A Case for Immunization of Human Papillomavirus (HPV) 6/11–Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma

Journal of Infectious Diseases, May 2014

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease caused by intrapartum or perinatal transmission of human papillomavirus (HPV) types 6 and 11 from an infected mother to the newborn. Immunization of a pregnant woman who has condyloma or HPV-6/11 infection with the quadrivalent HPV vaccine will result in a high neutralizing antibody response to HPV 6 and HPV 11 in her serum, and these antibodies transferred to the newborn will likely protect the child against the development of JORRP. Because of the low incidence of disease in at-risk children, it may be difficult to test the effectiveness of maternal immunization for prevention of JORRP.

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A Case for Immunization of Human Papillomavirus (HPV) 6/11–Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma

JID A Case for Immunization of Human Papillomavirus (HPV) 6/11-Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma Keerti V. Shah () 0 0 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease caused by intrapartum or perinatal transmission of human papillomavirus (HPV) types 6 and 11 from an infected mother to the newborn. Immunization of a pregnant woman who has condyloma or HPV-6/11 infection with the quadrivalent HPV vaccine will result in a high neutralizing antibody response to HPV 6 and HPV 11 in her serum, and these antibodies transferred to the newborn will likely protect the child against the development of JORRP. Because of the low incidence of disease in at-risk children, it may be difficult to test the effectiveness of maternal immunization for prevention of JORRP. - Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease of young children caused by infection with nononcogenic human papillomavirus (HPV) types 6 and 11. The reservoir of HPV-6 and HPV-11 is the genital tract where the infection may be subclinical or is manifest as genital warts (condyloma). The child who develops JORRP acquires the infection at birth, or perinatally, from the infected maternal genital tract. Few cases of JORRP occur in the first 6 months of life, and most occur at 2–5 years of age. The number of cases decreases after that age, but those with onset until the age of 14 are classified as JORRP. The same disease with onset at older ages is also caused by infection with HPV-6 or HPV11, but is probably acquired by sexual contact and is classified as adult-onset recurrent respiratory papillomatosis. CHARACTERISTICS OF JORRP JORRP is rare, with an estimated incidence of about 820 cases annually and an estimated annual medical cost of $123 million in the United States [1]. Although the papillomas are benign, they may grow rapidly and need repeated surgery to keep the airway open; in some cases as many as 100 surgeries may be required by the age of 10 years (Figure 1). In addition to respiratory blocking, extension of the disease to trachea and lungs and transformation to malignancy may threaten life [2]. The disease is more severe if it is associated with HPV-11 or has an onset by the age of 3 years [3]. None of the recommended nonsurgical treatments for JORRP (interferon, cidofovir, celecoxib, photodynamic therapy, and others) have been successful enough to avoid frequent surgical intervention. That infection is transmitted from mother to child at birth was first suggested by Hajek, who reported laryngeal papilloma in a child born to a mother who had extensive condylomas late in pregnancy [4]. Subsequently, several investigators have reported additional clinical cases, and mothers of children with JORRP frequently give a history of genital warts. In the early 1980s, HPV-6 and HPV-11, viruses that are responsible for >90% of genital warts, were also shown to be responsible for nearly all cases of JORRP [5, 6]. Maternal HPV infection appeared likely to have been transmitted intrapartum by contact of the fetus to the infected maternal genital tract. However, cesarean delivery does not fully protect against JORRP [7], suggesting that infection may also be transmitted in the perinatal period. The antibody response to HPV-6/11 in women who have condyloma [8] and in children who have JORRP [9] is low or not detectable. CONDYLOMA IN PREGNANCY AND JORRP This association was examined in a population-based study in Denmark [10]. Over a period of 20 years, between 1974 and 1993, 1 206 213 births were recorded. Of these, 3033 (0.25%) were born to women who had condyloma recorded during pregnancy. Fifty-seven cases of JORRP were identified to have occurred between January 1974 and December 1999, thus ensuring at least a 5-year period