al. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ 2010;340:c671
9. Edwards KM, Maldonado Y, Byington CL, Jefferson T, Demicheli V. Is the timing of recommended childhood vaccines evidence based? BMJ 2016;352:i867 doi: 10.1136/bmj.i867.
10. World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 -- conclusions and recommendations. Wkly Epidemiol Rec 2014;89(21):221-36
11. Higgins JPT, Soares-Weiser K, Reingold A. Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. Available at: http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiol..., 2014.
Competing interests: No competing interests
Re: Is the timing of recommended childhood vaccines evidence based?
I start my response to this "Head to Head" debate with a 2015 quote:
" In relation to the large variability vaccination schedules in the European Union (EU), it is not realistic to test each vaccination schedule in clinical studies. Requiring clinical trials for each vaccination schedule used only for the needs of regulators is more of an ethical issue than a scientific one" (1)
This introductory remark places my opinion in the 'no' camp of timing being evidence based. It has triggered further reflections as to why records are not quite straight in this area of medical research, albeit much effort is put in.
Public health deals with many facets in the area of disease prevention and at this point I deliberately leave, almost completely, out the health economics when I respond with a few arguments:-
Schedules and timings differ enormously among countries, for example: from 4 to 7 dosages of DT until the age of 18 years across 29 European countries (2); despite this, there are similarities in a few countries (3). Within countries there are also delays in timing with/ without inequalities (summer months; or, some groups of children delayed more than others). And the delays (in timing) are not negligible (4).
The G8 visualisation is very clear (3) yet the timings in a country are arbitrary features; I could not see references at the basis of which were those timings chosen individually for each vaccine.
A Cochrane Systematic Review concluded in 2012 that "studies addressing clinical end points whenever possible, using correct methodology and a large enough sample size should be conducted" and reviewers stated to begin with: "there were no data on clinical outcomes for the primary outcome (prevention of disease) and all studies used immunogenicity and reactogenicity (adverse events)"(5)
I fully respect that those going ahead with their respective opinions have their own evidence to back up as to why they believe that timing of recommended vaccines is evidence based. Yet this evidence is either thin or not easily accessible to practitioners and researchers. One would expect, for example, that studies and systematic reviews with a 'time-to-effect' events are readily and easily available to researchers, doctors and nurses.
On reflection I believe we need more answers on many aspects and not only the timing in schedules:
1) What role do various 'stakeholders' play when it comes to having had the 'timing' set at 1 month or two months intervals? Why the big variations among countries for total dosages and/or timing? Is there any 'information asymmetry'?
2) Moreover, how did those who campaign for vaccination and immunisation advise when it came to timing and what differences were noted when compared with those who advise otherwise: a) against any vaccination in general or b) against vaccination by different types of vaccines: polyvalent vs single disease vaccines? Are there any papers on inter-cultural dimensions to explain differences? Are there any papers or protocols which have recorded primary outcomes such as 'time to event' (proportions of defined outcomes in various cohorts)?
3) Furthermore, if say timing was surely evidence-based set, what role does it play in the polyvalent vs single disease vaccines debate, when some evidence suggests that the first approach may not lead to the most effective immunogenicity e.g. at the age of 5? (6) If the purpose of vaccination was to immunise and prevent more (rather than a few) diseases, then can we consider that timing is arbitrarily set; and that policies got a 'clear' regulator pass from single to triple, pentavalent, hexavalent vaccines for as long as they are 'safe'? Most polyvalent vaccines have just been introduced in schedules. Have we got answers from trials on all combinations used? The key question is: have any of these approaches been tested for a) the type of benefits to individuals and the community health and b) has the cost-effectiveness of each and every type of (new) schedule been measured before being marketed?
To conclude it seems to me that the actual evidence is poorly documented and that field trials, like there were once done for single vaccines, are needed in this domain of public health due to a lot of anecdotal evidence which is still surrounding vaccination and immunisation in general.
And as a collateral response to the introductory quote I used I was highly surprised to see that the ethical aspects are not on a par with the scientific ones, particularly when it comes to regulators. Don't we all use the ICH - GCP when it comes to research?
