Description of the condition

The effectiveness of vaccinations has been proven repeatedly since the first introduction of the cowpox vaccine in the 18^th century (Delany 2014; Whitney 2014). In fact, vaccination is considered one of the major triumphs of modern medicine (Delany 2014; Whitney 2014). Vaccination prevents infectious diseases (Delany 2014; Whitney 2014), and the worldwide eradication of the highly contagious and deadly smallpox and the restriction of diseases such as polio, measles, and tetanus can largely be ascribed to the numerous successful mass vaccination programmes launched since the 1960s (Delany 2014; Whitney 2014). In the late 1940s and 1950s, prior to public vaccinations, the poliovirus caused infantile paralysis associated with high mortality in hundreds of thousands of children (Global Polio Eradication Initiative 2016; WHO 2016a). The measles virus was responsible for post‐infectious encephalomyelitis in 1 per 1000 infected individuals, leaving most with permanent impairment of the central nervous system (Miller 1964; CDC 2016). Today, polio is nearly eradicated (WHO 2016a), and global measles death has decreased by 79%, with an estimated 17.1 million deaths prevented from 2000 to 2014 (WHO 2016b).

Current routine vaccine programmes recommended by the World Health Organization (WHO) include vaccines against Bacillus Calmette–Guérin (BCG); hepatitis; polio; diphtheria, tetanus, and pertussis (DTP); haemophilus influenza type B; pneumococcal bacteria; rotavirus; measles; rubella; and human papilloma virus (HPV) (WHO 2017). Additional programmes are proposed for certain regions, high‐risk populations, and for fighting pathogens with certain characteristics (e.g. Bacillus anthracis causing anthrax).

Vaccination mimics infection in the body leading to activation of a potent immune response (Coffman 2010; Kool 2012; O'Hagan 2012; Oleszycka 2014). The vaccines are two types: traditional vaccines which contain vaccine antigens and excipients (substance formulated alongside the active vaccine ingredient) and do not use adjuvants (substance that aid the immune response to an antigen); and vaccines of a newer generation which typically require the addition of adjuvants to the vaccine antigens and the excipient (Coffman 2010; O'Hagan 2012). Vaccine antigens may comprise whole attenuated pathogens, pathogen components, virus‐like particles, or genetic material of the pathogen (Strugnell 2011).

Like other medicinal products, vaccines undergo preclinical testing for safety, for the ability to induce cancer, for the ability to induce immune response, and for overall efficacy before they are licensed. However, rare adverse events or adverse events with delayed onset are not easily detected during the relatively short duration of most preclinical and clinical phase studies, and as proven over the years, safety surveillance in the general population post marketing is essential (Ward 2000; Chen 2005). As an example, the childhood measles‐mumps‐rubella (MMR) vaccine was introduced in the late 1960s as a mixture of three live attenuated viruses, administered via injection (Offit 2007). Over time, doubts about its safety were raised when serious cases of fever seizures, meningitis, and allergic reactions were reported (Kimura 1996; Dourado 2000; Ward 2000). In Japan, a nationwide surveillance programme launched in the early 1990s screened more than 38,000 children vaccinated with four different Urabe‐containing MMR vaccines (Kimura 1996). Serious adverse events included convulsions and aseptic meningitis, and the incidence was shown to be linked to different vaccine strains of mumps virus (Kimura 1996). During the same time period, Brazil experienced a mass outbreak of aseptic meningitis following a Urabe‐containing MMR vaccine with an estimated risk of 1 in 14,000 doses (Dourado 2000). As another example, the DTP vaccine was licensed in the late 1940s as a preparation of three different antigen components (trivalent vaccine) adsorbed to aluminium salt. It was suspected to cause acute encephalopathy and chronic nervous system dysfunction (Cowan 1993). Reports, prepared by the Institute of Medicine (IOM) in the US, concluded that the evidence was insufficient to indicate a causal relationship between the DTP vaccine and acute or permanent neurologic damage (Cowan 1993). In 2000, the WHO published a critical bulletin on vaccine safety, including an overview of serious vaccine‐associated adverse events for which causality had been established or was highly likely (Ward 2000). Among several vaccine‐specific serious adverse events, they found a causal relationship between vaccines against DTP, hepatitis, MMR, and polio and disease dissemination, severe allergic reactions, or death (Ward 2000).

