L1 Virus-like Particle Vaccine Research Articles

Evaluation of antibodies induced by an HPV vaccine to cross-neutralize pseudovirions of vaccine-related HPV types

15008 Background: Human papillomavirus (HPV) is the causative agent of cervical cancer. The HPV types 6, 11, 16 and 18 quadrivalent L1 virus-like particle (VLP) vaccine has been shown to be highly efficacious in preventing HPV vaccine type-related disease. The HPV A7 species contains types 18, 45 and 59. The A9 species include types 16, 31, 33, 35, 52 and 58. The potential of the vaccine induced antibodies to cross-neutralize infection of pseudovirions (PsV) of HPV types within the A9 and A7 species was evaluated. Methods: Sera from quadrivalent, monovalent HPV 16, or monovalent HPV 18 vaccinees were evaluated. Sera were tested in a multiplexed competitive Luminex Immunoassay (cLIA) against vaccine types to demonstrate HPV type-specific seroconversion. A9 and A7 VLP type cross-reactive binding ability was assessed by a total IgG LIA. HPV L1 and L2 PsV containing secreted alkaline-phosphatase (SEAP) sequences were constructed using native HPV sequences for 16 and 31 and with mammalian codon-optimized sequences for 18 and 45. Demonstrated expression of SEAP was used as an indirect measure of PsV infection of 293TT cells. Results: All subjects seroconverted to high titers against the vaccine HPV types. Cross-reactive antibodies were generated. Quadrivalent vaccinee sera bound to HPV 31, 45, 52 and 58 VLPs. These total IgG titers were 1.5–2 logs lower than the titers to the vaccine types. PsV types 18 and 45 were neutralized using the 18 monovalent and the quadrivalent sera. At month 7, the PsV 18 neutralization titer was ∼1–1.5 logs less than that required for PsV 45 cross-neutralization. Neutralization studies using PsV of the A9 species are in progress. Conclusions: High titers of anti-HPV antibodies are elicited by vaccination with HPV VLP vaccines. These antibodies can prevent in vitro PsV infection of vaccine-HPV types. Cross-reactive, cross-neutralizing antibodies are generated, however at reduced titers compared to the vaccine-specific types. Antibody titers required for cross-protection against non-vaccine types are not known. [Table: see text]

Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only

An effective virus-like particle (VLP) based prophylactic vaccine designed to protect against persistent infection with human papillomavirus (HPV) types 16 and 18 and subsequent lesion development will need to induce a strong humoral and cellular immune response capable of providing long-term protection. Our objective was to evaluate the ability of an HPV16/18 L1 VLP vaccine formulated with the AS04 adjuvant system (3- O-desacyl-4′-monophosphoryl lipid A (MPL) and aluminium salt) to induce an immune response of higher magnitude and persistence compared to a vaccine formulated with aluminium salt only. We demonstrated that MPL adsorbed onto aluminium salt retains its capacity to activate an innate immune response as assessed by the production of TNFα by human monocytes (U937). In addition, vaccination of mice, monkeys or human subjects with AS04 formulations induced higher total anti-L1 VLP16 and L1 VLP18 antibody responses (1.6–8.5-fold) than the aluminium salt only formulations. The enhanced antibody response induced by the AS04 vaccine formulation (1.6–4.1-fold) in monkeys and humans was shown to be targeted to functional neutralising L1 VLP16 and L1 VLP18 epitopes as assessed by V5/J4 specific ELISAs or HPV16 and HPV18 pseudo-neutralization assays. The enhanced immune profile observed with the AS04 formulation in terms of both total, V5/J4 specific and neutralizing antibodies was shown to persist for at least 3.5-year post-vaccination in human subjects. Finally, using the newly developed B cell ELISPOT assay we also demonstrated that the AS04 formulation elicited an increased frequency (2.2–5.2-fold) of HPV L1 VLP specific memory B cells when compared with the aluminium salt only formulations. These data strongly support the role of the AS04 adjuvant, which includes the immunostimulant MPL, in triggering a persistent vaccine-induced immune response of high quality.

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were ∼12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.

