Wednesday, October 7, 2009

20 Monkeys

Last Wednesday (9.30.09), Age of Autism posted an unsurprising announcement of a soon-to-be published study by Hewitson et al., Delayed Acquisition of Neonatal Reflexes in Newborn Primates Receiving a Thimerosal-Containing Hepatitis B Vaccine: Influence of Gestational Age and Birth Weight in an upcoming issue of Neurotoxicology. Naturally, the author, Mark Blaxill not only inflates the results of the study but also manages to implicate influenza vaccines too:
Consequently, the finding that early exposure to potentially toxic vaccine formulations can cause significant neuro-developmental delays in primates has explosive implications for vaccine safety management. These implications go far beyond the domestic HBV program and raise concerns about HBV formulations sold abroad as well as the domestic influenza vaccine program. Most influenza vaccines, including the vaccines in the upcoming swine flu program, contain thimerosal and are routinely administered to pregnant women and infants.
Primate studies are not trivial to perform and it is imperative to implement a robust study design with sufficient statistical power. This is why we discuss the study design in more detail here. Before we dive into this study, let's backtrack a bit. Back in May of 2008, Hewitson et al. presented 3 posters at the International Meeting for Autism Research (IMFAR). Dr. David Gorski provided and excellent summary of these 3 abstracts on Science-Based Medicine so there is no need to discuss these at length here and now. We mention these abstracts since they are clearly parts of a single study that this Hep B/thimerosal study is also part of and there are discrepancies between them.

The authors claim that the animals were selected on a "semi-random" basis to receive either thimerosal-containing Hepatitis B vaccines at birth (TCV or thimerosal-containing vaccine) (n=13), a saline placebo (n=4), or no injection (n=3). We would like to point out that there isn't any accepted term such as "semi-random". Selection is either random or non-random and while there are numerous ways to randomise ones' selection randomisation is never a sliding-scale. Next, the 3 aforementioned abstracts state that there were 13 treatment animals (TCV) and 3 receiving saline placebo. Since these animals are all undoubtedly from the same group and protocol, that means that either 4 animals (1 saline placebo and 3 no injection) were not used for inclusion on the abstract results or that 4 animals were added for the purposes of this study. This discrepancy, along with their "semi-random" selection require explanation since they could certainly affect the results and subsequent interpretation.

Given the authors' hypothesis, i.e. ethylmercury affects infant (macaque) neurodevelopment, and to ensure they are controlling for all conceivable bias, it is puzzling as to why their treatment and control group sizes were alloted in the manner they were. The Hep B vaccine, with or without thimerosal will have a physiological effect upon recipients, which may easily manifest in outward symptomology e.g. fever, fussiness and/or injection site swelling and soreness. A more robust study design would have, for example, been TCV Hep B (n=10), thimerosal-free Hep B (n=5) and saline placebo (n=5). This would have controlled for the absolute effects between the TCVs, Hep B and placebo.

The authors also describe how the animals were divided into peer groups such that each group contained animals from either exposed or unexposed study groups for later "social testing". Not only is this social testing never mentioned again in the present paper, but placing the animals in such groupings introduced observer bias for the reasons mentioned above. Even though the animals were in separate cages, the cages containing exposed or unexposed animals were grouped together. An observer could subconsciously note that an animal was fussy and had visible swelling at the injection site and thus, be able to guess that the rest in the group were also TCV-exposed. Conversely, animals in the unexposed peer groups would likely be behaving differently and no outward signs of having received a vaccination.

Appropriate randomisation and blinding of the observer to the treatment are essential elements of a good study, animal studies that do not utilize randomisation and blinding are up to 5 times more likely to report a difference between study groups than studies that employ these methods. Neither were apparently done properly in the present paper.

The neonatal assessments for reflexes, perceptual and motor skills were carried out by a single assessor, L.A.H. On at least 2 other studies of neonatal Rhesus Macaque behaviour using the same metrics, i.e. the Brazelton Neonatal Behavioral Assessment Scale, co-authored and authored by some of the same investigators as this study, multiple assessors were used. From Sackett et al. (2006):
Reflex and sensory motor responses were measured 5–6 days per week from birth through 30 days. The purpose was to assess neural integrity during the neonatal period, as reflected in the development of motor and sensory reflexes required for the survival of macaque monkeys in a natural environment. Similar procedures for a similar purpose have been used to assess both humans (Brazelton, 1973) and rhesus monkeys (Schneider & Suomi, 1992).
Reliability was assessed from the simultaneous observations of pairs of testers for each response that could be scored simultaneously and by immediately repeated observations by the second tester for items requiring handling the neonate by the tester. The latter values combine reliability with response repeatability. Periodic retesting maintained reliability at 80% or better on each type of scoring.
And from Dettmer et al. (2007):
Neonatal assessment and social data were collected by multiple observers. Interrater reliability for social behavior was achieved by computerized calculation of a kappa score (k) of .80 or above for each of five consecutive randomized focal animal sessions. Reliability for nursery assessments was achieved when observers obtained an 89% agreement on three consecutive randomized assessments.
Now given the intense scrutiny most of the authors had to know this study would be given, why use just one assessor? What was the possible observer error of one assessor if such a high discordance is acceptable for 2 or more observers?

The authors state that they had to right-censor the data because a further intervention on day 14 precluded them from assessing the animals longer (right-censoring data is a statistical technique to account for subjects that don't reach the a threshold value by the end of the study period). But not only do they fail to mention what this intervention was, but it appears as though they did assess the animals until at least day 30, as indicated in one of their IMFAR abstracts. Why was this data not reported in the present paper? authors also did not include any biochemical analyses, such as baseline and post injection blood-mercury levels. If they went to such considerable effort to prepare and verify TCVs for this study, it seems almost absurd to ignore the relatively easily-obtainable data points that mercury testing and a chemistry panel could provide.

In summary, the present study has significant flaws in experimental design. Groups size varied greatly, animals were not randomised properly, and the observer was not properly blinded. These are all conditions under which the likelihood of finding a significant difference between groups (a 'false positive') is artificially increased. Furthermore, 4 animals seem to have been added long after the initial study (as reported at the 2008 IMFAR meeting). While this may have been to satisfy reviewer requests, it certainly contributed to the problems mentioned above. These problems will also carry through to all subsequent studies reporting on the same cohort of monkeys.

There are further problems in the data reported and how they are presented and interpreted. According to the results:
All infants remained healthy during the study testing period reaching all criteria for maintaining health including appetite, weight gain, and activity level, and achieved temperature regulation by Day 3.

Neonatal reflexes and sensorimotor responses were measured daily from birth until post-natal Day 14. Datasets from the two unexposed groups (with or without a saline injection) were combined when no differences were found for all measures (p>0.5). There was a significant delay in time-to-criterion for exposed vs. unexposed animals for three survival reflexes including root (Fig. 1A; p=0.004), suck (Fig. 1B; p=0.002) and snout (Fig, 1C; p=0.03) and approached significance for startle (p=0.11). The effect of exposure also approached significance for grasp hand (p=0.07), one of the motor reflexes. There were no reflexes for which the unexposed animals took significantly longer to reach criterion than the exposed animals (Table 2).
So for all of the thirteen measurements, only 3 reached statistical significance. And one of these, snout, the unadjusted main effects of exposure, did not maintain significance using the Cox regression models, nor did it reach statistical significance when exposure was measured against gestational age (GA). The data from Tables 3 and 4 were sufficiently explained in the body of the text, and since they were attempts to squeeze every last bit of possible associations between TCV exposure and development, the tables themselves were redundant. It would have been far more interesting and informative to have instead included a table that had animals, exposure and assessment results for each measurement. It is also worth noting that all animals in the exposed groups reached root, suck and snout criterion well-prior to reaching censor and unexposed animals did not reach criterion for some measurements prior to censor.

Three measurements out of 13 were statistically significant when comparing TCV exposed and unexposed animals but are they biologically important? Maybe, maybe not; it's difficult to say due to the low quality of the study design in terms of control groups and observation. It is worth noting this gem from Mark Blaxill about the results interpretation:
To make the point more simply, it would have taken only modest differences in the management of the data analysis to make over half of the measured reflexes show significant delays instead of a third of them. Pointing this out is not intended as a criticism of the study, however, but rather a demonstration of how conservative the authors were in their interpretation of the results.
"Modest difference in the management of the data analysis"?! What exactly are you suggesting here Mr. Blaxill? A little more data massaging would have been justified?

