Human papillomavirus (HPV) is the most prevalent sexually transmitted infection (STI) in the U.S. HPV infections stem from a DNA virus in the Papillomaviridae family and target skin, genital or oral mucosa (though the virus does not enter the bloodstream). HPV also causes several types of cancers, including cervical and throat cancers, making early detection and preventive medical interventions vital.
"HPV infections and HPV-related diseases are a public health issue," said Katie Au, M.D., IBCLC, an assistant professor of obstetrics and gynecology at Oregon Health and Science University. "It's one of the few cancers that is preventable, and where timely care and appropriate screening can really make a difference in terms of incidence and outcomes. We can make a great public health impact, both from a screening and from a vaccination standpoint."
With more than 100 known strains of HPV, how can vaccines and preventive medical interventions mitigate the spread of the virus? What is best practice for routine screening, and how could future vaccine technology improve prevention strategies?
Symptoms and Infection Prevention
Most instances of HPV infection are asymptomatic (about 70-90% of cases), and about 90% of HPV infections will clear on their own. Low-risk genital strains of HPV can trigger the development of adverse health conditions, including genital warts caused by HPV6 or HPV11.
However, persistent infections can develop into precancerous lesions and eventually cancer. Twelve high-risk HPV strains are known to cause cervical cancer, oropharyngeal cancers (impacts the throat, tonsils and/or tongue), anal cancer, penile cancer, vaginal cancer and vulvar cancer. This is why screening to detect high-risk HPV strains-most importantly HPV16 and HPV18, which cause the majority of HPV-related cancers-is so critical.
All patients are not at the same risk of developing adverse health conditions. Risk factors for cancer include smoking, older age, immune suppression, rare or delayed screening, not being vaccinated, an increased number of sexual partners and infection with other STIs. Like other STIs, the spread of HPV may be greatly reduced through the use of protection.
Screenings and Diagnostics
Screenings can help providers monitor the development of potential cancer precursor lesions and determine if a surgical (or other) intervention is required.
How to Test for HPV and Cervical Cancer
There are 2 primary ways in which health care professionals will screen patients with a cervix for cervical cancer: cytology (i.e., Pap test) or an HPV test (for high-risk HPV strains). For a Pap test, clinicians gather a sample of superficial cells from the cervix, which is subsequently evaluated by a pathologist. A Pap test can identify abnormal cells in the cervix. A co-test may also be used, which screens for cervical cancer and can be done with cytology and/or an HPV test. HPV tests can involve amplification of viral DNA (with or without genotyping) via real-time or conventional polymerase chain reaction (PCR) or identify specific HPV oncoprotein expression via mRNA detection.
When to Test for HPV
HPV screening of the cervix doesn't start until a patient is 21 or older, though for patients who are immunocompromised (and are at a greater risk of developing adverse health conditions related to HPV), screenings may start sooner. Some new guidelines recommend performing an HPV test alone in younger individuals, but it is more common to wait until a patient is older (in their 30s), unless the patient has an abnormal Pap test. Currently, it is not common practice to screen people assigned male at birth for HPV.
"Because HPV is so prevalent, most young adults who are healthy and have an intact immune system will actually clear the infection on their own. For this reason, pre-cancerous and cancerous lesions that need treatment are rare in young adults," Au said. "However, if someone is 30 or older and tests positive for HPV, that is more likely to reflect a persistent infection associated with dysplasia."
How Frequently Should HPV Testing Occur?
Currently, there are differing opinions regarding what is best practice for HPV screening. The U.S. Preventive Services Task Force and the American Society for Colposcopy and Cervical Pathology recommend a Pap test every 3 years for patients 21 to 29 years-old, and a Pap test (every 3 years), a co-test (every 5 years) or primary real-time PCR HPV testing (every 5 years) for patients 30 to 65 years-old.
The American Cancer Society advocates for primary HPV testing every 5 years for patients 25 and older. "The main theme [in HPV screening] is to not initiate an HPV test as a primary test until someone is older, and then it can be acceptable to do co-testing or HPV testing alone," Au explained. "Clinical disease occurs with persistence of HPV infection, so catching a transient infection in a young adult under the age of 30 is less clinically meaningful and could lead to excessive or unnecessary procedures."
Cytology vs. HPV Screening
"The more we learn about HPV and the pathogenesis of HPV-related disease and infection, the more we understand that nearly all cervical cancers are driven by HPV, particularly high-risk subtypes, and we pick up more clinically relevant disease if we look for HPV rather than the cytology. [In] the last 5-10 years, the field has moved toward HPV testing, as opposed to relying as heavily on cytology," Au said. As unusual cytology could be related to abnormalities other than HPV, HPV testing is sometimes considered a more targeted diagnostic approach.
HPV screening is not considered a standard test for routine STI testing. Clinical justifications behind this include that, unlike STIs such as gonorrhea and chlamydia, there is no direct treatment (e.g., antiviral, antibiotic) that can be administered to a patient. Thus, providers primarily rely on screenings to first, determine if the patient has been infected with a high-risk strain, and second, monitor the patient more closely if they have been infected with a high-risk strain.
What to Do if One Tests Positive for HPV
If a patient tests positive for HPV, their provider may consider them to be at a higher risk for dysplasia and monitor them more closely (i.e., the provider will need to more frequently screen for cancerous lesions to determine if they need to be removed and/or determine if more aggressive intervention is required). If a precursor lesion is identified, excision (dysplasia) in the cervix is well tolerated and dramatically reduces risk of progression to cervical cancer.
