HPV vaccine in men – where to?

Abstract

Introduction: HPV – human papilloma virus is one of the most widespread human pathogen. For
a long time it was treated as an opportunist but it proved to be one of the most dangerous
carcinogens. It is held responsible for many malignancies: cervical, penile, oropharyngeal,
vaginal, vulvar and some anal neoplasia. The need for a long term solution appeared and so the
HPV vaccines proved to be a viable solution. Women, men who have sex with men and young
men are included in the vaccination template.

Matherial and methods: A thorough review using PubMed and other databases revising vaccine
templates and targeted male patients has been made.

Conclusions: HPV vaccine is a very efficient immunization method. Women are obviously the
first target but there are still many contradictions regerding men. Most of the reasons reside in
the cost-efficiency aspect, but there is still great debate regarding which vaccine is more efficient
in the male population.
Key words: HPV, vaccine, neoplasia

Introduction

Human papillomavirus (HPV) is one of the most important carcinogens in humans, classified in
Group 1, carcinogenic to humans, of the International Agency for Research on Cancer (IARC). It
has been demonstrated its implication in neoplasia. The need for a cure arose and a vaccine was
created. Nowadays there are more types of vaccines targeting from two up to nine viral strains.
Some of them have proven effective in women like the two strains type; others seem to have
higher efficiency in men like the nine strains type. The bivalent vaccine has proven his
effectiveness in ano-genital neoplasia (HPV 16 AND 18 strains), now the nonavalent is adding
the HPV 31, 33, 45, 52 and 58 [1,2]
This vaccination overhaul started in 2006 for women and 2011 for men. The Advisory
Committee on Immunization Practices (ACIP) has also recommendations for men who have sex
with men, for men and women over 26 and 21 years respectively.[3,4]
The biggest problem is that every country introduced and applied their variant of vaccination
programme. The Nordic countries from Europe are the most adherent to HPV vaccination and
many studies come from them.
Some countries use the bivalent, the quadrivalent and the nonavalent are also available. USA for
instance uses the nonavalent vaccine from 2015. The most adherent country to use the HPV
vaccine is Australia. In this country there is a proper vaccination programme. The proportion of
those vaccinated with three doses is there, 30% and 70%, respectively, for women in the age
range of 20-26 and 12-13. In contrast, vaccination with at least one dose of the vaccine in the
cohorts of women is at the level of 52% and 83%.[5]
There is still no consensus regarding which one should be used. In some countries like Japan the
quadrivalent vaccine comprising strains 6, 11, 16 and 18 is the one that is the most frequently
used.

Material and method

Pub Med and Scopus databases were searched for reviews and original articles regarding
HPV vaccination in men. Cost effectivness and efficacity were looked after. Side effects were
taken also in consideration.

Results

Women vaccination is a well established point in the vaccination agenda. There are still debates
age related but most of the isuues have been addressed. Many questions appeared regarding
vaccination in men. There is much discussion related to men who have sex with men. They are
prone to more frequent HPV infections and HPV related neoplasia than other population groups.

The HPV vaccine is used in more than 70 countries and in at least 11 boys are also included.[6]