Vaccine toxicity may originate from a plethora of factors, including the vaccine components (e.g. the antigen itself, the adjuvant, or the excipients), interaction between different vaccine components, vaccine manufacture, overall vaccine composition, route of administration, dose, and number of vaccinations (Kocourkova 2016).

One of the latest programmes added to the mass vaccination portfolio is the public HPV vaccination programme launched in the US a decade ago (WHO 2014a). Human papilloma virus causes cervical cancer; the second most common cancer form in women (WHO 2014a), and thus, the aim of the HPV vaccination is to prevent development of cervical cancer. More than 60 countries included the HPV vaccine in their routine vaccinations after its market approval (Bruni 2016). In recent years, concerns were raised about adverse events possibly related to the HPV vaccines. Since the US approval of Gardasil® in 2006 and up until 2012, a total of 21,265 adverse events was reported to the national Vaccine Adverse Event Reporting System (VAERS) (Tomljenovic 2012). HPV vaccines have been blamed for giving rise to more reported adverse events than other types of vaccines (Tomljenovic 2012). In the European Union, the European Medical Agency (EMA) has received similar reports, but found no scientific evidence for an association (EMA 2015). Several observational studies also failed to identify associations with clinical diagnoses (Klein 2012; Arnheim‐Dahlstrom 2013; Donegan 2013; Grimaldi‐Bensouda 2014; Scheller 2015), but reasons to oppose these findings have been put forward (Brinth 2015a; Brinth 2015b; Dyer 2015; Gøtzsche 2016; Gøtzsche 2016a). The symptoms reported following HPV vaccination are varied and include headache, orthostatic intolerance, fatigue, cognitive dysfunction, blurred vision, feeling bloated, abdominal pain, light sensitivity, and involuntary muscle activity (Brinth 2015a; Brinth 2015b). Despite the consistency in reported symptoms, they do not fit into a well‐defined category of diseases or diagnoses, but rather present themselves as a constellation of nonspecific symptoms (Brinth 2015a; Brinth 2015b). Consequently, the observational studies, which based their results on registered diagnoses, may have excluded an important fraction of eligible participants with unclear adverse symptoms, as most young girls that claim to suffer from adverse events following HPV vaccination receive no clinical diagnosis, and are therefore unlikely to appear in medical registers. Moreover, the randomised clinical trials on HPV vaccines, which formed the basis for the safety assessment, have been blamed for not using true placebo (e.g. placebo not containing adjuvants) as the control intervention (Exley 2011).

Description of the intervention

Adjuvants are added to vaccines to enhance the ability to provoke an immune response of weak antigens and improve the overall potency of the vaccine (O'Hagan 2009; Coffman 2010). Adjuvants may also pose other benefits, such as reducing the frequency of vaccination and the dose of antigen per vaccine, and some may provide cross‐clade immunity (i.e. immunity against different clades of viruses or different clades of bacteria descending from different ancestors) or improve the stability of the final vaccine formulation (Carter 2010; Reed 2013). Currently, five adjuvants with completely different mechanism of action are approved for use in vaccine production. These include: aluminium salts (EU, US), MF59 (EU), AS03 (EU), AS04 (EU, US), and virosomes (EU) (Rambe 2015). Virosomes consist of a lipid membrane incorporating virus‐derived proteins, while MF59 and AS03 are squalene‐based adjuvants and AS04 combines aluminium hydroxide with monophosphoryl lipid A. Aluminium salts, also referred to as alum, are most commonly used and encompass aluminium potassium sulphate, aluminium hydroxide, aluminium phosphate, and amorphous aluminium hydroxyphosphate sulfate (Carter 2010).

