On 2014 May 26, Marc Girard commented:

As a drug specialist with a more than 30-year experience in safety, I was often missioned as a medical expert witness in criminal or civil inquiries on vaccine litigations, where I repeatedly pointed out the worrying lack of knowledge of most vaccine experts regarding the basic scientific and regulatory requirements normally applicable to pharmaceutical products – esp. as far as adverse reactions were concerned: this represents a tragic shortcoming for such preventive drugs, targeted towards people in perfect health with the problematic aim of protecting them against diseases the occurrence of which in a severe form is often an unlikely event, and for which therefore the risk of side-effects should not go beyond extremely narrow limits… Amongst many others examples, this paper by Tozzi et al. is an impressive illustration of this lack of expertise a far as drug safety is concerned.

Whatever the authors’ views on the matter, the primary tool to assess drug safety is not “epidemiological studies” but double-blind investigations versus placebo (a genuine placebo, namely a completely inert product and not another vaccine…) performed during development on a sufficient duration: as everybody knows, vaccine makers have managed the exploit to get exempted of this otherwise inescapable step. Additional indicators of amateurism in vaccine development include “fast track” procedures (whose consequences have been recently illustrated by the narcoleptic risk of Pandemrix), as well as the striking poverty of the dose-ranging studies (which account for regular turmoil in “experts” recommendations regarding the scheme of immunization as well as the timing of boosters).

As far as “epidemiological studies” are concerned, their main default is of being inextricably polluted by major conflicts of interests, as in most cases, they are performed either by the manufacturers or, even more frequently, by national or international health agencies (or their “experts”) whose most obvious interest is to hide the – sometimes tragic – drama they may have triggered by their irresponsible campaigns to promote some vaccines: this is the reason why, amongst a dozen of such studies performed on the neurological risks of hepatitis B vaccination, the only one showing a clear increase was also the sole whose financing was independent of any promoters of this immunization…

To come now to the assessment of causality of individual adverse reactions, the first remark is that the methodological inspiration of Tozzi et al. is regrettably obsolete. The use of algorithms has been almost completely abandoned by most regulatory bodies, for one reason which was pointed out more than 25 years ago [1]: namely, that use of algorithms (or decision table) is a tool for clinical decisions (e.g. to perform a laparotomy in view of such and such signs or symptoms), whereas assessing causality in drug toxicity is a process of knowledge, and not of decision (there is not the slightest signification in “deciding” whether a drug is, or not, the cause of an effect – and the reader has just to consider that this incredible way of reasoning is never used to assess drug efficacy, yet another pharmacological effect…). Lack of validation regarding the inter-raters agreement is an additional indicator of the methodological amateurism of the authors: this step should have been a strong prerequisite, taking account the vague of some items (e.g. that concerning an “appropriate time window after vaccine administration”, when experience of such an assessment with academic vaccine “experts” shows that it is almost invariably assessed as too short or too delayed… The same holds true for the item of “biological plausibility”, when experience, once again, teaches the fanatical obstinacy of most vaccine experts to challenge even the biological mechanisms which are most probable or convincing [2]).

Jacob Puliyel has listed a number of cases where Tozzi et al.’s algorithm would miss obvious vaccine causality. Let’s suggest another, that I witnessed in a number of sad instances: 3 weeks after a first injection, a person develops unexplained asthenia associated with paresthesia; one week after the second immunization, he/she develops motor symptoms, dysuria and visual disturbances; the day following the third injection, he/she is admitted to hospital where the diagnosis of multiple sclerosis is rapidly established. For any specialist in drug safety, the causal role of the vaccination would be highly probable: but not for Tozzi et al.…

Actually, amongst the 20 items of their checklist, no less than 15 (75%) are devoted to refute a vaccine-induced causality: no need to have read the Complete Psychological Works of Sigmund Freud to recognize the “resurfacing of the repressed” in such a bias. After all and as the authors confess with an astonishing ingenuousness, the main point is it not to “maintain public confidence in immunization programs”? Tell me: in any of the “immunization programs” – including those devised by vaccine makers [3]?...

REFERENCES

[1] Girard M. Quality of ADRs. Adv Drug React Ac Pois Rev 1987;4:231-232

[2] Comenge Y, Girard M. Multiple sclerosis and hepatitis B vaccination: adding the credibility of molecular biology to an unusual level of clinical and epidemiological evidence. Med Hypotheses 2006; 66: 84-86

[3] Cohen D, Carter P. WHO and the pandemic flu "conspiracies". BMJ 2010; 340:c2912

On 2014 Apr 18, Amitav Banerjee commented:

When death is the outcome temporally associated with an intervention such as immunization, it is better to err on the side of safety by presuming all deaths as probably AEFI unless other etiology is established beyond reasonable doubt. Establishing the cause of adverse event or death may not always be possible in developing countries as health facilities are lacking in rural and remote areas. In such situations, "Counting" without "Classifying" would be a more appropriate strategy to establish any AEFI by comparing with baseline data which can again be established by "Counting." Frequent exercises of classification of AEFI, though conceptually sound will not be sensitive enough to detect all cases of AEFI, without the backup facilities required to establish the correct cause of all deaths or adverse events following immunization in remote areas of developing countries. In such resource poor settings better penetration and more equitable distribution of health services and attention to under five malnutrition, in which we fare very badly, would prevent more cases of deaths due to pneumonia in children rather than adding on more and more vaccines. After promoting the pentavalent vaccine in developing countries, one would expect the same experts to promote the pneumococcus vaccine in these countries. One would wish that the policy makers concentrate more on "Health Promotion" which implies better sanitation, nutrition and education rather than on "Vaccine Promotion" which is a piecemeal solution to the problem of communicable diseases at an exorbitant cost. Amitav Banerjee, Professor Community Medicine, Dr D Y Patil Medical College, Pune, India

On 2014 Apr 09, B M Hegde commented:

"Any intelligent fool can make things bigger, more complex, and more violent. It takes a touch of genius and a lot of courage to move in the opposite direction,” wrote E. F. SCHUMACHER some time ago. We have many such expert groups in science and, more so, in medicine. “The algorithm should provide countries and health officials at the global level with an instrument to respond to vaccine safety alerts, and support the education, research and policy decisions on immunization safety.” This statement in the last part of the abstract tells the whole story. With the new instrument the response to every ‘vaccine safety alert’ will be denial. The new AEFI algorithm makes it possible to declare almost every vaccine related death as ‘unrelated to the vaccine’ based on the fact that deaths were not attributed to vaccine in the pre licensure studies.

