Should female sex workers be offered HPV vaccination?

ABSTRACT

Prophylactic vaccines are efficacious in preventing Human Papillomavirus (HPV) infection and subsequent cervical intraepithelial neoplasia (CIN), cervical cancer, other anogenital cancers, and anogenital warts. Female sex workers (SW) are at increased risk of acquiring sexually transmitted infections, including HPV. There are several reasons to offer HPV vaccination to SW: they are at high risk for HPV and often unvaccinated, and the immunogenicity of the vaccine is also excellent in previously HPV exposed women. Furthermore, women with disease caused by HPV may still benefit from vaccination. The efficacy of vaccinating mid-adult women (26–44 years old) against persistent HPV infection and CIN2+ is good. Although an SW may have been infected or exposed to HPV, she may not have been exposed to all vaccine-included hrHPV types. Vaccination induces mucosal immunity via the production of neutralizing antibodies on the surface of the female genital tract, thus preventing potential transmission to clients.

Nevertheless, some considerations argue against offering vaccination to SWs. Current vaccines are only prophylactic and as such, do not affect current HPV infections. Women who have previously cleared HPV infections, may do so again and thus not need vaccination. Fewer SW might be naïve to HPV-types than currently thought. HPV vaccination has probably no effect on latent infections. Vaccinating sometime after sexual debut could be too late, as infections have already occurred.

Taken together, some data suggest that vaccination of SW may offer health benefits, also for the community, but sufficient evidence is lacking. In certain cases, HPV vaccination of SW may be recommended. Evidence-based, public health decisions concerning vaccination of SW are challenging and could be facilitated with more research in this high-risk group.

KEYWORDS:

• Human Papillomavirus
• sex worker
• vaccine
• effectiveness

Introduction

Since about 10 years, there are efficacious prophylactic vaccines able to prevent Human Papillomavirus (HPV) infection, thereby averting cervical intraepithelial neoplasia (CIN), the precursor of cervical cancer, and eventually cervical cancer.^1–6 The vaccines also prevent other anogenital cancers caused by HPV, and two of the HPV vaccines protect against anogenital warts.

Female sex workers (SW) are known to be at increased risk for sexually transmitted infections, including HPV infection.^7,8 Condoms offer only limited protection against HPV infection,^9–12 presumably because HPV may infect mucosa and skin of the anogenital area, not just the glans penis or cervix. Condom use among SW varies between populations and settings (e.g., very high among SW in Amsterdam, ^12,13 but much lower in some other settings¹⁴). Female SW tend to be relatively young women, with almost half under 26 years of age.¹⁵ There are several strong arguments why HPV vaccination should be offered to SW.

Reasons to offer HPV vaccination to SW

First, SWs are indeed at high risk for HPV infection, the precursors of cervical cancer,^7,15–19 and thus cervical cancer. They are also at higher risk for anogenital warts and may be at higher risk for other anogenital cancers.

Second, women currently working as SW are unlikely to have been offered HPV vaccination in the past. This could have been due to [1] lack of HPV vaccination programs in their country of upbringing, [2] having an age outside the age range recommended for HPV vaccination, [3] access issues for the immunization program, or [4] opting out of vaccination. Many SW do not practice in their home country or region, but abroad. In high-income European countries SW often originate from Eastern European, Latin American or African countries, ^7,8,13 where many countries have not (yet) included HPV vaccination in their National Immunization Programmes.²⁰ It comes as no surprise then that many women currently working as SW in Europe or other high-income countries have not been vaccinated, which is expected to be even more so in low-income countries.

Third, immunogenicity of the vaccine is excellent in all women, including those previously exposed to HPV-types contained in the vaccine.^21–23

Fourth, women with disease caused by HPV may still benefit from vaccination. Recent studies have shown that the recurrence rate of disease after surgical treatment is lower among vaccinated women than among those non-vaccinated.^24–26

Fifth, several randomized control trials (RCT) have demonstrated the efficacy of vaccinating mid-adult women (26–44 years) against persistent HPV infection and CIN2+, ^{21–23,27,28} which is important given that a substantial proportion of SW is aged 26 or higher. In one RCT vaccine efficacy in mid-adult women was less than that shown in RCTs of women aged 26 years or less, and efficacy was only shown in women not currently infected with the relevant HPV types. Nevertheless, analysis of data from the PATRICIA RCT showed that the vaccine was efficacious in preventing persistent infection and CIN1+ in women with serological evidence of previous HPV 16/18 infection.²⁹