Human papillomavirus vaccines

A wealth of epidemiological and molecular evidence has led to the conclusion that 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 infection by prophylactic vaccination would be an effective anti-cancer strategy. The papillomaviruses cannot be grown in large amounts in culture in vitro, but the ability to generate HPV virus like particles (VLPs) by the synthesis and self-assembly in vitro of the major virus capsid protein L1 provides for a potentially effective sub unit vaccine. HPV L1 VLP vaccines are immunogenic and have a good safety profile. Published data from proof of principle trials and preliminary reports from large Phase III efficacy trials suggest strongly that they will protect against persistent HPV infection and cervical intra epithelial neoplasia. However, the duration of protection provided by these vaccines is not known, the antibody responses induced are probably HPV type specific and immunisation should occur pre-exposure to the virus. Second generation vaccines could include an early antigen for protection post-exposure and alternative delivery systems may be needed for the developing world.

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

Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.

Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia

Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2-3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. A total of 2,391 women, aged 16-23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 mug HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2-3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65-100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88-98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128-150 mMU/mL). The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. I.

PS10 Late breaking Prophylactic use of quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine reduces cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS) risk

PS10 Late breaking Prophylactic use of quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine reduces cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS) risk

Minimum serum antibody levels associated with protection from human papillomavirus 16 (HPV 16) reinfection among placebo subjects

5024 Background: We have shown that prophylactic administration of a prototype HPV 16 L1 coat protein virus-like particle (VLP) vaccine was 100% effective in preventing acquisition of persistent HPV 16 infection. Given this efficacy, a minimum protective anti-HPV 16 level could not be defined. Using such subjects within the placebo arm, we assessed the minimal anti-HPV 16 level needed to protect against reacquisition of HPV 16 infection. Methods: 2391 women aged 16–23 years were enrolled in a 4 year randomized, double-blind study of an HPV 16 L1 VLP vaccine, as part of the development of a quadrivalent HPV vaccine. Genital samples for HPV 16 DNA were obtained at Day 1, Month 7 and then every 6 months through Month 48. Serum was collected for anti-HPV 16 testing by immunoassay at Day 1 and Months 7, 12, 18, 30, 42, and 48. Antibody levels were reported in arbitrary units (mMU/mL). HPV 16 re-infection was defined as HPV 16 DNA detection in genital samples collected at ≥2 consecutive visits, or on the last visit on record. Results: At Day 1, 111 placebo subjects were free of HPV 16 DNA but anti-HPV 16 seropositive. Of these, 14 reacquired HPV 16 infection. Risk for reacquisition of HPV 16 infection was inversely related to Day 1 anti-HPV16 levels. Please see table below. Conclusions: Anti-HPV 16 levels >20 mMU/mL at baseline appeared to be generally protective against re-acquisition of HPV 16 infection over a 4-year interval. This observation is consistent with previously reported data, whereby HPV 16-naïve women who were vaccinated with an HPV 16 L1 VLP vaccine (and thus had anti-HPV 16 levels >20 mMU/mL) were protected from HPV 16-related infection or disease. These data suggest that anti-HPV16 levels >6 mMU/mL may confer some degree of protection, while anti-HPV16 levels >20 mMU/mL may predict protection against HPV 16 over a sustained interval. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Merck

Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection With Human Papillomavirus Types 16 and 18 in Young Women: A Randomized, Controlled Trial

