This is especially important if you or your loved one is pregnant (or likely to become pregnant in the near future) because these vaccines have not been tested in pregnant women, only in animals (see later). Pregnant women are at higher risk of developing severe H1N1 infections, which is why most governments have put them at the top of priority lists for vaccination. Some countries like the US are only using unadjuvanted vaccines, for which there is a fair amount of experience for use in pregnancy. Some (eg Canada) that are using adjuvanted vaccines have nevertheless ordered additional doses of unadjuvanted vaccines for pregnant women. And then there are others, like the UK, that are recommending the AS03-adjuvanted vaccine to pregnant women, because, as far as I can determine from their publicity...sorry, information...leaflet, - only 1 dose is required (but so is the unadjuvanted vaccine eg used in the US or Australia or Canada), and
- "the European Commission recommended them for use".
I don't know about you, but if someone in my family was pregnant, those are not good enough reasons, to trust that the vaccine is safe for either mother or child. Especially when the Committee for Medicinal Products for Human Use (CHMP) in the EMEA is made up of one representative from each member state, irrespective of expertise or accountability. I'm sorry if this sounds bigoted, but my idea of safety does not include the (unproven and untested) assumption that representatives from Bulgaria or Cyprus or Romania are just as honest and competent as those from Sweden or Germany or the UK. Note that Bulgaria and Romania, for example, rank last in this perception of corruption ranking for EU member states, and globally are behind Saudi Arabia and barely ahead of Columbia, but they all have equal votes, on approving vaccines to be injected into lesser mortals like you and I, pregnant women and unborn offsprings included.
So, if it takes 1 hour, 3 hours, 5 days to read the stuff, remember what is balanced against that is only the rest of your lifetime and that of your unborn child.
OK, I can put away the soapbox now, thank you for your patience. Let me show you some information about the AS03 vaccine that make me very concerned (and very angry) about recommending it for use in pregnant women or women of child-bearing age (note that as much as 50% of pregnancies are unplanned). Remember that even though they are known by different trade names (Pandemrix in Europe and Arepanrix in Canada) they are the same formulation. I've read the EMEA file for Pandemrix a while back, and commented on the fetal toxicity findings from that file here. The product information from Canada (available in pdf here), I read only recently and have not posted about it. The findings appear to be different from those in the EMEA file. Although I cannot be 100% certain, it reads to me like 3 different studies: 1 from the EMEA file, 2 in the Canadian file. So the following is in addition to what I posted before.
The pdf is interesting because if you are reading it from the beginning, you will find the following, on page 7, under Warnings and Precautions:
Pregnancy and Lactation
No data have been generated in pregnant women with Arepanrix™ H1N1 nor with the prototype AS03 adjuvanted H5N1 vaccine. Data from vaccinations with seasonal trivalent influenza vaccines in pregnant women do not indicate that adverse foetal and maternal outcomes were attributable to the vaccine.
CONSIDERATION SHOULD BE TAKEN OF ANY RECOMMENDATIONS MADE BY THE PUBLIC H EALTH AGENCY OF CANADA.
Animal studies have not demonstrated harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or post-natal development.
For anyone reading this the first time, I suspect they'd probably be:
- a little concerned that this vaccine has not been tested in pregnant women
- somewhat reassured that animal studies "have not demonstrated harmful effects"
Strictly speaking, English is not my first language, but I have been educated in it since high school. More importantly, all of my medical education was conducted fully and solely in English. But even for me, if that paragraph was the only information I read about this vaccine, I would have arrived at the same interpretation, that animal studies have been done, and they didn't show any harmful effects in the areas listed.
Which makes it all the more amazing when, on page 18 of this 24 page document, I found the following, under the much more technical-sounding title of Pre-clinical Safety Data:
Two reproductive studies were conducted with AS03-adjuvanted H5N1 antigen and evaluated the effect on embryo-fetal and peri-and post-natal development in rats, following intramuscular administration. Although no definite conclusion could be reached, regarding a possible relation to treatment with the H5N1 vaccine and/or the adjuvant AS03, and other findings were considered normal, the following observations deserve to be mentioned: In the first study, there was an increased incidence of fetal malformations with markedly medially thickened/kinked ribs and bent scapula as well as an increased incidence of dilated ureter and delayed neurobehavioral maturation. In the second study, there was an increased incidence of post-implantation loss, and the fetal variation of dilated ureter. Not all findings were observed in both studies, and hence the toxicological significance is uncertain.
Let me repeat that last sentence, even though I didn't highlight it
Not all findings were observed in both studies, and hence the toxicological significance is uncertain.
