L1 Virus-like Particle Vaccine Research Articles

Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine

The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity, while others require booster doses. Vaccines that induce long-term protection are usually characterized by the generation of immune memory. Recent trials of a quadrivalent (types 6, 11, 16, 18) human papillomavirus (HPV) vaccine have demonstrated high efficacy through 5 years of follow-up. We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory. A total of 552, 16-23-year-old women were enrolled in a double-blind, placebo-controlled study. At enrollment, subjects were randomized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years' follow-up. A subset of 241 subjects (n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group) underwent 2 further years of follow-up. All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series. Serum anti-HPV levels declined post-vaccination, but reached a plateau at month 24 that remained stable through month 60. Administration of a challenge dose of vaccine induced a classic anamnestic response, with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series. At 1 month post-challenge, anti-HPV responses were higher than those observed 1-month post-dose 3. A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years. Vaccination also induces robust immune memory. These findings suggest that the efficacy of this vaccine will be long lasting.

Noninferiority of Antibody Response to Human Papillomavirus Type 16 in Subjects Vaccinated with Monovalent and Quadrivalent L1 Virus-Like Particle Vaccines

The incorporation of multiple antigens into a single human papillomavirus (HPV) vaccine may induce immune interference. To evaluate whether interference occurs when HPV type 16 (HPV16) virus-like particles are combined in a multivalent vaccine, we conducted a study to evaluate anti-HPV16 responses among subjects receiving three-dose regimens of either a monovalent HPV16 vaccine or a quadrivalent HPV (types 6, 11, 16, and 18) vaccine.

Long-term follow-up of a quadrivalent HPV vaccine

Evaluation of: Villa LL, Costa RL, Petta CA et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow up. Br. J. Cancer 95(11), 1459–1466 (2006).Human papillomavirus (HPV) infection causes genital warts and cervical cancers. A number of preventive HPV vaccines have been developed. Follow-up of patients who were enrolled in initial efficacy trials of these vaccines is ongoing. Such trials have proven HPV vaccines to be effective in preventing persistent infection and cervical disease; however, long-term safety, efficacy and immunogenicity can only be ascertained by longer-term follow-up. At 5 years’ follow-up, the prophylactic quadrivalent HPV vaccine targeting HPV 6/11/16/18 demonstrates an excellent safety profile and continues to prevent persistent infection and disease. The need for booster immunizations continues to be under review.

Incidence and Duration of Cervical Human Papillomavirus 6, 11, 16, and 18 Infections in Young Women: An Evaluation from Multiple Analytic Perspectives

To estimate the incidence and duration of cervical human papillomavirus (HPV)-6, HPV-11, HPV-16, and HPV-18 infections in a population of young American women. The study population consisted of U.S. women who at baseline were 16 to 23 years of age, reported zero to five lifetime sexual partners, never having been pregnant, and never having had a prior abnormal Papanicolaou test and were enrolled in the placebo arm of a randomized multicenter clinical trial of a HPV-16 L1 virus-like particle vaccine. Women underwent type-specific endocervical/ectocervical swab HPV DNA testing at approximately 6-month intervals for up to 48 months of follow-up. To contribute person-time in the analyses of type-specific HPV incidence, a woman must have had at least three satisfactory swab specimens available and been negative for the relevant HPV type (HPV-6, HPV-11, HPV-16, or HPV-18) on her first two trial swabs. The duration of incident HPV infections was estimated using Kaplan-Meier survival analysis methods. Person-years of exposure ranged by type-specific analysis from 2,645 to 3,188, with an incidence rate per 100 person-years of 3.6 for HPV-6, 0.4 for HPV-11, 5.4 for HPV-16, and 2.1 for HPV-18. With censoring at the time of treatment for cervical intraepithelial neoplasia, where done, the mean duration of incident infections was 9.3, 8.4, 18.2, and 16.4 months, respectively, for HPV-6 (n = 103), HPV-11 (n = 13), HPV-16 (n = 142), and HPV-18 (n = 62). When the duration of HPV infections was truncated at the time of cervical intraepithelial neoplasia detection (any grade), where applicable, mean duration figures were 8.4, 8.1, 14.0, and 15.1 months for HPV-6, HPV-11, HPV-16, and HPV-18 infections, respectively. Previous studies of the mean duration of cervical HPV infection have been based on prevalent infections and/or featured relatively short duration of follow-up. This study tested women for HPV infection over a period of up to 48 months and observed a mean duration of incident HPV-16/HPV-18 infections approximately twice that of HPV-6/HPV-11.

