Are we able to establish a relation between these results and the Hill’s criteria [21]? Is there a causal relationship between the HB vaccination and the incidence of MS in France? The Hill’s criteria for causation include nine items detailed in Table 1. We will detail now the most important criteria in the text, the other being a simple bibliographic reference mentioned in this table.

Table 1 Study of Hill’s criteria Full size table

The current study satisfies the first criterion. The association is highly statistically significant between reported MS (Yt + 2) to pharmacovigilance and the series of HB vaccines that were sold 1 and 2 years before (p < 0.01 for sold vaccines 2 years before (Xt) and p < 0.05 for sold vaccines 1 year before (Xt + 1); adjusted R 2 = 0.9497). Although it is possible to demonstrate here a statistical relationship between the number of sold vaccines and MS reported to the pharmacovigilance, it is not enough to affirm an absolute causality. This is a strong signal that requires further epidemiological studies.

The positive and statistically significant correlation between HB vaccine exposure and reported MS incidence is consistently observed in different places, circumstances, and times (criterion 2).

First, this result is consistent with the Hernan’s case–control study [12] that found in the British population an increased risk of MS (OR 3.1; CI 1.5–6.3) in the 3 years following HB vaccination. Moreover, in this same study, the risk was greater when the last immunization took place within the second or third years before first symptoms of MS (OR 4.1; CI 1.3–13.6).

The results of the case–control study by Geier [11] in USA are also consistent with the French pharmacovigilance data. There is a very significant change in the risk of developing MS after HB vaccine in adults in the VAERS database (OR 5.2, p < 0.0003; CI 1.9–20).

The Costagiola’s study [10] found underreporting of post-vaccine reported MS during the observation period (1994–1996) of an epidemiological study requested by French pharmacovigilance [9]. The combination of these two studies suggests a real number of cases significantly higher (RR = 1.66) than the expected number of MS during the 3 years of the collection.

Most publications where there is no link between HB vaccination and the onset of MS [2–5] received grants from pharmaceutical industry. Other criticism that can be raised for some of these negative case–control studies is the limited period (2–24 months) of their survey [4, 7–9]. Moreover, the Hernan’s publication [12] shows also a negative result (OR 1.8; CI 0.5–6.3) for a period of 1 year and becomes significant between 2 and 3 years of follow-up after HB immunization.

The case–control study nested in the Nurses’ Health by Asherio [4] presents several biases. The vaccination status was obtained retrospectively like the date of first symptoms of the disease assessed by questionnaires. This process may cause selection bias leading to a downwardly biased OR as the specific (nurses) selected population [26].

At last, a meta-analysis [27], based on six epidemiological case–control studies [4–7, 11, 12], did not find significant change in the risk of developing MS after HB vaccine in adults (OR 0.92; CI 0.84–1.004). This paper can also be criticized. Strangely, the statistical computing of this meta-analysis attributes a non-significant value to the Hernan’ study [12], with an OR 1 (CI 0.5–2.1) by using the cases’ date of diagnosis as the index date instead of the date of first symptoms as the author does. But as Hernan wrote [12], “the use of dates that are posterior to the true date of first symptoms may cause a downward bias of the OR for acute exposures such as vaccinations”. In addition, the most significant study by Geier [11] is removed, being regarded as a “source of heterogeneity”. So, withdrawal of a positive study and changing the result of another one more easily allows a negative outcome.

Generally speaking, we know that a low risk of adverse post-vaccination cannot be demonstrated by studies of low statistical power with small numbers of exposed people. Therefore, results in a population of over 20 million vaccinated people should attract attention and require further epidemiologic studies. Moreover, studies with a short period of post-vaccination monitoring are inadequate because they do not take into account the long biopersistence of immunostimulatory vaccine compounds (such as aluminum hydroxide) in the body. In this, vaccines derogate from the rule generally used for side effects of drugs.