I don't know exactly what it means, but it sure looks like that is the reason/excuse for not putting down these findings in the Warnings and Precautions section. They may be right, technically - I confess to being ignorant as to how frequently all findings have to be observed in all studies, to be considered significant. But if we were to ignore such statistical niceties, and strip them all down to just raw data, here are the findings, from these 2 studies from the Canadian file and the one in the EMEA file:
- Grossly visible fetal malformations
- markedly medially thickened/kinked ribs
- bent scapula
- dilated ureters
- Delayed neurobehavioral maturation - in the EMEA file as well as one of the studies in the Canadian file
- Post-implantation loss = miscarriage/abortion
To help you understand or evaluate the above findings, let me share a few points from the EMEA guidelines Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling.
Type of effects:
Morphological effects have more weight in estimating the concern for reproductive toxicity in humans, than general effects (e.g. growth retardation). The latter, possibly a reversible effect, might be induced by maternal stress or other maternal toxicity.
'Morphological effects' means alterations to the appearance, of specific body parts and/or organs. Did they find any, in the GSK studies? I'd say the answer is Yes.
Multiplicity of effects
Multiplicity of effects usually increases concern for reproductive toxicity in humans. Multiplicity refers to the observation, in a single species or animal model, of two or more effects with related biological endpoints, e.g. on foetal examination, abnormal shaped vertebrae plus abnormal number of vertebrae would give rise to increased concern, more than just a single observation with regards to vertebral development.
Are we seeing multiplicity of effects? They found both kinked ribs and bent scapula. Although not strictly equivalent, they also found the same effect, dilated ureters, in more than one study. So, I'd say again the answer is Yes.
Adverse effects at various stages of the reproductive process:
This refers to observations in a single species or animal model, of effects during different stages of the reproductive process, e.g. increased early intrauterine death plus some cardiac malformations would give rise to increased concern with regards to developmental toxicity.
Well, they didn't report increased early intrauterine deaths, but they did report post-implantation loss in addition to the fetal malformations. So, a third Yes.
Statistically significant differences alone should not necessarily constitute a positive signal. Other criteria of importance include biological plausibility, reproducibility, medicinal product- or species specific mode of action, relationship to an animal-specific metabolite, and/or clear dose-response relationship.
Most of these criteria are beyond our reach - if GSK does not do the research, we would never know, whether such relationships exist. However, we can still take a look at biological plausibility, because the effects of maternal immune activation (MIA) during pregnancy have been studied in many contexts, and there are many important observations relevant to our discussion. Here we'll look at the effects of MIA on fetal development. Early pregnancy loss will be discussed separately with other adverse pregnancy outcomes associated with MIA, eg pre-eclampsia and preterm labor.
We have previously discussed how adjuvanted vaccines cause more systemic reactions and how changes in cytokine response , such as induction of IL-6, may accompany these reactions. When a pregnant woman receives a dose of vaccine that strongly stimulates her immune system, there may be far-reaching consequences beyond a sore arm and a day or two of 'flu-like illness'.
For example, cytokines play important roles in fetal brain development:
Deverman 2009 Cytokines and CNS Development
Cytokines are pleotrophic proteins that coordinate the host response to infection as well as mediate normal, ongoing signaling between cells of nonimmune tissues, including the nervous system. As a consequence of this dual role, cytokines induced in response to maternal infection or prenatal hypoxia can profoundly impact fetal neurodevelopment.... The extensive and diverse requirements for properly regulated cytokine signaling during normal nervous system development revealed by these studies sets the foundation for ongoing and future work aimed at understanding how cytokines induced normally and pathologically during critical stages of fetal development alter nervous system function and behavior later in life.
Interestingly, a lot of research on the effects of MIA on fetal brain development was stimulated as a result of epidemiological evidence (reviewed in Ellman 2009) suggesting an association between maternal influenza infection and schizophrenia in the adult offspring. Since then, a large body of research has evolved around this issue, and associations with a bewildering variety of pathogens have been found. The following quote (from Meyer 2006) gives a good summary of the issues, and contains many useful citations:
Maternal bacterial and viral infections during pregnancy represent a risk factor in several neuropsychiatric disorders with a presumed neurodevelopmental origin, including schizophrenia (Mednick 1988, O'Callaghan 1994, Brown 2004), autism (Rodier 1998, Miller 2005), and mental retardation (Rantakallio 1985, Revello 2004). Although the mechanisms underlying this epidemiological relationship remain unclear, the maternal cytokine-associated inflammatory response to infection may be the crucial link, because the identity of the pathogen seems irrelevant (Gilmore 1997, Buka 2001, Pearce 2001, Brown 2004). Similar inflammatory mechanisms have also been suggested to underlie the association of chorioamnionitis and the development of cerebral palsy (Dammann 1997, Dammann 2000, Wu 2000, Wu, 2002). Animal experimentation has also confirmed that, in the absence of a pathogenic agent, cytokine-releasing treatment to pregnant mothers is sufficient to induce multiple psychopathology in the offspring later in adulthood (Shi 2003, Zuckerman 2003, Meyer 2005, Meyer 2006).
