The novel tuberculosis vaccine,AERAS-402, is safe in healthy infants previously vaccinated with BCG,and induces dose-dependent CD4 and CD8T cell responses

Background

Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine.

Methods

In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6–9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity.

Results

Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402.

Conclusions

AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population.     

The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected,BCG-vaccinated adults with CD4+ T cell counts >350 cells/mm3

BackgroundThe safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm³.MethodsSubjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4⁺ and CD8⁺ T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination.Results26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N = 13) or placebo (N = 13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm³, all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS-402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4⁺ T-cell and CD8⁺ T-cell responses to Ag85B. The CD4⁺ T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS-402/AD35.TB-S predominantly induced CD4⁺ T-cells expressing three (IFN-γ, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination.ConclusionAERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4⁺ and CD8⁺ T-cell responses to vaccine.     

Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy,BCG-vaccinated,QuantiFERON®-TB Gold (+) Kenyan adults without evidence of tuberculosis

In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON^®-TB Gold In-Tube test (QFT-G)(−) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(−) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(−) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.     

A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity

Background

Despite the availability of Bacille Calmette Guérin (BCG) vaccines, Mycobacterium tuberculosis currently infects billions of people and millions die annually from tuberculosis (TB) disease. New TB vaccines are urgently needed.

Methods

We studied the ability of AERAS-402, a recombinant, replication-deficient adenovirus type 35 expressing the protective M. tuberculosis antigens Ag85A, Ag85B, and TB10.4, to boost BCG immunity in an area of low TB endemicity.

Results

In volunteers primed with BCG 3 or 6 months prior to AERAS-402 boosting, significant CD4⁺ and CD8⁺ T cell responses were induced. Ag85-specific responses were more strongly boosted than TB10.4-specific responses. Frequencies of TB-specific CD8⁺ T cells reached > 50 fold higher than pre-AERAS boosting levels, remarkably higher than reported in any previous human TB vaccine trial. Multiparameter flow cytometric assays demonstrated that AERAS-402-boosted CD4⁺ and CD8⁺ T cells were multifunctional, producing multiple cytokines and other immune effector molecules. Furthermore, boosted T cells displayed lymphoproliferative capacity, and tetramer analyses confirmed that antigen-specific CD8⁺ T cells were induced. BCG and AERAS-402 vaccinations given 3 and 6 months apart appeared equivalent.

Conclusions

Our results indicate that AERAS-402 is a promising TB vaccine candidate that can significantly enhance both CD4⁺ and CD8⁺ TB-specific T cell responses after BCG priming.ClinicalTrials.gov Identifier: NCT01378312.     

A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen,ChAdOx1 85A prime – MVA85A boost in healthy UK adults

BackgroundThis phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults.MethodsWe enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime – MVA85A boost) or Group C (n = 12; ChAdOx1 85A – ChAdOx1 85A prime – MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17.ResultsAEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A.ConclusionA ChAdOx1 85A prime – MVA85A boost is well tolerated and immunogenic in healthy UK adults.     

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials

BackgroundNovel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant.MethodsBCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150 μg) and adjuvant (0, 100, 500 nmol) doses of the H4:IC31 vaccine (n = 106) or placebo (n = 18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4⁺ T cell responses.ResultsH4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4⁺ T cell proliferation and cytokine production that persisted 18 weeks after the last vaccination. CD4⁺ T cell expansion, IFN-γ production and multifunctional CD4⁺ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50 μg of H4 in combination with the 500 nmol IC31 adjuvant dose.ConclusionsThe novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4⁺ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50 μg of H4 and 500 nmol of IC31.Trial registration: ClinicalTrials.gov, NCT02066428 and NCT02074956.     

Delayed BCG vaccination results in minimal alterations in T cell immunogenicity of acellular pertussis and tetanus immunizations in HIV-exposed infants

BackgroundBacille Calmette–Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, in utero or perinatal HIV infection is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants.MethodsInfants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens.ResultsDelaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p = 0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p = 0.032 and p = 0.0035, respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age.ConclusionDelaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants.Clinical Trial Registry: NCT02062580.     

