Safety and immunogenicity of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV (HVTN 107): A phase 1/2a randomized trial.

BACKGROUND: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration). METHODS AND FINDINGS: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses. CONCLUSIONS: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen. TRIAL REGISTRATION: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710).

Protein dose-sparing effect of AS01B adjuvant in a randomized preventive HIV vaccine trial of ALVAC-HIV (vCP2438) and adjuvanted bivalent subtype C gp120.

BACKGROUND: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled HIV vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at two dose levels in healthy HIV-uninfected adults. Trial registration URL https://clinicaltrials.gov/ct2/show/NCT03122223 and registration number NCT03122223. METHODS: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200µg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40µg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. RESULTS: We enrolled 160 participants, 55% females, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40µg gp120/AS01B group were higher than in either of the 200µg gp120 groups. CONCLUSIONS: The 40µg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses.

Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. METHODS: From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. RESULTS: A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Phase 1 Human Immunodeficiency Virus (HIV) Vaccine Trial to Evaluate the Safety and Immunogenicity of HIV Subtype C DNA and MF59-Adjuvanted Subtype C Envelope Protein.

BACKGROUND: The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention. METHODS: In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector. RESULTS: All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61). CONCLUSIONS: Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired. CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969).

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines.

BACKGROUND: HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses. METHODS AND FINDINGS: A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain. CONCLUSIONS: In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Persistence of HBsAg-specific antibodies and immune memory two to three decades after hepatitis B vaccination in adults.

The duration of protection after hepatitis B vaccination is not exactly known. This phase IV study evaluated antibody persistence and immune memory 20-30 years after adult immunization with recombinant hepatitis B vaccine (HBsAg vaccine, Engerix-B) in routine clinical practice. Men and women 40-60 years old, with documented evidence of vaccination with three or four HBsAg vaccine doses 20-30 years earlier and without subsequent booster, were enrolled and received HBsAg vaccine as challenge dose. HBsAg-specific antibodies (anti-HBs) and frequencies of HBsAg-specific circulating memory B cells and CD4+ T cells expressing combinations of activation markers (CD40L, IL2, IFNγ, TNFα) were measured prechallenge, 7 and 30 days postchallenge. Of 101 participants in the according-to-protocol cohort for immunogenicity, 90.1% had anti-HBs concentrations ≥ 10 mIU/mL prechallenge administration; 84.2% and 100% mounted an anamnestic response 7 and 30 days postchallenge, respectively. HBsAg-specific memory B and CD4+ T cells expressing at least two activation markers were low prechallenge and increased markedly postchallenge. These results suggest sustained immune memory and long-term protection 20-30 years after a complete primary HBsAg vaccination course during adulthood, in line with current recommendations that a booster is not needed in fully vaccinated immunocompetent adults.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

BACKGROUND: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B. METHODS: HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination. RESULTS: From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose. CONCLUSIONS: The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.

Gene polymorphism in toll-like receptor 4: effect on antibody production and persistence after acellular pertussis vaccination during adolescence.

BACKGROUND: Toll-like receptors play an important role in the regulation of adaptive immunity. This study aimed to investigate whether Toll-like receptor 4 (TLR4) polymorphisms influence the production and persistence of antibodies after acellular pertussis booster vaccination during adolescence. METHODS: Seventy-five subjects received a single dose of diphtheria and tetanus toxoids and acellular pertussis vaccine 10 years ago, during adolescence. The same cohort was followed up at 3, 5, and 10 years after this booster vaccination. Pyrosequencing was used for detecting polymorphism in TLR4. Concentrations of anti-pertussis vaccine antibodies were measured by standardized enzyme-linked immunosorbant assay and published elsewhere. RESULTS: The fold increase in antibodies to pertussis toxin after original vaccination 10 years ago was significantly lower in subjects with TLR4 polymorphism than in those without (55% vs 86%; P = .028). At the 3-year follow-up evaluation, geometric mean concentrations of anti-pertussis vaccine antibodies were significantly lower in subjects with TLR4 polymorphism, compared with those without the polymorphism (for pertussis toxin, P = .028; for filamentous hemagglutinin, P = .047; and for pertactin, P = .046). CONCLUSIONS: This study suggests that TLR4 Asp299Gly polymorphism might influence production and persistence of antibodies after pertussis booster vaccination in adolescents. However, the results should be interpreted with caution as the number of subjects included in this study was limited.