There were 3 authors involved with this study that have considerable conflicts of interest, Dr.s Hewitson, Wakefield and Stott. Here is their COI statement as it appears in the galley of the manuscript:
Prior to 2005, CS and AJW acted as paid experts in MMR-related litigation on behalf of the plaintiff. LH has a child who is a petitioner in the National Vaccine Injury Compensation Program. For this reason, LH was not involved in any data collection or statistical analyses to preclude the possibility of a perceived conflict of interest.
Now here is the COI declaration in Neurotoxicology Instructions to Authors:
All authors are requested to disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. See also

NeuroToxicology requires full disclosure of all potential conflicts of interest. At the end of the manuscript text (and in the cover letter of the manuscript), under a subheading "Conflict of Interest statement", all authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. If there are no conflicts of interest, the authors should state, "The authors declare that there are no conflicts of interest." Signed copies of the NeuroToxicology Conflict of Interest policy form are required upon submission. The Conflict of Interest policy form can be downloaded here. In order to minimize delays, we strongly advise that the signed copies of these statements are prepared before you submit your manuscript. The corresponding author is responsible for sharing this document with all co-authors. Each and every co-author must sign an individual disclosure form. The corresponding author is responsible for uploading their form and those of their co-authors.
None of these 3 authors fully declared their conflicts of interest. Now they may think they have some wiggle room with the way the COI declaration instructions are worded, but they don't. They have certainly violated full disclosure of actual or potential conflicts of interest. Dr. Hewitson has failed to mention her affiliation with DAN! and her husband's employment by Thoughtful House and his associations with decidedly anti-vaccine organisations such as SafeMinds, whom, not-so-coincidentally co-funded this study and may or may not have had significant input into the study design. Dr. Wakefield goes without saying but as the executive director of a medical practise that unabashedly treats autism as vaccine damage, the mission of his organisation has a considerable vestment in any positive results for such studies and should have been declared as such. Dr. Stott is employed by Thoughful House as a Senior Research Associate as well and may still be offering her services as paid 'expert' for 'vaccine injury' litigation.

Dr. Carol Stott has undeclared conflicts of interest, not to mention she has a history of rather deranged behaviour related to the MMR-autism scare originated by Dr. Wakefield (she was disciplined by the British Psychological Society), yet she was allowed to handle the data analyses for this study.
Finally, let's take a look at their funding sources:
This work was supported by the Johnson Family, the late Liz Birt, SafeMinds, the Autism Research Institute, The Ted Lindsay Foundation, the Greater Milwaukee Foundation, David and Cindy Emminger, Sandy McInnis, Elise Roberts and Vivienne McKelvey.
Most of these individuals and organisations have considerable investment in a vaccine-autism association, particularly with regards to mercury. Sally Bernard has demonstrated her vitriolic dedication to the mercury-autism causation claim when she was invited to take part in a CDC study examining TCVs and autism. A study that was published in a 2007 NEJM issue had her input and cooperation until the results were announced; she flounced off, claiming that the study design was poor. Given that SafeMinds is a supporter of Thoughtful House and has funded dubious research such as the "Rain Mouse" study by Hornig et al., it is clear that they exert substantial pressure for results they may want.

Primate studies come with significant financial and ethical costs. These are sentient creatures, their use in animal research should not be broached lightly and their sacrifice should come with a significant contribution to the literature. It is a shame that the design of the current study did not ensure the optimal benefit from this investment.

Please visit Respectful Insolence for Orac's undoubtedly thorough critique of this study.

ETA: The authors of this blogpost, Catherina and Science Mom have absolutely no conflicts of interest either real or perceived to declare.

Friday, September 25, 2009

EU approves GSK's Pandemrix and Novartis' Focetria H1N1 vaccine

The European Medicines Agency (EMEA) has approved GlaxoSmithKline's "Pandemrix" and Novartis' "Focetria" H1N1 vaccines for use for adults and children from 6 months up as well as pregnant women. The current product characteristics can be downloaded through the EMEA, here (Pandemrix) and here (Focetria). The Committee is recommending a two shot series, three weeks apart for all vaccinees, although clinical trials of other H1N1 vaccines have recently shown one shot to be effective in most vaccinees older than 10 years.

The UK has made provisions to acquire 132 million doses of the GSK vaccine. The following 2 vaccines have been approved by the EMEA

GSK's Pandemrix:
Description: Pandemrix is a suspension and emulsion for injection, meaning fluid from 2 vials must be mixed to form a multidose container that stays usable for 24 hours.
After mixing, 1 dose (0.5 ml) contains: Split influenza virus, inactivated, containing 3.75 µg A/California/7/2009 (H1N1)v-like strain (X-179A) (haemagglutinin ) (propagated in eggs). AS03 adjuvant composed of squalene (10.69 mg), DL-α-tocopherol (11.86 mg) and polysorbate 80 (4.86 mg). The suspension (2.5ml) and emulsion (2.5ml) vials once mixed form a multidose container (10 doses) containing 5 micrograms thiomersal (0.5 µg per dose). There does not seem to be a single dose container planned for Pandemrix at this time.
Indications and Usage: H1N1 Pandemrix is indicated for the active immunisation of individuals 18 years and up against influenza disease caused by pandemic (H1N1) 2009 virus. Adults aged 18-60 years of age, one dose can be given although 2 doses are recommended at an interval of 3 weeks between the first and second doses. Adults >60 years old should receive 2 doses, 3 weeks apart.

Children 6 months to 17 years may receive this vaccine if medically indicated: Children and adolescents aged 10-17 years: If vaccination is considered to be necessary, consideration may be given to dosing in accordance with the recommendations for adults. However, the choice of dose for this age group should take into account the available data on safety and immunogenicity in adults and in children aged from 3-9 years. See sections 4.8 and 5.1.
Children aged 3-9 years: If vaccination is considered to be necessary, the available data suggest that administration of 0.25 ml of vaccine (i.e. half of the adult dose) at an elected date and a second dose administered at least three weeks later may be sufficient.
There are very limited safety and immunogenicity data available on the administration of AS03-adjuvanted vaccine containing 3.75 μg HA derived from A/Vietnam/1194/2004 (H5N1) and on administration of half a dose of the same vaccine (i.e. 1.875 μg HA and half the amount of AS03 adjuvant in 0.25 ml ) at 0 and 21 days in this age group.
See sections 4.8 and 5.1.
Children aged from 6 months to 3 years: If vaccination is considered to be necessary, consideration may be given to dosing in accordance with the recommendation in children aged 3-9 years.
Contraindications: History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium deoxycholate) of this vaccine. If vaccination is considered to be necessary, facilities for resuscitation should be immediately available in case of need. Please consult the full package insert for other warnings and precautions.
Clinical Trials: There are numerous phase II and III trials listed here although it is unclear the antigen concentrations and adjuvanted or non-adjuvanted vaccines used.
Safety and Efficacy: Clinical data from trials are not yet available.
Novartis' Focetria:
Description: Focetria comes as a suspension for injection in pre-filled syringes. It is an H1N1 pandemic influenza vaccine (surface antigen, inactivated, adjuvanted) containing (per 0.5ml dose) haemagglutinin and neuraminidase 7.5 µg (expressed in µg haemagglutinin) from A/California/7/2009 (H1N1)v like strain (X-179A) virus propagated in eggs. The adjuvant MF59C.1 contains 9.75 mg squalene, 1.175 mg polysorbate 80, and 1.175 mg sorbitan trioleate. Other excipients include: sodium chloride, potassium chloride, potassium dihydrogen phosphate, disodium phosphate dihydrate, magnesium chloride hexahydrate, calcium chloride dihydrate, sodium citrate, citric acid and water. The single dose vial comes in a thimerosal free formulations of pre-filled syringes.
Indications and Usage: Novartis H1N1 monovalent vaccine is indicated for adults 18 years and older with 2 doses given at a ≥ 3 week interval. Children between the ages of 6 months and 17 years can also receive this vaccine with 2 doses given at a ≥ 3 week interval.
Contraindications: History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide (CTAB)) of this vaccine. If vaccination is considered to be necessary, facilities for resuscitation should be immediately available in case of need. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and Immunogenicity of A/H1N1-SOIV (Swine Flu) Vaccine With and Without Adjuvant in Children (3 to less than 9 years old) is a randomized, single blind, dose comparison, single group assignment, safety/efficacy study. The anticipated primary outcome date is November, 2009. Immunogenicity, safety and tolerability of 2 doses of adjuvanted and non-adjuvanted swine origin A/H1N1 Monovalent Influenza Vaccine (egg-derived) in healthy subjects from 6 months to 17 years of age is a randomized, single blind, uncontrolled, parallel assignment, safety/efficacy study. The anticipated study completion date is April, 2011, but the primary outcome data will be completed in November, 2009. More trials can be found here.
Safety and Efficacy: Titers of the hemagglutination-inhibition antibody exceeded 1:32 in 88% of subjects who had received one vaccine dose by this time and in 92 to 100% of subjects who had received both doses (Figure 2A). All subjects had microneutralization antibody at a titer exceeding 1:40 by day 21 (Figure 2B).

Edited 30 November 2009

Wednesday, September 23, 2009

The end of the idea of an autism epidemic?

NHS (National Health Service in the UK) Statistics released a study Autism Spectrum Disorders in adults living in households throughout England – report from the Adult Psychiatric Morbidity Survey 2007 detailing the results of a very intensive survey on psychiatric health of 7500 adults in the UK. They give as key facts:

1. Using the recommended threshold of a score of 10 or more on the Autism Diagnostic Observation Schedule, 1.0 per cent of the adult population had ASD. Published childhood population studies show the prevalence rate among children is also approximately 1.0 per cent.
2. The ASD prevalence rate was higher in men (1.8 per cent) than women (0.2 per cent). This fits with the gender profile found in childhood population studies.
3. There is no indication of any increased use of treatment or services for mental or emotional problems among adults with ASD. This is borne out by the recent National Audit Office publication “Supporting People with Autism Through Adulthood”.
4. A greater proportion of single people were assessed with ASD than people of other marital statuses combined. This was particularly evident among men.
5. Prevalence of ASD was associated with educational qualification, particularly among men. The rate for men was lowest among those with a degree level qualification and highest among those with no qualifications.

