Immunologic non-inferiority and safety of the investigational pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) 4-dose vial presentation compared to the licensed PHiD-CV 1-dose vial presentation in infants: A phase III randomized study

BackgroundTo support vaccination programs in developing countries, a 4-dose vial presentation of pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was developed. This study assessed immunologic non-inferiority and safety of the investigational PHiD-CV 4-dose versus licensed 1-dose vial presentation in infants.MethodsIn this phase III, mono-center, observer-blind study in Bangladesh, 6–10-week-old infants were randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geometric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of antibody GMC ratios [1DV/4DV] <2-fold). Immune responses were measured. Solicited, unsolicited and serious adverse events (AEs) were evaluated.ResultsOf 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for most VT, ≥97.9% of infants in each group had antibody concentrations ≥0.2 μg/mL; for 19A ≥ 80.1% reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT and 19A were within similar ranges between groups after primary and booster vaccination, as were anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were within similar ranges for both presentations.ConclusionImmunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV 1-dose vial (preservative-free) was demonstrated. Immune responses and reactogenicity following primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial would help improve access and coverage in resource-limited countries.Clinical Trial Registry: NCT02447432.     

Estimation of the potential overall impact of human papillomavirus vaccination on cervical cancer cases and deaths

Background

Human papillomavirus (HPV) vaccination offers potential for primary prevention of HPV-related pre-cancers and cancers as demonstrated in clinical trials. Mathematical models have estimated the potential real-life impact of vaccination on the burden of cervical cancer (CC). However, these are restricted to evaluations in a limited number of countries.

Methods

Potential decline in CC cases and deaths with the AS04-adjuvanted HPV-16/18 vaccine of young girls naïve to HPV, was estimated at steady-state (vaccine coverage: 0–100%) based on clinical trial and country-specific incidence data. Data on vaccine efficacy were taken from the end of study PATRICIA trial of the AS04-adjuvanted HPV-16/18 vaccine. The numbers of cases and deaths due to HPV-16/18 were estimated and compared with those due to any HPV type to estimate the additional cases prevented. This difference estimates CC cases and deaths avoided due to protection against non-vaccine HPV types. Cost-offsets due to reductions in CC treatment were estimated for five countries (Brazil, Canada, Italy, Malaysia and South African Republic) using country-specific unit cost data. Additionally, cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3)-related burden (cases and treatment costs) prevented by vaccination were estimated for two countries (Italy and Malaysia).

Results

HPV vaccination could prevent a substantial number of CC cases and deaths in countries worldwide, with associated cost-offsets due to reduced CC treatment. Cross-protection increased the estimated potential number of CC cases and deaths prevented by 34 and 18% in Africa and Oceania, respectively. Moreover, vaccination could result in a substantial reduction in the number of CIN2/3 lesions and associated costs.

Conclusion

HPV vaccination could reduce the burden of CC and precancerous lesions in countries worldwide, part of disease burden reduction being related to protection against non HPV-16/18 related types.     

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

Background

Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741).

Methods

Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N = 65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N = 50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration.

Results

Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated.

Conclusion

A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.     

Immunogenicity,safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2–17-year-old children with asplenia or splenic dysfunction: A phase 3 study

BackgroundImmunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population.MethodsThis phase III, multi-centre, open-label, controlled study, in which at-risk children with asplenia or splenic dysfunction were enrolled (age strata: 2–4, 5–10 and 11–17 years), was conducted in Poland and the Russian Federation. For the 2–4 years at-risk group, healthy age-matched children were enrolled as control. Unprimed children (not previously vaccinated with any pneumococcal vaccine) received 2 PHiD-CV doses (≥2 months apart) and pneumococcal vaccine-primed children received 1 dose. Immune responses were assessed pre-vaccination and one month post-each dose. Solicited and unsolicited adverse events (AEs) were recorded for 4 and 31 days post-vaccination, respectively, and serious AEs (SAEs) throughout the study.ResultsOf 52 vaccinated children (18 at-risk primed, 28 at-risk unprimed and 6 control unprimed), 45 (18, 23 and 4, respectively) were included in the according-to-protocol cohort for immunogenicity. Post-vaccination (post-dose 1 in primed and post-dose 2 in unprimed children), for each vaccine pneumococcal serotype and vaccine-related serotype 6A all at-risk children had antibody concentrations ≥0.2 µg/mL, and for vaccine-related serotype 19A at least 94.4%. Increases in antibody geometric mean concentrations were observed. For most serotypes, all at-risk children had post-vaccination opsonophagocytic activity (OPA) titers ≥8 and increases in OPA geometric mean titers were observed. No safety concerns were raised. One non-fatal SAE (respiratory tract infection, considered not vaccine-related) was reported by one at-risk unprimed child.ConclusionPHiD-CV was immunogenic and well tolerated in 2–17-year-old children with asplenia or splenic dysfunction.Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108.     