Prophylactic HPV vaccines: prospects for eliminating ano-genital cancer

Virtually all cases of cervical cancer and its precursor intra-epithelial lesions are a result of infection with one or other of a subset of genital human papillomaviruses (HPVs), suggesting that prevention of HPV infection by prophylactic vaccination would be a highly effective anticancer strategy. Two HPV L1 virus-like particle vaccines have been developed, a quadrivalent HPV16/18/6/11 product and a bivalent HPV16/18 product; both have been shown to be highly immunogenic with a good safety profile and 100% efficacy against HPV16/18-related high-grade cervical intra-epithelial neoplasia (CIN2/3), implying that they will be effective at preventing HPV16/18-related cervical cancer.

Safety and Persistent Immunogenicity of a Quadrivalent Human Papillomavirus Types 6, 11, 16, 18 L1 Virus-Like Particle Vaccine in Preadolescents and Adolescents

Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment. In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card. At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P < 0.001). At month 18, > or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported. In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.

Cervarix™ – a bivalent L1 virus-like particle vaccine for prevention of human papillomavirus type 16- and 18-associated cervical cancer

Cervical cancer continues to have a devastating impact on women worldwide. An estimated 470,000 women are diagnosed with the disease every year and, of these, > 230,000 die from it. Recent decades have witnessed considerable advances in our understanding of cervical carcinogenesis, in particular the causal role that oncogenic human papillomavirus infection plays in its etiology. In countries that lack organized cervical screening programs, prophylactic vaccination against human papillomavirus may offer the most effective way of reducing mortality from the disease. Cervarix™, a bivalent L1 virus-like particle vaccine targeted against human papillomavirus types 16 and 18, has been developed to address this possibility. The clinical experience of Cervarix and its potential role in reducing the global burden of cervical cancer is discussed.

Sustained Efficacy Up to 4.5 Years of a Bivalent L1 Virus-like Particle Vaccine Against Human Papillomavirus Types 16 and 18: Follow-up From a Randomised Control Trial

Sustained Efficacy Up to 4.5 Years of a Bivalent L1 Virus-like Particle Vaccine Against Human Papillomavirus Types 16 and 18: Follow-up From a Randomised Control Trial

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16–23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy=100%; 95% CI:12–100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

Comparison of the Immunogenicity and Reactogenicity of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine in Male and Female Adolescents and Young Adult Women

Prophylactic vaccination of 16- to 23-year-old females with a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine has been shown to prevent type-specific human papillomavirus infection and associated clinical disease. We conducted a noninferiority immunogenicity study to bridge the efficacy findings in young women to preadolescent and adolescent girls and boys, who represent a primary target for human papillomavirus vaccination. We enrolled 506 girls and 510 boys (10-15 years of age) and 513 females (16-23 years of age). Participants were vaccinated on day 1, at month 2, and at month 6, and serology testing was performed on day 1 and at months 3 and 7 on blinded samples. Neutralizing antibody concentrations were determined using type-specific immunoassays and summarized as geometric mean titers and seroconversion rates. Vaccine tolerability also was assessed. By month 7, seroconversion rates were > or = 99% for all 4 human papillomavirus types in each group. By month 7, compared with women, anti-human papilloma virus geometric mean titers in girls or boys were noninferior and were 1.7- to 2.7-fold higher. Most (> 97%) injection-site adverse events were mild to moderate in intensity. Significantly more boys (13.8%) and girls (12.8%) than women (7.3%) reported fevers > or = 37.8 degrees C within 5 days of vaccination. Most (96.4%) fevers were mild (< 39 degrees C). Noninferior immunogenic responses to all 4 human papillomavirus types in the quadrivalent vaccine permit the bridging of efficacy data that were generated in young women to girls. The results in boys lend support for the implementation of gender-neutral human papillomavirus vaccination programs. This vaccine generally was well tolerated.

