In our last issue, we talked about the ravages of cancer and the slow but steady progress being made on the immunological front to combat this multi-faceted disease. Since 2006, Canadian citizens have had access to a vaccine against human papillomavirus (HPV), the primary cause of cervical cancer as well as an etiological agent in many oropharyngeal and anogenital cancers. This vaccine has been shown to be safe and effective, and is provided free as part of many provincial elementary school vaccination programs. So why don’t more people get it?

HPV_TEM

Despite its long history, vaccination continues to have its critics. Between unfounded accusations of links to autism and media-fuelled public concern over the safety of well-established vaccines, the decision to vaccinate oneself and one’s children is often seen as a legitimate question in the eyes of the layperson, and already the effects of this supposed controversy are being felt. With declining rates of childhood vaccination and a corresponding decrease in herd immunity, diseases like measles that were once nearly eliminated in Canada – and that are entirely preventable – are making a comeback. In this context, introducing new childhood vaccines is becoming increasingly difficult. And while the HPV vaccine is not new, having been incorporated into Canadian elementary school immunization programs in 2007, vaccination rates against this prevalent virus remain around only 60% across the country.

Let’s Talk About HPV
Human papillomavirus is a member of the Papovaviridae family, which consists of non-enveloped, icosahedral viruses with a circular double-stranded DNA genome. Over 200 variants of the virus have been identified to date, at least 40 of which are known to affect the anogenital region. The virus primarily infects the actively dividing basal cells of squamous epithelia.

HPV is easily spread through skin-to-skin sexual contact, just one of the reasons why it is the most common sexually transmitted infection (STI). The majority of individuals contract the virus within a few years of sexual debut, and it is estimated that over 75% of sexually active individuals will become infected with the virus at some point during their lives, many more than once. 90% of the time, these infections clear up on their own within a few months to a few years without ever presenting symptoms, and the individual may never know that they have been infected. However, it is possible for the virus to persist, especially in the case of immunocompromised individuals, and with no treatment available for the viral infection itself, serious complications can arise.

HPV variants that infect mucosa are divided into high-risk or low-risk depending on their potential outcomes. Low-risk HPV types can cause genital warts, which while non-life threatening, are fairly common and present a significant burden in terms of emotional and physical discomfort. High-risk HPV types, on the other hand, are associated with the development of malignant lesions, and the most serious disease associated with high-risk HPV infection is cervical cancer. Cervical cancer is the second most common female cancer worldwide, affecting approximately 530,000 women each year and causing over 270,000 deaths, yielding a global mortality rate of 52%. HPV has been shown to be the exclusive cause of cervical cancer, with over 99% of cases linked to persistent HPV infection. In Canada, the gold-standard for cervical cancer screening is the Pap smear, and the screening program established in 1994, which recommended annual tests for anyone over 18, has been able to curb the incidence of cervical cancer by almost 80%. However, as a preventative measure, screening has its limitations. Most of the disease burden associated with cervical cancer comes from developing countries, which often lack the resources necessary for proper screening or for treatment of the pre-cancerous lesions that may be detected. Furthermore, there is no standard method of screening for HPV infection in males, despite the fact that persistent HPV infection can significantly increase the risk of anal or penile cancer, especially in men who have sex with men. With all of this in mind, a vaccine against HPV seems like the obvious solution.

Easy as 1, 2, 3
There are currently two HPV vaccines available in Canada. Gardasil, the more well-known of the two, is produced by Merck and was first approved for use in 2006. It is a quadrivalent vaccine administered in three doses over half a year (0, 2 and 6 months), and has been approved for use in females and males aged 9 to 26, with this range recently extended to 45 years of age for women. Cervarix, produced by GlaxoSmithKline, is very similar to Gardasil, also administered in three doses over 6 months (0, 1 and 6 months) and approved for use in individuals up to age 26. However, while Gardasil provides protection against HPV types 6 and 11, which are responsible for 90% of genital warts, and types 16 and 18, which cause 70% of HPV-associated cervical cancers, Cervarix only protects against the latter two.