Safety and reactogenicity of DTPa-HBV-IPV/Hib and DTPa-IPV/I-Hib vaccines in a post-marketing surveillance setting.

Combination vaccines have been shown to improve the timeliness of vaccination and vaccine coverage. Safety and reactogenicity of combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib, Infanrix IPV+Hib, GlaxoSmithKline Biologicals) was assessed in two clinical studies. In Study A, 2,590 subjects received DTPa-IPV/Hib at 3, 4 and 5 months of age with a booster at 18 months. In Study B, 702 subjects received the same schedule but with DTPa-hepatitis B-IPV/Hib (DTPa-HBV-IPV/Hib, Infanrix hexa, GlaxoSmithKline Biologicals) vaccine administered at 5 months of age. Reactogenicity was assessed for four days after each dose using diary cards. Serious adverse events (SAEs) were assessed until 24 months of age. The vaccines were well tolerated. After primary vaccination, irritability was the most frequently reported grade 3 general symptom (0.8% of doses in both studies). Fever (axillary) > 39 degrees C was infrequent (0.3% of doses in Study A; 0.5% of doses in Study B). After the booster dose, the most frequently reported grade 3 symptom was redness (5%) in Study A and pain (0.5%) in Study B. An axillary temperature > 39 degrees C was reported in 1.1% of subjects. Throughout the study period, 646 SAEs were reported, of which 6 SAEs were considered to be vaccination-related. The reactogenicity and safety profile of the combined DTPa-IPV/Hib vaccine was good when used for primary and booster vaccinations in over 3,000 Singaporean infants. Substitution of DTPa-IPV/Hib with DTPa-HBV-IPV/Hib at Month 5 reduced the number of injections required at this age by one.

Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults.

BACKGROUND: Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a-lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS: Eighty-two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS: A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00610168 .

Lasting immune memory against hepatitis B in children after primary immunization with 4 doses of DTPa-HBV-IPV/Hib in the first and 2nd year of life.

BACKGROUND: Few studies have assessed long term persisting immunity against hepatitis B virus (HBV) in children vaccinated during infancy with combined vaccines containing recombinant HBV surface antigen (HBs). We assessed antibody persistence and immune memory in children 4-5 years of age, previously vaccinated with four doses of combined hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix hexa). METHODS: Immune memory was assessed in 301 children through administration of a challenge dose of monovalent HBV vaccine. RESULTS: At 4-5 years of age, 85.3% of subjects had persisting anti-HBs antibody concentrations >or= 10 mIU/mL, rising to 98.6% after the HBV challenge dose. All but 12 subjects (95.8%) achieved post-challenge anti-HBs concentrations >or= 100 mIU/mL. The post-challenge anti-HBs GMC rose by 100-fold compared to pre-challenge concentrations. An anamnestic response to the HBV vaccine challenge was observed in 96.8% of subjects, including 17/21 (81.0%) of children with initially undetectable antibodies (<3.3 mIU/mL). All but 4 of 42 subjects (90.5%) with anti-HBs antibodies <10 mIU/mL prior to the challenge dose, achieved seroprotective levels afterwards. A 4-fold rise in antibody concentration after the challenge dose was observed in 259/264 (98.1%) of initially seropositive subjects. The magnitude of the post-challenge responses was proportional to pre-challenge anti-HBs levels. No serious adverse events were reported during the study. CONCLUSION: The combined DTPa-HBV-IPV/Hib vaccine induced lasting immune memory against hepatitis B. Long term protection afforded by DTPa-HBV-IPV/Hib is likely to be similar to that observed following priming with monovalent HBV vaccines. TRIAL REGISTRATION: http://www.clinicaltrials.gov 106789 NCT00411697.

Repeated administration of a reduced-antigen-content diphtheria-tetanus-acellular pertussis and poliomyelitis vaccine (dTpa-IPV; Boostrix™ IPV).