Different insoluble aluminium salts have been used as vaccine adjuvants since 1926 (Glenny 1926). Aluminium potassium sulphate was the first used. However, because of poor reproducibility, it has been almost completely replaced by aluminium hydroxide and aluminium phosphate, as they can be prepared in a more standardised way, and capture antigens by direct adsorption (Marrack 2009). Aluminium has been the standard adjuvant in vaccines such as those against diphtheria, tetanus, and pertussis, haemophilus influenza type B, pneumococcus conjugates, hepatitis A, and hepatitis B (Tritto 2009). More recently, it was co‐formulated with vaccines against HPV in the form of AS04 (containing aluminium hydroxide) and amorphous aluminium hydroxyphosphate sulfate. Amorphous aluminium hydroxyphosphate sulfate is commercially produced in nanometre‐scale, and represents one of the latest marketed aluminium adjuvants.

The mechanism of action of aluminium, like for most adjuvants, is poorly understood, and widespread beliefs change according to continuously new insights into immunology and physiochemical properties of aluminium (see How the intervention might work) (Carter 2010; Tomljenovic 2011). Despite our incomplete understanding of its effects, the repeated use of aluminium in vaccines is justified by its apparent safety profile, ease of preparation, stability, potent immunostimulatory ability (O'Hagan 2009; Tritto 2009; Mbow 2010), and importantly, due to the lack of suitable alternatives.

How the intervention might work

Aluminium is the third most abundant element in the earth’s crust, but the metal has no known biological or physiological role (Reinke 2003). It is absorbed into the blood through the gastrointestinal tract, and rapidly eliminated by the kidneys and bile (Reinke 2003). While aluminium is considered safe and regularly ingested with food and water, it is toxic in high concentrations (Kisnieriené 2015). The toxicity, however, not only depends on the concentration, but on the chemical form and the environment as well (Kisnieriené 2015). In the blood, aluminium is bound to transferrin with high affinity, where it competes with iron at the binding site (Kisnieriené 2015). Aluminium also affects cellular processes and physiological functions (Kisnieriené 2015). For instance, aluminium competes with magnesium for membrane transporters; disturbs calcium metabolism; increases oxidative stress; binds to the phosphate groups of nucleoside di‐ and triphosphates; and also binds to metal‐binding organic compounds (amino acids) and membrane lipids (Kisnieriené 2015). In high concentrations, aluminium is predominantly accumulated in bone and brain tissue (Yokel 2000; Malluche 2002). In animal and human studies, it has been shown to act as a powerful neurological toxicant and provoke toxic effects in foetuses and embryos if exposed during pregnancy (Reinke 2003). This is supported by recent data indicating that aluminium is able to cross the blood‐brain barrier by directly affecting the cerebral blood vessels (Chen 2008; Sharma 2010).

Despite its unclear biological role, aluminium seems to have an impact on the immune system, which has rendered it useful as a vaccine adjuvant (Tritto 2009; Kool 2012). Aluminium binds antigens with high affinity (antigen adsorption) and was originally thought to exert its function by forming a depot, which allows for a high antigen concentration at the site of injection, and a continuous desorption and dispersion of antigens from the aluminium particles (Kool 2012). Nowadays, aluminium is believed to exert its adjuvantic effects by stimulating Th2‐type responses and antibody production through B cells activation (Grun 1989; Awate 2013), by activating the complement system, and by recruiting immune cells to the site of injection (Ramanathan 1979; Goto 1997; Awate 2013). At the injection site, aluminium promotes antigen uptake by specialised antigen‐presenting immune cells, termed dendritic cells, and dendritic cell maturation (Mannhalter 1985; Morefield 2005; Kool 2008).

