Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: A partially-blind randomised placebo-controlled study

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18–25 years (N = 120) were stratified by CD4⁺ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix^®; GlaxoSmithKline Vaccines) or placebo (Al[OH]₃) at 0, 1 and 6 months (double-blind). HIV-negative women (N = 30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4⁺ T-cell responses, CD4⁺ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4⁺ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4⁺ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4⁺ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection.     

Increases in HPV-16/18 antibody avidity and HPV-specific memory B-cell response in mid-adult aged men post-dose three of the quadrivalent HPV vaccine

Strong quantitative and functional antibody responses to the quadrivalent human papillomavirus (HPV) vaccine were reported in mid-adult aged men, but there are limited data on the avidity of the antibody response and the memory B-cell response following vaccination. Although circulating antibodies induced by vaccination are believed to be the main mediators of protection against infection, evaluation of avidity of antibodies and memory B cell responses are critical for a better understanding of the vaccine immunogenicity mechanisms. Both the modified enzyme-linked immunosorbent assay (ELISA) and the enzyme-linked immunosorbent spot (ELISpot) assay are tools to measure the humoral and cellular immune responses post vaccination to characterize vaccine immunogenicity. The avidity of HPV-16 and HPV-18 specific IgG in the serum of mid-adult aged men (N = 126) who received three quadrivalent HPV vaccine doses was examined using a modified ELISA. HPV-16 memory B-cell responses were assessed via ELISpot at month 0 (prior to vaccination) and 1-month post-dose three of the vaccine (month 7). The quadrivalent vaccine induced an increase in HPV-16 and HPV-18 antibody avidity at month 7. HPV-18 avidity levels moderately correlated with anti-HPV-18 antibody titers, but no association was observed for HPV-16 antibody titers and avidity levels. The HPV-16-specific memory B-cell response was induced following three vaccine doses, however, no association with anti-HPV-16 antibody avidity was observed. Three doses of quadrivalent HPV vaccine increased antibody affinity maturation for HPV-16/18 and increased the frequency of anti-HPV-16 memory B-cells in mid-adult aged men.     

HPV-specific antibodies at the oral cavity up to 30 months after the start of vaccination with the quadrivalent HPV vaccine among mid-adult aged men

BackgroundHPV-16 and HPV-18 cause most oropharyngeal cancers, which are increasing in incidence among males. Although HPV vaccines are highly effective against a number of HPV-associated cancers, efficacy for oropharyngeal cancers has not yet been demonstrated. In addition, the level of antibodies required for protection against oral HPV infection is unknown.Methods150 men ages 27–45 years from Tampa, FL, USA, and Cuernavaca, Mexico, received Gardasil at Day 1, Months 2, and 6. Then, sera and oral gargles were collected one month, 12 months, and 24 months after completion of the three doses (Month 7, 18 and 30 of the study) and tested for anti-HPV-16 and HPV-18 IgG antibody levels by a L1 VLP ELISA.ResultsAll participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies and most had detectable antibodies in oral gargles at Month 7 (HPV-16: 93.2%; HPV-18: 72.1%). By months 18 and 30, oral antibodies were detectable in a lower number of participants (HPV-16, 39.8% and 29.6%; HPV-18, 10.7% and 4.6% of individuals, respectively). Overall, oral HPV-16- and 18-specific antibody levels, normalized to total IgG at months 7, 18, and 30, correlated with serum levels (HPV-16, R² = 0.93; HPV-18, R² = 0.91).ConclusionsReduced detectability of oral and serum HPV-16 and HPV-18 antibodies was observed at months 18 and 30 after initiation of the quadrivalent vaccination. However, when detectable, serum and oral HPV-16 and HPV-18 antibody levels were strongly correlated.     

Efficacy,safety, and immunogenicity of a quadrivalent HPV vaccine in Japanese men: A randomized,Phase 3, placebo-controlled study

Background

The quadrivalent (q) human papillomavirus (HPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, and 18. We report efficacy, immunogenicity, and safety of qHPV vaccine in a Phase 3 study in Japanese men.

Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix

Background

We previously demonstrated that Cervarix^® elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix^®-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women.

Methods

A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory.

Results

In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p = 0.009) and HPV-45 (month 12, p = 0.003), but then persisted up to month 36 (HPV-31, p = 0.01; HPV-45, p = 0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p = 0.04) and lower in HPV-16 infected women at month 12 (p = 0.006) compared to the HPV negative women.

Conclusions

The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in protection against infection.     

Impact of malaria and helminth infections on immunogenicity of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Tanzania

Background

Endemic malaria and helminth infections in sub-Saharan Africa can act as immunological modulators and impact responses to standard immunizations. We conducted a cohort study to measure the influence of malaria and helminth infections on the immunogenicity of the bivalent HPV-16/18 vaccine.

Methods

We evaluated the association between malaria and helminth infections, and HPV-16/18 antibody responses among 298 Tanzanian females aged 10–25 years enrolled in a randomized controlled trial of the HPV-16/18 vaccine. Malaria parasitaemia was diagnosed by examination of blood smears, and helminth infections were diagnosed by examination of urine and stool samples, respectively. Geometric mean antibody titres (GMT) against HPV-16/18 antibodies were measured by enzyme-linked immunosorbent assay.

Results

Parasitic infections were common; one-third (30.4%) of participants had a helminth infection and 10.2% had malaria parasitaemia. Overall, the vaccine induced high HPV-16/18 GMTs, and there was no evidence of a reduction in HPV-16 or HPV-18 GMT at Month 7 or Month 12 follow-up visits among participants with helminths or malaria. There was some evidence that participants with malaria had increased GMTs compared to those without malaria.

Conclusions

The data show high HPV immunogenicity regardless of the presence of malaria and helminth infections. The mechanism and significance for the increase in GMT in those with malaria is unknown.     

Association of serum bactericidal antibody and opsonic antibody levels after Neisseria meningitidis serogroup C conjugate vaccine in Brazilian children and adolescents infected or not infected with HIV

Neisseria meningitidis serogroup C (MenC) is the main causative agent of meningitis in Brazil. HIV infection affects the quality of the immune system. HIV⁺ children have an increased risk of infection to encapsulated bacteria such as N. meningitidis. We evaluated the opsonic antibody (OPA) levels and its correlation with serum bactericidal antibody (SBA) levels induced by one and two doses of a MenC conjugate vaccine in children and adolescents HIV⁺ and HIV-exposed but uninfected children (HEU) group. Overall the data show the importance of two doses of vaccine for HIV⁺ individuals. About 79% and 58% of HIV⁺ patients showed SBA and OPA positive response after two doses of vaccine, respectively. For HEU group, 62% and 41% of patients showed SBA and OPA positive response after one dose of vaccine, respectively. A positive and significant association between SBA and OPA levels was seen after two doses of vaccine in HIV⁺ patients.     

Comparing immunogenicity of the Escherichia coli-produced bivalent human papillomavirus vaccine in females of different ages

BackgroundThe safety and efficacy of a recently licensed Escherichia coli (E. coli)-produced bivalent HPV vaccine have been shown. Specific antibody levels are important indicators to evaluate the efficacy of vaccination. Therefore, we compared the immunogenicity of this HPV 16/18 vaccine in females of different ages in this study.MethodsImmunogenicity of the vaccine was analyzed in the per-protocol sets for immunogenicity (PPS-I) of a phase III trial and an immune-bridging trial. The serum samples were collected at month 0 and one month after the final dose (month 7) to assess the specific IgG antibody levels by ELISA. The seroconversion rates, geometric mean concentration (GMC), and geometric mean increase (GMI) were used to assess the immunogenicity of the test vaccine. The non-linear association of antibody levels with age was estimated via natural cubic splines and the Akaike information criterion was used to assess optimal model.ResultsBy combining the PPS-I data from the two trials, nearly all of the females seroconverted for both HPV types. In the 3-dose group, the GMC of IgG to both HPV types decreased with increasing age, especially in adolescent girls and young women. For HPV-16 and -18, the declining trend slowed down in women older than 32 and 35 years old, respectively. The GMI ranged from 648 to 80 for HPV-16 and from 218 to 42 for HPV-18. In the 2-dose group, the specific antibodies for HPV-16 and -18 peaked in girls aged 10 years with GMIs of 401 and 98, respectively, and then decreased with age.ConclusionsThe E. coli-produced bivalent HPV-16/18 vaccine induced specific antibody responses in females aged 9–45 years. The antibody levels were inversely associated with age, and the declining trends slowed down in women older than 32 or 35 years for HPV-16 and -18, respectively.     

