|First, a quick recap. The US government is stockpiling both antigens and adjuvants for the H1N1 vaccine, in anticipation of possible mass vaccinations in the fall. Other governments (eg UK, Canada) have placed orders for adjuvanted flu vaccines for the current pandemic. The use of adjuvants would mean a smaller amount of antigen required per dose, making it possible to vaccinate more people sooner. Sounds good? Except that these adjuvants are not yet licensed by the FDA, and their safety continues to be a cause for concern.
One controversy that refuses to die has its origins in the discovery of antibodies against squalene by researchers in Tulane University in Gulf War veterans, recipients of the anthrax vaccine, and participants in NIH trials who received the squalene-containing adjuvant MF59, all of whom suffering chronic multisystem disorders loosely described as Gulf War Syndrome (GWS). A recent exhaustive report from the Veterans Administration describes what happened next:
After its publication, the Asa/Tulane squalene antibody research was criticized by government scientists and panels. Critics questioned the idea that squalene, when injected, acted as an antigen, and whether the assay used had actually detected antibodies to squalene. Within months, however, investigators at Walter Reed Army Institute of Research (WRAIR) published research showing that squalene can act as an antigen and that antibodies could be detected in a model system.
Indeed, the DOD (Walter Reed) results show that squalene antibodies can be detected in a small percentage (7-15%) of normal population, comparable to the results from Tulane (5-16%), thus validating the Tulane tests. What they did NOT do, however, was to test actual GWS sufferers. Such an omission is particularly glaring, and the VA report remarked on it, in no uncertain terms:
Primary Gulf War squalene antibody question unanswered.
Eleven years after the squalene controversy was first publicly raised, studies have addressed several related questions....The observation from the Asa/Tulane studies that is most relevant to the health of Gulf War veterans, however, has not been further evaluated. Their initial study, reported in 2000, indicated that symptomatic Gulf War veterans had detectable levels of IgG antibodies to squalene, but that healthy veterans did not.This raised a testable hypothesis concerning an objective measure of an immunological abnormality that distinguished ill from healthy veterans. The Asa/Tulane studies may have correctly identified excess rates of squalene antibodies in ill veterans, whether or not they were caused by vaccines, by vaccine contamination, or by clandestine use of an unapproved adjuvant. It is important to determine whether the observed association between squalene antibodies and Gulf War illness is supported, or refuted, by more definitive research.
This story is important because, according to the VA report, GWS affects >25% of Gulf War veterans, and few have recovered. If squalene-based adjuvants are somehow responsible for (or at least associated with) GWS, and if we vaccinate millions of people as quickly as we can with an adjuvanted pandemic vaccine, the consequences could make the 1976 swine flu vaccine fiasco look like a cakewalk.
Now, after 11 years, the DOD has finally done a study comparing squalene antibody levels in ill vs well military personnel. The paper is available free at this link Antibodies to squalene in US Navy Persian GulfWar veterans with chronic multisymptom illness
ABSTRACT: Since the end of the 1991 Gulf War, there have been reports of unexplained, multisymptom illnesses afflicting veterans who consistently report more symptoms than do nondeployed veterans. One of the many possible exposures suspected of causing chronic multisymptom illnesses Gulf War veterans is squalene, thought to be present in anthrax vaccine. We examined the relationship between squalene antibodies and chronic symptoms reported by Navy construction workers (Seabees), n = 579. 30.2% were deployers, 7.4% were defined as ill, and 43.5% were positive for squalene antibodies. We found no association between squalene antibody status and chronic multisymptom illness (p = 0.465). The etiology of Gulf War syndrome remains unknown, but should not include squalene antibody status.
So they examined the serum of ill vs well veterans for squalene antibodies, and didn't find any difference between the two. Case closed, right?
Not so fast. The lesson, as we have learned many times throughout this series, lies in detailed examination of their methodology. This current study is based on serum collected during an earlier study Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans, which surveyed active duty personnel among Seabees (Navy contruction workers), who were among the earliest groups complaining of symptoms.
In late 1994 and early 1995, epidemiologic teams made three visits to each of the two Seabee Centers. Written informed consent was obtained from each participant. The study included an eight-page questionnaire, and the donation of clinical specimens (sera and whole blood) . The questionnaire was introduced by research staff and self completed by the study subjects. Clinical specimens were preserved at - 70 C. The questionnaire collected information regarding prewar medical history, war exposures, and symptoms occurring for 1 or more months since July 1990.