One important aspect of adjuvants is the size of the particles, which seems to have a considerable influence on the immune response. Aluminium hydroxide adjuvant is comprised of particles with a calculated dimension of 100 nm, while aluminium phosphate particles are around 50 nm (Hem 2007). In an aqueous (water) solution, particles of both aluminium salts aggregate to form 1 to 20 µm sized particulates (Hem 2007). This size is also known as microscale‐size. Aluminium hydroxide and aluminium phosphate can be produced in nanoscale‐size ≤ 200 nm, but so far, only amorphous (non‐crystalline solid) aluminium hydroxyphosphate sulfate is produced in nanoscale for use in vaccine preparations (Issa 2014; Li 2014). The particle size is directly linked to the adsorption efficiency of antigens (Oyewumi 2010). In line with this, recent evidence shows that nanoscale aluminium particles can adsorb more antigens compared to traditional aluminium‐based adjuvants because of the higher surface‐area‐to‐volume ratio, and that they are more potent than traditional micro‐particles (Caulfield 2007; Salvador 2011; Li 2014). Moreover, the efficacy of particle uptake by the specialised antigen presenting dendritic cells in vitro and in vivo is inversely proportional to the size of the particle with maximum efficiency for nanoscale particles < 100 nm (Foged 2005; Shima 2013). Dendritic cells scavenger and engulf particles of < 10 µm, having evolved to recognise pathogens of this size (Gupta 1995; Foged 2005). Other factors like structure, shape, and surface charge have also been demonstrated to greatly affect uptake by dendritic cells (Thiele 2001; Foged 2005; Bartneck 2012; Son 2013).

Why it is important to do this review

One previous attempt to assess the potential toxic effects of aluminium adjuvant with a systematic review was undertaken in 2004 by Jefferson and colleagues (Jefferson 2004). The systematic review covered existing evidence of adverse events after exposure to the aluminium‐containing DTP vaccine, but it did not assess benefits (Jefferson 2004). The authors included three randomised trials, four semi‐randomised trials, and one cohort study, and they were unable to demonstrate that aluminium adjuvant was responsible for any serious or long‐lasting adverse events (Jefferson 2004). The authors advised the ending of future research despite concluding that their finding was based on poor‐quality evidence (Jefferson 2004).

More than 10 years has passed since the systematic review by Jefferson and colleagues, new adjuvants are being introduced continuously, and FDA and WHO do not require genotoxicity or cardiotoxicity studies of new aluminium adjuvants (WHO 2014b; FDA 2015). Lately, symptoms following HPV vaccination have been suspected of being caused by the addition of aluminium adjuvant (Tomljenovic 2011; Lee 2012; Poddighe 2014; Brinth 2015b; Gruber 2015; Martinez‐Lavin 2015). A recent animal study by Inbar and colleagues managed to spark further controversy by demonstrating behavioral abnormalities in mice administered the aluminium‐containing HPV vaccine Gardasil (Inbar 2016a). Compared to previous animal studies on HPV vaccines, the authors included two control groups: one where mice were administered aluminium adjuvant alone and another with placebo without adjuvant (Inbar 2016a). Inbar and colleagues concluded that Gardasil via both its aluminium adjuvant and HPV antigens can trigger neuro‐inflammation and autoimmune reactions, leading to behavioural changes in mice (Inbar 2016a). Upon submission to a peer‐reviewed journal, the paper was accepted with revisions, and published. However, it was soon withdrawn by the editor (Inbar 2016), only to be published in a competing journal shortly thereafter (Inbar 2016a). The initial withdrawal was allegedly due to "unsound scientific results"; an assertion which was not supported by the final publisher.

The theory that aluminium adjuvant is responsible for symptoms following HPV vaccination is impossible to refute or prove based on the current data. Aluminium adjuvant has been administered to both experimental and control group in the vast majority of randomised clinical trials on HPV vaccines, thus masking its potentially harmful effects (Exley 2011). Clinical trials designed to administer vaccine adjuvants to the experimental group as well as the placebo group do, de facto, not compare an intervention against a true placebo, and therefore, do not adequately assess safety (Exley 2011). Indeed, aluminium adjuvants, new or old, should be evaluated for benefits and harms on their own merits.

Aluminium is the most frequently used adjuvant, introduced in vaccination programmes worldwide (Tritto 2009). While the consequences of adding aluminium to vaccines have been discussed broadly, no systematic review has been conducted to assess the effects of aluminium adjuvants across vaccines. The effects of aluminium adjuvants remain to be properly assessed using Cochrane methodology to determine whether they are beneficial, or causally linked to the numerous adverse events reported following immunisation.