Immunogenicity and safety of the 9-valent HPV vaccine in men

ObjectivesThis study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16–26 years of age in comparison to young women 16–26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16–26 year old women to 16–26 year old men.MethodsThis study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼12 months.ResultsThe geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16–26 year old men and women was generally well tolerated.ConclusionsThese results support bridging the efficacy findings with 9vHPV vaccine in young women 16–26 years of age to men 16–26 years of age.     

Antibody avidity measurements in recipients of Cervarix vaccine following a two-dose schedule or a three-dose schedule

The HPV-16/18 vaccine (Cervarix^®) is a prophylactic vaccine for the prevention of cervical cancer and contains recombinant virus-like particles (VLPs) assembled from the L1 major capsid proteins of human papillomavirus (HPV) strains 16 and 18. Although a correlate of protection has yet to be identified, HPV-specific antibodies are thought to prevent virus infection of the genital mucosa. Therefore, antigen-specific antibodies as assessed by ELISA or pseudovirion-based neutralisation assay are frequently measured in clinical trials to substantiate the immune responses induced by the vaccine. Measuring antigen-antibody binding avidities, which reflects the degree of affinity maturation in the B-cells, is another valuable method to assess the quality of the antibody responses. Here we describe the antigen-specific antibody avidities in samples taken from a clinical trial examining the feasibility of adopting a two-dose (Months 0 and 6) schedule for 9–14 year olds instead of the three-dose schedule (Months 0, 1 and 6). Antibody avidity (i.e. avidity index [AI]) was determined in the ELISA by the ratio of antibody concentrations in serum samples treated or not with the chaotropic agent NaSCN. Importantly, in the comparison between the groups of two-dose and three-dose recipients, no differences in AIs were observed at Months 7, 24 and 48. The results suggest that from Month 7 to 48, the quality of the antibody response in terms of avidity was similar in the two-dose recipients to that in the three-dose recipients. Hence these results support the adoption of a two-dose schedule in 9–14 year-old girls.     

Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: Results from two randomized trials

Background

A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in addition to HPV-16 and -18 may broaden protection against cervical cancer. Two Phase I/II, randomized, controlled studies were conducted to compare the immunogenicity and safety of investigational tetravalent HPV L1 virus-like particle (VLP) vaccines, containing VLPs from two additional oncogenic genotypes, with the licensed HPV-16/18 AS04-adjuvanted vaccine (control) in healthy 18–25 year-old women.

Methods

In one trial (NCT00231413), subjects received control or one of 6 tetravalent HPV-16/18/31/45 AS04 vaccine formulations at months (M) 0,1,6. In a second trial (NCT00478621), subjects received control or one of 5 tetravalent HPV-16/18/33/58 vaccines formulated with different adjuvant systems (AS04, AS01 or AS02), administered on different schedules (M0,1,6 or M0,3 or M0,6).

Results

One month after the third injection (Month 7), there was a consistent trend for lower anti-HPV-16 and -18 geometric mean antibody titers (GMTs) for tetravalent AS04-adjuvanted vaccines compared with control. GMTs were statistically significantly lower for an HPV-16/18/31/45 AS04 vaccine containing 20/20/10/10 μg VLPs for both anti-HPV-16 and anti-HPV-18 antibodies, and for an HPV-16/18/33/58 AS04 vaccine containing 20/20/20/20 μg VLPs for anti-HPV-16 antibodies. There was also a trend for lower HPV-16 and -18-specific memory B-cell responses for tetravalent AS04 vaccines versus control. No such trends were observed for CD4⁺ T-cell responses. Immune interference could not always be overcome by increasing the dose of HPV-16/18 L1 VLPs or by using a different adjuvant system. All formulations had acceptable reactogenicity and safety profiles. Reactogenicity in the 7-day post-vaccination period tended to increase with the introduction of additional VLPs, especially for formulations containing AS01.