Public Health Doctor
1 Vladimir O et al How do we evaluate and manage many different vaccination schedules in the EU? Cent Eur J Public Health. 2015 Sep;23(3):218-22.
2 Lopalco PL et al Childhood vaccination schedules in Europe vary widely. Is this a problem? Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2009 Nov;52(11):1095-8. doi: 10.1007/s00103-009-0960-z.
3 Doshi et al Feature. Visualising childhood vaccination schedules across G8 countries BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h5966 (Published 16 November 2015)
4 Riise OR et al BMC Pediatr. 2015 Nov 13;15:180. doi: 10.1186/s12887-015-0487-4 Monitoring of timely and delayed vaccinations: a nation-wide registry-based study of Norwegian children aged < 2 years. Accessed at http://www.ncbi.nlm.nih.gov/pubmed/26563381
5 Bar-On ES et al Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB): Cochrane Database Syst Rev. 2012 Apr 18;4:CD005530. doi: 10.1002/14651858.CD005530.pub3.
6 Silfverdal SA et al Immunological persistence in 5 y olds previously vaccinated with hexavalent DTPa-HBV-IPV/Hib at 3, 5, and 11 months of age. Hum Vaccin Immunother. 2014;10(10):2795-8. doi: 10.4161/21645515.2014.970494 Accessed at http://www.ncbi.nlm.nih.gov/pubmed/25483640
Competing interests: No competing interests
This head-to-head debate tries to answer an important question at a time when families and clinicians are under pressure from vaccine mandates and must beg for some personal autonomy and flexibility in vaccine administration. I was confused, however, by the debaters' circumlocutions and hope that certain points will not be overlooked.
Most vaccines are licensed after relatively small trials showing an adequate antibody response and the infrequency of major adverse effects, but evidence for real clinical effectiveness has to wait for surveys showing a decline in frequency of the target disease. For some vaccines (e.g. measles) time has provided convincing evidence, but this is not true for every vaccine on the schedule, especially since the evidence is a secular trend in whole populations and not a controlled trial that distinguishes between subjects who were vaccinated or unvaccinated. The frequency of infectious diseases can decline on their own; meningococcal disease is just one example (Meissner, JAMA, 2/8/16. Interview, kqed.org, 2/17/16).
Effectiveness is one issue, safety is another. Knowledge of rare but serious adverse effects is not actively pursued by the manufacturers, and our passive reporting systems vastly underestimate adverse events following vaccination. For example, less than 1% (one percent) of cases of Kawasaki Disease are reported to VAERS even though this is a rare and serious disease of unknown cause whose frequency is greatest in young (and frequently vaccinated) children. Meanwhile, the incidence of KD in the last 40 years has marched upward in lockstep with expansion of the vaccination schedule (Cunningham, "Underreporting vaccine adverse events," BMJ rapid responses, 6/11/10 and 7/6/10). Incidentally, we should not dismiss the non-specific effects of vaccines, singly or in combination, on other infections (Sorup & Aaby, JAMA 311:826, 2014).
The question of vaccine timing is secondary to questions about the safety and cost-effectiveness of individual vaccines. If I were the U.S. "vaccine czar" I would mandate (based on the evidence) MMR (though we need a better mumps vaccine), DTaP and Tdap (though we need a better pertussis vaccine), IPV and Hib, and I would provide them free to all children. PCV might be included, although it frequently causes high fever in young infants, and the phenomenon of serotype replacement leaves us with some uncertainty about PCV's true impact on the incidence of pneumococcal meningitis and empyema. All other vaccines would be strictly voluntary for the time being.
You can always find evidence supporting a vaccine's place in the schedule, but scientific quality varies, and acceptance of the evidence depends to some extent on non-scientific considerations. U.S. pediatric offices, for example, depend heavily on the vaccination schedule to establish and maintain their clientele, and to augment income.
Some of our vaccines are wonderful lifesavers and are wonderfully cost-effective. However, I have the sense that the success of these vaccines have prompted officialdom to give a pass to the inadequate evidence for safety and cost-effectiveness of other vaccines.
Competing interests: No competing interests