This double-blind, multicenter, randomized, placebo-controlled study was performed to test the efficacy of a bivalent HPV-16/18 L1 virus-like particle vaccine against human papillomavirus (HPV)-16/18 infection and associated cervical abnormalities, including precancerous lesions. Study participants, from 32 participating centers in Brazil, the United States, and Canada, were randomized to receive 3 doses of either vaccine or placebo delivered at 0 months, 1 month, and 6 months. Eligibility criteria included age 15 to 20 years, 6 or fewer sexual partners, no history of abnormal cervical smears or cervical treatment, no present treatment for condylomata, negative cytology, and seronegativity for HPV and HPV-18 antibodies and other high-risk HPV types. The vaccine was administered in 0.5-mL doses using monodose vials containing 20 μg each of HPV-16 and HPV-18 L1 virus-like particles. Placebo doses were administered in identical doses and were identical in appearance. Patients kept a record of dose reactions for 7 days after each injection. All participants who completed all components of the study were included in an “according-to-protocol” analysis. They were also included, along with those who had an incomplete record, in an “intention-to-treat” analysis. Analyses were performed at 18 and 27 months. A total of 1113 women participated in the study, 560 in the vaccine arm and 553 in the placebo arm. Both groups had similar demographic characteristics with an average age of 20 years. Incident HPV-16 and HPV-16/18 infections were significantly less common in the vaccine cohort at 18 and 27 months, but protection against HPV-18 did not reach significance in the according-to-protocol cohort. At 27 months in the according-to-protocol participants, there was 100% vaccine efficacy against persistent HPV-16 and HPV-16/18. Protection against persistent HPV-18 was significant in this cohort at 27 months but not at 18 months. In the intention-to-treat group, there was a highly significant difference in the number of cervical abnormalities between the 2 groups. Twenty-seven women in the placebo group had abnormal Pap smears compared with only 2 in the vaccine group (P <.0001). Similarly, in the according-to-protocol cohort, the vaccine efficacy was 93.5% (95% confidence interval 52, 3–99; P = .0002). HPV-51 and HPV-56 were detected at 9 months in 1 vaccinated woman. A cervical biopsy at 12 months showed CIN 1 and HPV-51, which persisted through month 21. In the placebo group, 3 participants developed CIN 1, and 2 developed CIN 2, all of which were associated with HPV-16. The vaccine group had significantly more pain, swelling, and redness associated with the injection (P = .0004). There were no other side effects associated with vaccination in either group. General symptoms such as fatigue, headache, itching, and so on, were equally common in both groups. Serology results showed that 100% of the vaccinated patients had converted to HPV-16- and HPV-18-positive by 18 months. The difference between the 2 groups for each antibody type was significant by month 7 (P <.0001). Compared with antibodies to HPV-16 and HPV-18, which developed as a result of naturally occurring infections, antibodies to HPV were 10 to 16 times greater in the vaccine group at the 18-month evaluation.

Immunogenicity and Reactogenicity of a Novel Vaccine for Human Papillomavirus 16: A 2-Year Randomized Controlled Clinical Trial

To evaluate the immunogenicity, reactogenicity, and tolerability of a prototype human papillomavirus (HPV) 16 viruslike particle (VLP) vaccine directed against the L1 capsid protein. We enrolled healthy nonpregnant women aged 18 to 26 years into a 2-year, double-blind, dose-ranging multicenter trial (October 12, 1998, to September 30, 2001). Subjects were assigned to study groups to receive a 3-dose regimen (day 0, month 2, and month 6) of 1 of 4 vaccine doses: 10 microg, 20 microg, 40 microg, or 80 microg or placebo. Serum anti-HPV 16 L1 antibody (sL1Ab) geometric mean titers (GMTs) were measured at day 0, at month 3, at month 7, and every 6 months for a total of 2 years using a radioimmunoassay. The primary immunogenicity analyses evaluated GMTs at month 7 in L1Ab-seronegative subjects at baseline. Vaccine tolerability was also assessed. A total of 480 subjects were randomized to receive placebo (n=52) or 10 microg (n=112), 20 microg (n=105), 40 microg (n=104), or 80 microg (n=107) of HPV 16 L1 VLP vaccine. At baseline, 75% of subjects were L1Ab seronegative. All vaccine doses produced a statistically significant sL1Ab response vs placebo (P<.001). At the completion of the vaccination regimen, sL1Ab GMTs in baseline-seronegative subjects were 36- to 78-fold higher than the sL1Ab GMT at day 0 observed in subjects who had mounted an immune response to HPV 16 infection before enrollment. Serum L1Ab GMTs remained high throughout the 1.5-year postvaccination period. Postvaccination sL1Ab GMTs were 1.1- to 2.4-fold higher in women who had detectable sL1Ab levels at enrollment compared with those in baseline-seronegative subjects, particularly in the persistence phase. The vaccine was generally well tolerated with no statistically significant differences in injection site or systemic adverse experiences among treatment groups. Immunization with this novel HPV 16 L1 VLP vaccine was well tolerated and produced an immunogenic response that persisted for at least 1.5 years after the final dose.

