Are too many vaccines too soon harmful?

By Grant Jacobs 29/04/2013

Parents want the best for their children. One concern raised by those holding off giving their children vaccines[1] are if too many vaccines too soon might be bad for their child, in particular if several vaccines given together might increase the risk of their child suffering neurological damage.[2]

A recent study addresses specifically this question.

Things that trigger an immune response are called antigens.

To compare how much “stuff” in vaccines you gave to different children, you want to compare the number of antigens you gave them.

Autism spectrum disorder is a neurological condition.

By comparing the number of vaccine antigens given to children with if they had autism or not, you can ask if the number of vaccine antigens affected the neurological condition of the children. (At least for autism.)

Autism spectrum disorders become apparent when the child is around 2-3 years old, so vaccines given up to two years of age were studied.

The researchers used data gathered during a previous study, using data from 256 children with ASD and 752 matched controls.

Two main different types of comparisons were made:

  1. The total number of antigens from vaccines given up to either of 3 months, 7 months or two years old
  2. The largest number of antigens given in any one day

They found that children that received different numbers of vaccine antigens all had the same chance of getting autism – the number of antigens the child received from their vaccines did not make a difference to the chance the child would develop autism.

This applied whether to both the total number of antigens from vaccinations up to two years old, or to the largest number of antigens given in one day. Similar results were found whether the child had ASD (autism spectrum disorder), autistic disorder or ASD with regression.

The authors put it a little more formally,

We found no evidence indicating an association between exposure to antibody-stimulating proteins and polysaccharides contained in vaccines during the first 2 years of life and the risk of acquiring ASD, AD, or ASD with regression. We also detected no associations when exposures were evaluated as cumulative exposure from birth to 3 months, from birth to 7 months, or from birth to 2 years, or as maximum exposure on a single day during those 3 time periods. These results indicate that parental concerns that their children are receiving too many vaccines in the first 2 years of life or too many vaccines at a single doctor visit are not supported in terms of an increased risk of autism.

The justification for this paper is mainly to offer straight-forward evidence that might address parents’ concerns,

A recent survey found that parents’ top vaccine-related concerns included administration of too many vaccines during the first 2 years of life, administration of too many vaccines in a single doctor visit, and a possible link between vaccines and learning disabilities, such as autism. All of the foregoing concerns were reported by 30%-36% of all survey respondents, and were reported by 55%-90% of parents who indicated that their children would receive some, but not all, of the vaccines on the recommended schedule.

A New Zealand study found similar concerns were held by some parents.

For scientists working in a particular area it’s common to draw many small pieces of evidence together to form to a conclusion. Scientists are used to working with little details and putting them together. That’s how biologists thought it very unlikely that vaccines would be linked to autism before the many studies[3] (two links) that have found that vaccines are not linked to autism.

It’s a bit of a pain for anyone else wanting to know what the deal is, though — even for scientists who work in other areas of biology. And certainly a collection of many small points doesn’t fare well on the ’Web. Hopefully this simpler study will help address parents’ concerns.

This study is retrospective, looking at how things went. It complements tests done prior to licensing a vaccine for a schedule as our new immunisation blogger, Dr. Helen Petousis-Harris, tells us in her first blog post at Sciblogs,

All infant vaccines are assessed for concomitant administration. This is a requirement for licensure if they are to be added to a schedule.

Visit her blog, Diplomatic Immunity, and welcome her to sciblogs.[4]

Those that prefer videos, can hear Paul Offit speak on this at the MedScape website.

A brief aside on autism

Personally, I’d like to see the focus on autism be on tracking down causes, rather than convincing people of things most scientists consider well-established.[5] I know I’m not alone in saying that. The authors briefly summarised the likely causes of autism (their citations removed for clarity),

The possibility that immunologic stimulation from vaccines during the first 1-2 years of life could be related to the development of ASD is not well supported by the known neurobiology of ASD, which tends to be genetically determined with origins in prenatal development, although possible effects in early infancy cannot be ruled out completely. It can be argued that ASD with regression, in which children usually lose developmental skills during the second year of life, could be related to exposures in infancy, including vaccines; however, we found no association between exposure to antigens from vaccines during infancy and the development of ASD with regression.