In a series of elegant experiments scientists from CalTech (below) demonstrated that influenza infection, or immune stimulation without an infectious agent, or just IL-6 on its own, reproduces the same set of symptoms in offsprings, and that these effects are prevented in the absence of IL-6, thus showing that it is the cytokine response to immune stimulation (specifically induction of serum IL-6), not the virus per se, that is responsible for the pathology.
Smith 2007 Maternal immune activation alters fetal brain development through interleukin-6.
Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism,.....A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA.
These results bring up a major dilemma. If infection by influenza and immune activation by vaccines are both associated with increased risk of neuro-developmental disorders in offsprings, doesn't it seem like pregnant women are between a rock and a hard place? Unfortunately, that is true, to a certain extent. We are not totally helpless, though. For example, maybe we should consider the difference in degree of maternal immune activation associated with each of the following:
- influenza infection not treated with antivirals till day 4
- influenza infection treated with antivirals <48 hr after onset
- vaccination with adjuvanted vaccines
- vaccination with unadjuvanted vaccines
Logic would suggest that #2 is better than #1, and #4 is better than #3. But how do you compare between #2 and #4? And what if #4 is not available? We can deduce part of the answer, but, like many aspects of influenza, there are areas where no clear answer exists.
Schizophrenia or autism are just examples of the neurodevelopmental consequences of MIA or IL-6 induction; the specific outcomes probably vary by species and timing, and are subject to interaction with genetic factors (Clarke 2009). As far as mechanisms are concerned, among cytokines, those from the IL-6 family appear to have a critical role in nervous system development in general. There are 2 main types of cells in the nervous system - neurons or nerve cells, the primary functional units of the nervous system, and glial cells which act as support to the neurons, both physically and functionally. During fetal development, neural cells are formed before glial cells. The timing of this switch is crucial for normal development, and is controlled by cytokines. (Bauer 2007 and diagram below) IL-6 acts to inhibit the formation of neurons, which favor differentiation of stem cells into glial cells instead. An excessive or premature IL-6 effect could result in premature termination of neurogenesis, at least theoretically.
The role of cytokines in modulating the differentiation of stem cells is not limited to the nervous system. Similar mechanisms are the norm, for development of other organs and tissues. For example, cytokines of the IL-6 family are involved in activation of the Wnt signaling pathway (Katoh 2007), which is critical for embryogenesis.
Davis 2008 Mesodermal fate decisions of a stem cell: the Wnt switch
Wnt signaling must be tightly controlled in vivo and in vitro in all lineages to regulate proliferation and differentiation and thus the development of tissues.
Many of these molecular mechanisms are still being discovered, partly encouraged by stem cell research. The key issue is the commonality of molecular pathways in seemingly different and unrelated human experiences.
Peifer 2000 Wnt Signaling in Oncogenesis and Embryogenesis--a Look Outside the Nucleus
Some of the most profound questions in biology were first asked by ordinary people confronting events in their everyday lives. The miracle of a newborn baby raises questions about how an egg assembles itself into an animal. The tragedy of a cancer diagnosis leads to questions about how normal cells go wrong. Although seemingly distinct, biological processes like embryogenesis and carcinogenesis both rely on cell communication via identical signaling pathways. For example, in the larva of the fruit fly Drosophila, cells determine their position within each body segment by communicating with one another. One of the key signaling molecules is the secreted Wnt family protein Wingless (Wg), which acts as a "Be posterior" signal.
What all this means is that irrespective of whether, technically speaking, the findings in the GSK documents suggest demonstrate increased risk of fetal malformation and neurodevelopmental disorders, we must bear in mind that we cannot compartmentalize the human body. The vaccine we use for the purpose of protecting against an infection like influenza has other effects beyond that single specific outcome. These effects take time to discover in human subjects (eg schizophrenia associated with maternal infection does not manifest till young adulthood) which is why animal models are useful to give us a rough idea, of what kind of issues need to be considered, when balancing risks vs benefits of receiving a shot in the arm, with the adjuvanted flu vaccines. |