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection With Human Papillomavirus Types 16 and 18 in Young Women: A Randomized Trial

This double-blind, multicenter, randomized, placebo-controlled study was conducted to assess the efficacy of a bivalent human papillomavirus (HPV)-16/18 L1 virus-like particle vaccine in preventing cervical infection with HPV-16/18. The study participants were recruited among healthy women aged 15 to 25 years from 32 healthcare facilities in Brazil, Canada, and the United States. A total of 1113 women enrolled in the study. Enrollees had 6 or fewer lifetime sexual partners, no history of cervical abnormality, and were negative for high-risk HPV types. The subjects were randomized to receive placebo injections or the vaccine that contained 20 μg each of HPV-16 and HPV-18 virus-like particles. Women received 1 0.5-mL dose of vaccine or placebo at enrollment, 1 month, and 6 months. Cervical smears were taken at 6, 12, and 18 months. In addition, participants collected self-administered cervicovaginal samples at enrollment, 6 months, and every 3 months thereafter. Serologic testing for immunogenicity was performed at 0, 1, 6, 12, and 18 months. The women kept a diary of symptoms for 1 week after each injection, and symptoms were evaluated by telephone interview 1 month after each injection. Outcome results at 27 months were available for 81 women in the vaccine group and 59 in the placebo group. Study subject data were analyzed in two different cohorts. One analysis was performed including women who received all 3 injections and who had complete follow-up data. They comprised the ′according-to-protocol′ cohort (ATP). Another analysis was performed using data from the ′intention-to-treat′ cohort (ITT), which consisted of all enrolled participants who had at least one dose of vaccine or placebo and had any data available for analysis. There were 560 subjects randomized to receive vaccine and 553 randomized to receive placebo. The average age was 20 years. The two groups had similar patterns of risk factors for HPV infection. There were no cases of persistent HPV-16/18 among ATP women who received the vaccine. The vaccine was 100% effective against HPV-16, HPV-18, and HPV-16/18 (P < 0.0001). The effectiveness against HPV-18 infection was not significant until 27 months. In comparison, 13 (2.1%) women in the ATP group who received placebo developed a persistent HPV-16 infection, 4 (0.6%) had persistent HPV-18, and 16 (2.6%) had persistent HPV-16/18. In the ITT cohort, there were 4 women in the vaccine group who were positive for persistent HPV-16 (0.5%: efficacy 84.5%, P < 0.0001), 1 positive for persistent HPV-18 (0.1%: efficacy 91.1%, P = 0.003) and 4 with HPV-16/18 (0.5%: efficacy 87.5%, P < .0001). In the ITT placebo group, 25 women (3.2%) were positive for persistent HPV-16, 11 (1.4%) had persistent HPV-18, and 31 (4.0%) persistent HPV-16/18. Among the 560 women who received the vaccine, 2 developed cervical abnormalities associated with HPV types 16 or 18. One had atypical squamous cells of unknown significance (ASGUS) and 1 had a low-grade squamous intraepithelial lesion (LSIL). Of the 553 women who received placebo, 27 developed cervical abnormalities, including 15 ASCUS, 14 LSIL, and 1 high-grade squamous intraepithelial lesion (HSIL). The vaccine had an efficacy of 95.2% against HPV-16 (P < 0.0001), 91.2% against HPV-18 (P = 0.003), and 92.9% against HPV-16/18 (P < 0.0001). Cervical intraepithelial neoplasia (CIN) 1 or 2 was seen in 7 women, including 1 CIN 1 in the vaccine group, and 3 each CIN 1 and CIN 2 in the placebo group.