This means three things:

1. These data do not support the notion of an "autism epidemic" or more precisely, there appears to be an administrative increase in prevalence, not an actual increase of cases, since they found just as many autistic adults per 100 as there are kids. This is not necessarily surprising. While anti-vaccine organisations, like Generation Rescue, liked to exaggerate the increase of autism, claiming an increase of 6000% in rather bold adverts, more thorough research in Europe and the US has shown that the prevalence of autism had been systematically underestimated. A hat tip is due to blogger Joseph, who had predicted the 1% rate in adults some years ago, using prevalence studies of adults (see here). There is no indication that the prevalence of autism in the UK would be any different from the prevalence in the United States. While this survey is not conclusive for a steady prevalence of ASDs, taken with other data, is strong evidence that ASD prevalences have not actually increased.

2. There is a huge gap in services for autistic adults, which is one of the main reasons the NHS commissioned the study in the first place and also the main point that the NAS (National Autistic Society in the UK) stresses in their press release in response to the study:

… The NAS has long campaigned to raise awareness of the fact that services and support for adults with autism are woefully inadequate. Nearly two thirds (63%) of adults with autism told us they do not have enough support to meet their needs. Many thousands feel isolated and ignored and are often completely dependent on their families. This study gives us further evidence to demand that more vital support is put in place….

And, as the BBC and Guardian immediately clued in on:

3. It seems that the MMR is completely off the hook here, since the MMR was not introduced in the UK until the birth year of the youngest adult in this cohort, therefore is unlikely to have contributed to their autism.

Bad news for the "vaccine caused your child's autism but I can cure her" peddlers. Good news for many parents who suffered from the idea that it could have been the vaccines they 'allowed' to be given that caused their child's autism, and hopefully for the autistic adults, whose needs might get more attention now.

Most interestingly, a well known pediatrician, who calls this study "bogus" without having read it, gave an impromptu explanation for the apparent rise in autism diagnosis in comparison to official autism numbers in previous decades. He writes (intended to support the notion of an "autism epidemic"):

I see a NEW child with autism that I diagnose or suspect myself at least once or twice a month. NOT kids who come to me because of their child's problems - I've talking kids that the parents had no idea.

How wonderfully this supports the current finding. Reasonably young doctors with training in current DSM criteria will find autism even in cases in which not even the parents were aware of any developmental issues. That alone would explain a large percentage of autism diagnoses made today, compared to 20 or 30 years ago, when DSM criteria for autism were more narrow and doctors not as aware as they are today. It should not surprise anyone that if today’s doctors take a second look at “yesterday’s children” that they will find a lot of cases of ASD who went undiagnosed.

Preliminary reaction to the results of this survey by some have been perplexing. We have seen comments such as, “Claiming there's no autism epidemic is an insensitive slap in the face to all families affected by autism.” and “Anyone who is around young children can see there is an alarming increase in ASD - along with allergies.” Identifying the autism prevalence amongst adults and enacting services will undoubtedly benefit today's autistic children, hardly a "slap in the face". In fact, we would hope that the NHS will expand this survey to produce results that would more accurately reflect adult autism prevalence and gaps in services and that other countries will follow suit.

Research objectives such as those in the NHS survey are relatively inexpensive to conduct and will profoundly benefit everyone in the autistic community. The farther reaching implications being that if autism prevalence has remained steady for several decades then not only does that severely weaken the vaccine-autism claims but limited research funding can be directed towards studies that will also positively impact the autism community such as genetics and therapies research. The only ones benefiting from an "autism epidemic" are those making money from perpetuating the myth of "vaccine-damaged" children. So who really has the autistic community's best interest in hand?

Sunday, September 20, 2009

2009/2010 H1N1 Vaccines for U.S. Distribution: Update 9.24.09

We have put together what the upcoming H1N1 vaccines will look like that will be distributed in the U.S. We wish to stress that some of this information is provisional and subject to change as more data become available. Such changes will be announced as updates in the title. The parental seed strain for the H1N1 vaccines is A/California/7/2009 (H1N1)v, however, several seed strains have been developed and sent to the WHO for distribution to the vaccine manufacturers to be tested for development as candidate vaccine H1N1 strains such as X‐179A, NIBRG-121, CBER-RG2 and IVR‐153. The following 4 vaccines have been approved by the FDA:

MedImmune's Monovalent H1N1 FluMist:
Description: FluMist is a live, attenuated vaccine administered intranasally manufactured on the same platform as their seasonal trivalent vaccine, FluMist. Each pre-filled sprayer is a single 0.2 mL dose that contains 10^6.5-7.5 FFU of the live attenuated influenza virus reassortant of the pandemic (H1N1) 2009 virus: A/California/7/2009 (H1N1)v, 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, 0.96 mg/dose monobasic potassium phosphate, and 0.015 mcg/mL gentamicin sulfate. The vaccine contains no preservatives.
Indications and Usage: FluMist is a vaccine indicated for the active immunization of individuals 2-49 years of age against influenza disease caused by pandemic (H1N1) 2009 virus. Children 2 through 9 years of age should receive two 0.2mL doses approximately 1 month apart. Children, adolescents and adults age 10 through 49 years should receive a single 0.2 mL dose.
Contraindications: Hypersensitivity to eggs, egg proteins, gentamicin, gelatin or arginine or life threatening reactions to previous influenza vaccination. Concomitant aspirin therapy in children and adolescents. Pregnant women, those with asthma and those with certain underlying immunocompromised disorders should not receive FluMist. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and immunogenicity in healthy adult (18-49 years old) is to evaluate the safety and immunogenicity of the H1N1 FluMist and is a randomised, placebo-controlled study. The anticipated study completion date is March, 2010 but the primary outcome data was completed in August, 2009. Safety and Immunogenicity in healthy children (2-17 years old) is to evaluate the safety and immunogenicity of the H1N1 FluMist and is a randomised, placebo-controlled study. The anticipated study completion date is March, 2010, but the primary outcome data was completed in August, 2009.
Safety and Efficacy: Clinical data from trials are not yet available.

CSL Limited's Monovalent H1N1 Injectable:
Description: The 2009 Monovalent H1N1 Vaccine is an inactivated split-virion vaccine manufactured on the same platform as their seasonal trivalent vaccine, Afluria. CSL H1N1 vaccine is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. It is formulated to contain 15 mcg HA per 0.5 mL dose of influenza A/California/7/2009 (H1N1)v-like virus, contains 4.1 mg sodium chloride, 80 mcg monobasic sodium phosphate, 300 mcg dibasic sodium phosphate, 20 mcg monobasic potassium phosphate, 20 mcg potassium chloride, and 1.5 mcg calcium chloride. From the manufacturing process, each dose may also contain residual amounts of ≤ 10 ppm sodium taurodeoxycholate, ≤ 1 mcg ovalbumin, ≤ 0.2 picograms [pg] neomycin sulfate, ≤ 0.03 pg polymyxin B, and less than 25 nanograms beta-propiolactone. It is available in 0.5 mL preservative-free (thimerosal-free), single-dose, pre-filled syringes and 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 24.5 mcg (micrograms) of ethylmercury.
Indications and Usage: CSL H1N1 Monovalent Vaccine is indicated for adults 18 years of age and older against influenza disease caused by pandemic (H1N1) 2009 virus. Adults 18 years of age and older should receive a single 0.5 mL intramuscular dose.
Contraindications: Hypersensitivity to eggs or chicken protein, neomycin, or polymyxin, or life-threatening reaction to previous influenza vaccination. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and Immunogenicity in healthy children (6 months to less than 9 years old) is a randomised, observer-blinded study to evaluate the safety and immunogenicity of H1N1 Monovalent Vaccine. The anticipated study completion date is March, 2010, but the primary outcome data will be completed in October, 2009. Immunogenicity and dose response in healthy adults (18-64 years old) is a randomised, observer-blind study to assess the immunogenicity elicited by 15 mcg and 30 mcg of H1N1 HA doses. The anticipated study completion date is March, 2010, but the primary outcome data will be completed in September, 2009. Immunogenicity and dose response in healthy children (6 months-9 years old) is randomised, observer-blind study to assess the immunogenicity elicited by 7.5 mcg and 15 mcg of H1N1 HA doses. The anticipated study completion date is April, 2010, but the primary outcome data will be completed in October, 2009. Immunogenicity and dose response in healthy adults (≥18 years old) is randomised, observer-blind study to assess the immunogenicity elicited by 7.5 mcg, 15 mcg and 30 mcg of H1N1 HA doses. The anticipated study completion date is April, 2010, but the primary outcome data will be completed in October, 2009.
Safety and Efficacy: Preliminary data from the HHS report that 80% of healthy 18-60 year old adults demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine. Sixty percent of adults aged 65 and over demonstrated a robust immune response. The vaccine was well-tolerated.
Novartis' Monovalent H1N1 Injectable:
Description: The 2009 Monovalent H1N1 Vaccine is an inactivated sub-unit vaccine manufactured on the same platform as their seasonal trivalent vaccine, Fluvirin. Novartis H1N1 vaccine is a sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. It is formulated to contain 15 mcg hemagglutinin (HA) per 0.5-mL dose of the following virus strain: A/California/7/2009 (H1N1)v-like virus. Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), ≤ 3.75 mcg polymyxin, ≤ 2.5 mcg neomycin, ≤ 0.5 mcg betapropiolactone and ≤0.015% w/v (weight/volume) nonylphenol ethoxylate. It is available in 0.5 mL single-dose, pre-filled syringes and contains trace amount of thimerosal (≤ 1 mcg mercury per 0.5-mL dose) left over from manufacturing. It is also available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 25 mcg (micrograms) of ethylmercury.
Indications and Usage: Novartis H1N1 Monovalent Vaccine is indicated for children and adults 4 years and older against influenza disease caused by pandemic (H1N1) 2009 virus. Children 4 through 9 years of age should receive two 0.5mL doses by intramuscular injection approximately 1 month apart. Children 10 years of age and adults should receive a single 0.5-mL intramuscular injection.
Contraindications: History of systemic hypersensitivity reactions to egg proteins, or any other component of Influenza A (H1N1) 2009 Monovalent Vaccine, or life-threatening reactions to previous influenza vaccinations. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and Immunogenicity and dose response of non-adjuvanted and adjuvanted H1N1 in healthy adults (≥ 18 years old) is a randomised, single-blind study to assess the immungenicity elicited by both adjuvanted and non-adjuvanted, one and two doses and high or low dose monovalent H1N1 HA. The anticipated study completion date is March, 2011, but the primary outcome data will be completed in October, 2009. There are numerous other trials that are planned and/or in process that can be viewed here although are not applicable to the current U.S. H1N1 vaccine recommendations.
Safety and Efficacy: Clinical data from trials are not yet available.