While these vaccines differ slightly in their scope and composition, they are prepared the same way. Unlike other well-studied viruses, HPV cannot be grown in culture, making manipulation of the virus itself for the purpose of vaccine creation unfeasible. It was discovered, however, that the HPV viral protein L1 is able to self-assemble into a virion-like particle (VLP), which provides the necessary source of antigen for the vaccine. When complemented with adjuvant, these VLPs are able to induce levels of HPV-specific antibodies that far surpass those produced during a natural infection, and these antibodies are able to protect HPV-naïve individuals up to 8 years after inoculation. Furthermore, because the vaccine is composed of a protein, rather than viral DNA, there is no risk of HPV-associated infection or cancer in immunocompromised individuals following vaccination. [pullquote]HPV has been shown to be the exclusive cause of cervical cancer, with over 99% of cases linked to persistent HPV infection.[/pullquote]

One drawback of the current vaccine structure is that the VLPs are not conserved between different types of HPV, which limits the protective effect to the specific type of HPV from which the L1 protein is derived. One solution to this is a nine-valent vaccine currently in clinical trials, which extends the coverage to include more high-risk HPV types and is estimated to increase protection against squamous cell cancers by an additional 20%. Another option is to use the viral protein L2 as the source of antigen in the vaccine, as it is more highly conserved between HPV types. While achieving sufficient immunogenicity with the L2 vaccine has been difficult, studies done in mice have shown that oral administration of Lactobacillus casei expressing L2 on their cell surface results in production of protective IgA antibodies against HPV in the genital mucosa. The universal HPV protection afforded by such a vaccine would completely eliminate the need for cervical cancer screening, which is still required with the existing vaccines. Further work remains to be done to determine how many doses would be required for long-term protection and whether sufficient levels of IgA persist over time.

Will they do it?
While many countries now possess a national program to promote and facilitate HPV vaccination, numerous factors continue to impede the reception and dissemination of the vaccine, not the least of which is the link between HPV infection and sexual activity. Many parents believe that 9 to 12 years old, the age at which vaccination generates the optimal antibody response, is too young to vaccinate for a disease transmitted solely through sexual contact, despite many studies showing that parents frequently overestimate the age of sexual debut in their teenage children. Others fear that vaccinating against an STI will implicitly condone earlier or riskier sexual activity; however, the alternative has been found to be true, as women who received the vaccine were more likely to be invested in their sexual health in terms of continued screening and were no more likely to engage in risky sexual behaviour.

Another reason for the continued reluctance comes down to cost. While the vaccine is provided free in Canada for children in elementary or high school, each dose costs $150 for women or men who fall outside of that age range and the vaccine has minimal benefit if the individual has been sexually active for many years and had previous exposure to HPV. Furthermore, it has been shown that vaccination of young women alone is sometimes sufficient to decrease rates of HPV infection in similarly-aged heterosexual men, which may lead policy makers to conclude that widespread vaccination of males is an unnecessary expenditure. In Canada, however, the coverage of the vaccine in females is currently insufficient to induce adequate levels of herd immunity.

Finally, the most oft-cited reason by parents for rejecting the HPV vaccine is concerns over its safety, despite extensive evidence that the vaccine is both safe and effective. The most common side effects reported upon administration of the vaccine are mild local and systemic effects on par with other approved immunizations, such as temporary soreness at the site of injection or mild fever or headache. However, inflated reports of adverse reactions and misattributed fatalities during the early days of Gardasil’s release resulted in widespread backlash against the vaccine that even now casts a shadow on years’ worth of data demonstrating the vaccine’s safety.

Conclusion
In 2011, 1,300 Canadian women were diagnosed with cervical cancer, and another 250 women died from the disease. While this pales in comparison with the staggering number of cervical cancer cases in the developing world, any method of combating this disease that has been repeatedly and empirically shown to be effective and safe is worth investing in, something that Canadian policy makers have recognized. With new guidelines from the Canadian Task Force on Preventative Medicine now recommending Pap screening only once every three years after the age of 25, it is more important than ever for young women (and men) to be educated about the risks of HPV and the benefits of timely vaccination.

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Kieran Manion

Design Director
Kieran Manion is a senior PhD student studying the breakdown of B cell tolerance in systemic lupus erythematosus in the Department of Immunology at the University of Toronto. In her spare time, she practises using digital platforms for general artwork and graphic design.
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