It was Charles Sherrington, a Nobel Laureate in physiology, who wrote in 1899 when he became the professor of Physiology at the age of 42 in Liverpool University that “positive sciences can never answer the question “why”. They can, at best, answer “how or how much” but NOT “why?” As a physiologist I can say how the heart contracts, but not “why” the heart contracts. In reductionist science of medicine we take shelter under this wisdom to bury all the inconvenient questions. No one can for sure say “why” the child died after vaccination, new AEFI notwithstanding. Common sense, circumstantial evidence, emotional and spiritual quotients in our rounded education to be doctors should help us to answer such questions of cause-effect most of the time. Now even if a healthy child dies within minutes following vaccination and there is no alternate explanation for the AEFI, even then the powers that be could easily declare that death as coincidental and not due to the vaccine, thanks to the new AEFI. This is dangerous ‘science’.

B. M. Hegde MD, FRCP(Lond.), FRCP(Edin.), FRCP(Glas.), FRCP(Dub.), FACC(U.S.A.). Formerly Vice Chancellor, Manipal Academy of Higher Education, Manipal India

On 2014 Mar 26, J Stone commented:

None

On 2014 Mar 24, Toni Bark commented:

None

On 2014 Mar 12, Lokesh Tiwari commented:

There is conceptual flaw in the ‘Assessment of causality of individual adverse events following immunization (AEFI): A WHO tool for global use’ developed by Tozzi et al. If we apply common sense, fundamental safety rule is to identify threats to safety and fix them. Having so many deaths reported after immunization, particularly following pentavalent vaccine in the developing countries, it is important to develop a more sensitive tool to identify AEFI and classify them according to severity of threat they impose to human life and thoroughly investigate them. As pointed out by Puliyel J and Madhvi Y, Tool developed by Tozzi et al will under report AEFI. Considering sequence of events in the world pertaining to development of vaccines, their business, conflict of interests of health agencies and members of guideline committees, it seems that huge business in vaccine industry is affecting science of vaccines and we are developing various ways to promote the business at the cost of human lives. Compared to Brighton classification, tool developed by Tozzi et al has much less sensitivity to detect adverse events following immunization as it masks probable and possible reactions related to immunization and classifies them as inconsistent or indeterminant categories, giving ways to continue the use of potential risky vaccines. Going for a less sensitive tool for safety concerns is not only illogical but risky for the children of the world.

On 2014 Feb 20, Jacob Puliyel commented:

None

On 2014 Apr 26, Meenakshi Girish commented:

The admonition "be scientific" - whenever one does not back one's argument by scientific data - now sounds so hollow! Every scientific 'fact', it seems, has two sides. Of late this has become truer for medical science. And if, I as a clinician can get confused, imagine the plight of the lay public for whom it is confusion confounded. While preparing for a debate recently on vaccinations, I was perplexed that the IAP Committee on Immunisation states "The committee reviewed studies on the distribution and prevalence of different pneumococcal serotypes in the country, including some recent studies done by vaccine manufacturers in India like Pneumonet by M/s Pfizer and Alliance for Surveillance of Invasive Pneumococci (ASIP) by M/s GSK (unpublished). The committee concluded that the data on prevalence of different pneumococcal serotypes in the country was sparse and limited to few hospital based studies. On the basis of available data, it is difficult to evaluate the coverage of serotypes included in the existing Pneumococcal conjugate vaccine (PCV) formulations" [Indian Pediatrics July,2012]. Despite this the vaccine has been included in the IAP immunisation recommendations. Is the IAP justified in doing so? On the other hand, would they be wrong if they were to withold the recommendations till large scale studies are carried out.

On 2014 Mar 24, Paul King commented:

Dear Jacob Puliyel,

 The points you have raised are excellent.

 However, from the scientists' point of view, the reality is that all adverse events following inoculation (AEFIns) should be reported and, unless a causal relationship has been proven or unequivocally disproved, no attempt should be made to classify such AEFIns as they occur.

 Instead, a centralized open database system, like the U.S. Vaccine Adverse-Events Reporting System (VAERS), but one which has meaningful penalties for any healthcare provider's failure to report any possible AEFIn to those maintaining this AEFIn database, who after confirming the source of the report, its general validity, the vaccine's identity and lot identifier, and, in as much detail as possible, the temporal and symptoms information associated with that AEFIn, will post it to the database where an open search tool is provided for anyone to examine the data as they see fit (e.g., a search engine like the one available at <http://www.medalerts.org>).

 Then, on  vaccine type and specific vaccine source, temporal clustering and, for multiple-dose vaccines, the dose effect should be continually assessed for evidence of a signal (temporal clustering or associated much more with one manufacturer's vaccine than another manufacturer's comparable vaccine or a disproportionate number of AEFIns after the first dose as compared to the second dose when dosing occurs within a several weeks pattern). 

For new vaccines, all observed AEFIns following vaccination, regardless of the events found in the clinical trials used to get the vaccine approved for use, should be treated as possibly causally related UNLESS an in-depth autopsy clearly establishes that the vaccine could not possibly have been a causal or aggravating factor.

 In addition, for new vaccines, the government should require the manufacturer to distribute each lot in a suitable small contiguous population segment such that, if there is any possible "lot" effect, the "lot" effect should be more easily ascertained.

 Furthermore, before any vaccine is administered to a child, the child' temperature, pulse rate, weight, apparent health and the child's general health history should be recorded and, 30 to 60 minutes after the inoculations given, the child's temperature and pulse rate should be again recorded along with any apparent inoculation-site effects (e.g., redness and swelling) and inoculation-triggered reactions (e.g., fainting).

 Finally, absent unequivocal proof that a vaccine inoculation could not have caused conditions that led to a vaccinated individual's death or been a contributing factor thereto, all AEFIns that have death as an outcome should be labeled as probably vaccination related.

 From the viewpoint of the scientific method, any classification that establishes artificial barriers and criteria to the inclusion of observed events into the body of knowledge (as the WHO's proposed system so clearly does) should be REJECTED because it interferes with the scientific method's ability to observe all of the data and to generate testable hypotheses and draw inferences from the entire body of post-inoculation AEFIn information that has been generated by the actual events that have transpired. 

 Finally, in speaking of post-inoculation adverse events, term "immunization" should be replaced by "inoculation" because, as others have noted, it takes some time (weeks to months) for any significant level of protection to be generated after an inoculation; not all who are inoculated will develop that protection; and many, if not most, AEFIn events occur shortly after inoculation.

 The sooner all start being honest about the realities surrounding vaccine inoculation, the more likely it will be that the public will rely on the information provided.

 However, if, as the WHO seems to be doing and, in the USA, the U.S. Centers for Disease Control and Prevention (CDC) has been doing for years, public health officials continue to inflate the benefits of vaccination (by at least a factor of 10) and minimize the risks associated with vaccine inoculation (by a factor of 100), then, as is increasingly being observed in the USA and other developed countries, the public will become increasingly wary of vaccination.

 In much of the world, people understand that there are no true coincidences -- only events that have been made to appear to be coincidental by either a genuine lack of understand of the overall facts leading to the "coincidence" reported or by the deliberate suppression of the facts, including when, for example, AEFIns that result in death are made to "disappear". 