The results in a little more detail

For those who would like to dig deeper, here’s start. (Those that don’t might want to skip to the end for further reading. Or check out Helen’s blog.)

The full paper is available on-line free (PDF file). A summary is also available (web page). Details on the case controls are in the paper; I won’t repeat them here.

The results are presented as adjusted odd-ratios (aORs). Simple odds ratios are the odds that a child a with one level of antigens from vaccination will have autism compared to a child with a different level of antigens from vaccination.

An odds ratio of 1.0 would mean that the two sets of children being compared have the same odds of having autism despite different levels of antigens from vaccines – indicating that different levels of antigens don’t change the odds of having autism later.

Similarly, an odds ratio significantly greater than 1.0 would suggest that a higher antigen level was associated with autism. Conversely, an odds ratio significantly less than 1.0 would suggest that a higher antigen level was associated with a lower incidence of autism.

Lets look at the statistics reported.[6] Here are the two key summaries, Tables II and III from the paper:



You’ll see that the lowest level of antigens (first column of results) is set to be the reference (set to 1.0) to which the other levels (next two columns) are compared to. So the first results of the second column of data of Table III (immediately above) are a comparison of the odds of ASD in children who received 26-50 antigens up to 3 months of age compared in children who received -25 antigens up to 3 months of age. The average odds was 0.98, very nearly 1.0, with a 95% confidence interval of 0.47 to 2.08 (more on that in a moment).

That table is a bit hard to read, so let’s zoom in on the key columns:




For each there is a lowest value and a highest value, shown in brackets to the right of the average (boxed in the table below). These values are 95% confidence intervals – the range of odds values that would have a 95% probability that the ‘true’ odds ratio value would fall within.


The rightmost column show results for looking at the data as whole using “a 25-unit increase in vaccine antigen exposure, analyzed as a continuous variable”.

The paper reports adjusted odds ratios. Adjusted odds ratios (aORs) take into account things that might confuse (confound) the results. I’ve included the full list of these in the footnotes at the end of this article as the list is rather long.

An explanation of odds ratios, including adjusted odds ratios, can be found in the short, open-access, paper Explaining Odds Ratios by Magdalena Szumilas (M.Sc.). It has links to further reading for those who might be interested.

As you can see every comparison overlaps with one. In particular, the ‘continuous variable’ approach has values that cluster tightly around one. These results indicate there is no relationship between vaccine antigen exposure and autism (ASD, AD or ASD regression).[6]

As David Gorski concludes you can quibble about details, as always,

Yes, there were limitations to DeStefano et al in that it was retrospective. In addition, as the authors discussed, not all antigens are equal in evoking an immune response. Some have more epitopes (areas on the antigen molecule that can trigger an immune response) than others, and the study didn’t weight the antigens for the intensity of the immune response that they evoke. Even so, the antigenic load has fallen dramatically, and this study is based on the vaccine schedule of the 1990s. Indeed, the authors note that the antigen load due to the vaccine schedule has fallen from several thousand in the late 1990s to an estimated 315 in 2012.

It’s very hard to do truly ‘clean’ work on subject matter that has many complex issues.

One issue is that the number of antigens in the whole-cell vaccines (pertussis, typhoid) is much more that the number of antigens that the other vaccines. As the authors noted the large number of antigens in the whole-cell vaccines meant the data had two peaks, one for the children that did not receive the whole-cell vaccines and another peak with a higher antigen exposure for those that did receive these vaccines. (There is a large jump from 1-69 antigens per vaccine to over 3000 antigens for the DTP and typhoid vaccines, as seen in Table I from the paper below.)