Sanofi Pasteur's Monovalent H1N1 Injectable: The 2009 Monovalent H1N1 Vaccine is an inactivated split-virus vaccine manufactured on the same platform as their seasonal trivalent vaccine, Fluzone. Sanofi Pasteur H1N1 vaccine is prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. It is formulated to contain 15 mcg hemagglutinin (HA) of influenza A/California/07/2009 (H1N1) v-like virus per 0.5 mL dose. 0.05% Gelatin is added as a stabilizer. Each 0.5 mL dose may contain residual amounts of ≤100 mcg formaldehyde, ≤0.02% polyethylene glycol p-isooctylphenyl ether, and ≤2.0% sucrose. It is available in 0.25 mL or 0.5 mL single-dose, pre-filled syringes, single dose 0.5 mL vials and contains no preservative (thimerosal). It is also available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 25 mcg (micrograms) of ethylmercury.
Indications and Usage: Sanofi Pasteur H1N1 Monovalent Vaccine is indicated for infants, children and adults 6 months old and older against influenza disease caused by pandemic (H1N1) 2009 virus. Children 6 through 35 months of age should receive two 0.25 mL intramuscular doses approximately 1 month apart. Children 36 months through 9 years of age should receive two 0.5 mL intramuscular doses approximately 1 month apart. Children 10 years of age and older and adults should receive a single 0.5 mL intramuscular dose.
Contraindications: Severe hypersensitivity to egg proteins or any component of the vaccine or life-threatening reactions after previous administration of any influenza vaccine. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Sanofi H1N1 Influenza Vaccine Administered at Different Dose Levels With and Without AS03 Adjuvant in Healthy Adult and Elderly Populations is a randomised, double-blind study to assess the immunogenicity by both adjuvanted and non-adjuvanted and either 3.75 mcg, 7.5 mcg and 15 mcg of H1N1 HA doses. The anticipated study completion date is October, 2010. There are numerous other trials that are planned and/or in process that can be viewed here although are not applicable to the current U.S. H1N1 vaccine recommendations.
Safety and Efficacy: Update: Preliminary data from the HHS report that 76% of children aged 10-17 years old demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine with 15 mcg of HA. Thirty-six percent of 3-9 year olds demonstrated a strong response to a single (15 mcg- HA containing) dose and 25% of children, 6-36 months demonstrated a strong response to a single dose. Results from a second dose are pending. Preliminary data from the HHS report that 96% of healthy 18-60 year old adults demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine. Fifty-six percent of adults aged 65 and over demonstrated a robust immune response. The vaccine was well-tolerated.

The following vaccine has not yet been approved by the FDA:
GSK's Monovalent H1N1 Injectable: The The 2009 Monovalent H1N1 Vaccine is an inactivated split-virion vaccine (most likely) manufactured on the same platform as their Pandemrix vaccine, which incorporates the same manufacturing process as Fluarix. GSK H1N1 vaccine is a split-virion influenza vaccine that will probably be formulated to contain 15 mcg hemagglutinin (HA) per 0.5-mL dose of the following virus strain: A/California/7/2009 (H1N1)v-like virus. The virus is propagated in fertilised hens’ eggs. Each 0.5-mL dose also contains ≤0.120 mg octoxynol-10 (TRITON® X-100), ≤0.1 mg α-tocopheryl hydrogen succinate, and ≤0.380 mg polysorbate 80 (Tween 80). Each dose may also contain residual (≤0.0016 mcg) amounts of hydrocortisone, ≤0.15 mcg gentamicin sulfate, ≤1 mcg ovalbumin, ≤50 mcg formaldehyde, and ≤50 mcg sodium deoxycholate from the manufacturing process. It should be available in 0.5 mL single-dose, pre-filled syringes and contains no preservative (thimerosal). It may also be available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 5 mcg (micrograms) of ethylmercury.
Indications and Usage: GSK H1N1 Monovalent Vaccine is indicated for active immunization of adults (18 years of age and older) against influenza disease caused by pandemic (H1N1) 2009 virus. Adults 18 years of age and older should receive a single 0.5 mL intramuscular dose.
Contraindications: This vaccine should not be administered to anyone with known systemic hypersensitivity reactions to egg proteins (eggs or egg products), to chicken proteins, or to any component of FLUARIX or who has had a life-threatening reaction to previous administration of any influenza vaccine. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Immunogenicity of the H1N1 candidate flu vaccine in infants (6-35 months old) is a randomised study to asses the immunogenicity of their H1N1 pandemic vaccine in infants using differing dosage schedules. The anticipated study completion date is June, 2011. Safety and immunogenicity of the H1N1 candidate vaccine in children and adolescents (3-17 years old) is a study to assess the immunogenicity elicited by a 3 dose schedule. The anticipated study completion date is April, 2011. Safety and immunogenicity of the H1N1 candidate vaccine in adults (≥18 years old) is a randomised, double-blind study to assess the safety and efficacy of 2 H1N1 vaccines. The anticipated study completion date is December, 2010. Safety and immunogenicity of the H1N1 candidate vaccine in infants and children (6 months to less than 9 years old) is a randomised, double-blind study to assess the safety and efficacy of 2 H1N1 vaccines. The anticipated study completion date is September, 2010.
Safety and Efficacy: Clinical data from trials are not yet available.

This vaccine will probably not be approved by the FDA for use during the 2009/2010 influenza season but is an interesting technology that doesn't require the use of eggs for production and instead a novel cell line. It is anticipated that their trivalent, seasonal recombinant influenza vaccine will be available in November, 2009:
Protein Sciences' PanBlok: The Monovalent H1N1 Candidate Vaccine is a recombinant hemagglutinin (rHA) virus cultured on a proprietary cell line that is non-transformed and non-tumourigenic (expressSF+Ⓡ insect cells), grown in serum-free medium. It would be manufactured on the same platform as their seasonal, trivalent rHA FluBlok vaccine. Protein Sciences PanBlok would be formulated to contain 45 mcg rHA of an H1N1 viral seed stock and stored in sterile, phosphate-buffered saline; there will be some trace excipients left over from the purification process. This vaccine does not contain adjuvants, antibiotics or any preservatives such as thimerosal.
Indications and Usage: It is not known, at this time, the age groups that this vaccine will be indicated for. A phase III trial for FluBlok TIV has been completed (see Clinical Trials) for adults 18-49 years old and the results can be found here.
Contraindications: Unknown at this time.
Clinical Trials: There are no clinical trials listed for PanBlok but the following trials have been listed for FluBlok: Immunogenicity and Safety of Trivalent Recombinant Hemagglutinin Influenza Vaccine in Healthy Adults is a study for safety and efficacy in adults (18-49 years old) which has been completed. The following four studies are listed as active but past estimated completion dates: Safety and Reactogenicity of FluBlok and Comparison of Immunogenicity, Efficacy and Effectiveness Against TIV is a study for safety and efficacy in older adults (50-64 years old). Immunogenicity, Safety, Reactogenicity, Efficacy, Effectiveness and Lot Consistency of FluBlok is a study for safety and efficacy in adults (18-49 years old). Comparison of the Immunogenicity, Safety and Reactogenicity of FluBlØk™, To a Licensed Vaccine In Elderly Adults is a study for safety and efficacy in older adults (≥65 years old). Safety and Immunogenicity of FluBlok in Pediatrics is a study for safety and efficacy in infants and children (6-59 months old).

As you can see, these vaccines are based upon widely used platforms with only an antigen change, just as is done every year with seasonal influenza. One concern is the association between Guillain-Barré syndrome (GBS) and the 1976 Swine Flu vaccine. In 2004, the Institute of Medicine (IOM) issued an Immunization Safety Review: Influenza Vaccines and Neurological Complications which concluded:
The committee concludes that the evidence favors acceptance of a causal relationship between 1976 swine influenza vaccine and Guillain-Barré syndrome in adults.
It has not been fully elucidated as to why there was an increased risk of GBS with receipt of the 1976 swine flu vaccine, however, there have been some postulations:

Although the 1976 influenza vaccine was produced under atypical conditions, with the four manufacturers given less time than usual while being asked to produce much larger quantities than in previous years, there is no evidence that the speed of manufacture or volume of production produced lapses that could have led to a faulty vaccine. The increased risk of GBS associated with the 1976 swine influenza vaccine appeared consistent for vaccine from the four different manufacturers, for the monovalent and bivalent vaccines, and for the whole- and split-virus vaccines.