In a study that included more than 1000 men age 16-26 from Japan the quadrivalent vaccine was
tested. The majority of the participants were heterosexual but the study also included a small lot
of men who have sex with men. The efficacy was 83,3% at more than six months. Local side
effects like pain and swelling were present in 59,6% of the cases. Systemic side effects like
headache and pyrexia were present in 14,4% of the cases. The immune response was strong in
the vast majority of the participants with more than 97% of them maintaining it at month 36.
More importantly the authors noted a strong decline in immunization appeared after 2013 when
some side effects were suspected.Still other long term studies(more than 10 years) support the
safety of this vaccine. The authors recognize the major limitation of their study which is the short
timeline. They emphasize the need for men vaccination given the low rate of vaccination of
Japanese women.[7]
Giuliano et al in long time study(10 years) found a 85,6% efficacy. They also noted high efficacy
against external genital lesions, external warts not only on short but also on long term – ten
years. Also the immune response was strong and sustained over time. Systemic side effects were
present in relatively higher proportion than in the Japanese study – 31, 6%. [8, 9, 10]
As mentioned earlier Australia was one of the countries to fully implement the vaccination. They
included males in the vaccination programme for numerous reasons: equity in gender was the
ethical one; the real reason was the expected incremental reduction of disease burden in women
given the fact that men are the real reservoirs for this disease. HPV is also an oncogen for other
types of neoplasia: penile, anal and oropharyngeal . Up to 95% of the anal cancers are associated
with HPV, also a great proportion of oropharyngeal neoplasia is HPV associated. Also a gender
neutral vaccination programme assured the general acceptance of the population.[11, 12]
One particular category of male patients is that of men who have sex with men. In heterosexual
patients the herd effect is very useful but for this particular segment there are no real benefits
from the women vaccination programme. Furthermore men who have sex with men are more
prone to other HPV related infection diseases like genital warts and anal cancer. Some countries
like UK have implemented pilot studies in which this category also received vaccination. It is
estimated that in UK there were 3,1% gay or bisexual males in 2014.[13]
Besides the real benefits of vaccination there are also benefits regarding the bisexual population.
Not all the countries have really implemented this vaccination programme, infact UK for
instance has started from april 2018 a gender neutral vaccination, so covering also the bisexual
population can prove convenient.[14]
Another problem that appeared was the population adherence to this programme. Boakye et all in
their study discovered that young adults from USA that have high school diploma or less, or
those born outside the country had a lesser adherence to the vaccination schedule. They studied
young adults between 18 and 26 years old from 2014 and 2015 from the National Interview
Survey. Apparently gender – men were less willing to participate in the vaccination.[15]
Nyi Nyi Soe et al in their work approached the financial aspect of expanding the vaccination to
women over 26, heterosexual men and men who have sex with men. They split the countries in
two categories: those with high income and those with low income. From the 26 studies selected
three were from low income countries and the rest from high income countries. The majority of
the studies (20) were on quadrivalent vaccine while the rest was split in 2 for the dual vaccine
and four for the nonavalent. Sixteen out of 26 proved cost effective. What the authors noted was
that all 4 studies on nonavalent vaccine proved cost effective; also they observed that the closer
the year the cost – effectiveness increased.
Age also seemed to be a very important factor in these studies. Some of them supported the need
to extend vaccination to schoolboys, others emphasized not to if the vaccination of women was
extended up to 26 years. Other studies underlined the useless of vaccination in heterosexual men
and boys if the vaccination in women was 75% or more.
Their conclusion was that beyond 26 years old the vaccination in women would not be cost
effective. They stressed the need for vaccination for MSM and also the need to attain higher rates
of vaccination in this population. Vaccine price is a milestone unfortunately, also the number of
doses and the length of coverage of the vaccine.[16-28]
One interesting study comes from Jach et al. Their approach in terms of limitations and
shortcomings is very realistic. They underlined the surrogate cut –off value of all these studies as
being the apparition of CIN lesions which is a reasonable end point but not an ironclad. Also the
monitoring of different sites and HPV strains differ from study to study and no study can rule out
all sites and strains henceforth the need for a protocol which is not ready. From all the
manifestations of HPV genital warts are the most easy to follow up and the results are
encouraging even in men without vaccination – a reduction of 81,8% and 51,1% in under 21 and
between 21 and 30 years old men is impressive. The information is contradictory one study from
the Nordic countries failed to report any improvement in heterosexual men regarding genital
warts. They support the idea of men vaccination specially in men who have sex with men given
the risk of anal cancer. Recent studies demonstrated that anogenital warts have decreased in
incidence since the vaccination for HPV in females have started in more developed countries.
This concept reflects the herd protection because this disease is usually transmitted from females
to their sexual males partners. Therefore the disease reduction in male patiets is directly
proportional to the vaccination for female patients. This is the reason why it is difficult to
implement the vaccine against HPV in males population, because the results are inffluenced by
the females vaccination, therefore the need for an overall increase in vaccination programs that
cover both sexes [29,20,31].
There is also a very comprehensive study regarding the cost effectiveness of vaccination of men
age 21 to 26 in the USA. Chesson et al studied the cost efficiency of the nonavalent HPV
vaccination for an age specific men population. The hypothesis was the age harmonization
vaccination between men and women by increasing the upper recommended catch-up age of
HPV vaccination for males from age 21 to age 26. Their conclusion was catastrophic in financial
terms the cost for implementing such a change would be almost ten times more per year than the
actual vaccination scheme. Still they recognize there are many limitations to their study starting
with the fact that there is no financial limit established by ACIP. The potential differences in
immnunity status between male and female seem to be in in the favor of the latter so the
efficiency of male vaccination in terms of protection could be much lower so the cost could
escalate. Least but not the last besides financial considerations ACIP has to take into account
also other problems like logistics for example which may seem simple but in the end is a very
bothersome matter.[32]
An interesting comment coming from Tam et al underlines the other side of the HPV burden
which is left behind. HPV is also responsible for other neoplasia like oropharyngeal carcinoma
which has become a problem lately in the developed countries. It is five times more common in
middle aged men than middle aged women and its incidence is steadily increasing. There is a
grimm prediction that in four years the incidence of this type of neoplasia will surpass the
incidence of cervical cancer in USA. Infact thereis proof that this already has happened.
Unfortunately there is no screening method for this type of cancer so prevention is the best
measure of defence. The authors highlight the fact that there is a true possibility that the costs of
treating this type of cancer greatly exceed the actual estimations.[33,34,35]
On the other side Qendri et al in their study based on a Bayesian synthesis framework and
assuming equal vaccine coverage in both sexes reached a very troublesome conclusion: below
60% coverage women benefit the most, at 80% coverage only 15% goes to heterosexual men and
35 % goes to MSM. Even if a hypothetical 90% coverage is reached 85 -100% of the boys gain
goes to MSM given the fact that they are the most prone to oropharyngeal and anal neoplasia.
The authors recognize that this is a simple iteration but it is still based on real models. They
consider that the most important effect of this vaccination is the herd effect.[36]
It is known that the primary objective of male vaccination against HPV is to document the
possible changes regarding the appearance of HPV infection or the diseases that occurs from this
disease. The second objective is of course, the investigation of the effectiveness of the vaccine
on male subjects regarding the infection of female with HPV and the diseases that it can produce.
This information can be of use, in order to extend and support the male vaccination program. It’s
an important program because these changes may be entirely new, if the program targets both
sexes or female and male who have sex with male.
There are some challenges regarding the HPV impact vaccine on male patients. Anogenital warts
and respiratory papilloma can be well surveilled in male populations because their diagnostic and
reports are the same as for female patients.
Regarding female surveillance for sexually transmitted infections in women which includes large
population screening, opportunistic testing at different laboratories that includes HPV
surveillance, for men this may present a problem because these test are not routinely performed,
as there are no national screening programs regarding HPV in males.