 Hopefully, the WHO will realize the scientific falsity of its current approach to classifying AEFIns in a manner that, in essence, pretends that the death did not occur after the vaccination or that it was a "coincidence" or "is unclassifiable", and abandon that approach.

 If the WHO does not recognize the preceding reality, then all of the scientists who study AEFIns in a given country need to demand that their governments reject the WHO scheme as vigorously as they are able!

On 2014 Mar 18, Jacob Puliyel commented:

Dr Malik, as part of the India Government Ministry of Health, has information on the AEFIs with Pentavalent vaccine and their investigation. I mention individual instances because Dr Malik is familiar with them and it best illustrates the harm done by the new system of AEFI classification.

Of the 54 deaths reported to the Government of India some have been investigated and the AEFI reports are available here

The deaths as described below could well have been caused by ‘multisystem generalized reaction to one or more vaccine components’ (page 50 of the CIOMS/WHO report). But a case definition for this entity has not been developed as yet by the Brighton group. When such multisystem reactions occur they appear like the multiple organ dysfunction syndrome (MODS) that follow sepsis but it must not be confused with it. The AEFI committee assumes that all MODS are due to due to sepsis or, if it is associated with unconsciousness, it must be meningitis/encephalitis. The new AEFI algorithm seems to promote and propagate this confusion.

1) The manner in which the deaths are declared as unrelated to the vaccine is instructive. The first of these deaths was in a child who was vaccinated at 11 AM. That evening at 5 PM the child had fever for which she was given paracetamol. The baby woke up several times that night crying. She was found dead in her bed next morning. There was blood around the nostrils.

On postmortem examination a large swelling around the injection site 9.8 x 7.9 x 4.7 cm with edema and infiltration involving muscle and subcutaneous tissue was noted. The internal organs including brain, kidneys and lungs were congested. There were petechiae on the surface of the lungs and bilateral adrenal bleeds. The report said the autopsy findings were consistent with death due to hypersensitivity reaction.

The AEFI report however says the death is unlikely to be a programme error or ‘due to vaccine associated to the vaccination’ (sic)

2) The central team looked at the 15 deaths in Kerala . One death in Pathanamthitta is reported in detail. The healthy 6 week baby was vaccinated on 26 December 2012 at 12 noon. The mother noted swelling of legs and the baby was ‘grunting’ and reluctant to feed. She was given 4 drops of paracetamol syrup for 'fever and crying' at 5 PM and 2 times on the next day. The baby was found dead with blood stained discharge from the nose at 4-30 AM on the morning of the 28th. No postmortem examination was performed.

The AEFI report classified this death as “Unknown unclassifiable category” in spite of the fact that the parents are available and gave a detailed history as part of the verbal autopsy.

3) The AEFI report has more interesting details that I quote verbatim: “Temporality of vaccination with death cannot be established as a causal relationship since it may also be possible that in the child had a subclinical infection (therefore no obvious signs and symptoms) and it aggravated in cold conditions, led to Bronchiolitis and death. This may be the reason for death due to pulmonary edema (manifesting as blood from the nose and in some postmortem findings of blood in respiratory tract).”

The cold conditions reported as leading to pulmonary edema and death is intriguing. Kerala has a climate that borders between a tropical savanna climate and a tropical monsoon climate. As a result it does not experience distinct seasons. The mean maximum temperature is 34 °C mean minimum temperature is 21 °C and the lowest temp recorded in December in Thiruvanthapuram was 20 °C..

The death in babies in Kerala who were apparently completely well in the morning when they went for immunization but who became unwell soon after vaccination and deteriorated rapidly to death cannot rationally be attributed to ‘subclinical bronchiolitis infection aggravated by cold conditions’ leading rapidly to pulmonary edema and death.

Any explanation no matter how outlandish seems adequate but the likelihood of there being a causative association with the vaccination, which is obvious, is not considered.

This is akin to a person found dead under the rubble after a house collapse. The house-insurance-company may refuse to pay the next of kin, saying the house collapse could have been coincidental and cannot be blamed for the death till it is proved that the deceased had not suffered a heart attack just before the house collapsed.

4) 8 deaths in Kashmir were investigated by the AEFI team.

There had been 1 death each in June September and December 2013, but in October there were 11 deaths according to a RTI response (AD/FW/K/RTI/822-24).

Many local newspapers reported the deaths in October were associated with use of a brand of Pentavalent vaccine called Easyfive which vaccine had previously been disqualified because of quality concerns but had just been reintroduced. Easyfive is not being used in the Kashmir Government immunization programme currently.

Like in Kerala, the deaths in Kashmir were attributed blithely to sepsis with metabolic disorder (in Aisha who had convulsions and normal CSF and no blood culture evidence of sepsis), meningitis (in Mozim based on persistent vomiting, metabolic acidosis, convulsions and crying excessively), pneumonia with aspiration (in Nida with fast breathing and gasping respiration with a family history of sibling death following pneumonia), liver disorder with metabolic acidosis (in Karneez with fever followed by repeated seizures but no CSF examination), sepsis with metabolic acidosis (in Shaistha crying excessively and irritable for 3 days after vaccination, convulsions on the third day, put on ventilator till death on 9th day). It is paradoxical, these diagnoses were reached on the clinical symptoms and laboratory findings of MODS without specific blood culture evidence of sepsis or CSF evidence of meningitis, suggesting the criteria for making these diagnoses are not strict like the algorithm needed to arrive at a diagnosis of death caused by vaccine. No death was attributed to MODS due to ‘multisystem generalized reaction to one or more vaccine components’. The most obvious possibility is not even mentioned in the differential diagnosis.

5) The doctors in the Kashmir hospital who noted the sudden increase in cases of deaths in October (11 cases in one month against the previous rate of 1 case in 2 months) sent telephonic text messages to senior government officials in the central government and state government to appraise them of these events but the AEFI team comes down heavily on them for sending these messages "as if to report 'breaking news'". Apparently they were expected not to take notice of these deaths and continue with business as usual and perhaps not to alert anyone.

It seems that after the October spike in incidence of AEFI deaths, the brand of vaccine was changed and the numbers of death have come down but the Government AEFI report does not mention it. It appears that although all brands of the vaccine have been associated with AEFI deaths in different countries, some brands may be particularly lethal.

A good AEFI reporting system must have picked up all these linkages which the new algorithm makes studious efforts to avoid.

On 2014 Mar 13, Jacob Puliyel commented:

6500 PENTAVALENT-VACCINE AEFI-DEATHS IN INDIA EACH YEAR CANNOT BE ACCEPTABLE

I thank Dr Malik for endorsing the opinion that the AEFI guidelines need to be revised. Unfortunately neither Tozzi and colleagues, nor Bonhoeffer et al (Bonhoeffer J, 2009) have responded and we do not know if the authors agree with us.