BACKGROUND: The rising incidence of pertussis amongst adults and adolescents in industrialized countries could be reduced by replacing tetanus and diphtheria (Td) boosters with reduced-antigen-content dT-acellular pertussis (dTpa)vaccines. Repeated administration of a dTpa-IPV (dTpa-inactivated poliomyelitis; BoostrixTM Polio, GlaxoSmithKline)booster to adolescents, 5 years after their previous dose was evaluated. RESULTS: Before the second dTpa-IPV booster, the percentage of subjects who were seroprotected/seropositive was: 98.2% (D); 98.5% (T); 40.6% (PT); 99.7% (FHA); 97.0% (PRN); 98.8% (anti-polio 1); 99.7% (anti-polio 2); 97.0% (anti-polio 3). One month after the second dTpa-IPV dose, all subjects were seroprotected against D, T and polio and anti-pertussis booster responses (seroconversion or ≥2-fold increase) were seen in 93.3% (PT), 93.4% (FHA) and 95.2% (PRN) of subjects.During 4-day follow-up, 4.1% subjects recorded grade 3 pain; 4.6% and 3.6% recorded redness or swelling >50 mm, respectively. No serious adverse events were recorded. The incidence of symptoms was not higher than after the previous booster. METHODS: 415 subjects (mean age 11.4 years) who had received either dTpa-IPV or dTpa + IPV at age 4­8 years, all received one dose of dTpa-IPV in this open, phase IV trial. Blood samples were taken before and one-month post-vaccination. Antibody concentrations against D, T, pertussis toxoid (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and polio antigens were determined. Reactogenicity and safety was assessed. CONCLUSIONS: A second dTpa-IPV booster was highly immunogenic and well tolerated in this population of adolescents, supporting the repeated administration of BoostrixTM Polio. This study is registered at www.clinicaltrials.gov NCT00635128.

Persistence of vaccine-elicited immune response up to 14 years post-HIV gp120-NefTat/AS01B vaccination.

BACKGROUND: Vaccines eliciting protective and persistent immune responses against multiple human immunodeficiency virus type 1 (HIV-1) clades are needed. This study evaluated the persistence of immune responses induced by an investigational, AS01-adjuvanted HIV-1 vaccine as long as 14 years after vaccination. METHODS: This phase I, open-label, descriptive, mono-centric, extension study with a single group (NCT03368053) was conducted in adults who received ≥3 doses of the clade B gp120-NefTat/AS01B vaccine candidate 14 years earlier in a previous clinical trial (NCT00434512). Binding responses of serum antibodies targeting a panel of envelope glycoproteins, including gp120, gp140 and V1V2-scaffold antigens and representative of the antigenic diversity of HIV-1, were measured by binding antibody multiplex assay (BAMA). The gp120-specific CD4+/CD8+ T-cell responses were assessed by intracellular cytokine staining assay. RESULTS: At Year 14, positive IgG binding antibody responses were detected in 15 out of the 16 antigens from the BAMA V1V2 breadth panel, with positive response rates ranging from 7.1% to 60.7%. The highest response rates were observed for clade B strain V1V2 antigens, with some level of binding antibodies against clade C strains. Anti-V1V2 IgG3 response magnitude breadth, which correlated with decreased risk of infection in a previous efficacy trial, was of limited amplitude. Response rates to the antigens from the gp120 and gp140 breadth panels ranged from 7.7% to 94.1% and from 15.4% to 96.2% at Year 14, respectively. Following stimulation with gp120 peptide pool, highly polyfunctional gp120-specific CD4+ T-cells persisted up to Year 14, with high frequencies of CD40L tumor necrosis factor alpha (TNF-α), CD40L interleukin-2 (IL-2), CD40L TNF-α IL-2 and CD40L interferon gamma (IFN-γ) TNF-α IL-2 CD4+ T-cells, but no CD8+ T-cells detected. CONCLUSIONS: Persistent antibodies binding to HIV-1 envelope glycoproteins, including the V1V2-scaffold, and gp120-specific cellular immunity were observed in volunteers vaccinated 14 years earlier with the gp120-NefTat/AS01B vaccine candidate.

Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

OBJECTIVES: To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01E) candidate tuberculosis (TB) vaccine up to 3 years post-dose 2 (Y3) in human immunodeficiency virus (HIV)-positive (HIV+) and HIV-negative (HIV-) Indian adults. METHODS: This phase II, double-blind, randomised, controlled clinical trial (NCT01262976) was conducted at YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015.Three cohorts (HIV+ participants stable on antiretroviral therapy [ART; HIV+ART+], HIV+ ART-naïve [HIV+ART-], and HIV- participants) were randomised (1:1) to receive 2 doses of M72/AS01E (M72/AS01E groups) or saline (control groups) 1 month apart and were followed up toY3. Latent TB infection was assessed at screening using an interferon-gamma (IFN-γ) release assay (IGRA). Safety and immunogenicity results up to Y1 post-vaccination were reported elsewhere. Here, we report serious adverse events (SAEs), humoral and cell-mediated immune (CMI) responses to M72 recorded at Y2 and Y3. RESULTS: Of 240 enrolled and vaccinated participants, 214 completed the long-term follow-up part of the study.In addition to SAEs previously described, between Y1 and Y2 1 M72/AS01E recipient in the HIV+ART+ cohort reported 2 SAEs (sinus cavernous thrombosis and gastroenteritis) that were not considered as causally related to the study vaccine.Vaccination elicited persistent humoral immune responses against M72. At Y3, seropositivity rates were 97.1%, 66.7%, and 97.3% and geometric mean concentrations (GMCs) were 22.0  ELISA units (EU)/mL, 4.9 EU/mL, and 24.3 EU/mL in the HIV+ART+, HIV+ART-, and HIV- cohorts, respectively. Humoral immune response was lowest in the HIV+ART- cohort.In M72/AS01E recipients, no notable decrease in the frequency of M72-specific CD4 T-cells expressing ≥2 immune markers among interleukin-2 (IL-2), IFN-γ, tumour necrosis factor alpha (TNF-α) and CD40 ligand (CD40L) was observed at Y3 post-vaccination. Median values (interquartile range) of 0.35% (0.13-0.49), 0.05% (0.01-0.10), and 0.15% (0.09-0.22) were recorded in the HIV+ART+, HIV+ART- and HIV- cohorts, respectively. CD4 T-cell response was lowest in the HIV+ART- cohort.No CD8 T-cell response was observed. CONCLUSION: The cellular and humoral immune responses induced by M72/AS01E in HIV+ and HIV- adults persisted up to Y3 post-vaccination. No safety concerns were raised regarding administration of M72/AS01E to HIV+ adults. CLINICAL TRIAL REGISTRATION: NCT01262976 (www.clinicaltrials.gov).

Persistence of antibodies 20 y after vaccination with a combined hepatitis A and B vaccine.

Vaccination is the most effective and well-tolerated method of conferring long-term protection against hepatitis A and B viruses (HAV; HBV). Long-term studies are required to characterize the duration of protection and need for boosters. Following primary immunization of 150 and 157 healthy adults with 3-doses of combined hepatitis A/hepatitis B vaccine (HAB; Twinrix™, GSK Vaccines, Belgium) at 0-1-6 months in 2 separate studies, we measured vaccine-induced antibody persistence against HAV and HBV annually for 20 y (Study A: NCT01000324; Study B: NCT01037114). Subjects with circulating anti-HAV antibodies < 15 mIU/mL or with anti-hepatitis B surface antigen < 10 mIU/mL were offered an additional monovalent hepatitis A and/or B vaccine dose (Havrix™/Engerix™-B, GSK Vaccines, Belgium). Applying the immunogenicity results from these studies, mathematical modeling predicted long-term persistence. After 20 y, 18 and 25 subjects in studies A and B, respectively, comprised the long-term according-to-protocol cohort for immunogenicity; 100% and 96.0% retained anti-HAV antibodies ≥ 15 mIU/mL, respectively; 94.4% and 92.0% had anti-HBs antibodies ≥ 10 mIU/mL, respectively. Between Years 16-20, 4 subjects who received a challenge dose of monovalent hepatitis A vaccine (N = 2) or hepatitis B vaccine (N = 2), all mounted a strong anamnestic response suggestive of immune memory despite low antibody levels. Mathematical modeling predicts that 40 y after vaccination ≥ 97% vaccinees will maintain anti-HAV ≥ 15 mIU/mL and ≥ 50% vaccinees will retain anti-HBs ≥ 10 mIU/mL. Immunogenicity data confirm that primary immunization with 3-doses of HAB induces persisting anti-HAV and anti-HBs specific antibodies in most adults for up to 20 y; mathematical modeling predicts even longer-term protection.

Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib in Indian infants.

Multivalent combination vaccines have reduced the number of injections and therefore improved vaccine acceptance, timeliness of administration and global coverage. The hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib; Infanrix hexa™) vaccine, administered according to various schedules, is widely used for the primary vaccination of infants worldwide. In the current publication, we are presenting the immunogenicity and safety of 3 doses of DTPa-HBV-IPV/Hib vaccine when administered to Indian infants. 224 healthy infants (mean age 6.8 weeks) were vaccinated at 6-10-14 weeks (W) of age (n = 112) or 2-4-6 months (M) of age (n = 112). One month after the third vaccine dose, the seroprotection/seropositivity status against diphtheria, pertussis, tetanus, polio, hepatitis B and Hib antigens ranged from 98.6% to 100% in both groups. The vaccine response rate to the pertussis antigens ranged from 97% to 100%. Pain (6-10-14W group: 25.2%; 2-4-6M group: 13.4%) and fever (15.3% and; 15.2%, respectively) were the most frequently reported solicited local and general symptoms. Unsolicited adverse events were reported for 35.7% (6-10-14W group) and 22.3% (2-4-6M group) of subjects. No vaccine related serious adverse events were reported. In conclusion, the hexavalent DTPa-HBV-IPV/Hib vaccine was immunogenic and well tolerated, irrespective of the dosing schedule.

Safety, immunogenicity and persistence of immune response to the combined diphtheria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b conjugate vaccine (DTPa-IPV/Hib) administered in Chinese infants.

We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile.

Immunity to hepatitis B persists in adolescents 15-16 years of age vaccinated in infancy with three doses of hepatitis B vaccine.

OBJECTIVE: Vaccination of infants against hepatitis B virus (HBV) using hepatitis B vaccine is effective in preventing the infection during early childhood and there is a growing evidence of long-term protection. So far, no need for a booster dose has been identified in healthy subjects; however further follow-up continues to determine the exact duration of protection. We evaluated antibody persistence and immune response to a hepatitis B vaccine challenge dose in children aged 15-16 years, previously vaccinated with 3-doses of the same vaccine in infancy (third dose received before 18 months of age). METHODS: A single hepatitis B vaccine challenge dose containing 10µg hepatitis B surface (HBs) antigen was administered to adolescents aged 15-16 years. Blood samples were taken before and one month after the challenge dose to measure anti-HBs antibodies using a chemiluminescence immunoassay. Solicited local and general symptoms, as well as unsolicited and serious adverse events were recorded after the challenge dose. RESULTS: 303 subjects were enrolled, of whom 302 and 293 subjects formed the total vaccinated and according-to-protocol cohorts, respectively. Pre-challenge, 65.4% (95% CI: 59.6-70.9) subjects were seroprotected (anti-HBs antibody concentration ≥10mIU/mL). One month post-challenge, 97.9% (95% CI: 95.6-99.2) were seroprotected, while 90.8% (95% CI: 86.8-93.8) had anti-HBs antibody concentrations ≥100mIU/mL. The post-challenge geometric mean concentration (GMC; 4134.9 [95% CI: 3114.2-5490.1]) was 150-fold higher than the pre-challenge GMC. Overall, 96.9% (95% CI: 94.2-98.6) subjects mounted an anamnestic response. The safety and reactogenicity profile of the hepatitis B vaccine challenge dose was consistent with previous experience. CONCLUSIONS: Immunity to hepatitis B persists in 15-16 year old adolescents following primary vaccination in infancy. TRIAL REGISTRATION: http://www.clinicaltrials.govNCT01847430.