Miti Joshi – Vaccine Paper on HPV

The HPV Vaccine paper – in this paper I have explained the virus and the vaccine developed to
combat the virus, the impact on public health, my opinions on the pricing controversy and the
prospects for pharmaceuticals in the HPV space.

Introduction to HPV and History –

Human papillomavirus (or HPV) is the most sexually transmitted disease in the United States. It is
caused by the HPV virus (shown in Image 1). The HPV virus is a DNA tumor virus1 that causes
proliferation at mucosal and cutaneous surfaces. There is 100+ different HPVs, however there is a
segregation within those 100 into high risk/oncogenic types and non-oncogenic/low-risk types. From
the oncogenic variety – type 16 is the most oncogenic, causing about 50% of all cervical cancers.
Another high-risk type is type 18, which along with type 16 accounts for 70%+ cervical cancer.
Among the low risk category – type 6 and type 11 are the ones that cause most of the genital warts.
HPV’s infection’s link to cervical cancer was being noticed in the 1950s, and the infectious nature of
this cancer piqued the interest of Harold Zur Hausen. Zur Hausen went on to win an award as he
successfully isolated and identified HPV in 1974.

Pathophysiology and Effects of HPV –

The virus enters the body via disruption of the skin/mucosa and infects basal stem cells. The viral
DNA has 7 E genes (early stage genes) and 2 L genes (late genes). Out of all these genes, E6 and E7
are responsible for the pathophysiology of the virus. The E6 proteins (translated from the gene)
inhibit the p53 gene and this gene is responsible for apoptosis (cell death). The E6 protein also
responsible for the expression and activity of telomerase, which seems to be responsible for cell
immortalization. The E7 protein also inhibits apoptosis induced by another gene- p105Rb. The E7
gene also have various other interactions (with p-proteins and cyclins) which ultimately result in cell
immortalization.
Another protein that is important for the pathophysiology is the E5 protein which is responsible for
the initiation of tumorigenesis.
Significance of the L1 gene – The reason I mention this is because it is a key component of the
vaccine that I will be discussing. The L1 gene is responsible for capsid formation which in turn is
responsible for virus assembly.
From the pathophysiology, HPV infections cause cancer – more specifically cancers of the vulva,
anal and cervical cancer.
The low risk HPV types cause anogenital warts and respiratory papillomatosis.
Miti Joshi – Vaccine Paper on HPV

Vaccine for HPV –

The first vaccine for HPV is – Gardasil, which is developed by Merck. It is a quadrivalent vaccine
that protects individuals against the infections caused by HPV types 6, 11, 16, and 18. Given below
in Figure 1 is a timeline of the vaccine

Timeline for Development –

Figure 1
Mechanism of Action –
The over-arching mechanism of action of Gardasil is that it is prophylactic and works by inducing a
high initial serum type antibody against HPV.
Before diving into the Mechanism of Action it is important to understand the components of the HPV
vaccine (shown in Table 1)

Virus Like protein HPV-6 L1, HPV-11 L1, HPV-16 L1, HPV-18 L1
Recombinant Saccharomyces pombe (type of yeast)
Adjuvant Amorphous Aluminum Hydroxy phosphate sulfate (AAHS)
Table 1
VLPs (virus-like proteins) are highly immunogenic and induce concentrations of neutralizing Ab to
L1, the immune response is heterogenous or polyclonal and the antigen dose for VLPs is much
higher than in natural infection and capsids are directly exposed to systemic immune response.
The L1 gene antibodies will inhibit the formation of virus particles in the host and consequently
inhibit replication. The AAHS adjuvant further supplements an immune response as Aluminum binds
to antigens with high affinity and forms a depot of antigens at the site of infection, with continuous
desorption and dispersion of antigenic particles. Aluminum also promotes the antigen uptake by
antigen presenting cells (like dendritic cells)

Given below (in Figure 2) is a diagrammatic representation of the working of Gardasil in eliciting an
immune response
Miti Joshi – Vaccine Paper on HPV

Figure 2

Dosing schedule for Gardasil –

In the US, a dosing schedule of three doses was recommended in all targeted age groups and this is
because the antibody titer reaches its peak after the third dose and then starts to plateau. However, I
2016 a study by ACIP showed non-inferior antibody response after two does in ages 9-14. This
means that the efficacy of the vaccine did not improve (the antibody titer did not show a significant
increase) Hence the dosing schedule was changed for the age group of 9-12 years and made it to two
doses.