HPV vaccination with Gardasil®: a breakthrough in women’s health

Human papillomavirus (HPV) represents one of the most common sexually transmitted infections. Although infection is often self-limited, a percentage of women with HPV infection will go on to develop cervical precancerous or cancerous lesions. It is estimated that HPV16 is responsible for approximately half of all cervical cancers worldwide. Several studies have tested vaccines directed against specific HPV types, namely types 6, 11, 16 and 18. This paper reviews these studies, particularly focusing on a quadrivalent (type 6, 11, 16 and 18) HPV L1 virus-like particle vaccine under investigation in Phase III trials at present. Data indicate that this vaccine, referred to as Gardasil®, can prevent precancerous cervical lesions and early in situ cervical cancers with few adverse effects, and the vaccine has been approved by the FDA for this indication. Another vaccine, HPV16 L1, directed solely against HPV16, has also been demonstrated to be effective (at present, follow-up has been for up to 48 months) in providing protection against persistent infection with this viral strain and preventing HPV16-related cervical intraepithelial neoplasia 2/3, while producing minimal adverse effects in recipients. Given the lack of a pharmacological intervention that can eradicate HPV in infected individuals and the prevalence of cervical cancer secondary to HPV infection across the world, the HPV vaccine represents a significant breakthrough in women’s health.

Sustained Efficacy up to 4.5 Years of a Bivalent L1 Virus-Like Particle Vaccine Against Human Papillomavirus Types 16 and 18: Follow-Up From a Randomized Control Trial

The following abstracts of articles from leading journals have been selected on the basis of their importance to the practice of obstetrics and gynecology.

HPV VACCINES: PROSPECTS FOR ERADICATING ANO‐GENITAL NEOPLASIA

The ability to generate human papillomavirus (HPV) virus like particles (VLPs) by the synthesis and self‐assembly in vitro of the major virus capsid protein L1 has transformed our prospects for preventing cervical carcinoma in women. Immunisation with L1 VLPs provides type specific protection in all the animal infections so far tested. In Phase I trials in humans HPV L1 VLP vaccines are safe and highly immunogenic stimulating robust B and T cell responses and generating high titres of neutralising antibody. Phase II and Phase III trials are in progress with preliminary data suggesting that antibody levels persist at measurable levels for at least 48 months post vaccination. Phase II proof of principle efficacy trials are immensely encouraging with evidence that these vaccines protect against infection and data from Phase III trials confirms this and shows, importantly that these vaccines protect against the development of high grade intra epithelial cervical neoplasia. At present the assumption is that the protection achieved by these vaccines against incident HPV infection and HPV associated ano‐genital pathology is mediated via serum neutralising IgG. However, since there have been very few vaccine failures thus far, immune correlates of protection have not been established. The available evidence is that the immunodominant neutralising antibodies generated by L1 VLPs are type‐specific and are not cross‐neutralising although highly homologous HPV pairs share minor cross‐ neutralisation epitopes. Cross reactive and cross neutralising antibodies are generated in vaccinees but at significantly lower titres and the duration of any cross protection that might be elicited is uncertain. VLP vaccines are likely to be expensive, require a cold chain and medical or para medical personnel for delivery. Furthermore L1 vaccines must be delivered before the sexual debut to prepubertal females (or males) and social and cultural issues may be important in determining vaccine take‐up. L1 based vaccines are not protective against established infections and in post exposure HPV infection, cell mediated immunity is critical. Studies in animal papillomavirus infections suggest that immunisation with specific early proteins, particularly E1 and E2, could be effective and immunotherapies for established lesions such as ano‐genital warts and low‐grade intra‐epithelial lesions are realistic. Such vaccines are likely to be combined with immunomodulators such as cytokines in order to maximise the response. Prime/boost strategies combining DNA and/or protein and/or recombinant viruses look to have significant potential as immunotherapies for benign or low grade HPV induced disease. Immunotherapies for HPV associated high‐grade pre‐cancers and invasive cancers are problematic. There is increasing evidence that high grade CIN and invasive cervical carcinomas are characterised by an immunosuppressive cytokine milieu and dominated by regulatory T cells. To be effective immunotherapies must reverse this in favour of effective cell mediated immunity and this represents a major challenge. In order to maximise the response. Prime/boost strategies combining DNA and/or protein and/or recombinant viruses look to have significant potential as immunotherapies for benign or low grade HPV induced disease. Immunotherapies for HPV associated high‐grade pre‐cancers and invasive cancers are problematic. There is increasing evidence that high grade CIN and invasive cervical carcinomas are characterised by an immunosuppressive cytokine milieu and dominated by regulatory T cells. To be effective immunotherapies must reverse this in favour of effective cell mediated immunity and this represents a major challenge.Reference: Stanley MA Human papillomavirus vaccines Reviews in Medical Virology 2006 16 139–49