The use of eggs to produce vaccine-strain influenza virus suggests the possibility that unrecognized antigens might have been present in the 1976 vaccine. C. jejuni infection is a recognized risk factor for GBS, possibly acting through molecular mimicry, and C. jejuni commonly infects chickens. Although the committee concluded that molecular mimicry is only theoretically possible as an immune mechanism by which influenza vaccines may cause GBS, the evidence that C. jejuni antigens can trigger GBS is strong, and the possibility cannot be excluded that C. jejuni antigens were present in swine influenza vaccine from all four manufacturers of the 1976 swine influenza vaccine.
Since this IOM report, there have been some studies conducted which have described the possible mechanism by which that particular vaccine could have facilitated GBS in the recipient. A study by Nachamkin et al. (2008) reports:
We found that commercial influenza vaccines containing A/NJ/1976 induced IgG and IgM antibodies to GM1, but not to C. jejuni, after immunization in mice. Unexpectedly, this was not restricted to the 1976 vaccines but was also observed in both the 1991–1992 and 2004–2005 commercial vaccines. All tested 1976 vaccine lots retained HA activity and induced antibodies to HA in mice after the rather lengthy storage period. There was, however, variability in the HA titers among 1976 vaccine lots, which may represent some, but not complete, degradation of the product during storage.

One of the best‐studied examples of a precedent infection associated with GBS development is C. jejuni–mediated gastroenteritis. C. jejuni expresses ganglioside‐like mimicry in the core region of its bacterial surface LOS, and these structures can induce anti‐ganglioside antibodies, such as anti‐GM1 [16, 27], and reproduce the disease in rabbits [14]. It is currently postulated that loss of tolerance to naturally occurring gangliosides in susceptible hosts is a mechanism for how these antibodies arise after C. jejuni infection and trigger autoimmune‐mediated disease [13, 33, 34]. Activation of autoreactive T cells to self‐glycolipids after infection may also play a role in the development and progression of disease [35]. Nonetheless, most patients infected with C. jejuni strains expressing ganglioside‐like mimicry do not develop GBS [32]; thus, host susceptibility factors may contribute to GBS development [36].

The vaccines produced in 1976, as well as the more contemporary formulations examined here, were produced in eggs and purified by physical and chemical procedures. These vaccine preparations contain not only HA but also other viral components—such as NA, nucleoprotein, and other viral structural proteins [37]—as well as egg proteins and other excipient remnants from production [18]. One hypothesis for why the 1976 vaccines elicited GBS was that bacterial antigens, such as those from C. jejuni, contaminated the eggs and/or were introduced during processing of the vaccine and thus elicited anti–C. jejuni immune responses in susceptible vaccinated individuals, leading to the development of GBS. However, this is an unlikely scenario, because C. jejuni is not transmitted vertically from hen to egg [38]. Alternatively, external egg contamination with C. jejuni through residual fecal material on the exterior of the eggs may have increased during the massive ramping up of swine flu vaccine production. We provide evidence, however, that C. jejuni contamination is probably not the cause of the anti‐GM1 antibody production in animals immunized with A/NJ/1976 and other influenza vaccines. Importantly, antibodies to C. jejuni antigens were not detected in mice immunized with the various vaccine preparations, nor did any of the vaccines contain bacterial DNA.

On the other hand, we present preliminary evidence that influenza HA may be involved in eliciting anti‐GM1 antibodies in mice, on the basis of 2 experiments. First, commercial monoclonal and polyclonal antibodies to GM1 had low but detectable antibody activity against HA, and this was not detected with irrelevant monoclonal antibody or with mouse anti–C. jejuni polyclonal antibody. The specificity of the reaction was further underscored by the absence of HAI activity in an anti–asialo GM1 (the related, nonsialyated form of GM1) polyclonal antibody preparation. Serum samples from mice immunized with a C. jejuni isolate expressing GM1 ganglioside mimicry, which contained anti‐GM1 antibodies (figure 2), did not have HAI activity. This is likely explained by different fine specificities of the anti‐GM11 response in animals immunized with ganglioside‐like structures borne on different chemical entities [13]. Second, experiments with recombinant HA of the H5 subtype also showed that immunized mice developed low but significant responses to GM ganglioside (figure 5).

Influenza viruses enter the host cell by binding to sialic acid receptors on cell surfaces; this is mediated by HA, a viral surface glycoprotein with a receptor‐binding pocket that can bind to specific sialylglycoproteins and cellular gangliosides [39–41] to facilitate host cell entry by influenza viruses. After intracellular viral replication, influenza viruses bud from the cell membrane but may become bound to the cell membrane through sialic acid receptors (e.g., a sialyated ganglioside [41]). Viral NA mediates virus release by removing sialic acid. It is unclear whether sialic acid is completely removed from the viral HA on virus release, and it is possible that sufficient sialic acid–associated HA occurs to mimic a GM1 epitope. This is supported by our ability to detect GM1 epitope mimicry in the egg‐grown virus preparation as well as in commercial vaccine preparations.

It had been reported elsewhere that influenza viruses and the commercial influenza vaccines derived from them contained varying amounts of viral NA and the A/NJ/1976 vaccine contained little to no detectable NA activity [37, 42], compared with other vaccine formulations. This leads us to speculate that the low levels of viral NA in the 1976 vaccine may have allowed for sufficient sialic acid to remain bound to viral HA, forming a sialic acid–HA complex that mimics GM1 ganglioside. Higher levels of viral NA in other vaccines could be sufficient to reduce the amount of sialic acid–HA complex so that it is less immunogenic and therefore did not trigger GBS, as observed for the 1976 vaccine. Thus, given that the immunogenicity of HA differs among influenza virus strains [43], one possibility is that A/NJ/1976 HA had different immunogenic properties than other influenza vaccine HA, resulting in a more potent anti‐GM1 (or other ganglioside) antibody response and GBS in susceptible hosts.

Several studies have examined the risk of GBS after various influenza immunization programs [1, 9, 44–47]. Compared with the risk associated with the A/NJ/1976 vaccines used in the 1976 vaccine program, the risk of GBS after immunization with other influenza vaccines, if there is one, is much smaller, perhaps contributing 1 excess GBS case per million individuals vaccinated. Thus, it has been difficult to establish a link between GBS and influenza vaccine–related GBS in recent years.

This study suggests that it may have been the ratio of HA to NA antigens present in the 1976 Swine flu vaccines that could have been responsible for provoking GBS in susceptible individuals, rather than the specific genetic sequences used in the vaccines. Since this has not been observed with subsequent influenza vaccines, the manufacturing processes that the current H1N1 vaccine producers employ are well tested, there is little reason to conjecture that the upcoming H1N1 vaccines will come with the same risk.

Wednesday, August 19, 2009

Catherina and Science Mom on Respectful Insolence

Yesterday, Orac blogged about a comment that Dr. Bob Sears made about us on his Vaccine Discussion Forum, entitled Weekly Disclaimer about SM and Catherina by Dr. Bob - posted on 8/17/2009 and here it is in its entirety:
Those of you who are regulars here know them well, but I want to make sure those of you are new know about Science Mom and Catherina.

Although it would seem that with the frequency with which their names appear on these posts that they work for this site, they actually have no official affiliation with myself or this site. Although much of their scientific information seems to be accurate, I do not trust their opinions, their conclusions, or their advice. So, follow their advice are you own, and your children's, risk.

Many of us don't appreciate the way they redicule and demean anyone who is anti-vaccine. Most of us who are pro-vaccine, such as myself, are happy to offer advice or opinions to those who are not pro-vaccine, but we manage to do so in a respectful way. Because SM and Catherina don't seem able to do this, I suggest you simply ignore their posts and pretend they aren't there.

If you don't agree with them, don't bother trying to tell them so, no matter how solid you think your science is. Their science is better, or so they would think. I wouldn't waste your time arguing with them anymore, unless you enjoy that sort of thing - then, by all means, go for it.

There are rumors that SM and Cath are "secret agents" for vaccine manufacturers, planted here to combat my "anti-vaccine" advice. Although I wouldn't put it past any company to do just that (makes perfect sense - have a couple of "scientific" parents work the blogs and posts instead of doctors or professionals - some parents would listen more to another parent), I have no evidence that such is the case. SM and Catherina claim they spend hours on this site each week for almost two years now out of the goodness of their hearts. I would love to believe that, but I would also expect such good-hearted people to come across good-heartedly in their posts toward people who question vaccines. That clearly is NOT the case, so that makes me question what type of people they really are.

Anyway, just wanted to post this warning to any newcomers. I'm just going to pretend they aren't there and answer everyone's questions as usual. I'm sure ignoring them isn't going to make them go away, but they are SO NOT WORTH MY TIME anymore.

Where to begin? This infantile screed put forth by Dr. Bob smacks of anti-vax rhetoric, replete with accusations of "secret agents for vaccine manufacturers". How does one recognise that our scientific information is accurate but doesn't agree with it? What does that say of his 'scientific information'? Right, it's sorely lacking in every facet of his information and vaccine recommendations. A comprehensive review of this in his Vaccine Book: Making the Right Decision for Your Child a can be found on Science-Based Medicine.