Sixth, although many SW may previously or currently be infected with several HPV types, they might not have been exposed to or infected with all relevant hrHPV types. For example, we found HPV infection to be very common among SW in Amsterdam, the Netherlands, with 78% having at least one vaginal HPV infection. However, 64% were not currently infected with HPV-16 in the anus or cervix and were seronegative for HPV-16, suggesting that no previous HPV-16 infection had taken place. These percentages were even higher for the other hrHPV types.⁸ This means SW can still benefit from HPV vaccination; vaccination may not protect against types they are currently infected with, but will still offer protection against types they are currently not infected with.

Finally, another reason for vaccinating SW could be to reduce transmission. Vaccination is thought to induce mucosal immunity via vaccine-induced neutralizing antibodies on the surface of the female genital tract, thus preventing further spread and potential transmission to clients.³⁰ SW are core-transmitters of STI and vaccination could play an important role in limiting transmission to male clients and subsequently to other women. Stopping onward transmission from SW to their clients could have a downstream effect on reducing overall HPV burden in the population. For example, in Amsterdam, the Netherlands, around 5,000 female SW are working, and they have a mean of 660 sex contacts per SW per year (Unpublished data STI clinic, Amsterdam), suggesting about 3.3 million sex contacts per annum. Assuming that 40% of SW are infected with at least one high-risk HPV contained in the nine-valent vaccine, ⁸ and further assuming a low per-sex act transmission risk of 20%, and 25% of clients already being infected with the HPV type concerned, then nearly 500,000 HPV transmissions could be prevented per year.

Reasons not to offer vaccination to SW

Notwithstanding these reasons, there are also some considerations arguing against offering vaccination.

The first problem is that currently available vaccines are prophylactic and as such, do not affect existing HPV infections.²⁹ Since SW have been highly exposed to HPV and may have persistent infections or CIN/AIN (anal intraepithelial neoplasia), vaccinating SW against HPV would have limited effectiveness. Although there are no data from RCTs on vaccine efficacy in SW, there is one trial on vaccination of presumably heavily pre-exposed people, conducted by the AIDS Clinical Trials Group (protocol A5298). In this RCT, which included HIV-positive people, 82% of whom were men who have sex with men (MSM) and 18% women, no efficacy of the quadrivalent vaccine was demonstrated against persistent anal HPV infection compared to placebo.^31,32 There are good reasons to assume that HIV infection or immunodeficiency per se do not strongly affect the immunogenicity and efficacy of HPV vaccines.^33–35 Therefore, the underlying cause of non-protection by vaccination might have been due to a study population highly pre-exposed to HPV, similar to SW, rather than HIV-infection itself.

A second consideration is that women who have apparently cleared HPV infection of a given HPV type can be assumed to mount immune responses against subsequent infections of the same type, resulting in a cleared re-infection. In this instance, vaccination would not provide any additional effects to the host’s natural immune response. There are no data to support or refute this hypothesis. However, Schiller³⁶ does point out that, unlike vaccination, natural infection does not induce strong neutralizing protection in previously infected women. This implies that transmission to sexual partners could occur prior to clearing re-infection in unvaccinated women, whereas transmission to others could be prevented by protection against re-infection in vaccinated women.

A third problem is the challenge of how to unambiguously ascertain a woman’s HPV status. As in the Amsterdam data cited above, ⁸ it appears, for a specific HPV type, that being HPV DNA negative would indicate no current infection and being seronegative would indicate no previous exposure. However, not all women seroconvert after infection with HPV.^37,38 The actual number not currently or previously infected with a certain HPV type could be conceivably overestimated and thus the fraction of women possibly benefiting from vaccination could also be overestimated.