of observation for children born in 1993. Condyloma during pregnancy was strongly predictive of JORRP in the child; it conferred a >200-fold risk of JORRP in these children (6.9 cases per 1000 women), compared to children born to mothers who did not have condyloma recorded during pregnancy (0.03 cases per 1000 women) (Table 1). Nevertheless, a majority of children with JORRP were born to mothers who did not have condyloma recorded during pregnancy; these mothers probably had subclinical HPV-6 or HPV11 infection of the genital tract. Although condyloma during pregnancy was an overwhelming risk factor for JORRP in the child, the incidence of JORRP in the at-risk child was low, and only 1 case of JORRP occurred per 144 women with condyloma. It is probable that all children considered to be “exposed” were not infected and that some infants may have been protected by the low-level antibodies to HPV-6/11 transferred from the mothers. THE QUADRIVALENT GARDASIL HPV VACCINE ADMINISTERED TO INFECTED PREGNANT WOMEN WILL PROTECT THE NEWBORN The quadrivalent Gardasil HPV vaccine is a prophylactic vaccine that contains virus-like particles (VLPs) of the major capsid (L1) proteins of HPV-6 and HPV11 in addition to the VLPs of the oncogenic HPV types 16 and 18. In clinical trials, immunization with 3 doses of Gardasil has markedly reduced the incidence of HPV-6 and HPV-11 infections and of genital warts [11]. The vaccine induces a high and uniform level of antibody response, much higher than that by natural infection with HPV-6 and HPV-11 [12]. The vaccine has been administered to millions of women all over the world and has been found to be safe. With respect to the immunization of pregnant women, the vaccine does not contain live virus, so there is no risk of inadvertently infecting the fetus. It has not been purposefully tested in pregnant women, but in 1796 women who inadvertently became pregnant during phase 3 clinical trials of the vaccine, there were no negative pregnancy-related outcomes attributable to the vaccine [13]. Its use in pregnancy is not prohibited, and the Gardasil package insert states that it “should be used in pregnancy only if clearly needed.” It is most likely that there will be a very much lower risk of JORRP in children whose mothers have been prophylactically immunized with Gardasil, but these data are not yet available. However, Gardasil Respiratory Papillomatosisa Pregnant Women With genital warts Without genital warts JORRP Cases, No. JORRP Cases/1000 Relative Risk (95% CI) Abbreviations: CI, confidence interval; JORRP, juvenile-onset recurrent respiratory papillomatosis. a Modified from Silverberg et al [10]. vaccine uptake has been variable. In the Immunization of pregnant women has been effective in preventing infectious dis17 years in 2010 had received all 3 doses of eases in the women, in their newborn chilHPV vaccine [14]. Therefore, despite the dren, or in both. Maternal immunization availability of the Gardasil vaccine, there with tetanus toxoid has dramatically will be many pregnant women, mostly unreduced the risks of both maternal as well vaccinated, who are infected with HPV-6 as neonatal tetanus in communities where or HPV-11 subclinically or have condyloma. Administration of the Gardasil HPV this disease is common [17]. Inactivated influenza vaccines protect pregnant women vaccine to these women holds promise to as well as their infants against the disease markedly reduce, or even eliminate, the [17]. Acellular pertussis vaccine is recomrisk of JORRP in their children. Although mended for pregnant women to protect the vaccine will not alter the course of the newborn against pertussis [17]. AlHPV-6 and HPV-11 genital tract infecthough JORRP is rare, the disease is an tions in the infected women, it will enormous challenge for the young patients produce high levels of neutralizing antiand their families. A vaccine found to be body in their sera, and these antibodies safe and effective for women is already will be transferred transplacentally to the available. Screening for HPV-6 and HPVnewborn at birth. In Gardasil-vaccinated 11 infection of the genital tract or diagnosas well as in unvaccinated women, the ing condyloma in pregnant women is HPV-6 and -11 antibody titers in the simple, and it may identify about 3% of the newborn match maternal antibody titers pregnant women who are infected. The [15]. The presence of these antibodies may Centers for Disease Control and Prevenbe expected to protect the newborn tion and the learned societies in obstetrics, against the establishment of HPV-6 or pediatrics, and otolaryngology should conHPV-11 infection in much the same way sider endorsing and providing guidelines as they protect the prophylactically