Safety and prophylactic efficacy of a quadrivalent HPV (types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine in women with virologic evidence of HPV infection

Safety and prophylactic efficacy of a quadrivalent HPV (types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine in women with virologic evidence of HPV infection

Post-infection prophylaxis of a quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine

Post-infection prophylaxis of a quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine

Population Benefit of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Viruslike Particle Vaccine for Prevention of Human Papillomavirus-related Disease

Population Benefit of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Viruslike Particle Vaccine for Prevention of Human Papillomavirus-related Disease

Sustained Efficacy Up to 4.5 Years of a Bivalent L1 Virus-Like Particle Vaccine Against Human Papillomavirus types 16 and 18: Follow-Up From a Randomized Control Trial

Sustained Efficacy Up to 4.5 Years of a Bivalent L1 Virus-Like Particle Vaccine Against Human Papillomavirus types 16 and 18: Follow-Up From a Randomized Control Trial

Efficacy of a quadrivalent HPV (types 6/11/16/18) L1 virus-like particle (VLP) vaccine against vaginal and vulvar pre-cancerous lesions: a combined analysis

5011 Background: In the US, 6000 cases of vulvar or vaginal cancer are diagnosed annually. HPV is detected in 75–100% of vulvar cancers in younger women. The most common HPV type detected is HPV 16, followed by HPV 18. These two types also cause a majority of HPV-related vaginal cancers. Treatment to prevent progression to vaginal/vulvar cancer is challenging. Here, we present a combined analysis of 3 randomized, placebo-controlled trials to evaluate the impact of a prophylactic quadrivalent HPV vaccine on the rates of HPV 16- and 18-related vulvar and vaginal neoplasia grade 2/3 (VIN 2/3 and VaIN 2/3). Methods: 18,150 women (16–26 yrs) from the Americas, Europe and Asia were enrolled in 1 of 3 trials. Subjects were randomized to either quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. Genital tract specimens were obtained at day 1 and at 6–12 month intervals thereafter for a maximum of 48 months. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Cytology, histology, and HPV detection were conducted centrally. Analyses were done per protocol (PP) (subjects received 3 doses, had no major protocol violations, were HPV 16 or 18 seronegative at Day 1 and HPV 16 or 18 DNA negative Day 1 through month 7) and modified intention to treat (MITT) (received ≥1 dose and were HPV 16 or 18 negative at Day 1 by serology and DNA). Endpoint counts began after Month 7 and Day 30 in the PP and MITT analyses, respectively. Results: In PP analysis, after an average of 18 months of follow-up, the vaccine was 100% effective (95% CI: 56–100%) in preventing HPV 16- or 18-related VIN 2/3 or VaIN 2/3. There were 10 cases in the placebo group and 0 cases in the vaccine group. In the MITT population, after an average of 2 years of follow-up, there were 24 histologically confirmed cases of HPV 16- or 18-related VIN 2/3 or VaIN 2/3, all in the placebo group (100% efficacy; 95% CI: 83–100%). Conclusions: Quadrivalent HPV VLP vaccine prevented HPV 16 and 18-related vaginal and vulvar high-grade precancerous lesions for at least 2 years post-immunization. This intervention is expected to greatly reduce the risk of vulvar and vaginal cancers. [Table: see text]