Fourth, related to the issue above, there is an ongoing debate around clearance versus latency.³⁹ In the literature, most studies infer clearance of an HPV type if that type was detected at one or more visits and is no longer detected at a subsequent visit(s). However, previously detected HPV types that are no longer detectable may have in fact entered into a latent stage. Various studies have suggested that latency is not a rare state.^40,41 Latent HPV infections could later become reactivated, e.g., during menopause, after HIV seroconversion, ^42–44 or due to local inflammation. If this is indeed the case, then seemingly HPV-uninfected SW may harbor various latent HPV infections. Considering that the virus is intracellular and vaccine-induced antibodies cannot bind to virus involved in these established infections, HPV vaccination would probably have no effect on latent infections. Perhaps vaccination could protect against recrudescent latent infections, but there are no data to support this claim.

Fifth, a recent study by Silverberg and colleagues⁴⁵ assessed the effectiveness of catch-up vaccination (vaccinating from age 14 years) using the quadrivalent vaccine against CIN2+ and CIN3+. They observed significant protection by vaccination among women offered catch-up vaccination at ages 14–20 years, but there was no conferred protection against CIN2+ or CIN3+ when providing the first dose at age 21–26. This result suggests that vaccinating sometime after sexual debut could be too late, as infections have already occurred.

Discussion

There are several ways in which the impact of HPV vaccination of SW needs to be considered. Are we aiming for an impact on individual SW, on the population of SW, or on the general population?

The question raised in the title of this article is meant for public health services considering HPV prevention in SW. There are no clear-cut data about the effectiveness of HPV vaccination of highly, pre-exposed women, while indirect evidence suggests some degree of effectiveness. An evidence-based decision cannot, therefore, be made to include HPV vaccination as part of a health-care package aimed at SW.

This question could also be raised by public health services wanting to protect the community at large against HPV-induced disease. Because vaccination induces mucosal immunity, thereby making SW unable to further transmit HPV of vaccine-related types (even though their pre-existing HPV infections would not be cured), vaccinating SW could provide health benefits for the (male and female) population at large.

This question could also be raised by a clinician or health professional offering care and prevention to an SW. Not all SW are the same and in individual cases, the balance may favor vaccination. For example, many of the arguments above are under the assumption that women self-identifying as SW have been working in the sex industry for some time. These SWs may have already had scores of sex partners and thus have been exposed multiple times to many HPV types, and vaccination would not be warranted. However, if a woman in contact with health services indicates that she has recently started or plans to start sex work, has had few previous sex partners, or has had little or no vaginal or anal sex, then HPV vaccination should certainly be recommended, alongside other relevant health advice, such as condom use.

Finally, although not discussed above, one key advice to all women of reproductive age, especially SW, is to regularly attend a screening for cervical cancer, a proven way of preventing cervical cancer.⁴⁶

Clearly, much is still unclear, and studies are needed to clarify some of the issues. Key research questions to be addressed in a public health research setting would be the uptake of vaccination and the completion rate of vaccine doses. Conducting an RCT or observational study to assess the vaccine effectiveness in this group will be difficult, because of the required large sample size and the need for several years of follow-up in a group that is very mobile.

In conclusion, there are data suggesting that vaccination of SW offers some health benefits, also extending to the community, but strong evidence is lacking. Evidence-based public health decisions concerning vaccination of SW are therefore challenging and could be facilitated with more research in this high-risk group. Research into uptake and completion of vaccination when offered is needed, as are long-term studies on the effectiveness of vaccination in highly pre-exposed women. In individual cases, HPV vaccination of SW may be recommended.

Disclosure of potential conflicts of interest

The institution of MFSvdL received study funding from Sanofi Pasteur MSD and Janssen Infectious Diseases and Vaccines; he was a co-investigator in a Merck-funded investigator-initiated study; he was an investigator on a Sanofi Pasteur MSD sponsored trial; he served on a vaccine advisory board of GSK; his institution received in-kind contribution for an HPV study from Stichting Pathologie Onderzoek en Ontwikkeling (SPOO).

The institute of AV and PVD received unrestricted educations grants from Sanofi Pasteur MSD, Merck, and GSK. AV and PVD participated in advisory board meetings of Merck.

The other authors have no conflicts of interest.

Acknowledgments

We thank Dr. Anders Boyd (GGD Amsterdam) for his feedback and advice on an earlier version of this manuscript.