New Concepts for Vaccines1

New technologies have created opportunities to develop novel vaccines, including vaccines for sexually transmitted infections, influenza, and arthropodborne viruses. A GlaxoSmithKline (GSK) vaccine for genital herpes combines a recombinant herpes simplex virus (HSV) glycoprotein D (gD) with AS04, a novel proprietary adjuvant containing aluminum salts, and 3-deacylated monophosphoryl lipid A. Two recently completed efficacy trials with the gD-AS04 vaccine demonstrated protection against infection with genital herpes in HSV-1 and -2 seronegative women, but not in seronegative men. Herpes simplex DNA and live attenuated or replication-impaired virus vaccines are in early development. Human papillomavirus (HPV) vaccine uses L1 virus-like particles (VLP) to immunize against HPV-16 and -18, two oncogenic types of HPV responsible for most cervical cancers. A HPV-16 L1 VLP vaccine (Merck Research Laboratories) and an HPV-16/18 L1 VLP vaccine (GSK) have recently been shown to prevent infection with the corresponding HPV types. In a double-blind, placebo-controlled efficacy trial, the GSK vaccine induced type-specific antibody responses that were higher than elicited by natural infections and resulted in protection against incident and persistent HPV-16 and -18 infections. Additional challenges for vaccines against sexually transmitted infections include assessing the duration of protection, identifying optimal target populations, and designing implementation strategies. Cold-adapted, live attenuated strains of influenza have been developed in the United States (CAIV-T/USA) and Russia (CAIV-T/Russia) for use as vaccines. From master donor strains of influenza A or B, reassortant viruses can be produced annually with contemporary hemagglutinin (HA) and neuraminidase (NA) from wildtype influenza and six internal genes from the attenuated strains. Reactogenicity of the reassortants is generally mild; effectiveness is high. Expanded age indications are expected. Reverse genetics may be employed in the future to rapidly generate PR-8–based reassortant viruses. Reverse genetics could be used to eliminate the polybasic cleavage site of highly pathogenic avian influenza viruses and to rapidly make the PR-8 reassortants. New approaches to trivalent inactivated vaccine include high-dose HA vaccines, synthesis of recombinant HA antigen, addition of adjuvants, and intranasal transdermal administration and tissue culture production of whole viruses. Tissue culture production of antigen could shorten production time, increase the quantity of antigen, and exactly match the genetic sequence of HA in circulating viruses. Recombinant HA is effective as an immunogen and would reduce the reactogenicity associated with egg-grown trivalent inactivated vaccine. Use of adjuvants has the potential to stretch the vaccine supply in the event of vaccine shortage. Platform technology makes use of live, recombinant viruses or bacteria to express one or more foreign genes that encode the antigen(s) of interest to deliver naked DNA encoding the vaccine antigen(s). The live vector may or may not be replication competent. Examples of such vector platforms include poxviruses, adenoviruses, alphavirus replicons, flaviviruses, and enteric bacteria (e.g., Salmonella, Lactobacillus). Preexisting immunity to the vector can limit the effectiveness of this approach, except with flaviviruses. In flavivirus vectors, e.g., yellow fever 17 D vaccine-virus platform, the genes encoding the antigens of the vector are entirely replaced by the genes of interest, e.g., West Nile virus, St. Louis encephalitis, Japanese encephalitis, or dengue virus. In clinical trials, several of these chimeric viral vaccines have been well-tolerated and highly immunogenic in clinical trials.

Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial

Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions. We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5-99.3) against persistent cervical infection with HPV-16/18 and 92.9% (70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic. The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine

Human papillomavirus (HPV) infection can cause genital warts and cervical cancer. HPV types 6 and 11 cause >90% of genital wart cases; HPV16 and 18 cause 70% of cervical cancers. A prophylactic HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine may substantially reduce the incidence of these lesions. This report describes the results of a phase I study of the HPV18 component of such a vaccine. Forty women were randomized to receive either HPV18 L1 VLP vaccine or placebo. Anti-HPV18 responses were measured using a competitive radioimmunoassay (cRIA). Tolerability was evaluated using vaccination report cards (VRC). The study showed that the HPV18 L1 VLP vaccine was generally well-tolerated and highly immunogenic. Peak anti-HPV18 geometric mean titers (GMT) in vaccines were 60-fold greater than those observed in women following natural HPV18 infection. Further studies of a multivalent HPV L1 VLP vaccines are warranted.

Dose-ranging studies of the safety and immunogenicity of human papillomavirus Type 11 and Type 16 virus-like particle candidate vaccines in young healthy women

Two candidate vaccines to prevent infection with human papillomavirus (HPV) Types 11 and 16 were studied in similar double-blind, placebo-controlled, dose-escalation trials. L1 virus-like particle (VLP) vaccines were made from recombinant L1 capsid protein of HPV11 or HPV16. Participants received 10, 20, 50, or 100 μg of HPV11 L1 VLPs, 10, 40, or 80 μg of HPV16 L1 VLPs, or placebo at Months 0, 2, and 6. Serum geometric mean antibody levels at Month 7 were 258, 644, 647, and 1112 milli-Merck units (mMU)/ml for the 10, 20, 50, and 100 μg doses of the HPV11 L1 VLP vaccine, respectively, and 479, 808, and 732 mMU/ml for the 10, 40, and 80 μg doses of the HPV16 L1 VLP vaccine, respectively. Antibody to HPV11 and 16 was still present at Month 36 in 96.8 and 93.5% of vaccinees, respectively. Both vaccines were well tolerated and were associated with only mild to moderate injection-site reactions.

Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine

A post hoc analysis was performed using combined data from two Phase I tolerability/immunogenicity studies of monovalent human papillomavirus type 11 (HPV11) or HPV16 L1 virus-like particle (VLP) vaccines. The goal was to determine if the HPV16 L1 VLP vaccine protected against HPV16 infection. Vaccine or placebo was given at 0, 2 and 6 months. HPV16 infection was defined by positive polymerase chain reaction (PCR) results following vaccination. The incidence of HPV infection was observed to be 0 cases per 100 person-years at risk in the vaccine group, and 5 cases per 100 person-years at risk in the control group. These results support the institution of larger efficacy trials for HPV L1 VLP vaccines.

Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems.

To develop more potent and convenient mucosal human papillomavirus (HPV) vaccines, we tested the effect of thermosensitive mucoadhesive vaginal vaccine delivery systems on the local and systemic antibody responses to HPV 16 L1 virus-like particles (VLP). HPV 16 L1 VLP expressed from recombinant baculovirus-infected Sf21 insect cells were delivered in phosphate-buffered saline (PBS) or thermosensitive mucoadhesive delivery systems, composed of poloxamers (Pol) and varying amounts of polyethylene oxide (PEO). Pol/PEO-based vaginal vaccine delivery systems existed in liquid form at room temperature, but gelled at 37 degrees C. The mucoadhesiveness of Pol/PEO-based delivery systems increased with PEO, but the formulations with PEO higher than 1.0% were too viscous to be administered into the vagina. Vaccine vehicles affected the vaginal and salivary immune responses to HPV 16 L1 VLP intravaginally administered into mice. At 42 days after the first intravaginal immunization of HPV 16 L1 VLP with cholera toxin, vaginal and salivary IgA titers were the highest in the group given in Pol/PEO 1.0% vehicle followed by Pol/PEO 0.4% and PBS vehicles. Intravaginal coadministration of HPV 16 L1 VLP and cholera toxin in Pol/PEO 1.0% showed 31- and 39-fold higher titers compared to the PBS-based HPV 16 L1 VLP groups administered by intravaginal and intramuscular routes, respectively. Following intravaginal administration, Pol/PEO 1.0%, but not Pol/PEO 0.4%, showed significantly higher HPV 16 L1 VLP-specific serum IgG titers as compared to the PBS vehicle. Our results indicate that the use of in situ-gelling vaginal vaccine delivery systems with increased mucoadhesiveness would be beneficial for more effective induction of mucosal and systemic immune responses to intravaginally administered HPV 16 L1 VLP vaccines.

Safety and Immunogenicity Trial in Adult Volunteers of a Human Papillomavirus 16 L1 Virus-like Particle Vaccine

The following abstracts are taken from journals of interest to our readers and are reviewed by Thomas M. Julian (TMJ), L Stewart Massad (LSM), Leo B. Twiggs (LBT), and Kenneth D. Hatch (KDH).

Antibody, cytokine and cytotoxic T lymphocyte responses in chimpanzees immunized with human papillomavirus virus-like particles

We evaluated antibody, cytokine (IFN-γ, IL-5, TNF-α), and cytotoxic T lymphocyte (CTL) responses in chimpanzees immunized with monovalent or quadrivalent (HPV-6, -11, -16, -18) L1 virus-like particle (VLP) vaccines administered i.m. on aluminum hydroxyphosphate (alum) at weeks 0, 8 and 24. Maximum serum antibody titers to type-specific, neutralizing, conformational epitopes on HPV-11 or -16 L1 VLPs were detected by radioimmunoassay (RIA) four weeks after the second and third immunizations. HPV-11 and -16 neutralizing antibodies were also detected at similar time points with an Human papillomaviruses (HPV) neutralization assay using pseudovirions. Depending on the VLP type used for immunization, HPV type-specific cytokine responses were most frequently seen four weeks after the second or third immunizations and between weeks 44–52. Transient HPV-16 L1-specific CTL activity was observed only between weeks 16–24 in 3 of 22 (13.6%) chimpanzees immunized with HPV-16 L1 VLPs. These findings provide evidence that immunization with multivalent L1 VLPs on alum can evoke both neutralizing antibodies and Th1 and Th2 cytokine responses to several HPV types; however, induction of CTLs is infrequent.