While we are certainly thankful that he made it perfectly clear that we are not affiliated with him or his site, we can't help but laugh at the ad hominem attacks and his call for ignoring us, particularly with the caveat that our science is better. There aren't numerous branches of science; there are numerous disciplines of course, but all reside under the rubric of science and follow the scientific method. There aren't equally valid opinions or points of view; the whole point of science is to test hypotheses in an objective and repeatable manner, to minimise bias and allow us to determine if what we observe is real or not. This really shouldn't be difficult to understand, yet self-proclaimed experts like Dr. Bob continue to insist that there is somehow 'other science'. Yes there is, it's called pseudo-science and is not accepted by the scientific and medical communities for a very good reason. This does not make him or others like him Brave Maverick Doctors or open-minded; quite the contrary in fact given the very limited scope of what their pseudo-science parameters are.

We have nothing personal against Dr. Bob; we don't know him personally and given his chosen profession, we would certainly think that he is probably a nice man. But that is irrelevant really, for we are more interested in the bad science he and others like him espouse and the blatant misinformation they disseminate that put children in danger.

Friday, August 7, 2009

Seroconversion after measles or MMR vaccine

or: Dr. Bob strikes again

Dr. Bob Sears has a great sense of humour. He likes to drop a completely batty or offensive post, only to backpedal with a “just kidding” in response to expert critiques of his book. A recent gem on his blog on the upcoming H1N1 vaccines (which is astonishingly content free):

Just how bad is the H1N1 flu? Our experience so far indicates that it is a little worse than the regular flu, but it is not the rampaging epidemic that will sweep through the country and kill everybody. So why is the government so worried? It’s because the evil drug companies are paying them to act worried and create hype over the H1N1 flu so that the drug companies can make billions of dollars selling a vaccine that everyone will be scrambling for. The companies can then hand some of that money back to the government officials who helped them out.
Followed by an immediate

I jest.

In my opinion, he is not jesting, but rather “probing” his audience to see just how far out towards the fringe he will find most customers for his “alternative” schedule and books. This is all reasonably subtle, although Dr. Bob probably underestimates (or does he) how thoroughly his posts are read.

A couple of days ago, Dr. Bob struck again, although I am afraid, this one might turn into an explicit “recommendation” in the revision of “The Vaccine Book”:

Dr. Bob Answers by Dr. Bob - posted on 8/4/2009

I just found out some interesting info. I'd known this already, but hadn't realized it's [sic] implications.
ONE dose of the MMR vaccine creates immunity in 97% of kids. I had thought that the reason for the booser [sic] was that because this wears off, so another dose is needed. At an AAP lecture last month, this topic came up.
It turns out the second dose isn't a booster at all. A booster means that immunity wears off and needs to be re-boosted. The second MMR isn't given because imunity [sic] wears off (although eventually it does in adulthood). It's given to try to induce immunity in the 3% of children who don't respond to the first MMR shot. Doctors were also suggesting that it would make more sense to give two MMR doses during toddlerhood, so these 3% don't go through young childhood without protection.

So, this means that technically 97% of kids don't need that second MMR. It would make more sense to check titers on all kids, then only give the second dose to those who need it. some of the peds in my area actually do just that (they aren't anti-vaccine at all).

So, I'm thinking that this might be a good general policy for everybody. So, I'm considering not recommending a second dose, unless titers show it is needed. I will likely make this an official change in my alternative schedule. I just have to put a little more thought into this before I make this official.

However, the government doesn't recommend this because the healthcare costs of coordinating this type of thing for everybody would be very high - it's much cheaper just to give everyone a second dose, since the vaccine is harmless (?)

I (or YOU) may have just opened a can of worms.

(from this post - typos are his)

This is Dr Bob at his best, which unfortunately is not very good. Since his measles/MMR vaccine recommendations have major public health implications, let me summarize what we know (from the biomedical literature).

A good place to start are the vaccine package inserts. Here is the one for Attenuvax, the monovalent measles vaccine, usually produced by Merck, but on backorder at the moment (presumably until 2011) and the only monovalent measles vaccine licensed in the US. I am assuming this is where the “97%” that Bob quotes comes from. The package insert states that “97% or more” seroconvert, but “1 to 5% remain unprotected”. Seroconversion means that vaccinees who had no antibodies to the specific vaccine/disease show specific antibodies after disease or vaccination (the blood serum "converts" from negative to positive).

There is some (not much under that brand name) literature:

A small study looked at seroconversion depending on age. They vaccinated 15 15-months olds with Attenuvax, all 15 seroconverted (i.e. 100%). Then they vaccinated 6-months olds, 74% of 19 6-months olds vaccinated seroconverted, but had a lower titer than the older children. Significantly, upon boosting, all infants seroconverted and developed a higher titer. This is further confirmed by Erdmann and colleagues who find that titers can increase after revaccination or measles infection after one measles shot.
While these are small studies, they illustrate the principle that titers after one shot can be low and poor responders will be boosted by the second measles shot. This boosting effect of the second measles containing vaccine has also been observed in a very systematic MMR study from Sweden.

To dissect the 97%/100%-1 to 5% number in the package insert further, we can look at this larger study of over 600 children: Watson et al find that 5.4% of children at school entry who were initially vaccinated with monovalent measles vaccine at 15 to 17 months are non immune. This is the most realistic study I can find. The authors do not see an influence of age on seroconversion, so based on this available literature, we can assume that between 94 and 95% of children would seroconvert after vaccination with monovalent measles vaccine and remain immune until school entry.

The other possible vaccine, we can use to immunize against measles, is the MMR. The MMRii package insert states that seroconversion for measles is 95%. This is consistent with the majority of the available biomedical literature (see for example here and here). A huge number of studies using different measles containing vaccines consistently show a better immune response to the measles component in children older than a year (12, 15, or 18 months) vs infants (6 or 9 months). Dr. Bob consistently implies that the MMR vaccine given at age 4 would lead to sufficient seroconversion in most children (maybe extrapolating from the better responses in toddlers vs infants), however, the only paper systematically comparing the effect of age on seroconversion beyond the age of two finds that younger children respond better than the school age vaccinees.

Taken together, clinical data from Attenuvax and MMRii indicate a realistic rate of seroconversion of about 95% which would mean that up to 200’000 children per year/birth cohort in the US remain susceptible to measles after their first MMR/monovalent measles vaccine.

When devising a general vaccine recommendation, one cannot ignore the mumps and rubella components of the MMR. While the initial rubella seroconversion is consistently reported as excellent and near 100%, secondary vaccine failure occurs and leads to susceptibility during pregnancy. Currently, up to 9% of women in the US are found to be susceptible to rubella, having received a booster is highly predictable of protection at reproductive age. Even more dramatically, initial seroconversion to mumps can be variable (rates as low as 75% are reported in the literature, although values around 90% are more typical) and mumps immunity wanes with time, therefore putting a child who is not boosted at a significant risk (see for example here and here ).

So how practical is Dr Bob’s suggestion of one MMR at age 4 and a subsequent titer check and revaccination for the non immune as a “general recommendation”?

1. Children would go entirely unprotected for the first 4 years of their lives, leaving them vulnerable at an age when measles have a particularly high risk of complications, including SSPE.
2. After MMR vaccination at age 4, ALL children would need to have their titers tested. This involves a (sometimes very painful and traumatic) blood draw and titer tests for measles, mumps and rubella. Presumably, insurances will not pay for this (which doesn’t bother a doctor in private practise, like Dr Bob, but may lead to reduced compliance in the general public).
3. 5% of all children tested will not be immune against measles – more will have a low titer, up to 20% will not be immune against mumps, 1% or so will not be immune against rubella. Therefore, up to 20% of all children (or more, if you include the ones with low titer) would benefit from the second MMR.
4. All women would have to be re-screened before trying to conceive to see whether they are still immune to rubella.

I cannot give out medical advice, I am not an MD. However, given all available data, the strategy suggested by Dr Bob Sears seems to present a significant threat to public (and individual) health due to the long period he intends to leave children unprotected. His strategy is unnecessarily costly and complicated which may lead to a decrease in compliance and further increase in the number of susceptible children, then in a school setting where measles and mumps spread particularly well. In the long run, children who tested “immune” against measles, mumps and rubella and did not get the second MMR might lose measles, mumps and rubella immunity, contributing to outbreaks in high schools and colleges/universities. Women may lose rubella immunity, leading to a re-emergence of congenital rubella syndrome.