Immunogenicity and safety of 11- and 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccines (11vPHiD-CV, 12vPHiD-CV) in infants: Results from a phase II,randomised, multicentre study

Background

We assessed 2 investigational 11- and 12-valent vaccines, containing capsular polysaccharides of 10 serotypes as in the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and CRM₁₉₇-conjugated capsular polysaccharides of serotypes 19A (11-valent) or 19A and 6A (12-valent).

Incremental cost-effectiveness evaluation of vaccinating girls against cervical cancer pre- and post-sexual debut in Belgium

Background

Vaccination against human papillomavirus (HPV) to prevent cervical cancer (CC) primarily targets young girls before sexual debut and is cost-effective. We assessed whether vaccination with the HPV-16/18 AS04-adjuvanted vaccine added to screening remains cost-effective in females after sexual debut compared to screening alone in Belgium. The role of protection against non-HPV-16/18 was also investigated.

Methods

A published Markov cohort model was adapted to Belgium. The model replicated the natural history of HPV infection, the effects of screening, and vaccination. Vaccine efficacy (VE) included non-HPV-16/18 protection based on the PATRICIA clinical trial data. Pre- and post-HPV exposure VE were differentiated. Lifetime vaccine protection was assumed. Input data were obtained from literature review, national databases and a Delphi panel. Costing was from a healthcare payer perspective. Costs were discounted at 3% and effects at 1.5%. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained and the number of lesions prevented with vaccination from age 12 to 40 was evaluated. The specific effect of non-HPV-16/18 protection was investigated. Univariate sensitivity analysis was performed on key variables.

Results

The model estimated that vaccinating a cohort of 100,000 girls at age 12 would prevent 646 CC cases over a lifetime (102 non-HPV-16/18) with an ICER of €9171/QALY. Vaccinating at age 26 would prevent 340 CC cases (40 non-HPV-16/18) with an ICER of €17,348/QALY and vaccinating at age 40 would prevent 146 CC cases (17 non-HPV-16/18) with an ICER of €42,847/QALY. The ICER remained under the highly cost-effective threshold (1×GDP/capita) until age 33 years and under the cost-effective threshold (3×GDP/capita) beyond age 40.

Conclusion

Extending HPV vaccination to females post-sexual debut could lead to a substantial reduction in CC-related burden and would be cost-effective in Belgium.     

Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: A randomised placebo-controlled study

The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4⁺ T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4⁺ and CD8⁺ T-cell responses, absolute CD4⁺ T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4⁺ T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p < 0.05). Vaccine-induced HIV-1-specific CD4⁺ T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8⁺ T-cells or change in CD8⁺ T-cell activation marker expression profile was detected. Absolute CD4⁺ T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4⁺ T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4⁺ T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.     

Efficacy, safety and immunogenicity of RIX4414 in Japanese infants during the first two years of life

A phase III, randomized, double-blind study evaluated the efficacy, reactogenicity, safety and immunogenicity of a human rotavirus vaccine, RIX4414 in Japanese infants aged 6-14 weeks when administered as two doses (0, 1-month schedule). Efficacy against any and severe rotavirus gastroenteritis leading to medical intervention caused by circulating wild-type rotavirus from two weeks post-Dose 2 until two years of age was 79.3% (95% CI: 60.5-89.8%) and 91.6% (95% CI: 62.4-99.1%), respectively. Solicited, unsolicited symptoms and serious adverse events were reported at a similar frequency in both groups. Serum anti-rotavirus antibody seroconversion rate one-month post-Dose 2 was 85.3% (95% CI: 68.9-95%) in RIXX4414 group. RIX4414 was efficacious, well-tolerated and immunogenic in Japanese infants and introduction of vaccination could help in reducing the disease burden.