Conclusions

HPV-16 and -18 antibody responses were lower when additional HPV L1 VLPs were added to the HPV-16/18 AS04-adjuvanted vaccine. Immune interference is a complex phenomenon that cannot always be overcome by changing the antigen dose or adjuvant system.     

Evaluation of HPV-16 and HPV-18 specific antibody measurements in saliva collected in oral rinses and merocel® sponges

BackgroundCurrent Human papillomavirus (HPV) L1 VLP vaccines protect against HPV-16 and HPV-18-associated cancers, in females and males. Although correlates of protection have not been identified, HPV-specific antibodies at sites of infection are thought to be the main mechanism of protection afforded by vaccination. Oral sampling has gained increased attention as a potential alternative to serum in monitoring immunity to vaccination and understanding local immunity in oral cancers.MethodsSerum was collected via venipuncture, and saliva was collected via oral rinses and Merocel® sponges from healthy volunteers: 16 unvaccinated females, 6 females (ages 24–41) and 6 mid-adult aged males (ages 27–45) recipients of three doses of the HPV-16/18/6/11 vaccine (Gardasil®). Mid-adult male vaccine trial participants were compared to female participants. Samples were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay (ELISA).ResultsAll vaccinated participants had detectable serum anti-HPV-16 and anti-HPV-18 antibodies. Optimal standard concentration range and sample serial dilutions for oral rinses were determined. The standard curve was not affected by the type of solution examined. Reproducibility of HPV-16 and HPV-18 antibody titers in mouthwash (overall CV < 10%) or in Merocel® extraction buffer was robust (CV < 13%). Excellent assay linearity (R² > 0.9) was observed for sera spiked controls in both solutions. HPV-16 and HPV-18 specific antibodies were detectable in saliva from vaccine recipients, both in mouthwash and in Merocel® sponges but levels were several logs lower than those in serum.ConclusionsThis study confirms the application of HPV-16 and HPV-18 ELISAs currently used in sero-epidemiological studies of immunogenicity of HPV vaccines for use with oral samples. Oral samples may be a useful resource for the detection of HPV-16 and HPV-18-specific antibodies in saliva following vaccination.     

Persistence of immune response following bivalent HPV vaccination: A follow-up study among girls routinely vaccinated with a two-dose schedule

BackgroundIn this cohort study, we examined antibody levels and avidity after a two-dose schedule (0, 6 months) of the bivalent HPV-vaccine in girls routinely vaccinated in the Dutch HPV-vaccination program, up to 2 years following vaccination.MethodsA blood sample at 7, 12 and 24 months after the first dose and questionnaire data were collected (n = 56). HPV type-specific antibody concentrations (lU/ml) against seven types (HPV16/18/31/33/45/52/58) were assessed using a validated virus-like particles (VLP) multiplex immunoassay. Avidity was tested using a modification of this assay.ResultsSeropositivity for vaccine types HPV 16 and 18 was 100% up to month 24, but declined for HPV-types 31/33/45/52/58, although not statistically significant for HPV45. All Geometric Mean Concentrations (GMCs) declined by months 12 and 24, but remained high for HPV16/18. Between month 7 and 12, GMCs declined more for other types. High avidity antibodies were induced up to 24 months for vaccine types (75%, 76–78% and 81–82% at months 7, 12 and 24, respectively), but for other types antibody avidity was 16–29% at month 7, 20–32% at month 12 and 19–32% at month 24.ConclusionsGMCs declined over time for HPV-types 16/18/31/33/45/52/58, but remained high for vaccine-types HPV16/18 up to 24 months of follow-up. Antibody avidity was >75% for vaccine types but <35% for other HPV-types. Further follow-up of this cohort will provide insight into antibody and avidity kinetics over time.     