Public Health Impact of Gardasil –

In the United States – the coverage rate increased progressively year on year, but a hurdle was that
the HPV receipts came with a provider recommendation and the providers usually delayed
recommending until late adolescence.

In Australia – the effect was tremendous, and this can be accounted to having a publicly funded
Gardasil school-based vaccination. Through this program, more than 70% of the schoolgirls in
Australia received this vaccine and boys were included from year 2013.
In European Countries – as of 2015, most of the countries had organized programs in place which
could include school-based vaccination or physical/health center vaccination. Denmark is one of the
few countries to achieve80% coverage among young girls.
In Middle – Low income countries – The first middle income countries to introduce this was
Mexico and Panama. In Rwanda, Africa the vaccine was obtained through an industry donation.
In 2009, GAVI (Global alliance for Vaccines and Immunization) prioritized the HPV vaccine in 2009
and in 2012 made it available to all GAVI-eligible countries, and there are two ways for a nation to
introduce a program – one is a nationwide program that should reach 50% of the target population
and the other option was a demonstration project which can involve school based vaccination.
In Figure 3 we can see the HPV vaccine impact across the globe
Miti Joshi – Vaccine Paper on HPV

Figure 3

Controversy around Pricing and how Gardasil Overcame it –

Merck priced Gardasil at a rocket price of $120/dose which is $360 for the total schedule. This type
of pricing was largely unprecedented and major controversies were spiked due to this. Merck priced
their dose at the highest price/dose at the time – the other contender here was a vaccine dose priced at
$117/dose. Merck had also suffered from the Vioxx scandal and had to reestablish their reputation in
the industry. There was a similar vaccine by GlaxoSmithKline (Cervarix) coming 9-12 months down
the line. With all these factors playing against Merck I wondered why Merck went with a high price.
However, I think the price was justified from an economic standpoint for Merck and the population.
The reasoning for this justification involves various factors – firstly, it is the price sensitivity or the
willingness to pay – preventative care like a vaccine would save patients large costs involved in
treatment. This brings me to the value add by the vaccine. At the time, the cost of cancer care could
go up to $100K and the diagnostic costs were ranging from $1400 to $3500. Compared to all these
high costs, paying a small upfront fee for preventative care seemed like a good deal and Merck
marketed that very well.
Merck’s vaccine was superior to it is incoming competition. It prevented genital warts and had “first-
mover” advantage in the vaccine market.

Figure 4
Miti Joshi – Vaccine Paper on HPV

All these factors combined with Merck’s marketing strategy (shown in Figure 4) helped Gardasil
gain popularity.

Prospects for HPV –

With two strong contenders, there is still some scope for new HPV vaccines to come and tackle the
remaining HPV types. Another important aspect is having a therapeutic benefit and there are some
that are being investigated and are currently in the early stages of clinical trials. Most of these include
E6 and E7 proteins and a therapeutic vaccine could take the burden of cervical neoplasia from
millions of women worldwide.
Another interesting aspect of the HPV which I feel is often overlooked is the role of the E5 protein –
it is a critical protein for the induction of tumorigenesis, and the traditional method of exploiting the
E6 and E7 proteins which target the late stage cancers overlooks the importance of targeting early
stages. This can be done by adding the E5 protein/peptide which can then broaden the spectrum of
treatment and combat early stage cancer. A therapeutic vaccine would need an adjuvant like AS04
which elicits a strong immune response from IFN-alpha cells (an interferon) and since peptides are
going to be utilized for therapeutics, they need a boost in immunogenicity which is currently being
investigated with dendritic cells.