Dr Malik’s comment points out that India lacks a strong system of AEFI surveillance and investigation. This is undisputable. The fact of this poor surveillance in some States is clearly illustrated by the data obtained under the Right to Information from the Government of India, published by the Center for Science and Environment in their magazine – Down to Earth. Goa - a State with good surveillance and a low infant mortality rate (IMR 10/1000 live births) reported 26 AEFI deaths per 100,000 infants vaccinated with the Pentavalent vaccine whereas Gujarat, with poorer health infrastructure and high IMR, reported only 0.4 deaths per 100,000 infants vaccinated (Gujarat IMR is 50/1000 live births). The correlation between reported AEFI rate and IMR is illustrated here (R2 = 0.458).

Clearly AEFI deaths (following Pentavalent vaccination) in States like Goa and Kerala is much higher than previously (with the older DPT vaccine). If the Goa 'AEFI-death-rate' (reliable data from the state with the lowest IMR and presumably the best health infrastructure and surveillance systems) is projected nationwide and 26 babies are to die among every 100,000 babies vaccinated, 6500 AEFI deaths can be anticipated when the year’s birth cohort of 25 million babies in India are vaccinated. This cannot be acceptable.

On 2014 Feb 21, Akash Malik commented:

In total agreement to my worthy colleagues, the AEFI guidelines do need a revision, but citing an example from India (pentavalent) for this is inappropriate, because India lacks a strong system of AEFI surveillance and investigation.

It has to be taken into account that deaths after pentavalent (2.0 per lakh 1st doses of pentavalent vaccine),is less than the expected number of deaths (3.56 deaths per lakh live births)in the state of Kerala (Best performing state in India in terms of IMR )and this rate of 2.0 per lakh 1st doses of pentavalent vaccine is still less than the expected number of adverse events due to DPT alone.

It is important not only to report and highlight numbers, but also to correctly analyse them.

On 2014 Feb 20, Jacob Puliyel commented:

Tozzi and colleagues state that their article describes the new tool for causality assessment of AEFI as set out in the User Manual for the Revised WHO Classification

1) However this manual it seems has been developed without adequate care and without thinking through the consequences of the changes.

a) One pointer to this is how the manual cites an example of vaccines being wrongly blamed for events unrelated to its administration (Page 13). It says that vaccines were wrongly blamed for deaths resulting from consumption of the Cassia occidentalis beans causing a syndrome of acute hepato-myoencephalopathy. However the article they quote describes Japanese B encephalitis being blamed for the deaths – not the vaccine Panwar RS, 2008

b) Dr Madhavi put the new classification to a simple test. She tested how the system would have responded if the revised AEFI classification been in place in 1999. She suggests that the intusussceptions following use of RotaShield would have been classified as ‘inconsistent with causal association’ because:

i) other qualifying factors like previous similar reaction (re-challenge equivalent) were not available

ii) nor was biological plausibility demonstrated at that time

iii) and background rate, other exposures etc were not ruled out.

Under this category ‘inconsistent with causal association’ it would never activate the analysis reserved for ‘indeterminate’ reactions – “Information on AEFIs that are classified as indeterminate should be pooled and analyzed by time and place, in order to understand if the AEFI represents a new signal of an unrecognized event. Should this be the case, a more comprehensive epidemiological investigation should be performed.” Tozzi AE, 2013

These intusussceptions would have continued for years before the vaccine was pulled off the shelves.

2) In my previous comment I had pointed out that the experts investigating the Sri Lanka deaths from Pentavalent vaccine deleted the categories ‘Probable’ and ‘Possible’ from the Brighton classification and reported that although they found no alternate explanation for the deaths, the deaths were unlikely to be related to the vaccine. An apologist for the distorted Brighton Classification told me at that time that it was ‘experts’ who developed the Brighton Classification and it is alright for other experts to alter the classification. That was prescient. The new system makes a virtue of this ability to disregard the algorithm when it suits any expert. It says “Finally, instead of assigning a final category through an automatic classification process, the final outcome of the case investigation depends on the personal judgment of the assessor.” Tozzi AE, 2013

3) Post marketing surveillance is used to monitor the safety of a drug. Since drugs are approved on the basis of clinical trials which involve a relatively small numbers of people who have been selected for this purpose - meaning that they normally do not have other medical conditions which may exist in the general population - post marketing surveillance can further refine, or confirm or deny, the safety of a drug after it is used in the general population by large numbers of people who have a wide variety of medical conditions. (Abridged from Wikipedia)

The effort of the revised WHO Causality assessment of an AEFI is to deny adverse events noticed on post marketing surveillance, are caused by the vaccine (unless they had been observed in the original small clinical trials).

Events that occur 1 in 10,000, for example the intussusceptions with RotaShield will be noticed only in post marketing surveillance.

The AEFI in individuals was responsible for the ‘signal’. Evidence of causality in the individual provided evidence of causality in the population. The new system stands this logic on its head when it says on Page 5 that causality in the population must be known before causality in the individual can be ascribed.

“Causality assessment of AEFI should be performed at several different levels. The first is the population level, where it is necessary to test if there is a causal association between the use of a vaccine and a particular AEFI in the population. Secondly, at the level of the individual AEFI case report, one should review previous evidence and make a logical deduction to determine if an AEFI in a specific individual is causally related to the use of the vaccine. The third level of assessment is in the context of the investigation of signals.”

I am not stating that there is something sacrosanct about the original Brighton Classification but one has to evaluate the two schemes (Brighton vs CIOMS) from the point of view of patient safety to see which scheme would react to rare RotaShield-like-reactions first. The causality scheme that insists on calling all reactions as ‘indeterminate’ or ‘inconsistent/coincidental’ just because they were not noticed in the original small clinical trials, undermines the very raison d'être of post marketing surveillance. Patient safety (meaning protecting patients) rather than vaccine safety (protecting vaccines) is what is important.

On 2014 Feb 15, Y. Madhavi commented:

The above responses have raised very pertinent and highly contentious issues regarding CIOMS/WHO tool for the causality assessment of AEFI presented in Tozzi et al paper. This tool has negative implications in resource poor settings with poor surveillance systems and inadequate infrastructure.

Tozzi et al’s model claim to establish the causality between vaccine and AEFI referring to the general and cause-specific definitions of CIOMS (2012), (pages 39-40). However, it is not that simple nor is it really helpful. For instance, intussusception is a known adverse event with rota virus vaccine. But intussusception can also happen without Rotavirus vaccination. Suppose, if it happens in the week after immunization, it is possible that it is caused either by vaccine or it could be that the child was to get it any way and vaccination was coincidence. Yet the CIOMS scheme will classify this as 2A Consistent causal association to immunization [http://www.who.int/vaccine safety/initiative/tools/vaccinfosheets/en/index.html].

On the other hand had the CIOMS scheme been in use since1999, it is interesting to speculate how these intussusceptions would have been classified given that there was no known causal association. The fact that the event could take place independently of vaccination and no clear biologically plausible explanation linking it to the vaccine, it would be classified as 1A or 4C ‘Inconsistent causal association to immunization’ or ‘C. Coincidental’ [http://www.who.int/vaccine safety/initiative/tools/vaccinfosheets/en/index.html].