Co-administration of human papillomavirus-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine: randomized study in healthy girls

Background

To evaluate co-administration of GlaxoSmithKline Biologicals’ human papillomavirus-16/18 AS04-adjuvanted vaccine (HPV) and hepatitis B vaccine (HepB).

Methods

This was a randomized, controlled, open, multicenter study. Healthy girls, aged 9-15 years, were randomized to receive HPV (n = 247), HepB (n = 247) or HPV co-administered with HepB (HPV + HepB; n = 247) at Months 0, 1 and 6. Antibodies against hepatitis B surface antigen (HBs), HPV-16 and HPV-18 were measured, and reactogenicity and safety monitored. Co-primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines, compared with vaccines administered alone, in the according-to-protocol cohort.

Results

The pre-defined criteria for non-inferiority were met for all co-primary immunogenicity endpoints at Month 7. Anti-HBs seroprotection rates ≥10 mIU/mL were achieved by 97.9% and 100% of girls, respectively, following co-administration or HepB alone. Anti-HBs geometric mean titers (GMTs) (95% confidence interval) were 1280.9 (973.3-1685.7) and 3107.7 (2473.1-3905.1) milli-international units/mL, respectively. Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99% of girls following co-administration or HPV alone. Anti-HPV-16 GMTs were 19819.8 (16856.9-23303.6) and 21712.6 (19460.2-24225.6) ELISA units (ELU)/mL, respectively. Anti-HPV-18 GMTs were 8835.1 (7636.3-10222.1) and 8838.6 (7948.5-9828.4) ELU/mL, respectively. Co-administration was generally well tolerated.

Conclusions

The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9-15 years.

Clinical trials registration

ClinicalTrials.gov registration number NCT00652938.     

Safety and Immunogenicity of the HPV-16/18 AS04-Adjuvanted Vaccine: A Randomized,Controlled Trial in Adolescent Girls

PurposeImmunization of girls against oncogenic human papillomavirus (HPV) types before sexual debut is important for cervical cancer prevention. This phase III blinded, randomized, controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine.MethodsGirls (mean age 12 years) in 12 countries received the HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine (N = 1,035) or hepatitis A virus vaccine as control (N = 1,032) at 0, 1, and 6 months. The primary objective was to compare the occurrence of serious adverse events (SAEs) between groups. HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination.ResultsUp to study month 7, 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs. The difference in SAE incidence between groups was .20% (95% CI, ?.78, 1.20). No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal. The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control. The incidence of unsolicited symptoms, new onset of chronic diseases, and medically significant conditions was similar between groups. All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies, respectively, in initially seronegative girls.ConclusionsThe HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females, the primary target of organized vaccination programs.     

Immunogenicity and safety of Gardasil among mid-adult aged men (27–45 years)—The MAM Study

BackgroundThe quadrivalent (types 6/11/16/18) human papillomavirus (HPV) vaccine, Gardasil, has demonstrated efficacy against persistent HPV infection and associated anogenital disease in males. The goal of this Phase II trial was to establish the immunogenicity and safety of Gardasil among mid-adult men ages 27–45 years.MethodsOne hundred and fifty men from Tampa, FL, US, and Cuernavaca, Mexico who met eligibility criteria (male, 27–45 years old, completed four years of follow-up in the HPV Infection in Men (HIM) natural history study) were enrolled. Subjects completed four visits over seven months, with Gardasil administered at Day 1 and Months 2 and 6. Sera were collected at Day 1 (pre-vaccination) and Month 7 (one month post-dose three). Anti-HPV6, 11, 16, and 18 IgG levels were determined by competitive Luminex immunoassay.Findings100% of men seroconverted to each of the four HPV vaccine components, and the vaccine was generally well-tolerated. Antibody responses to vaccine did not differ by age group or sexual orientation, regardless of HPV type, and were significantly higher at Month 7 among men who entered the trial seropositive for HPV 6 or 11.InterpretationThe immune response to HPV vaccination in men ages 27–45 was comparable to that observed in younger men, in whom clinical efficacy was demonstrated. Further trials to assess the efficacy of HPV vaccines to prevent persistent HPV infections in mid-adult men are needed.FundingMerck & Co. Inc. was the main sponsor of this trial (IISP39256) and provided the study product.     