A general vaccination schedule comprising 2x MMR, the first one at age 1 (12 to 15 months) and the second one between 4 and school entry is safer (immunity earlier, better long term immunity for every child), cheaper (no titer tests) and easier to follow (fewer doctors’ visits). Unless, of course, one considers the second MMR as some unmeasurable danger that is best avoided, which brings us back to Dr. Bob’s MMR recommendations and his true beliefs. Does he really believe the second MMR would be so traumatic that it is worth avoiding it at the above mentioned expenses (both medical and financial), or is this “new” recommendation a plot to keep the “brave Maverick doctor" label when all science points to no connection between MMR and neurodevelopmental disorders? Certainly, Dr. Bob is more brazen about his choice of professional alliances of late, moving further and further away from a position that would be acceptable for any "majority".

edited within first hour of posting to fix links and typo

Wednesday, July 29, 2009

The MMR-Autism Claim and Bad Science: Part II

Our previous post discussed the first 3 of 7 studies that appear in The Vaccine Book by Dr. Bob Sears that he claims supports Wakefield et al. (1998). We will now discuss the last 4 as they appear in the book on pages 258-259. The fourth is by Goldman and Yazbak (2004) and this is Dr. Sears' summary:
This group studied the incidence of autism in Denmark before the MMR vaccine was introduced compared to its incidence in the years thereafter. They found about a 400 percent increase in autism over those years. This group used the same data as the two Denmark studies listed on page 259, which concluded that there is not enough evidence to link mercury in vaccines to autism. In this study, however, Goldman's group concluded that there may be a link between the MMR vaccine and autism in Denmark.
It is important to mention that the Goldman and Yazbak study was published in a journal called the Journal of American Physicians and Surgeons is neither peer-reviewed nor indexed and is essentially an online magazine for those that fancy themselves scientists. Before we review the Goldman and Yazbak study, we have to discuss the study by Madsen et al. (2002) which the aforementioned study is predicated upon. Briefly, Madsen et al. examined records from entire birth cohorts born between January 1. 1991 to December 31. 1998 to look at autism diagnoses between those vaccinated with MMR and those unvaccinated with MMR. They found that there was the same risk of developing autism or an autism spectrum disorder (ASD) in both vaccinated and unvaccinated children. The adjusted relative risk of autistic disorder was 0.92; 95% confidence interval (0.68-1.24) and the adjusted relative risk of other ASDs was 0.83; 95% confidence interval (0.65-1.07) (these confidence intervals will become more relevant later). There was no association between autism diagnosis and age of vaccination or the interval since vaccination. There was also no clustering of autism or ASD diagnoses around the time of vaccination.
Goldman and Yazbak (2004) attempt to critique the Madsen et al. paper and conduct their own statistical analyses. They start by stating:
Because autism is usually diagnosed at age 5 or older in Denmark, many children born in 1994 and thereafter would not have been diagnosed by the end of the study period. The systematic error of missing a large number of autism diagnoses in the later years was a major shortcoming. Children with Asperger's Syndrome and high-functioning autism, who have minimal speech impairments and are thus not diagnosed as early as more profoundly affected children, are especially likely to be undercounted in this study.
The Madsen et al. group reported a mean age of autism diagnosis at 4 years, 3 months and the mean age of other autism spectrum diagnoses was 5 years, 3 months. They also cut-off study observations on December 31. 1999 allowing for an additional year of observation which Goldman and Yazbak fail to mention, so some children born after 1995 may have received an ASD diagnosis after the cut-off date. To be fair, however, the Cochrane Database Systematic Review criticized the unequal length of follow-up and the use of the date of diagnosis rather than symptom onset. However, they still used it in their review and concluded:
No credible evidence of an involvement of MMR with either autism or Crohn’s disease was found.
The Madsen et al. (2002) study had a total population of 537,303 (2,129,864 person-years), 440,655 (1,647,504 person-years) in their MMR-vaccinated group and 96,648 (482,360 person-years) in their unvaccinated group. They identified 738 cases of ASDs, which provides ample statistical power to their study to detect an association between MMR and ASDs, if there was one. They also relied upon autism diagnoses that are made by specialists in child psychiatry, rather than onset of symptoms which would have introduced reporting bias. Reporting bias can occur if the investigators relied upon parental reporting of symptom onset as many behaviours of ASDs could have existed prior to vaccination and missed. Whereas administration of a vaccine is a profound event and has confounded the actual onset of an ASD . If MMR causes regressive autism within days of vaccination, then a diagnosis would follow shortly thereafter and not deferred for years as Goldman and Yazbak imply. Additionally, Madsen et al. (2002) adjusted for age and time of follow-up. Goldman and Yazbak also state:
Additional flaws in the Madsen study included the unusual distribution of ages in the cohorts, censoring rules applied to cases, and failure to separate autism into regressive and classical cohorts. These and other cited methodological and statistical problems tended to mask the association with MMR vaccine, as unimmunized children were clustered in the earlier years of the study so that ascertainment was more complete in this cohort than in those immunized a few years prior to the end of the study period, when many cases of autism were missed owing to insufficient follow-up time to make the diagnosis.
yet didn't state exactly why these were a problem. There was not an unusual distribution of ages in the cohorts because Madsen et al. (2002) used population data so this ridiculous criticism can best be summed up by a quote from Adam Jacobs in his critique of the Goldman and Yazbak study, who said, “In any case, it seems a little harsh to blame the Danes for the rate at which they breed.They also mention censoring rules but fail to explain how they were a problem. Not only were the censoring rules in the Madsen et al. (2002) study very rational, but amounted to less than 1% of their entire study cohort.
Follow-up of 5811 children was stopped before December 31, 1999, because of a diagnosis of autistic disorder (in 316 children), other autistic-spectrum disorders (in 422), tuberous sclerosis (in 35), congenital rubella (in 2), or the fragile X or Angelman’s syndrome (in 8), and because of death or emigration in the cases of 5028 children, whose data were censored.
So what this means is that the 738 children that received ASD diagnoses were not followed up after that; there was no point as they were diagnosed and included in the final analyses. Forty-five children received an autism diagnosis disorder due to genetic disorders so weren't relevant to examining an MMR-autism causation. Madsen et al. (2002) did include these 45 children in an analysis and it didn't change the results. The rest, 5028 children either died or emigrated thus isn't possible to include them in the final analyses so this amounts to a loss of 0.94%; quite a negligible percent. Again Goldman and Yazbak's assertion that only older children were likely to be diagnosed with an ASD is completely contrary to their argument that MMR causes regression within days and not years.
Then what Goldman and Yazbak do defies logic; they don't do any statistical analyses that even remotely resembles what Madsen et al. did. In fact, they perform a statistical smoke and mirrors show that Penn and Teller would have a field day with (if that was their shtick). The MMR was introduced in Denmark in 1987 and a change in diagnostic criteria for ASD diagnoses changed in 1993. Goldman and Yazbak took the 3 years preceding the diagnostic change, 1990-1992, tortured the data, then extrapolated the rate of diagnoses out to 2000, then claim a 370% increase in ASDs after the introduction of the MMR vaccine. If you look at their Figure 1, there isn't any increase in ASDs following MMR introduction and even prior to the classification change, there would be if MMR vaccination was responsible for regressive autism according to their own claim. They say:
The true confidence intervals are wider than indicated because of error associated with linear regression of the trends both before and after 1994.
No, you don't do this, confidence intervals must always be reported; they tell you the reliability of an estimate and the higher the confidence level, the wider the interval will be, depending upon the reliability. That width indicates the true range of an estimate so if they are narrow, i.e. the confidence intervals reported by Madsen et al. and thus their relative risk is highly accurate. Compare this to the confidence intervals that Goldman and Yazbak failed to report; Grove and Jacobs were kind enough to calculate Goldman and Yazbak's 95% confidence interval, which was -3.57-82.6. This is absurd and most likely why they didn't report it; in other words, their 'predicted' autism prevalence based on their 1990-1992 data spanned negative numbers. This isn't even the best part; a crucial factor is missing from their analyses, intentionally:
Because we did not request population data stratified by vaccination status, we were unable to compare vaccinated and unvaccinated cohorts as had been done in historical studies. Instead, since the vast majority of children aged 5 to 9 years received MMR vaccine, we compared autism principally in this age group in periods before and after introduction of the vaccination program.
Hey, why let some trivial detail like whether a child received the MMR vaccine get in the way of statistical analyses to determine if MMR vaccination is causing an increase in ASD prevalence. They did not use the same data as Madsen et al. (2002) did nor did their data manipulation support an MMR-autism association as Dr. Sears claims. There is simply no defense for such abuse of statistics to intentionally deceive readers.
The fifth study is by Bradstreet et al. (2004) and is not only a little gem that appears in Journal of American Physicians and Surgeons but features Wakefield as a co-author. This is Dr. Sears' summary:
This group found measles virus RNA in the CSF and intestinal biopsies of three children who had gastrointestinal inflammatory disease and autism. The only known exposure these kids ever had was from the MMR vaccine. Three control patients did not have measles detected in their samples.
They don't get off to a very good start by reporting:
All have received multiple interventions ranging from dietary modification to intravenous immunoglobulin, though the details of these interventions and the relevant outcomes are not reported here.
That's like conducting a study on tomato yield of different plants, but using various watering and fertilisation strategies and deeming these variables unimportant to control for and report. Since they are testing for anti-measles antibodies, it is kind of important to control for the fact that the children are receiving immunoglobulin, at the very least. And once again, they are relying upon parental reports of regression without validating with medical records.
Their methods for viral detection rival those of what you would expect from "Sid the Science Kid". But in actuality, are worse for they sent their samples to Unigentics and all of the same parameters as Uhlmann et al. (2002) which were de-constructed in our first post of this series. They also used Singh et al. (2003) poorly defined immunoblotting and anti-MBP assays; neither of which has been validated nor standardised for diagnostic value.