Since this original survey was only conducted among active duty personnel, there is already some bias because the study excluded those who may have left service due to sickness since the end of the Gulf war in 1991. That is the first bias.
The current study goes further than that. It's common in studies to exclude certain subjects for reasons that are relevant to a particular study, but here, the exclusions defy comprehension or logic. First of all, and most eggregiously,
Potential subjects were excluded if they reported bad reactions to immunizations or injections,
Look, this study was supposed to discover or refute any relationship between chronic multisystem illness and possible reaction to vaccines containing squalene. The first thing they exclude is anybody who reacts to vaccines??
There are other exclusions:
or reported cancer, tumors, lung disease, hepatitis, neurological problems, digestive disease, or psychiatric illness. Additional exclusions included self-report of leishmaniasis, HIV infection or AIDS, malaria, any psychological disorder, sleep apnea, narcolepsy, thyroid disorders, or mononucleosis that resulted in at least a 1-week loss from work or school since age 16. Females were also excluded due to the small numbers of participants
Hmm, I don't know. This looks like a LONG list of exclusions to me (144 subjects were excluded). Does it seem like they were keen on INCLUDING those who might actually be sick?? Let's see what they DO include:
Subjects who reported unusual fatigue and at least three of the additional 38 symptoms listed in Table 1 were defined in these analyses as "ill." Those without any reported symptoms were categorized as "well"
In other words, fatigue is a required symptom (more on the 38 later) in order to be considered as 'ill' in this study, Here's the problem. GWS covers a wide range of symptoms, of which fatigue is only ONE of several possible symptom domains, and by no means the most common one. Many GWS sufferers have a variety of other symptoms but not necessarily 'unusual fatigue', as shown by this table from the VA report.
There are other exclusions, including 371 deemed to be "not well, not ill", in addition to the 144 above, and another 151 for whom there was 'insufficient serum'.
One telltale sign that this study group is NOT representative of GWS sufferers, is that they found only 7.4% of subjects fulfilling their criteria of being 'ill', whereas surveys by other researchers (with 1 exception) consistently show 25-30% excess illness in different study groups:
If you have read thus far, and have gotten thoroughly confused, it's time to start asking whether your confusion is accidental. The point is, by
the authors have managed to remove a lot of possible cases where the detection of squalene antibodies may be significant.
- artificially excluding vaccination-related issues eg history of reaction to vaccines, or
- symptoms commonly found in GWS eg gastrointestinal, neurological, or psychiatric conditions, and
- by restricting inclusion criteria to only those with 'unusual fatigue',
Also, the original authors of the 1994 study identified 22 commonest symptoms reported by 5% or more of study participants. This current study, however, expanded the list of symptoms to 38, including nightmares, crying spells, abdominal pain, swollen glands, asthma, fever, suicidal thoughts, inflammation of the eyes etc. This expansion of inclusion, of symptoms that were NOT commonly reported by the study subjects, increases the likelihood of subjects being included as 'ill' who are in fact not suffering from GWS but from the normal range of conditions that one would find in any military unit.
Next, we get to the squalene antibody test itself. Despite ALL of the above, we can still see some associations.
In the original 1994 survey, 30.2% of deployed and 1.4% of non-deployed personnel reported having received anthrax vaccination. With the current study, ignoring the authors' grouping of 'ill' vs 'well', and just looking at the deployment status, you'll find that 52% (91 out of 175) of those who had been deployed to the Gulf tested positive for squalene antibodies, vs 39.8% (161 out of 404) of those not deployed.
Is that significant? Is there a pattern here? I don't know, I'm not a research scientist, but as a parent who may have to decide whether adjuvants are safe for my kids, I can only say that the way this study was performed, after 11 years of foot-dragging, leaves me with very little confidence that we are anywhere near getting to the truth of the squalene antibody issue.
Finally, in what may be the most significant omission of this whole fiasco, the authors made no attempt to correlate squalene antibody status vs whether the subject reported having received anthrax vaccine. Since the original hypothesis was that these troops may have gotten sick from the vaccine, either because of contamination or because of illicit use of unlicensed adjuvants, wouldn't it be important to discover whether those who received the vaccine were more likely to test positive for squalene antibodies that those who did not? And, to turn the question the other way round, IF the DOD has found there is NO correlation between someone receiving the anthrax vaccine and testing positive for squalene antibodies, don't you think it would be SO much more confidence-building, if they can PUBLISH such a finding?