'The most efficient primary prevention measure now available to prevent cervical
cancer is a correct sexual education in order to avoid risk
behaviours.' ~ Dr Silvia Carlos.  Photo: iStock

Is cervical cancer caused by a sexually transmitted infection? Can the vaccine designed to prevent the STI prevent cervical cancer? Is the vaccine safe? These are questions that continue to trouble some people a decade after the human papillomavirus (HPV) vaccine was launched. They have been aired recently in Gardasil: Fast-Tracked and Flawed, which MercatorNet reviewed in August.

The book’s Australian author, Helen Lobato, answers these questions negatively, or at least casts strong doubt on claims that the HPV vaccine is a safe and effective way to prevent cervical cancer, a disease whose mortality rate in the developed world is already low.

Ms Lobato’s most contentious claims/doubts relate to:

a) the link between HPV and cervical cancer

b) the safety of the vaccine

We asked Dr Silvia Carlos, an expert on infectious diseases in the Department of Preventive Medicine and Public Health at the University of Navarre, Spain, for the evidence on these questions and two others: Does the HPV vaccine prevent cancer? Even if it does, is it an efficient and cost-effective method compared with other ways of preventing such diseases? Dr Carlos’ answers are necessarily somewhat technical, but we present them for the record.

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MercatorNet: Research cited in the book, Gardasil: Fast-Tracked and Flawed, advances an alternative theory of the cause of cervical cancer – namely, that it arises from chromosomal changes after exposure to carcinogens such as cigarette smoke and X-rays. How certain is it that HPV causes cervical cancer?

Silvia Carlos: There is convincing evidence of a causal relationship between HPV and cervical cancer. This is affirmed by the World Health Organization: “Virtually all cervical cancer cases (99%) are linked to genital infection with HPV. HPV can also cause other types of anogenital cancer, head and neck cancers in both men and women.”

The US National Cancer Institute fact sheet, “HPV and Cancer” gives the following information:

Low-risk HPVs, which do not cause cancer …High-risk HPVs, which can cause cancer. Cervical cancer: Virtually all cases of cervical cancer are caused by HPV

Anal cancer: About 95% of anal cancers are caused by HPV.

Oropharyngeal cancers (cancers of the middle part of the throat, including the soft palate, the base of the tongue, and the tonsils): About 70% of oropharyngeal cancers are caused by HPV.

Rarer cancers: HPV causes about 65% of vaginal cancers, 50% of vulvar cancers, and 35% of penile cancers.

How does high-risk HPV cause cancer? HPV infects epithelial cells. Once HPV enters an epithelial cell, the virus begins to make the proteins it encodes. Two of the proteins made by high-risk HPVs (E6 and E7) interfere with cell functions that normally prevent excessive growth, helping the cell to grow in an uncontrolled manner and to avoid cell death. Many times these infected cells are recognized by the immune system and eliminated. Sometimes, however, these infected cells are not destroyed, and a persistent infection results. As the persistently infected cells continue to grow, they may develop mutations in cellular genes that promote even more abnormal cell growth, leading to the formation of an area of precancerous cells and, ultimately, a cancerous tumor …

Other factors may increase the risk that an infection with a high-risk HPV type will persist and possibly develop into cancer. These include: Smoking or chewing tobacco (for increased risk of oropharyngeal cancer), having a weakened immune system, having many children (for increased risk of cervical cancer), long-term oral contraceptive use (for increased risk of cervical cancer), poor oral hygiene (for increased risk of oropharyngeal cancer), chronic inflammation.

The link is confirmed in Expert Views on HPV Infection, a special issue of the journal Viruses (August 2017) – for example, “Somatic Host Cell Alterations in HPV Carcinogenesis” as well as a review, “The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review”,  also published last month, and other recent papers.

The author and publishers of Gardasil: Fast-Tracked and Flawed express concerns over the presence of aluminium in the vaccine, particularly since the new two-dose version, Gardasil 9, has more than twice the amount in the current version. They say aluminium is a neurotoxin. Is aluminium a safety concern?

SC: The amount of aluminum present in vaccines is low and is regulated by the U.S. Food and Drug Administration (FDA). The amounts are as follows:

Bivalent vaccine: 500 mcg aluminum hydroxide

Quadrivalent vaccine: 225 mcg adjuvant

Nonavalent vaccine: 500 mcg AAHS (amorphous aluminum hydroxyphosphate sulfate)

The use of aluminium in vaccines is addressed by the Centers for Disease Control. The CDC says:

Aluminum salts, such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate have been used safely in vaccines for more than 70 years. Aluminum salts were initially used in the 1930s, 1940s, and 1950s with diphtheria and tetanus vaccines after it was found that this addition strengthened the body’s immune response to these vaccines.  

Another concern is that Gardasil 9 also contains more antigens (the HPV LI proteins) with the total number increasing from 120 mcgs to 270 mcgs.

SC: Obviously, as it protects against a higher number of strains (as in other polyvalent vaccines).

According to a WHO database cited in the book, there are now over 73,000 recorded adverse events after HPV vaccination. There have also been at least 324 deaths following Gardasil. This sounds a lot – is it cause for alarm?

SC: Keep in mind that these are absolute numbers that have to be compared to the total number of vaccinations administered, length of period of observation and other­ vaccines. They also have to be compared with people not vaccinated who could present with the same symptoms for other reasons. It is always dangerous to focus on absolute numbers.

100 can be “a lot” but 100/100000000 in 10 years could be “normal”.