Results of CNS autoantibody and virus IgG profiling are shown in Table 3. MBP autoantibodies were present in the serum of all three children and CSF of children 1 and 2. NFAP antibody was present in the serum of child 2 only. MV IgG antibody titers were reported as high in the sera of children 1 and 2, and detectable at a low level in the CSF of these same children. MVIgG antibody titer was reported as being within the normal range in the serum of child 3 and undetectable in his CSF. Where samples were analyzed for the previously reported MMR-associated antibody, they were negative. Human Herpesvirus-6 serology was unremarkable, and specific IgG antibody was not detected in CSF of the two samples in which it was sought (children 2 and 3).
It is curious that they reported anti-measles IgG antibody as high in some of the autistic children yet didn't report the results from their “control” children. There is no “normal range” of these antibodies and a high titre is not indicative of anything. And given that some or all of these children were treated with “immunoglobulin therapy”, it's not surprising that their titres would be elevated.
Bradstreet et al. (2004) too, did not sequence their PCR amplicons, which is standard practise, that is if investigators are actually interested in the accuracy of their results. What they lack in proper methods, they try to compensate for with a bloviated discussion, that of course, is corroborated by all of the junk science that preceded. While they test for anti-MBP autoantibodies in the autistic children, they do not test the “control” children and they don't explain their results which are presented as a throw-away sentence and merely buried in a table. One wonders why they would even mention their significance in their background, not test their “controls” for them and then not explain their results nor their significance, not that they really have any. We hope you aren't getting bored but this is nothing more than yet another foray into the world of pseudo-science.
The sixth article Dr. Sears cites as “showing a link between MMR vaccine and autism” is by Kushak et al. (2005) and is actually not a published study at all but a poster presentation and what you see is the extent of it unless you attended the conference that it was presented in. This is Dr. Sears' summary:
This Harvard group essentially reproduced Dr. Andrew Wakefield's work by finding chronic inflammation, lymphoid hyperplasia, and digestive enzyme deficiency in the gastrointestinal tract of numerous autistic children. It didn't explore a possible link to measles infection from the MMR vaccine, however.
We don't see what their Harvard affiliation has to do with anything. This group did not 'reproduce' Wakefield et al.'s work; they merely examined gastrointestinal problems in autistic and non-autistic children and some enzyme values. They didn't find any significant differences in gastrointestinal problems between autistic and non-autistic children but did find some abnormal enzyme levels in the autistic children as compared to the non-autistic children that were statistically significant. Which could be easily explained by diet. We don't see how Dr. Sears came to the conclusion that the investigators found “chronic inflammation, and lymphoid hyperplasia” in any of the children when that wasn't even reported. Since this was a poster presentation in abstract form, and has absolutely nothing to do with Wakefield's findings, there is really nothing to evaluate here.
Onto the seventh and final study by Geier and Geier (2004) and this is Dr. Sears' summary:
This group studied the increase in autism over the past twenty years compared with the timing of increased thimerosal vaccines and the introduction of the MMR vaccine and found evidence that these may play a role in neurodevelopmental disorders. They recommended taking thimerosal out of vaccines and finding a safer MMR vaccine.
It is important to first point out the Geier's conflict of interest statement in this publication, which is:
Dr. Mark Geier has been an expert witness and a consultant in cases involving adverse reactions to vaccines before the U.S. Vaccine Compensation Act and in civil litigation. David Geier has been a consultant in cases involving adverse reactions to vaccines before the U.S. Vaccine Compensation Act and in civil litigation.
Also of interest is that they were developing a patent application for their Lupron Protocol which was submitted later that year. For more about the Geier's situational ethics and conflicts of interest, you can read Kathleen Seidel and Respectful Insolence. Onto the actual study.
The Geiers used U.S. Department of Education (DOE) datasets to determine autism prevalences. These data are going to show children receiving services for autism as it was diagnosed at that time. They also used CDC birth surveillance data for the estimations performed on birth cohorts from 1981-1985 and 1990-1996, leaving out 4 years, 1986-1989. There was no explanation as to why. In order to 'determine' thimerosal exposure they used the Biologic Surveillance Summaries of the CDC, of course not knowing actual vaccines received by the infants. These methods alone render this 'study' completely useless but being the brave souls we are, will forge ahead anyhow.
They essentially did the same thing as above for the estimation of MMR vaccine and autism prevalence but had even larger gaps in their data. They only used the years 1982, 1985 and 1991-1996, with again, no explanation but their exclusion becomes obvious later with our discussion of Figure 3. Stay with us here because this makes little sense; they took their selected birth cohort years, pulled out the DOE autism prevalences corresponding to those years, estimated the autism prevalence for the birth cohort and banged them together for their MMR-autism prevalence estimate. The children receiving MMR would have been too young for an actual autism diagnosis. And why bother with pesky details about when and which children were actually vaccinated when the desired results have been pre-determined? For instance, they decided to use the 1984 birth cohort as a 'baseline' but their explanation as to why is nonsensical because they haphazardly used several birth cohorts instead of tracking one which seriously confounds results due to changes in diagnostic criteria, special education expenditures, birth cohort size and ages of diagnoses. None of which they controlled for.
What they also fail to account for, particularly in the earlier cohorts for their thimerosal exposure table (Table 1) is the 1982 recommendation for Hepatitis B vaccine for infants and contained thimerosal. In other words, their Table 1 is even more wrong and skews the mercury exposure higher for later birth cohorts. So on to their other results:
In Figure 2 we plotted the average mercury dose per child in comparison to the prevalence of autism per 100,000 children for successive birth cohorts (birth cohorts: 1981 through 1985 and 1990 through 1996). Figure 2 shows that as the prevalence of autism increased from the birth cohorts from the late 1980s through the early 1990s a corresponding increase in the average mercury dose per child occurred. A maximum occurred in the birth cohort of 1993 in both the average mercury dose per child and the prevalence of autism. A decrease in both the prevalence of autism and the average mercury dose per child occurred from 1993 through 1996.
This is best described by showing you Figure 2:
If their data crunching wasn't bad enough, they seem to happily torture them graphically. As you can see, they omitted the years 1986-1989 (with no reasoning) but still presented the gap as continuous data. You just don't do that, plain and simple so at best, they are buffoons and at worst, liars. They also claim that the prevalence of autism concomitantly decreased with thimerosal exposure. No, no and no; autism prevalence did not decrease, anyone reading this knows that and their thimerosal exposure estimates are rubbish to begin with. As for Figure 3:
Figure 3 shows the number of doses of primary pediatric measles-containing vaccine in comparison to the prevalence of autism for each birth cohort examined (birth cohorts: 1982, 1985, and 1991 through 1996). This figure shows that there was a potential correlation between increasing doses of primary pediatric measles-containing vaccine and an increasing prevalence of autism during the 1980s. We determined that the slope of the line was 4831, and the linear regression coefficient for the line was 0.91.
These are the estimates for which they omitted even more years and they came up with a correlation. They could have plotted the number of artificial satellites we have in orbit or the use of smilies in internet communication and come up with a correlation. As a rule of thumb, when you want to just 'eyeball' such a graph for potential problems, remove any 2 data points and if the trend line disappears, there could be a problem. Let's take off their 1982 and 1985 data points; the trend line completely disappears. We consider the imminent possibility that the other years were intentionally omitted because they didn't plot to their liking.
Figures 1 and 4 and their corresponding results are really nothing; garbage in, garbage out. They again, cherry-picked certain years to report for Figure 4 that had no statistical significance, in spite of what they report (overlapping confidence intervals bugger up significance like that). It is also curious that this 'study' was written in 2003 but the Geier's didn't bother to use data after1996 nor acknowledge that thimerosal has not been in vaccines, or in trace amounts since 2001 and yet autism prevalence has continued to rise. The Institute of Medicine's 2004 Immunization Safety Review: Vaccines and Autism said of this study and others by the Geiers:
Other studies reported findings of an association. These include two ecological studies4 (Geier and Geier, 2003a, 2004a), three studies using passive reporting data (Geier and Geier, 2003a,b,d) one unpublished study using Vaccine Safety Datalink (VSD) data (Geier and Geier, 2004b,c), and one unpublished uncontrolled study (Blaxill, 2001). However, the studies by Geier and Geier cited above have serious methodological flaws and their analytic methods were nontransparent, making their results uninterpretable, and therefore noncontributory with respect to causality (see text for full discussion).
Dr. Sears over-inflates the results and importance of this heavily-biased study. They did not examine 20 years worth of data, at best it was 12 years and a poor job at that and didn't find any evidence that MMR, or thimerosal played any role in neurodevelopmental disorders. They are a little late to the game too if they are recommending that thimerosal be removed from paediatric vaccines when that was done 2 years prior to their 'study'. What would a safer MMR look like anyhow?
This concludes our series critiquing the studies Dr. Sears uses to support Wakefield's findings. So are you sensing a theme here? That is, bad science manages to find an MMR-autism connection, whereas good science cannot. As parents that are concerned with these issues, you should be angry, very angry. You are being bamboozled, hoodwinked, taken for a ride by these charlatans that rely upon the scientifically unsophisticated to just read introductions and discussions but gloss over the methods and results. This is the way these 'scientists' can be broken down:
A.) They are too inept to perform sound, methodological science.
B.) They aren't too inept but believe these claims and don't mind cutting corners, being the mavericks they are.
C.) They have an agenda, financial or otherwise and laugh at the ease by which they can take advantage of the naive and desperate.
If anyone can come up with a valid, alternate explanation that doesn't involve Galileo or Copernicus, we're listening. Maybe we are preaching to the choir and if so, you can feel assured about your own conclusions, but if we are not, we hope that you can at least, begin to break free of the grip of pseudo-science that makes you feel overwhelmed by the glut of information. That there really isn't two sides of this issue that are equally valid and perhaps you are better equipped to spot junk science.