Immunogenicity of bivalent HPV vaccine among partially vaccinated young adolescent girls in Uganda

Background

Investigations of vaccine efficacy and immunogenicity for adult females receiving fewer than three doses of human papillomavirus (HPV) vaccine have suggested protection against infection and precancerous lesions. We investigated the immunogenicity of bivalent HPV vaccines among adolescent girls from Uganda who received one, two, or three vaccine doses.

Methods

Young girls vaccinated through a government program in Uganda were invited to participate. HPV16- and HPV18-specific antibodies were measured at ≥24 months after the last vaccine dose using an enzyme linked immunoassay in girls who received one (n = 36), two (n = 145), or three (n = 195) doses.

Results

Nearly all subjects (99%) were HPV16 and HPV18 seropositive at the time of blood-draw. Geometric mean antibody levels (GMTs) were: HPV16_1-dose = 230 EU/mL, HPV16_2-dose = 808 EU/mL, and HPV16_3-dose = 1607 EU/mL; HPV18_1-dose = 87 EU/mL, HPV18_2-dose = 270 EU/mL, and HPV18_3-dose = 296 EU/mL. The GMT ratio for 2:3 doses was 0.50 (HPV16) and 0.68 (HPV18) and did not meet the non-inferiority criteria (i.e., lower bound of 97.5% confidence interval of the GMT ratio greater than 0.50). The GMT ratio for 1:3 doses for HPV16 and HPV18 was inferior, but absolute GMTs for one dose were higher than adult women who received one dose (HPV16 = 124 EU/mL, HPV18 = 69 EU/mL) where efficacy has been demonstrated.

Conclusions

Even though immunogenicity with less than three doses did not meet a priori non-inferiority thresholds, antibody levels measured ≥24 months after last dose were similar to those of adult women who have been followed for more than eight years for efficacy.     

Antibody responses to prophylactic quadrivalent human papillomavirus vaccine at 48 months among HIV-infected girls and boys ages 9–14 in Kenya,Africa

ObjectivesHIV infected children remain at increased risk of HPV associated malignancies as they initiate sexual activity. Though they mount a vigorous immune response to the quadrivalent human papillomavirus (QHPV-6, -11,-16, and -18; Gardasil®) vaccine, durability of the immune response is uncertain. We assessed antibody responses to HPV 6, -11, -16 and -18 for up to 48 months following administration of quadrivalent human papillomavirus vaccine in HIV-infected girls and boys ages 9–14 years in Kenya.DesignOf 178 girls and boys who had previously received three doses of the quadrivalent HPV vaccine, 176 enrolled into extended follow up for 4 years. HPV antibodies to -6, -11, -16 and -18 were measured at 24, 36 and 48 months after the first vaccine dose using the total immunoglobulin G immunoassay (IgG LIA). We evaluated the magnitude and trend in HPV vaccine response and the effect of plasma HIV-1 RNA on HPV vaccine response from month 24 to month 48 of follow up.ResultsAt re-enrollment, 24 months after initial vaccination, median age of participants was 14 years (range 11–17); 167 (95%) were receiving antiretroviral therapy and 110 (66%) had plasma HIV RNA < 40 copies/mL. The rate of HPV seropositivity at 48 months was 83% for HPV-6; 80% for HPV-11; 90% for HPV-16; and 77% for HPV-18. There was a plateau in mean log10 HPV-specific antibody titer between month 24 and 48. The mean log10 HPV-type specific antibody titer for children with undetectable HIV viral load (<40) at the time of vaccination consistently remained higher for the 48 months of follow up compared to children with detectable viral load.ConclusionChildren with HIV infection may retain long term antibody response following HPV immunization. Further work to define whether HIV-infected children are protected from HPV acquisition with low levels of HPV antibodies is needed.     