A novel peptide-based pan-influenza A vaccine: A double blind,randomised clinical trial of immunogenicity and safety

BackgroundFP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population.MethodsFP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n = 49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response.ResultsFP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains.ConclusionsThis first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies.     

Safety,tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised,placebo-controlled phase 1/2 study

BackgroundA prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag.MethodsIn this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64 years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA).ResultsA high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported.ConclusionsSingle-dose vaccination of SA4Ag in healthy adults aged 18–64 years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571     

The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial

BackgroundNew, more effective vaccines to prevent tuberculosis (TB) disease are needed urgently. H4:IC31 is an investigational vaccine that contains a fusion protein of the immunodominant antigens TB10.4 and Ag85B, formulated in IC31^® adjuvant. We assessed the safety and immunogenicity of H4:IC31 in South African adults from a TB endemic setting.MethodsIn this double blind, placebo controlled, phase I trial, Mycobacterium tuberculosis-uninfected, HIV-uninfected, healthy adults with a history of childhood BCG vaccination were randomly allocated to two intramuscular vaccinations with 5, 15, 50 or 150 μg H4 formulated in 500 nmol IC31^®, two months apart. Vaccinees were followed for six months to assess safety; immunogenicity was measured by ELISpot and intracellular cytokine staining assays.ResultsThirty-two participants received H4:IC31 and 8 received placebo. Injection site adverse events were common but mild; mild fatigue was the most common systemic adverse event. Frequencies of adverse events did not differ between dosage groups. Detectable antigen-specific CD4 T cell responses were induced by all doses of H4:IC31, but doses below 50 μg induced the highest frequencies of CD4 T cells, comprised predominantly of IFN-γ⁺TNF-α⁺IL-2⁺ or TNF-α⁺IL-2⁺ cells. These memory responses persisted up to the end of follow up, on study day 182.ConclusionsH4:IC31 demonstrated an acceptable safety profile and was immunogenic in South African adults. In this trial, the 15 μg dose appeared to induce the most optimal immune response.     

H1:IC31 vaccination is safe and induces long-lived TNF-α+IL-2+CD4 T cell responses in M. tuberculosis infected and uninfected adolescents: A randomized trial

BackgroundControl of the tuberculosis epidemic requires a novel vaccine that is effective in preventing tuberculosis in adolescents, a key target population for vaccination against TB.MethodsHealthy adolescents, stratified by M. tuberculosis-infection status, were enrolled into this observer-blinded phase II clinical trial of the protein-subunit vaccine candidate, H1:IC31, comprising a fusion protein (H1) of Ag85B and ESAT-6, formulated with the IC31 adjuvant. Local and systemic adverse events and induced T cell responses were measured after one or two administrations of either 15 μg or 50 μg of the H1 protein.ResultsTwo hundred and forty participants were recruited and followed up for 224 days. No notable safety events were observed regardless of H1 dose or vaccination schedule. H1:IC31 vaccination induced antigen-specific CD4 T cells, co-expressing IFN-γ, TNF-α and/or IL-2. H1:IC31 vaccination of M.tb-uninfected individuals preferentially drove the emergence of Ag85B and ESAT-6 specific TNF-α⁺IL-2⁺CD4 T cells, while H1:IC31 vaccination of M.tb-infected individuals resulted in the expansion of Ag85B-specific but not ESAT-6–specific TNF-α⁺IL-2⁺CD4 T cells.ConclusionsH1:IC31 was safe and immunogenic in uninfected and M.tb-infected adolescents. Two administrations of the 15 μg H1:IC31 dose induced the greatest magnitude immune response, and was considered optimal (South African National Clinical Trials Register, DoH-27-0612-3947; Pan African Clinical Trial Registry, PACTR201403000464306).     