Reactions classified as ‘Indeterminate’ may at some point be evaluated if similar events are reported to identify a signal of a new potential causal association. Reactions classified as ‘Inconsistent causal association to immunization’ are not even reviewed later.

Dr. Puliyel is correct in suggesting that, a child who develops high fever within 2 hours, has convulsions, then lapsed into a coma and dies within 10 hours following immunization will be classified as ‘unclassifiable’ because ‘encephalitis’ as cause of the event cannot be ruled out.

Tozzi et al, argue that in the case of ‘events with a consistent temporal relationship but with insufficient evidence for the vaccine as a cause according to well designed epidemiologic studies… further studies are encouraged if other similar events are identified......’. This can be used to defer discontinuation of the vaccine despite adverse effect. Moreover, the requirement for ‘other similar events’ is vague, as it does not specify how many events are needed to suspend vaccination.

In a recent controversy on AEFI causality report on pentavalent vaccine in India, deaths following vaccination were attributed to sudden infant deaths (SIDS) without doing proper investigation. In the causality assessment of 15/2/13, the AEFI committee reported eight infant deaths as SIDS. However, in a new causality report, which is now available with the health ministry, only one death due to SIDS, three deaths with causal association with immunisation and seven deaths as 'unclassifiable' including those previously reported as SIDS [http://www.pharmabiz.com/NewsDetails.aspx?aid=79591&sid=1]. It is interesting that where sufficient information was previously available to arrive at the ‘diagnosis by exclusion’ of SIDS the information was later considered insufficient enough to merit the new classification as ‘unclassifiable’. “The final classification should be based on the personal judgment of the assessor”, according to Tozzi et al, (page no 5043, under 3.3 Algorithm), and this will result in numerous similar discrepancies in the classification directly related to the number of people whose ‘personal judgment’ is sought.

In India, there have been around 21 deaths and 83 adverse events reported following pentavalent vaccination which was introduced in a few states last year. Rather than halting the vaccination till its safety is proven, India extended its vaccination to the rest of the states under international pressure.

If the sole purpose of CIOMS/WHO tool of causality for AEFI is to ensure vaccine safety in the population, the pentavalent vaccination would have been halted in India, as it was done in countries like USA (rotavirus vaccine), till the vaccine safety is established.

The main emphasis of Causality assessment of AEFI approach seems to be to cite either the lack of strong evidence for causal association or the presence of strong evidence against causal association, to classify an adverse event as “Not an AEFI”.

On 2014 Feb 05, Brandon Horn commented:

Drs. Puliyel and King,

Thank you for the insightful observations. Just wanted to add that antibody response time is quite variable. Theoretically, we would see adverse events also happening weeks to months after introduction to an antigen. Varicella for example produces symptoms typically 10-21 days after exposure. Antibody detection for HIV occurs between 3 and 6 months. Therefore, we could expect some serious adverse events, for example related to autoimmune disease, to show signs up to 6 months+ post-inoculation. This is one of the reason it is so hard to study vaccine adverse events in the United States, because the vaccine schedule makes any pediatric autoimmune disease temporally associated with a vaccination. Animal studies have indicated that this indeed can occur.

On 2014 Feb 05, Paul King commented:

In general, as a scientist who studies vaccine safety, effectiveness, and cost-effectiveness issues, I support Dr. Puliyel's observations and suggestions.

Moreover, the use of the term "coincidental" should be limited to those instances where a full autopsy, including appropriate tissue section examinations fails to find any potential causal or contributory factor that may be related to a preceding vaccination. In science, while it is a reality that the relationship between a specific vaccination and a subsequent serious adverse event MAY be "coincidental", proof is required that all of the other scientifically plausible linkages between the vaccination and the AEFI have been properly considered and ruled out by scientifically sound and appropriate medical evidence BEFORE that AEFI should be labeled as "a coincidence".

Furthermore, intervening events between the vaccination and the adverse reaction reported should NOT preclude the possibility of the vaccines' given being a possible or probable causal factor UNLESS the intervening event completely accounts for "100%" of the symptoms and findings that may be attributable to the suspected vaccination/vaccinations.

In addition, when an adverse events occur after vaccination/vaccinations, such events should still be classified as "possibly" or "probably" associated with the suspected vaccine when other probable or possible causal factors are identified UNLESS the other factor(s) completely preclude the vaccine from being a causal factor.

Finally, when looking at a possible adverse event and a suspect antecedent vaccination set, one should consider ALL of the case's antecedent and concomitantly administered vaccines in light of the their possible contributions to the adverse outcome observed before attempting to assign a possible or probable linkage between a given vaccine and and the adverse-event observed.

Thus, UNLESS there is definitive proof that some intervening non-vaccine event caused the adverse outcome that was reported, an Adverse-Event Following Inoculation (AEFI) should always remain an AEFI [Note: As an example, a child's death is reported 2 weeks after as the child received an AEFI but the causal event is found to be that an appliance (e.g., a television) was knocked off onto the child while the child was sleeping -- causing the child's death. Only in such instances, should an initial AEFI could be reclassified as a not an AEFI.

In addition, whenever a "new" vaccination program is introduced, since the goal is to ensure the vaccine being introduced is "safe" and there is no real-world experience in the population as to what serious adverse events may occur or their rate of occurrence in that population, AEFIs that are serious should be presumed to be linked to the "new" vaccination program in question UNLESS there is definitive evidence that only other factors were causal -- especially in instances of deaths shortly after inoculation.

Furthermore, since most serious adverse events occur shortly after inoculation, the term "AEFI" should be redefined as "Adverse-Event Following INOCULATION" because the vaccine has not had time to generate any effective level of disease protection in the inoculee and, in some instances, the children having the adverse reaction do not develop any level of disease protection -- especially in those instances where the adverse-event is "death" shortly after inoculation.

Clearly, if the choice is between the Brighton criteria and those being proposed in the WHO "tool", obviously the Brighton criteria should be retained and the scientifically challenged criteria proposed by the WHO should be rejected.

On 2014 Feb 04, Jacob Puliyel commented:

DEATHS IN DEVELOPING COUNTRIES WILL COUNT FOR LESS

Tozzi et al describe causality assessment for AEFI using criteria from the CIOMS/WHO working group on pharmacovigilence . AEFI is any untoward medical occurrence following immunization. A causal relationship is not implied. The Brighton collaboration classified reactions as very likely/certain; probable; possible; unlikely; unrelated; unclassifiable, based on temporal criteria and evidence of alternate etiological explanation. Deaths soon after immunization without an alternate explanation were classified as ‘probably related to vaccine’.

