Drug products: Cervarix®
ATC code: J07BM02
Studies regarding immunogenicity, immune response, and efficacy show similar results in men/boys and women/girls. There are no published trials with the primary objective to assess sex differences in terms of pharmacokinetics, pharmacodynamics, and safety of vaccine against papilloma virus.
Cervarix is used for prevention of precancerous anogenital lesions (anus, cervix, vulva or vagina) in women (in Sweden) and men (in some countries) from the age of nine, caused by the two oncogenic types of human papillomavirus (HPV) 16 and 18 [1, 3]. Including males in the immunization program against HPV is thought to be necessary to break the cycle of sexual transmission of HPV-infection to females and to attain herd immunity against HPV-infection. HPV-vaccination is not a substitute for routine cervical screening due to the vaccine not having demonstrated protection against high-grade dysplastic genital lesions and cancers caused by non-vaccine types . HPV infects the squamous epithelium in men and women, causing cervical/vulvar/vaginal cancers in women, penile cancer in men as well as anogenital condyloma acuminate, oropharyngeal and anal cancers in both men and women .
The HPV infection natural history related to age is different in men compared to women. The probability of a sexually active man acquiring a new genital HPV-infection in any given 12-month period is 0.29-0.39 per 1000 person-months, which is comparable to reported estimates for women. The rate of acquisition of new HPV-infections in men is unlike women, constant with increasing age, while it declines in women. Compared to women, older median-age at diagnosis of HPV-related cancers has been observed in men. There may be differences in the immune response to natural HPV-infection between men and women. The reported proportion of HPV seropositive men is lower than in women. Antibody titers are higher in women who are HPV seropositive and appear to provide partial protection against subsequent HPV infection, while in men antibody titers are lower and do not appear to protect against subsequent HPV infection .
No pharmacokinetics studies on the active ingredients in Cervarix have been performed. This is in line with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95) .
Nine clinical studies regarding immunogenicity and efficacy against precancerous cervical lesions supported the licensure of Cervarix (24348 women). Five main post licensure randomized clinical trials (24801 women, 11832 men) have demonstrated similar immunogenicity, seroconversion and safety results between women and men [4-8].
Immune response in women 18-26 years at month 7 after receiving three doses of Cervarix expressed in Geometric Mean Antibody Titer, GMT, and anti-HPV-neutralizing antibodies was comparable to Gardasil . Girls (n=773) aged 10-14 years reached 100% seroconversion against HPV 16 and 18 which was non-inferior to adolescent girls/women 15-25 years. Twice as high GMTs were observed in the younger age-group of girls and is believed to result in longer antibody persistence . A two-dose schedule Cervarix demonstrated immunological non-inferiority one month post last dose to three-dose schedule .
Protective efficacy with 95% CI against CIN2+ in the per protocol (PP) population was 92.9 (79.9–98.3) in women (placebo/vaccine n=7312/7344) who received all three doses and were HPV-naïve for the vaccine HPV-types through the vaccination period. No efficacy studies have been performed with Cervarix in men .
The pivotal study Protocol 020 (P020) including 4055 men (3463 heterosexual men 16-23 years and 602 MSM 16-26 years) demonstrated 90,6% efficacy against external genital lesions (PIN penile/perineal/perianal cancer and genital warts caused by vaccine-matched HPV-types) in the per-protocol efficacy population (heterosexual men) .
Efficacy against precancerous anal lesions has been demonstrated indirectly through immunogenicity bridging trials to Gardasil. Gardasil has demonstrated efficacy against anal infection and associated anal intra-epithelial neoplasia (AIN) in MSM (n= 402), the PP efficacy against HPV6/11/16/18–related AIN of any grade and AIN2+ was 77.5% (95% CI 39.6, 93.3) and 74.9 (95% CI 8.8, 95.4), respectively. Efficacy studies against anal infection or AIN has not been performed in women for neither Cervarix or Gardasil, however the efficacy is believed to be similar for men and women since patterns of anal HPV infection and AIN are biologically indistinguishable in men and women .
Cervarix has been shown to be well tolerated in both men and women. Common side effects were short-term pain, swelling and erythema at the local site of injection, low-grade fever and headache. Several serious adverse events were recorded but a causal relationship to the vaccine could not be established .
In clinical trials 60% of women used hormonal contraceptives. There are no signs that hormonal contraceptives influence the effect of Cervarix . Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).
Cervarix should be avoided in pregnant women. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2017-01-09
Reviewed by: Mia von Euler, Expertrådet för vaccinationer
Approved by: Karin Schenck-Gustafsson