immufor the use of this vaccine in HPV-6/11–innized adult against these infections. While fected women and help set up studies to this is a reasonable expectation, it will be difficult to test it in a randomized controlled trial because of the rarity of the test its effectiveness for prevention of JORRP in the children of infected mothers. disease even in the high-risk group. In the Note the effectiveness of an immunization strat References Danish study, only about 7 of 1000 children born to mothers who had condyloma during pregnancy developed JORRP. The risk of JORRP might be even lower in children born to women who are subclinically infected with HPV-6 or HPV-11. To test egy, large numbers of HPV-6/11–infected pregnant women would have to be recruited for each arm of a randomized controlled trial, and the children born to these women would have to be observed for 3–5 years to identify the cases of JORRP. In noninstitutionalized US women aged 14–59 years, the prevalence of HPV-6 or HPV-11 infection is estimated to be 3.1% [16], so a large number of pregnant women will have to be screened for HPV6/11 infection to identify and recruit infected women eligible for such a trial. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Figure 1. A, Papilloma on the vocal cord . B, Papilloma obstructing the respiratory tract . United States , only 32 % of girls aged 13 - 1. Chesson HW , Ekwueme DU , Saraiya M , Watson M , Lowy DR , Markowitz LE . Estimates of the annual direct medical costs of the prevention and treatment of disease associated with human papillomavirus in the United States . Vaccine 2012 ; 30 : 6016 - 9 . 2. Derkay CS . Task force on recurrent respiratory papillomas . A preliminary report. Arch Otolaryngol Head Neck Surg 1995 ; 121 : 1386 - 91 . 3. Wiatrak BJ , Wiatrak DW , Broker TR , Lewis L. Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population . Laryngoscope 2004 ; 114 (11 Pt 2 suppl 104 ): 1 - 23 . 4. Hajek EF . Contribution to the etiology of laryngeal papilloma in children . J Laryngol Otol 1956 ; 70 : 166 - 8 . 5. Mounts P , Shah KV , Kashima H. Viral etiology of juvenile- and adult-onset squamous papilloma of the larynx . Proc Natl Acad Sci U S A 1982 ; 79 : 5425 - 9 . 6. Gissmann L , Diehl V , Schultz-Coulon HJ , zur Hausen H. Molecular cloning and characterization of human papilloma virus DNA derived from a laryngeal papilloma . J Virol 1982 ; 44 : 393 - 400 . 7. Shah KV , Unger ER , Derkay CS , Sternberg M. Recurrent respiratory papillomatosis: bright prospects for vaccine-based prevention . Papillomavirus Rep 2005 ; 16 : 333 - 8 . 8. Carter JJ , Wipf GC , Hagensee ME , et al. Use of human papillomavirus type 6 capsids to detect antibodies in people with genital warts . J Infect Dis 1995 ; 172 : 11 - 8 . 9. Maloney EM , Unger ER , Tucker RA , et al. Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis . Arch Otolaryngol Head Neck Surg 2006 ; 132 : 711 - 5 . 10. Silverberg MJ , Thorsen P , Lindeberg H , Grant LA , Shah KV . Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis . Obstet Gynecol 2003 ; 101 : 645 - 52 . 11. Munoz N , Kjaer SK , Sigurdsson K , et al. Impact of human papillomavirus (HPV)-6/ 11/16 /18 vaccine on all HPV-associated genital diseases in young women . J Natl Cancer Inst 2010 ; 102 : 325 - 39 . 12. Brown DR , Garland SM , Ferris DG , et al. The humoral response to Gardasil over four years as defined by total IgG and competitive Luminex immunoassay . Hum Vaccin 2011 ; 7 : 230 - 8 . 13. Garland SM , Ault KA , Gall SA , et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/ 16/18 vaccine: a combined analysis of five randomized controlled trials . Obstet Gynecol 2009 ; 114 : 1179 - 88 . 14. Jemal A , Simard EP , Dorell C , et al. Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels . J Natl Cancer Inst 2013 ; 105 : 175 - 201 . 15. Matys K , Mallary S , Bautista O , et al. Mother-infant transfer of anti-human papillomavirus (HPV) antibodies following vaccination with the quadrivalent HPV (type 6/ 11/16/18) virus-like particle vaccine . Clin Vaccine Immunol 2012 ; 19 : 881 - 5 . 16. Dunne EF , Sternberg M , Markowitz LE , et al. Human papillomavirus (HPV) 6 , 11 , 16, and 18 prevalence among females in the United States-National Health And Nutrition Examination Survey , 2003 - 2006 : opportunity to measure HPV vaccine impact? J Infect Dis 2011 ; 204 : 562 - 5 . 17. Healy CM . Vaccines in pregnant women and research initiatives . Clin Obstet Gynecol 2012 ; 55 : 474 - 86 .


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Keerti V. Shah. A Case for Immunization of Human Papillomavirus (HPV) 6/11–Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma, Journal of Infectious Diseases, 2014, 1307-1309, DOI: 10.1093/infdis/jit611