THE NEED FOR A NEW CLASSIFICATION

With use of Pentavalent vaccine (Diphtheria, Tetanus, Pertussis, Hib and Hepatitis B) in developing countries, there have been many AEFI deaths. WHO experts investigated these deaths in Sri Lanka. They could find no alternate explanation for 3 deaths. The experts write in the report that they deleted the categories ‘probable’ and ‘possible’ from the Brighton classification and after that, although they could not attribute deaths to another cause, they were declared unlikely to be related to the vaccine. The association to vaccine should have been classified as ‘probable’. The BMJ published a letter about this Saxena KB, 2010

1. The CIOMS/WHO report came after the BMJ letter. The committee, composed of 40 members (19 were vaccine-industry representatives), proposed changes to how AEFI are investigated and reported. The 194-page document has serious implications for developing countries.

2. Case definitions for different adverse events were developed. Illogically, the inclusion criteria for the proposed case definitions are too strict to be of scientific value in most countries. For example, to diagnose ‘encephalitis’ one needs the child with fever and encephalopathy to live at least 24 hours after AEFI onset, and have a CSF examination, an EEG or neuro-imaging and one of these investigations must be positive, to reach a level 2 diagnosis (page 73).

3. Presume that a healthy child is vaccinated. Suppose she develops high fever within 2 hours, has convulsions, then lapsed into a coma and dies within 10 hours. (Variations of this scenario have been enacted repeatedly with Pentavalent vaccine). Using CIOMS/WHO definitions, as the encephalopathy lasted less than 24 hours, it cannot be classified as encephalitis. In many countries, the facilities for a lumbar puncture may be unavailable, much less those for an EEG and CT/MRI. Under the report’s scheme, this would be labeled, “Insufficient information to distinguish both acute encephalitis and ADEM; Case unable to be definitely classified”.

4. Further, on page 170 (i) (in very small print), the report says, “Such a case must be classified as 'Not an AEFI'”. This last step, which classifies an “AEFI” as “Not an AEFI”, is patently unscientific, illogical and Orwellian.

5. The scenario described could well have been caused by ‘multisystem generalized reaction to one or more vaccine components’ (page 50). The encephalopathy, fever and convulsions could follow systemic inflammatory response but CIOSM does not have case definition for this, and inability to exclude causes of encephalopathy, is sufficient to classify the reaction as ‘not an AEFI’.

6. The risk is not merely theoretical. In March 2013 WHO investigated 12 deaths in Viet Nam from the same Pentavalent vaccine. The Viet Nam report stated, “no fatal AEFI has ever been associated with this vaccine”. The 2008 WHO experts had earlier classified the Sri Lanka deaths as AEFI unlikely to be related to vaccine. The Viet Nam report stating ‘no fatal AEFI has ever been associated with this vaccine’ suggests the Sri Lanka AEFI is now reclassified as “Not an AEFI”.

7. Tossi et al suggest that ‘events with a consistent temporal relationship but with insufficient evidence for vaccine as a cause, according to well designated epidemiological studies – in such cases, further studies are encouraged if other similar events are identified’. There have been 54 deaths temporally related to the vaccine in India. Instead of taking them as a group the new system looks at ‘individual adverse events’ and then labels them as ‘not an AEFI’ making way for many more deaths.

8. Tossi and colleagues report different clinical scenarios (Supplementary material). The scenario in Asia is also worth considering. Pentavalent vaccine is selectively promoted in developing countries with poor surveillance systems. Eighty three deaths following Pentavalent inoculation have been reported from Asian countries Puliyel J, 2013. There is no plausible alternate explanation. Most deaths occurred after the first vaccine dose, fewer after the second, and hardly any after the third. This pattern argues against the deaths being random events. Yet, the WHO to maintains that a cause and effect relationship has not been established.

9. This contrasts with what happened in 1998 when RotaShield was approved in the US. When intussusceptions were reported to the Vaccine Adverse Event Reporting System (VAERS) and only 12 children were affected the vaccine was withdrawn. No one needed to be ‘certain’.

10. A public health expert in India, Dr Y Jain has filed a public interest petition in the Supreme Court asking for these deaths to be investigated. The petition states that in the first six months, when the 40,000 doses were administered to children in the southern state of Kerala, at least five children died. Extrapolated to the 25 million babies born in India each year, 3,125 deaths can be expected from the vaccine each year. Using the best evidence from the Minz study Minz S, 2008 the incidence of Haemophilus influenzae type b meningitis in India is 7/100,000 children under 5. Using the Unicef rapid method to estimate Hib Pneumonia 350 deaths from Hib disease will be prevented over 5 years by vaccinating one birth cohort of 25 million. 3125 deaths from AEFI cannot be acceptable to prevent 350 Hib deaths.

11. The Infant Mortality Rate (IMR) in Kerala is 14. Seven of these deaths occur in the first month. The other seven deaths occur in the remaining 11 months of the infant’s first year. Pentavalent vaccine is administered six weeks after birth to babies who have survived neonatal life. Of the first five deaths from the vaccine, four occurred within 24 to 48 hours of the first dose of this vaccine. The death rate of babies in the first days after vaccination works out to be two to four times higher than Kerala’s post neonatal IMR.

12. The first 14 deaths in Kerala were investigated by AEFI experts. They reported 6 children had co-morbid conditions and the other 8 died of sudden infant death syndrome (SIDS). This SIDS rate on day after vaccination is higher than the all-cause IMR.

13. Under the new scheme, fatal AEFI in developing countries will be falsely recorded as ‘Not an AEFI’, simply because some time or test criterion was not met. Death is the worst AEFI possible. Continued use of the CIOMS/WHO scheme will result in missing an important opportunity to pick up signals that could save lives. This is dangerous. Perhaps we need to get back to the Brighton Classification.

On 2014 Feb 04, Jacob Puliyel commented:

DEATHS IN DEVELOPING COUNTRIES WILL COUNT FOR LESS

Tozzi et al describe causality assessment for AEFI using criteria from the CIOMS/WHO working group on pharmacovigilence . AEFI is any untoward medical occurrence following immunization. A causal relationship is not implied. The Brighton collaboration classified reactions as very likely/certain; probable; possible; unlikely; unrelated; unclassifiable, based on temporal criteria and evidence of alternate etiological explanation. Deaths soon after immunization without an alternate explanation were classified as ‘probably related to vaccine’.

THE NEED FOR A NEW CLASSIFICATION

With use of Pentavalent vaccine (Diphtheria, Tetanus, Pertussis, Hib and Hepatitis B) in developing countries, there have been many AEFI deaths. WHO experts investigated these deaths in Sri Lanka. They could find no alternate explanation for 3 deaths. The experts write in the report that they deleted the categories ‘probable’ and ‘possible’ from the Brighton classification and after that, although they could not attribute deaths to another cause, they were declared unlikely to be related to the vaccine. The association to vaccine should have been classified as ‘probable’. The BMJ published a letter about this Saxena KB, 2010

1. The CIOMS/WHO report came after the BMJ letter. The committee, composed of 40 members (19 were vaccine-industry representatives), proposed changes to how AEFI are investigated and reported. The 194-page document has serious implications for developing countries.

