HPV vaccine with four components

The four-component vaccine against human papillomavirus e (Silgard) is able to prevent not only cervical cancer but anogenital condylomatosis too.

The genital wart caused by human papillomavirus (HPV) is the most common sexually transmitted (STD) viral disease worldwide: 30 million cases are registered by WHO every year. The number of people infected with HPV is estimated to be one order of magnitude higher, around 300 million.

Fig.1. –Incidence of human papillomavirus infection worldwide

We have no accurate epidemiological data on the incidence of this disease in Hungary but according to the estimation of the STP consultant of National Center for Epidemiology patients visit a specialist with this complaint in more than 100.000 cases every year. Most of the patients have a consultation with a dermato-venereologist but –depending on the localization of the symptoms- gynecologists, urologists and surgeons also take a part in the treatment in many cases.

The human papillomavirus (Fig.2) attached to human epithelial cells infects the basal cells of epithelium through micro-abrasions where it starts to multiply following a shorter-longer incubation period.

Fig.2. – Human papillomavirus

Therefore warts start to appear as early as 3-12 weeks following the infection but the incubation period may last up to several months or even to 1-1.5 years in some cases.

The infection is usually a consequence of a sexual intercourse, but sometimes infected items or shared objects may transmit the infection and it may be transmitted from mother to baby during birth in the birth canal. The development of laryngeal papillomatosis or genital warts in infants and babies is the consequence of the infection during birth.

The replication of HPV virus is tightly linked to the differentiation program of the epithelial cells, mature viruses develop in the outer layers of the epithelium and they transmit the infection through the shedding epithelial cells (Fig. 3)

Fig.3. – Human papillomavirus infection and life cycle

Since virus infection is localized, the virus doesn’t get into bloodstream and the target cells don’t fall apart therefore the immune system is not able to develop an adequate antibody response or a cellular defense response.

The antibody response is expressed as a reaction on two types of antigens: the L1/L2 proteins or late capsid proteins trigger the relatively strongest neutralizing antibody production. The antibody response on the early virus proteins is typically minimal or absent. The HPV antibodies are mainly type specific. Induction of immune memory is rarely observable.

The cellular immune response can eliminate the HPV infection. Cellular immune response is induced by early proteins E6 and E7 expressed on every infected cell and at the same time they suppress the interferon signaling required to cellular immune response. No cellular immune response is induced against the L1/L2 proteins since they are not expressed in basal cells.

The clinical symptoms of genital warts may be eclectic: typically single or multiple, variable in number and size, papillar, cuticolor or pigmented growths on the area of genitals, perineum, around the anus, on the inguinal region, scrotum or pubic mount (Fig. 4.).

Fig.4. – Genital warts (Photo by Dr Várkonyi Viktória)

In certain cases they may appear on the anterior part of the urethra, inside the urethral opening, on the vaginal wall, the cervical os, or in the rectum. Warts in the oral cavity and around the mouth can be observed more and more often. Laryngeal papillomatosis may occur on babies infected during birth (Fig. 5.).

Fig.5. – Laryngeal papillomatosis (Glikman D., et al. N Engl J Med 2005; 352:e22)

Usually there are no subjective complaints of genital warts though the multiplication of growths and their displeasing look will encourage the patient to visit a physician. The aim of the treatment is to remove the warts since according to our knowledge there is no effective treatment of a human papillomavirus-infection.

Warts often reoccur following a physical or chemical destruction.  Local immune stimulation decreases the risk of reoccurrence due to its indirect antiviral effect but currently it is a very expensive treatment option. Methods of physical removal –excision, cryosurgery, cauterization, removal by laser- may require some special instruments and the intervention with instruments around the genitals may be dreadful for most of the patients. Chemical destruction – podophylin, podophyllotoxin, trichloro-acetic acid, 5-fluorouracil – triggers a strong local inflammatory reaction in almost every cases  accompanied with swelling, redness, development of wound and ulcers and they are pretty boresome, too.

Therefore the treatment of genital warts is a trying task both for the physician and for the patient too. The infectious nature of the disease and its way of transmission make the problem worse applying a severe psychic burden on the patient and implicating a real trial for his/her partnership.

During the development of the quadrivalent vaccine to prevent the infection scientists had not only the prevention of a fatal disease, the cervical cancer in view but the prevention of the genital warts, the most common sexually transmitted viral disease, too.

Fig.6. – Genome of human papillomavirus

During the production of VLP (virus like particles) required for the human papillomavirus vaccine the L1 gene is isolated from the DNA of HPV (Fig.6.) then it is introduced into the DNA of another microbe, the Saccharomyces cerevisiaea.  The produced recombinant microbe is fermented in large scale producing large quantities of L1 protein. The structure of the protein enables them binding together into virus-like particles (VLP). (Fig.7.)

Fig.7. – Virus-like particles (VLP) synthesized in Saccharomyces cerevisiae

Neutralizing antibodies are produced as the effect of the vaccine containing L1 VLP-s that can prevent the binding of new viruses to epithelial cells. The intramuscular application of the vaccine allows the quick and intensive absorption of the antigen that gets into the bloodstream where it stimulates the humoral immune response by activating the antigen presenting cells, and therefore the production of neutralizing antibodies.

The efficacy of the vaccine is almost 100% against four types of HPV (6, 11, 16 and 18). HPV type 6 and 11 are responsible for 90% of anogenital condylomatosis cases, while type 16 and 18 are known to cause 70% of cervical cancers.

The vaccination is recommended for women between 9 and 45 years of age, though the most effective prevention is achieved by the vaccination of 11-12 year girls, before starting their active sexual life. Boys can be vaccinated between 9-15 years of age.