Vaccine Mechanics and Dissemination
Vaccines are the most effective intervention to prevent the spread of the most common high-risk and low-risk HPV strains. The current HPV vaccine on the market targets 7 of 12-known strains that are considered "high risk" for the development of cervical cancer and 2 types (HPV6 and HPV11) that cause benign genital warts. Richard Roden, Ph.D., Co-Leader of the Cancer Prevention and Control Program for the Sidney Kimmel Comprehensive Cancer Center, said the HPV vaccine is most effective if the patient receives it prior to their first instance of sexual activity. The recommended age-range for receiving the vaccine is 11-12 years of age (though vaccines can be given as early as age 9 and as late as age 45), with 2 to 3 doses. The vaccine can only prevent infection, it cannot boost one's immune system to clear an existing infection.
The vaccine uses alum-based adjuvant and is based on HPV's major capsid protein, L1. If this protein is expressed recombinantly, it will self-assemble to form virus-like particles that look like the native virus particles on the outside, but they don't have the oncogenic viral DNA inside. The virus-like particles display the protective neutralizing antibody binding epitopes that mimic the native virus. "These virus-like particles are very effective in activating the immune system to produce a very long-lasting, neutralizing antibody response from 2 intramuscular vaccinations," Roden explained.
"One of the remarkable things about how the vaccine works is that the virus is never in the [patient's] serum. HPV is a very unusual infection; it only grows in the epithelium, or the mucosal epithelium, in the case of cancer-causing viruses," Roden said. So how can circulating antibodies offer protection? "It seems like during intercourse there are micro-traumas to the genital mucosa that are sufficient to allow the virus to infect the skin, or the epithelium." These micro-traumas are also sufficient for the serum or the plasma antibodies to meet the virus and prevent the initial infection.
Currently, there are ongoing efforts to develop multi-valent L1 vaccines to target even more sub-types of the virus. However, Roden noted that there is a challenge in terms of expanding efficacy versus cost, as to how many different L1 virus-like particle types can be contained within an L1-based vaccine. In addition to covering the remaining high-risk HPV types, a vaccine that could target intermediate risk types would greatly broaden the benefit of immunization.
Another major challenge is delivery of HPV vaccination, especially in under-resourced areas. "If you could also piggyback the HPV vaccine on another childhood vaccine-there are already multi-valent vaccines out there where you have multiple antigens from several different infectious agents in a single vaccine-then you could combine the HPV vaccine antigen with the Hepatitis B vaccine, for example, which is routinely given at an early age prior to sexual activity," Roden said.
Future vaccine technology could also benefit patients with persistent infections that have caused cancer. A 2023 study examined 3 mRNA vaccines in mice models that targeted HPV-related cancer cells. The study found that with just 1 shot, any of the 3 tested vaccines were successful in eradicating tumors from the mice. Furthermore, most of the mice remained cancer-free throughout the trial. Researchers are hopeful that the mRNA vaccines can be evaluated in human trials next.
Barriers to Vaccine Utilization
Among adolescents in the U.S., the HPV immunization rate has increased since the vaccines were first introduced in 2006. More than 50% of patients ages 13 to 17 were fully vaccinated for HPV in 2019. While providers and public health professionals are encouraged by this increase, the vaccination rate is currently below the Healthy People 2030 vaccine goal of 80%.
Sangini Sheth, M.D., MPH, FACOG, an associate professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine and member of the Yale Cancer Center, noted that, like COVID-19 vaccines, having a multi-dose vaccination may discourage patients from completing the shot series. "An ideal state would be having a single-dose vaccine that's more protective than the multi-dose series, which could increase utilization," Sheth said. A large clinical trial is presently looking at the efficacy of single dose vaccination, but current recommendations are for at least 2 doses based on age.
Stigma and myths surrounding the HPV vaccine have also contributed to lower vaccination rates. "Because HPV is a sexually transmitted infection, there's stigma around vaccinating such young individuals, with the incorrect assumption that this might increase initiation of sexual activity, or somehow label the adolescent as being promiscuous," Sheth explained. "Sometimes families consider their children to not be at risk, so they don't need the vaccine right now. One thing that we see is that there's a delay in giving the vaccine when the vaccine is most effective, which is prior to sexual activity." A 2019 study echoed this sentiment, indicating that the vaccine does not cause earlier initiation of sexual activity.
Additionally, many adults who have already tested positive for HPV but have not been vaccinated may not feel inclined to pursue immunization. However, even if someone tests positive for HPV, they may have only been exposed to 1 or 2 strains of the virus (i.e., it's unlikely they have been exposed to all 9 strains protected by the vaccine). "It is a preventive vaccine. It's not going to make an existing HPV infection go away, but it can protect against future infections," Sheth added.
Addressing Stigma
While HPV is considered to be fairly ubiquitous among sexually active adults, with 43 million infections reported in 2018, there is still a stigma surrounding testing positive for the virus. "A lot of people feel shame when they're diagnosed with HPV, but I think it's helpful to know that it's exceptionally common. Some gynecologists call it the common cold of the cervix," Au said. "I hope [the stigma surrounding the virus] doesn't prevent people from seeking care or seeking testing or doing their cervical cancer screening."