2. Case definitions for different adverse events were developed. Illogically, the inclusion criteria for the proposed case definitions are too strict to be of scientific value in most countries. For example, to diagnose ‘encephalitis’ one needs the child with fever and encephalopathy to live at least 24 hours after AEFI onset, and have a CSF examination, an EEG or neuro-imaging and one of these investigations must be positive, to reach a level 2 diagnosis (page 73).

3. Presume that a healthy child is vaccinated. Suppose she develops high fever within 2 hours, has convulsions, then lapsed into a coma and dies within 10 hours. (Variations of this scenario have been enacted repeatedly with Pentavalent vaccine). Using CIOMS/WHO definitions, as the encephalopathy lasted less than 24 hours, it cannot be classified as encephalitis. In many countries, the facilities for a lumbar puncture may be unavailable, much less those for an EEG and CT/MRI. Under the report’s scheme, this would be labeled, “Insufficient information to distinguish both acute encephalitis and ADEM; Case unable to be definitely classified”.

4. Further, on page 170 (i) (in very small print), the report says, “Such a case must be classified as 'Not an AEFI'”. This last step, which classifies an “AEFI” as “Not an AEFI”, is patently unscientific, illogical and Orwellian.

5. The scenario described could well have been caused by ‘multisystem generalized reaction to one or more vaccine components’ (page 50). The encephalopathy, fever and convulsions could follow systemic inflammatory response but CIOSM does not have case definition for this, and inability to exclude causes of encephalopathy, is sufficient to classify the reaction as ‘not an AEFI’.

6. The risk is not merely theoretical. In March 2013 WHO investigated 12 deaths in Viet Nam from the same Pentavalent vaccine. The Viet Nam report stated, “no fatal AEFI has ever been associated with this vaccine”. The 2008 WHO experts had earlier classified the Sri Lanka deaths as AEFI unlikely to be related to vaccine. The Viet Nam report stating ‘no fatal AEFI has ever been associated with this vaccine’ suggests the Sri Lanka AEFI is now reclassified as “Not an AEFI”.

7. Tossi et al suggest that ‘events with a consistent temporal relationship but with insufficient evidence for vaccine as a cause, according to well designated epidemiological studies – in such cases, further studies are encouraged if other similar events are identified’. There have been 54 deaths temporally related to the vaccine in India. Instead of taking them as a group the new system looks at ‘individual adverse events’ and then labels them as ‘not an AEFI’ making way for many more deaths.

8. Tossi and colleagues report different clinical scenarios (Supplementary material). The scenario in Asia is also worth considering. Pentavalent vaccine is selectively promoted in developing countries with poor surveillance systems. Eighty three deaths following Pentavalent inoculation have been reported from Asian countries Puliyel J, 2013. There is no plausible alternate explanation. Most deaths occurred after the first vaccine dose, fewer after the second, and hardly any after the third. This pattern argues against the deaths being random events. Yet, the WHO to maintains that a cause and effect relationship has not been established.

9. This contrasts with what happened in 1998 when RotaShield was approved in the US. When intussusceptions were reported to the Vaccine Adverse Event Reporting System (VAERS) and only 12 children were affected the vaccine was withdrawn. No one needed to be ‘certain’.

10. A public health expert in India, Dr Y Jain has filed a public interest petition in the Supreme Court asking for these deaths to be investigated. The petition states that in the first six months, when the 40,000 doses were administered to children in the southern state of Kerala, at least five children died. Extrapolated to the 25 million babies born in India each year, 3,125 deaths can be expected from the vaccine each year. Using the best evidence from the Minz study Minz S, 2008 the incidence of Haemophilus influenzae type b meningitis in India is 7/100,000 children under 5. Using the Unicef rapid method to estimate Hib Pneumonia 350 deaths from Hib disease will be prevented over 5 years by vaccinating one birth cohort of 25 million. 3125 deaths from AEFI cannot be acceptable to prevent 350 Hib deaths.

11. The Infant Mortality Rate (IMR) in Kerala is 14. Seven of these deaths occur in the first month. The other seven deaths occur in the remaining 11 months of the infant’s first year. Pentavalent vaccine is administered six weeks after birth to babies who have survived neonatal life. Of the first five deaths from the vaccine, four occurred within 24 to 48 hours of the first dose of this vaccine. The death rate of babies in the first days after vaccination works out to be two to four times higher than Kerala’s post neonatal IMR.

12. The first 14 deaths in Kerala were investigated by AEFI experts. They reported 6 children had co-morbid conditions and the other 8 died of sudden infant death syndrome (SIDS). This SIDS rate on day after vaccination is higher than the all-cause IMR.

13. Under the new scheme, fatal AEFI in developing countries will be falsely recorded as ‘Not an AEFI’, simply because some time or test criterion was not met. Death is the worst AEFI possible. Continued use of the CIOMS/WHO scheme will result in missing an important opportunity to pick up signals that could save lives. This is dangerous. Perhaps we need to get back to the Brighton Classification.

On 2014 Feb 20, Jacob Puliyel commented:

None

On 2014 Mar 12, Lokesh Tiwari commented:

There is conceptual flaw in the ‘Assessment of causality of individual adverse events following immunization (AEFI): A WHO tool for global use’ developed by Tozzi et al. If we apply common sense, fundamental safety rule is to identify threats to safety and fix them. Having so many deaths reported after immunization, particularly following pentavalent vaccine in the developing countries, it is important to develop a more sensitive tool to identify AEFI and classify them according to severity of threat they impose to human life and thoroughly investigate them. As pointed out by Puliyel J and Madhvi Y, Tool developed by Tozzi et al will under report AEFI. Considering sequence of events in the world pertaining to development of vaccines, their business, conflict of interests of health agencies and members of guideline committees, it seems that huge business in vaccine industry is affecting science of vaccines and we are developing various ways to promote the business at the cost of human lives. Compared to Brighton classification, tool developed by Tozzi et al has much less sensitivity to detect adverse events following immunization as it masks probable and possible reactions related to immunization and classifies them as inconsistent or indeterminant categories, giving ways to continue the use of potential risky vaccines. Going for a less sensitive tool for safety concerns is not only illogical but risky for the children of the world.

On 2014 Mar 24, Toni Bark commented:

None

On 2014 Mar 26, J Stone commented:

None

On 2014 Apr 09, B M Hegde commented:

"Any intelligent fool can make things bigger, more complex, and more violent. It takes a touch of genius and a lot of courage to move in the opposite direction,” wrote E. F. SCHUMACHER some time ago. We have many such expert groups in science and, more so, in medicine. “The algorithm should provide countries and health officials at the global level with an instrument to respond to vaccine safety alerts, and support the education, research and policy decisions on immunization safety.” This statement in the last part of the abstract tells the whole story. With the new instrument the response to every ‘vaccine safety alert’ will be denial. The new AEFI algorithm makes it possible to declare almost every vaccine related death as ‘unrelated to the vaccine’ based on the fact that deaths were not attributed to vaccine in the pre licensure studies.