The temporal relationship (criterion 4) clearly exists here. The annual incidence of MS recorded by the French insurance was stable about 5.5/105 until 1995. It rose sharply in 1996 to stabilize around 8/105 from 1998. But this sharp increase (65 %) closely follows a major peak in the number of vaccines sold between 1995 and 1997 in France (Fig. 1). The number of MS occurring in the aftermath of a HB vaccination reported to the French pharmacovigilance almost draws the same peak with a delay between 1 and 2 years (Fig. 2). Moreover, some papers report observations of MS relapses triggered by repeated injections of HB vaccine [28, 29].

The official explanations of the increase in this incidence are twofold, first a better screening of MS whose diagnosis has been made easier and faster by using radiological data provided by MRI. This is a dubious explanation. This new radiological technique has begun to develop gradually in French hospitals in 1990 and thus before the obvious increase in the recruitment of MS by French national insurance (1996). Otherwise, if this earlier diagnosis was really so important in the increased incidence of MS, we should have observed in France a decrease in the average age of newly diagnosed cases. And this rejuvenation was not observed [30].

The second factor involves the change in treatment protocol of this period with the introduction of treatment with interferon-beta in 1995, an innovative and very expensive drug that prompted physicians to quickly seek a total care by French health insurance. In 2004, the emergence of a new drug (glatiramer), indicated for the most common form of MS (relapsing–remitting), has not been followed by an increase in cases registered by CNAM that year and the following. The incidence remained the same. This explanation cannot alone explain a so rapid and significant increase (65 % over 4 years) in the incidence of a disease like MS.

A third factor must be considered in such a sudden increase in MS incidence. So the changing of an environmental etiological factor must be taken into account seriously. This therefore appears to be the case for the question of the potential role of HB vaccination carried out in France for a short time and in a massive way, about 20 million people concentrated in 4 years. It is interesting to compare these figures with those countries where routine vaccination has not been recommended. In Norway, the incidence of MS is higher than in France in the early 1990 s (8.7/105 between 1990 and 1995). Then, it decreases slightly in subsequent years (7.2/105 from 1996 to 2000) [31]. In the county of Värmland (Sweden), the incidence of MS has remained similar (6.4/105) during the periods 1991–1995 and 1996–2000 [32].

Specificity (criterion 3) is likely for a very specific population at a specific site and disease. This is not applicable to diseases such as MS. Genetic risk (HLA-DR2) and environmental factors (vitamin D insufficiency) or infectious factors (Epstein–Barr virus, endogenous retroviruses) are clearly involved in the occurrence of MS although its etiology and pathophysiology are not completely understood. These other environmental and genetic factors may have contributed to the raise in MS incidence and should be mentioned.

Biological plausibility (criterion 6): A plausible mechanism between cause and effect is helpful. Are there explanations regarding plausible mechanisms by which vaccines and particularly this vaccine may induce harm? This issue has been extensively studied in recent years. Various aspects of the causal and temporal interactions between vaccines and autoimmune phenomena are known, as well as the possible mechanisms by which different components of vaccines might induce autoimmunity [33]. A first hypothesis could be the similarity between the protein S (used in the vaccine against HB) and some myelin proteins such as PLP (proteolipid proteins) [34]. Another interesting track would be contamination by minor HB virus polymerase proteins. And we know that HB virus polymerase shares significant amino acid similarities with the human MBP (myelin basic protein) [35]. This process is called molecular mimicry: a foreign antigen that shares sequence or structural similarities with self-antigens.

Another runway about biological plausibility is to take into account the metabolism of vaccine adjuvants in the human body. The long-term persistence of aluminum adjuvant at the site of vaccine injection is now well established [36]. Furthermore, transferring of aluminum particles from muscle to brain is demonstrated in animals [37]. A new syndrome entitled ASIA, “Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants”, was recently described, grouping four similar illnesses [38]. These diseases (siliconosis, the Gulf war syndrome, the macrophagic myofasciitis syndrome and post-vaccination phenomena) were linked with previous exposure to an immune adjuvant (silicone, aluminum salts). In another publication, the same authors found common clinical characteristics of the ASIA criteria among 93 patients diagnosed with immune-mediated conditions post-HB vaccination, suggesting a common denominator in these diseases [39].