WHO safety data can be found here (PDF) and in Human papillomavirus vaccines: WHO position paper, May 2017 (PDF). From the latter document:

All 3 licensed HPV vaccines – bivalent, quadrivalent, and nonavalent [targeting nine types of HPV] – have excellent safety, efficacy and effectiveness profiles.”

Adverse events following HPV vaccination are generally non-serious and of short duration.”

In January 2016, WHO Global Advisory Committee for Vaccine Safety (GACVS) concluded that the available evidence did not suggest any safety concern regarding the use of HPV vaccines.”

Post-marketing surveillance indicates that systemic reactions were reported as generally mild and self-limiting. Post-vaccination syncope [fainting] has been reported, as for many vaccines, but can be minimized and its complications avoided with appropriate preparation.”

In pre-licensure trials, no serious adverse events attrib­utable to the vaccine were recorded for either the quadrivalent or bivalent vaccine. For the nonavalent vaccine, the rate of serious adverse events attributable to the vaccine was <0.1%.Comparison of the nonava­lent and quadrivalent vaccines yielded rates of serious adverse events of 0.4% and 0.2% respectively.”

Although case reports have identified a range of new onset chronic conditions occurring post-vaccination, including autoimmune diseases, a well-conducted population-based study on post-licensure safety surveillance showed no association between HPV vaccine and such conditions. Data are reassuring that HPV vaccine does not increase the risk of Guillain- Barré syndrome. A review of post-licensure safety surveillance during >4 years of routine use of the bivalent vaccine found no patterns or trends for potential immune-mediated diseases after vaccination, and observed incidences of Bell’s palsy and confirmed Guillain-Barré syndrome were within the expected range in the general population. Concerns have been raised about complex regional pain syndrome (CRPS) and postural orthostatic tachycar­dia syndrome (POTS) following HPV vaccination. Despite the difficulties in diagnosing both disorders, reviews of pre- and post-licensure data provide no evidence that these syndromes are a direct effect of the HPV vaccines.”

According to the CDC:

The HPV vaccine is very safe, and it is effective at preventing HPV. Vaccines, like any medicine, can have side effects. Many people who get the HPV vaccine have no side effects at all. Some people report having very mild side effects, like a sore arm from the shot. The most common side effects are usually mild. Common Side Effects of HPV Vaccine: Pain, redness, or swelling in the arm where the shot was given,Fever,Headache or feeling tired,Nausea, Muscle or joint pain.”

Brief fainting spells and related symptoms (such as jerking movements) can happen after any medical procedure, including vaccination. Sitting or lying down for about 15 minutes after a vaccination can help prevent fainting and injuries caused by falls.”

On very rare occasions, severe (anaphylactic) allergic reactions may occur after vaccination.”

HPV9 in female patients is as safe as the tetravalent vaccine.

Can it be said with confidence that the HPV vaccine prevents cervical (and other types of) cancer?

SC: There is still no evidence available about the effectiveness in the prevention of cancer as an endpoint. Other outcomes have been evaluated (HPV infection, preneoplasic lesions) but we still need a longer follow-up period to see what happens with cervical cancer. In the meantime, cervical cancer screening, which does prevent cervical cancer, needs to be promoted in addition to the vaccine.

A scientific paper just published in Lancet (September 2017) states that “On the basis of epidemiological studies, the 9vHPV vaccine could prevent around 90% of cervical cancers”. In this study the authors also remember that:

“The use of invasive cancer (cervical, vulvar, or vaginal) as an efficacy endpoint is not acceptable for ethical reasons; also, the time from infection with HPV to development of cancer usually exceeds 10 years. Thus, HPV vaccine efficacy trials evaluate the effect on HPV related high-grade (precancerous) lesions (CIN2 or 3, adenocarcinoma in situ, vulvar intraepithelial neoplasia grade 2/3, and vulvar vaginal intraepithelial neoplasia grade 2/3) used as surrogate efficacy endpoints for cancer.”

Even if it turns out that the vaccine does prevent genital and related cancers, is population vaccination an efficient and cost effective way to deal with such diseases — at least in the developed world where the incidence of cervical cancer is rather low?

SC: The most efficient primary prevention measure now available to prevent cervical cancer is a correct sexual education in order to avoid risk behaviours and therefore not only HPV infection, but also many other sexually transmitted infections.

Additionally, cervical cancer screening is a cost-effective secondary preventive strategy.

In terms of the vaccine efficiency, today there are some different aspects that need to be evaluated, such as: the real vaccine coverage (including the 2 or 3 doses needed for the different available vaccines), the specific country or region incidence, the effectiveness after a longer follow-up period, the effectiveness against other high-risk HPV types that could arise, the risk or age of the population, catch-up programmes, the possibility of reduction in vaccine costs, etc.

A systematic review that was recently published in BMC Public Health concludes that:

“A high degree of heterogeneity was found in terms of how HPV prevention strategies have been assessed in terms of their economic and epidemiological impact, with variation in screening practice and valence of HPV vaccination found to have large implications in terms of cost-effectiveness…New prevention strategies involving multi-valence vaccination, HPV DNA test screening, delayed commencement and frequency of screening could be implemented in the future. Strategies implemented in the future should be chosen with care, and informed knowledge of the potential impact of all possible prevention strategies. Highlighted in this review is the difficulty in assessing multiple strategies. Appropriate modelling techniques will need to be utilised to assess the most cost-effective strategies.” (Gervais et al. BMC Public Health (2017) 17:283)

Professor Silvia Carlos is an expert on infectious diseases in the Department of Preventive Medicine and Public Health at the University of Navarre, Spain.