Jane J. Kim performed a study where she studied the cost-effectiveness analysis of targeted HPV
vaccination of men who have sex with men in the United States. It is well known that 80% of
anal cancers are associated with type 16 and 18 of HPV infection, with a high incidence in male
population. Therefore the high risk populations that are represented by homosexuals can benefit
from HPV vaccination. This study discovered that HPV vaccination had a cost of 15,290 US
dollars per quality adjusted life year gained, compared to no vaccination. Also if homosexuals
are vaccinated earlier in life when the risk of being already infected with HPV is higher, the cost-
effectiveness ratios become less attractive. All the results were have been demonstrated to have a
sensitivity to rates of anal cancer incidence and the duration of vaccine protection [37].
After all the studies performed on this theme, there is a clear benefit for HPV vaccination for
men, but even with the introduction of national vaccine program for HPV for women and girls in
most developed countries, regarding the male vaccine program, few countries have established a
national program. Still a gender neutral vaccine remains a controversial issue. If the only
considered public health benefit is the reduction in female cancer, than all the mathematical
models indicate that male vaccine effectiveness is low and add only a small benefit regarding the
disease reduction. It is considered that if you immunize female mass, with time the heard
immunity can block some sexually transmitted diseases [38]. Nevertheless men also develop
cancers assigned to HPV infection (anus, oral cavity and oropharynx). Canfell et al.
demonstrated in his study that if there is a high female vaccine program, the vaccination for HPV
in men and boys is not cost-effective [39]. The only downfall of this case is the men who have
sex with men, where there is basically no heard protection, therefor they remain vulnerable to
HPV associated diseases.
Despite all the studies that suggest the benefit of the HPV vaccine in men, there is also the
problem of acceptability of these patients. Lea Hoefer et al performed study on a batch of 298
men

Conclusions

Indications for HPV vaccine are continuously changing. The principal factor for this
change unfortunately seems to be the financial one.
There are efforts made in some countries to enlarge the indication of vaccination in men. They
try to standardize the age for men and women alike. Evidence continues to accumulate and time
is needed to decide which vaccination scheme is better. The nonavalent vaccine seems to get the
better results in men, but it is still a work in progress. Financial issues are addressed one by one
in hope of lowing the price of immunization. The problem is that all the studies are based on
surrogate indicators, only timeline will prove if there is any beneficial aspect.

Moreover the adherence level to vaccination differs from country to country and depends solely
on the individual perspective. Guidelines are still changing and have to take into account other
issues like logistics if it were to introduce another population subset in the vaccination scheme.

Almost all the evidence points out to cervical cancer but there are also other types of neoplasia
that are not only women specific. One can argue that the herd effect is enough but given the
variable rate of vaccination the results are doubtful. There is also the MSM population subset
who gain little from the herd effect and they also should be taken into account.

What can we say at this moment is that there are firm indications for women, men who have sex
with men and men over 26. The main counter argument for expanding the immunization in men
is the herd effect, the fact that vaccinated women act as a protective umbrella for men also. Only
time based evidence will prove if it is enough. The decision to or not to expand immunization to
other segments of population is open for debate.

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