Quadrivalent HPV vaccine in HIV-1-infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine immunogenicity and correlation with immune status

IntroductionIn sub-Saharan Africa, a generation of HIV-1-infected children is approaching the age of sexual debut and becoming at risk for HPV infection and its sequelae. We assessed safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in HIV-1-infected adolescents.MethodsIn an open-label trial among Kenyan, HIV-1-infected adolescents aged 9–14 years, we administered the qHPV vaccine at 0, 2 and 6 months and measured antibody titers to HPV-16, 18, 6 and 11 at month 7 and 12 post-vaccination. Measures of immunogenic response from HIV-1-negative historical cohorts from Africa and HIV-1 positive adolescent cohorts from the USA were used for comparison.ResultsWe enrolled 100 girls and 80 boys with a median age of 12 years and median baseline CD4 cell count of 684 (IQR 478, 935) cells/µL. One hundred and fifty four (86%) were receiving antiretroviral therapy for a median of 4.5 (IQR 2.3, 6.3) years; 110 (71%) had <400 copies of plasma HIV-1 RNA/mL. Of 189 enrolled children, 179 received all three doses. Two hundred and eighty five (64%) of 445 adverse events were injection site reactions; none were greater than grade 2. Of 6 Serious Adverse Events (SAEs), none were considered vaccine related. Seroconversion to HPV-18, 16, 11, 6 at month 7 occurred in 93.3%, 98.3%, 97.2% and 99.6% of vaccine recipients; similar rates have been reported in historical controls. The mean log₁₀ HPV antibody titer measured at month 7 increased with each log₁₀ increase in CD4 by 1.4 (95% CI: 1.1–1.7) for HPV-18; 1.2 (0.9–1.4) for HPV-16; 1.1 (0.8–1.3) for HPV-11; 0.7 (0.5–1.0) for HPV-6 (all p < 0.0001).ConclusionAlmost all Kenyan HIV-1-infected adolescents mounted an immune response comparable to other immunized populations. HPV antibody titers were higher in those with preserved CD4 cell counts. Longer term-follow up will determine sustainability of the immune response.ClinicalTrials.gov number, NCT00557245.     

Immunogenicity and Safety of Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Vaccine in Healthy Boys Aged 10–18 Years

PurposeThe human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix?) has been shown to be well-tolerated and immunogenic in females aged 10 to 55 years, and up to 100% effective for the prevention of HPV-16/18 infection and associated precancerous cervical lesions in females aged 15 to 25 years. This study is the first to evaluate the immunogenicity and safety of the vaccine in males.MethodsHealthy males aged 10 to 18 years were randomized (2:1 ratio) to receive HPV-16/18 AS04-adjuvanted vaccine (n = 181) or hepatitis B virus (HBV) control vaccine (n = 89) at 0, 1, and 6 months, and were followed for 7 months.ResultsAll initially seronegative subjects in the HPV-16/18 group seroconverted for HPV-16 and 18 (ELISA) at month 2. At month 7, all subjects were seropositive, and the HPV-16 and -18 antibody levels were, respectively, four- and twofold higher than at month 2. The anti-HPV-16 and -18 antibody responses for males aged 10 to 18 years and 10 to 14 years, respectively, were higher than those reported for females aged 15 to 25 years and 10 to 14 years, respectively, in a previous study. The reactogenicity profiles of the HPV-16/18 AS04 and HBV vaccines were similar, except that pain and swelling at the injection site were more common in the HPV-16/18 group. However, vaccine-related symptoms did not affect compliance with the three-dose course, which was equally high (97%) in both groups.ConclusionsThe HPV-16/18 AS04-adjuvanted vaccine is immunogenic and well tolerated in boys aged 10 to 18 years. However, further data on the potential public health benefits of vaccination of boys are required before any recommendations can be made.