The continuous variable model (the rightmost column in Table II and III) avoids this as it looks at a 25 unit increase in antigens. Furthermore the authors did additional analysis on the number whole-cell pertussis vaccines received and found,

no statistically significant associations between number of whole-cell pertussis vaccine doses received between birth and age 2 years and any of the ASD outcomes; ORs (95% CI) for each increase of 1 whole-cell pertussis vaccine dose were 0.956 (0.793-1.152) for ASD, 0.989 (0.700-1.397) for AD, and 0.761 (0.380-1.525) for ASD with regression

There are, of course, other ways of looking at potential relationships between vaccines and autism. One is to look at the rate of autism in nations that elected to withdraw a vaccine, as Japan did in withdrawing the MMR vaccine: autism rates in Japan did not fall  after the withdrawal of MMR vaccine. (In fact, they spiked; see graph below.)



Dr. Gorski has previously offered coverage of this paper at the Science-Based Medicine blog, as have many others. My aim was to offer something shorter that might appeal to parents, with more detail that the press coverage but also less technical. Also as writing practice, I guess. Or at least that’s my excuse… Dr. Gorski’s post includes some background on where this notion might have arisen, and so on, that I haven’t covered here.

Further to the table given in the paper, this table lists vaccine antigen amounts in vaccines used in the USA.

Covariates for the adjusted odds ratios for ASD and AD models included:

[…] birth weight, maternal age, birth order, duration of breastfeeding, family income, maternal healthcare-seeking behavior (ie, Kotelchuck inadequacy of prenatal care, use of cholesterol screening, use of Pap smear screening), maternal exposures during pregnancy with the study child (ie, alcohol use, folic acid use, viral infection, lead exposure), and early childhood health conditions (ie, anemia at age 6-30 months, pica before age 3 years).

Covariates for the adjusted odds ratios for ASD with regression models included:

[…] birth weight, maternal age, family income, maternal education level, and maternal exposures during pregnancy with the study child (ie, alcohol use).

1. This survey of parents’ attitudes to the New Zealand Immunisation programme (PDF file) includes those who “believe the National Immunisation Schedule starts too early at six weeks.”

2. It’s a concern touted by groups opposing vaccines.

3. I believe there are (a few) more studies again; most of those listed in the linked articles are focused on the MMR vaccine.

4. While I will still write the odd article on vaccine-related issues, you’ll see fewer of them as this is certainly more her ‘patch’ than mine.

5. It can be exasperating. As one reader at Respectful Insolence put it,

Epidemiologists have looked at the *number* of vaccination and the risk of autism… no, no correlation found. So the atni-vaxxers shifted the goal-posts — “It’s the mercury!”

So epidemiologists looked at the number of Thiomersal-containing vaccinations… still no correlation. And the goal-posts shifted again — “It’s the timing!”

Epidemiologists looked for any difference between infants vaccinated by the usual time-table and those who received vaccinations late… the goal-posts shifted, they must on roller-skates or something — “It’s the total allergenic load!”

And now that DeStefano et al. have examined the total allergenic exposure, and found no neurological correlations, here is our serial spammer to complain “They should have looked at the total number of vaccinations!!”

However you interpret current figures for the incidence of autism and ASD, and whether or not that incidence is rising, the anti-vaxxers are the one group we know for a fact don’t care about it — because they have spent *decades* demanding that the maximum possible amount of research money and time is wasted on one factor that has been repeatedly shown not to matter.

6. Statisticians will quibble: I’m trying to offer a simplified presentation without confusing things too much. This article is for parents who left high school years ago, not scientists!

Other articles on Code for life:

Sources for medical information for non-medics and non-scientists

The Panic Virus

How vaccines work – a primer

Thoughts on, and for, those trying to choose to vaccinate or not

Fact or fallacy, a survey of immunisations statements in the print media

Immunisation then and now

Vaccination – why learn the hard way?

Autism – looking for parent-of-origin effects

Autism genetics, how do you copy?

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