Role of Human Papillomavirus Vaccination for Prevention of Male Infertility

1. Human Papillomavirus

The human papillomavirus (HPV) belongs to papillomavirdiae and is a non-enveloped double-stranded DNA virus. More than 200 species exist, with approximately 40 species known to cause diseases around the genitals and anus [15]. The HPV is one of the most common sexually transmitted infections worldwide, with an estimated 6.2 million new cases yearly [16]. The most common transmission routes of HPV are genital- to-genital contact and hand-to-genital contact. Although rare, transmission through breastfeeding and vertical transmission through the placenta in pregnant female have also been reported [17-19].

In addition to causing the onset of a benign disease called warts, the HPV is a major risk factor for cancer development. Since Dr. Zur Hausen first published the hypothesis linking HPV infection to the development of cervical cancer, HPV has been revealed as the main etiology of malignancies, such as oropharyngeal, anal, vulvar, and penile cancer [20].

The main route of HPV penetration into the male reproductive system is through the penile preputial mucosa. The practice of circumcision has been associated with a decrease in male HPV prevalence and can reduce the risk of HPV virus infections while improving the virus clearance rates. The HPV in infected male can be located in the perianal mucosa, glans penis, foreskin of the penis, urethra and seminiferous tubules, testes, and epididymis [21].

2. Human Papillomavirus and Infertility

Referring to a meta-analysis study on the HPV prevalence in 16 countries, the rate of HPV semen infection in male in the general population was 11.4%. The HPV semen infection rate of male visiting infertility clinics was 20.4%, suggesting that HPV-positive semen is highly correlated with infertility [22]. Studies examining the effect of HPV semen infection on pregnancy success in infertile couples show that HPV infection in semen is closely related to the pregnancy success rate. In a study examining the success rates of intrauterine insemination and intracytoplasmic sperm injection in 226 infertile couples, the success rate was 38% when HPV-uninfected semen was used. In contrast, the rate dropped significantly to 14% for HPV-infected semen [23]. Depuydt et al. [24] reported the results of successful insemination using HPV-infected and non-infected semen using the data from 3 Belgian sperm banks in 2018. This study found that HPV semen infection in male had a significant impact on the success rate of natural pregnancy and assisted reproductive technology, as no pregnancy occurred when HPV-positive semen was used. Based on this study, they suggested that HPV testing should be performed regularly for sperm donation [24].

Male HPV infection induces infertility through various mechanisms. First, the prevalence of HPV infections in the testicles and epididymis is very closely related to the occurrence of inflammatory diseases, such as nontuberculous epididymitis. Repeated occurrences of these inflammatory conditions appear to cause infertility by affecting sperm production and transport [25]. A HPV infection of sperm cells appeared to reduce the ability to penetrate the oocyte because of the HPV located on the sperm head [26]. Furthermore, HPV-infected sperm act as a vehicle for virus transmission, as the HPV can be transmitted from infected sperm to the oocyte and placenta of a pregnancy. In a HPV infection of sperm, unlike in the case of epithelial cell infection, the virus does not penetrate the sperm cells but binds to the equatorial segment located in the sperm head. The equatorial segment of the sperm head is the place where mammalian sperm starts to bind to the egg, and the sperm-egg interaction and fusion control process occur. The HPV translocates into the oocyte through interactions with the membrane protein tetraspanin, CD151, and integrin a6, and transfers the HPV gene. Using the division process of the host zygote cell, it replicates its gene, transcribes and produces necessary viral proteins, and repeats the process of self-replication [27]. As a result of such transmission, normal embryonic development and implantation are disrupted, increasing the likelihood of spontaneous abortion and premature birth [28].

The HPV decreases the quality of infected sperm and increases DNA fragmentation. Numerous studies have reported that sperm concentration and total sperm counts decrease significantly [29,30]. HPV sperm infection increased the rate of asthenospermia significantly, a condition in which sperm mobility is reduced. Sperm mobility is an important factor of fertilization because the sperm needs to travel a considerable distance to penetrate the oocytes. HPV infection increases the occurrence of DNA fragmentation [23,31,32]. This decrease in sperm quality and DNA fragmentation appears more significant in high-risk HPV types. The effect appears to differ depending on the HPV type [33]. While further research will be needed to understand the specific effects of particular HPV types on sperm, a HPV infection deteriorates sperm quality, leading to increased infertility rates.

The anti-sperm antibody (ASA) is a major risk factor for infertility. ASA is detected in a significant proportion of infertile couples (16.5% male, 21.5% female) [34]. Infertile couples in whom ASA is detected in serum and genital secretions have a significantly reduced pregnancy success rate [35]. Several studies have shown that a HPV infection in semen significantly increases the positive rate of ASA [36,37]. HPV acts as a stimulating antigen for ASA production, and the resultant ASA causes infertility by interfering with the migration and fertilization process of HPV-infected sperm and normal sperm [38,39].

3. Efficacy of Human Papillomavirus Vaccine on Infertility

In 2016, a 9-valent vaccine (Gardasil 9) was developed for 7 high-risk HPV types (16, 18, 31, 33, 45, 52, and 58) and 2 low-risk types (6, 11). The vaccine effectively showed almost 100% seroconversion against the 9 species, and the immunity was maintained for more than 6 years, proving the long-term effect of the vaccine [40]. A HPV vaccination program has dramatically reduced the incidence of HPV-related malignancies, such as cervical cancer [41]. As can be inferred from the effect of HPV on male infertility, studies are reporting the positive effect HPV vaccination can have on male infertility. Garolla et al. [42] published a randomized controlled study of the effect of the HPV vaccine on the success rate of pregnancy in infertile couples. When 151 infertile couples were divided into 2 groups of 79 vaccinated subjects and 72 non-vaccinated subjects, the HPV-vaccinated group had a significantly higher pregnancy success rate than the non-vaccinated group (15% vs. 38.9%) and a significantly lower miscarriage rate (63.6% vs. 3.3%). In addition, sperm motility of the semen of the HPV-vaccinated group was significantly higher than that of the non-vaccinated group. The detection rate of HPV DNA in sperm was reduced eightfold and ASA by more than twofold in the vaccination group, suggesting a reparative effect by the HPV vaccine in removing the HPV from semen [42]. Another study has also confirmed the positive effect of HPV vaccines. When 379 HPV semen-infected male were vaccinated with the HPV, the HPV was eradicated from the semen in 86% of male after 6 months, and the anti-sperm antibodies that had formed in approximately 38.6% disappeared [39]. These findings show that the HPV vaccine can restore fertility by improving sperm quality and removing anti-sperm antibodies. This suggests that the HPV vaccine is not limited to preventive purposes but can be used for therapeutic purposes, even in infertility patients who are already infected.