It was Charles Sherrington, a Nobel Laureate in physiology, who wrote in 1899 when he became the professor of Physiology at the age of 42 in Liverpool University that “positive sciences can never answer the question “why”. They can, at best, answer “how or how much” but NOT “why?” As a physiologist I can say how the heart contracts, but not “why” the heart contracts. In reductionist science of medicine we take shelter under this wisdom to bury all the inconvenient questions. No one can for sure say “why” the child died after vaccination, new AEFI notwithstanding. Common sense, circumstantial evidence, emotional and spiritual quotients in our rounded education to be doctors should help us to answer such questions of cause-effect most of the time. Now even if a healthy child dies within minutes following vaccination and there is no alternate explanation for the AEFI, even then the powers that be could easily declare that death as coincidental and not due to the vaccine, thanks to the new AEFI. This is dangerous ‘science’.

B. M. Hegde MD, FRCP(Lond.), FRCP(Edin.), FRCP(Glas.), FRCP(Dub.), FACC(U.S.A.). Formerly Vice Chancellor, Manipal Academy of Higher Education, Manipal India

On 2014 Apr 18, Amitav Banerjee commented:

When death is the outcome temporally associated with an intervention such as immunization, it is better to err on the side of safety by presuming all deaths as probably AEFI unless other etiology is established beyond reasonable doubt. Establishing the cause of adverse event or death may not always be possible in developing countries as health facilities are lacking in rural and remote areas. In such situations, "Counting" without "Classifying" would be a more appropriate strategy to establish any AEFI by comparing with baseline data which can again be established by "Counting." Frequent exercises of classification of AEFI, though conceptually sound will not be sensitive enough to detect all cases of AEFI, without the backup facilities required to establish the correct cause of all deaths or adverse events following immunization in remote areas of developing countries. In such resource poor settings better penetration and more equitable distribution of health services and attention to under five malnutrition, in which we fare very badly, would prevent more cases of deaths due to pneumonia in children rather than adding on more and more vaccines. After promoting the pentavalent vaccine in developing countries, one would expect the same experts to promote the pneumococcus vaccine in these countries. One would wish that the policy makers concentrate more on "Health Promotion" which implies better sanitation, nutrition and education rather than on "Vaccine Promotion" which is a piecemeal solution to the problem of communicable diseases at an exorbitant cost. Amitav Banerjee, Professor Community Medicine, Dr D Y Patil Medical College, Pune, India

On 2014 May 26, Marc Girard commented:

As a drug specialist with a more than 30-year experience in safety, I was often missioned as a medical expert witness in criminal or civil inquiries on vaccine litigations, where I repeatedly pointed out the worrying lack of knowledge of most vaccine experts regarding the basic scientific and regulatory requirements normally applicable to pharmaceutical products – esp. as far as adverse reactions were concerned: this represents a tragic shortcoming for such preventive drugs, targeted towards people in perfect health with the problematic aim of protecting them against diseases the occurrence of which in a severe form is often an unlikely event, and for which therefore the risk of side-effects should not go beyond extremely narrow limits… Amongst many others examples, this paper by Tozzi et al. is an impressive illustration of this lack of expertise a far as drug safety is concerned.

Whatever the authors’ views on the matter, the primary tool to assess drug safety is not “epidemiological studies” but double-blind investigations versus placebo (a genuine placebo, namely a completely inert product and not another vaccine…) performed during development on a sufficient duration: as everybody knows, vaccine makers have managed the exploit to get exempted of this otherwise inescapable step. Additional indicators of amateurism in vaccine development include “fast track” procedures (whose consequences have been recently illustrated by the narcoleptic risk of Pandemrix), as well as the striking poverty of the dose-ranging studies (which account for regular turmoil in “experts” recommendations regarding the scheme of immunization as well as the timing of boosters).

As far as “epidemiological studies” are concerned, their main default is of being inextricably polluted by major conflicts of interests, as in most cases, they are performed either by the manufacturers or, even more frequently, by national or international health agencies (or their “experts”) whose most obvious interest is to hide the – sometimes tragic – drama they may have triggered by their irresponsible campaigns to promote some vaccines: this is the reason why, amongst a dozen of such studies performed on the neurological risks of hepatitis B vaccination, the only one showing a clear increase was also the sole whose financing was independent of any promoters of this immunization…

To come now to the assessment of causality of individual adverse reactions, the first remark is that the methodological inspiration of Tozzi et al. is regrettably obsolete. The use of algorithms has been almost completely abandoned by most regulatory bodies, for one reason which was pointed out more than 25 years ago [1]: namely, that use of algorithms (or decision table) is a tool for clinical decisions (e.g. to perform a laparotomy in view of such and such signs or symptoms), whereas assessing causality in drug toxicity is a process of knowledge, and not of decision (there is not the slightest signification in “deciding” whether a drug is, or not, the cause of an effect – and the reader has just to consider that this incredible way of reasoning is never used to assess drug efficacy, yet another pharmacological effect…). Lack of validation regarding the inter-raters agreement is an additional indicator of the methodological amateurism of the authors: this step should have been a strong prerequisite, taking account the vague of some items (e.g. that concerning an “appropriate time window after vaccine administration”, when experience of such an assessment with academic vaccine “experts” shows that it is almost invariably assessed as too short or too delayed… The same holds true for the item of “biological plausibility”, when experience, once again, teaches the fanatical obstinacy of most vaccine experts to challenge even the biological mechanisms which are most probable or convincing [2]).

Jacob Puliyel has listed a number of cases where Tozzi et al.’s algorithm would miss obvious vaccine causality. Let’s suggest another, that I witnessed in a number of sad instances: 3 weeks after a first injection, a person develops unexplained asthenia associated with paresthesia; one week after the second immunization, he/she develops motor symptoms, dysuria and visual disturbances; the day following the third injection, he/she is admitted to hospital where the diagnosis of multiple sclerosis is rapidly established. For any specialist in drug safety, the causal role of the vaccination would be highly probable: but not for Tozzi et al.…

Actually, amongst the 20 items of their checklist, no less than 15 (75%) are devoted to refute a vaccine-induced causality: no need to have read the Complete Psychological Works of Sigmund Freud to recognize the “resurfacing of the repressed” in such a bias. After all and as the authors confess with an astonishing ingenuousness, the main point is it not to “maintain public confidence in immunization programs”? Tell me: in any of the “immunization programs” – including those devised by vaccine makers [3]?...

REFERENCES

[1] Girard M. Quality of ADRs. Adv Drug React Ac Pois Rev 1987;4:231-232

[2] Comenge Y, Girard M. Multiple sclerosis and hepatitis B vaccination: adding the credibility of molecular biology to an unusual level of clinical and epidemiological evidence. Med Hypotheses 2006; 66: 84-86

[3] Cohen D, Carter P. WHO and the pandemic flu "conspiracies". BMJ 2010; 340:c2912