Safety,tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial

BackgroundThe decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18–64 years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM₁₉₇) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted.MethodsIn this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65–85 years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays.ResultsThe results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels.ConclusionsSingle-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65–85 years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85 years. Trial registration number: NCT01643941.     

CD40 ligand enhances immunogenicity of vector-based vaccines in immunocompetent and CD4+ T cell deficient individuals

Impairment of host immunity, particularly CD4+ T cell deficiency, presents significant complications for vaccine immunogenicity and efficacy. CD40 ligand (CD40L or CD154), a member of the tumor necrosis factor superfamily (TNFSF), is an important co-stimulatory molecule and, through interactions with its cognate receptor CD40, plays a pivotal role in the generation of host immune responses. Exploitation of CD40L and its receptor CD40 could provide a means to enhance and potentially restore protective immune responses in CD4+ T cell deficiency. To investigate the potential adjuvanticity of CD40L, we constructed recombinant plasmid DNA and adenoviral (Ad) vaccine vectors expressing murine CD40L and the mycobacterial protein antigen 85B (Ag85B). Co-immunization of mice with CD40L and Ag85B by intranasal or intramuscular prime-boosting led to route-dependent enhancement of the magnitude of vaccine-induced circulating and lung mucosal CD4+ and CD8+ T cell responses in both normal (CD4-replete) and CD4+ T cell deficient animals, including polyfunctional T cell responses. The presence of CD40L alone was insufficient to enhance or restore CD4+ T cell responses in CD4-ablated animals; however, in partially depleted animals, co-immunization with Ag85B and CD40L was capable of eliciting enhanced T cell responses, similar to those observed in normal animals, when compared to those given vaccine antigen alone. In summary, these findings show that CD40L has the capacity to enhance the magnitude of vaccine-induced polyfunctional T cell responses in CD4+ T cell deficient mice, and warrants further study as an adjuvant for immunization against opportunistic pathogens in individuals with CD4+ T cell deficiency.     

The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized,factorial design,placebo-controlled study among Indian infants

BackgroundStrategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function.MethodsInfants 5 weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5 mg), probiotic (10¹⁰ Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10 weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14 weeks of age based on detection of VP6-specific IgA at ≥20 U/ml in previously seronegative infants or a fourfold rise in concentration.ResultsThe study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): −1.4%, 16.2%), p = 0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: −4.4%, 13.2%), p = 0.272). 16 serious adverse events were recorded, none related to study interventions.ConclusionsZinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation.Trial registrationThe trial was registered in India (CTRI/2012/05/002677).     

Safety and immunogenicity of experimental stand-alone trivalent,inactivated Sabin-strain polio vaccine formulations in healthy infants: A randomized,observer-blind,controlled phase 1/2 trial

BackgroundTo increase the global supply of affordable IPV vaccine, preferably using Sabin viruses to comply with GAPIII requirements, Takeda has assessed three dosages of a stand-alone sIPV.MethodsIn this phase I/II study two cohorts of 40 adults and 60 toddlers, respectively, were initially assessed for safety after receiving high-dosage sIPV compared with placebo (adults) or Salk IPV (toddlers). A cohort of 240 infants was then enrolled and randomized (1:1:1:1) to receive low-, medium- or high-dosage sIPV, or a reference Salk IPV in a three-dose primary schedule at 6, 10 and 14 weeks of age. Parents completed safety diaries for 4 weeks after each dose, and immunogenicity was measured as neutralization antibody titers at baseline and four weeks after vaccination.ResultsAll vaccinations were generally well-tolerated and sIPV had a comparable safety profile to the control arm in adults or the reference Salk IPV vaccine in toddlers and infants. Infants displayed dosage-dependent immune responses to sIPV when assayed using Sabin strains, which were equivalent to the reference IPV in the high-dosage sIPV group for serotypes 1 and 2, but not for Sabin and Salk serotype 3. Seroconversion rates (SCR) of the low- and medium-dosage groups were significantly lower than the Salk IPV group for both Sabin and Salk serotypes 1 and type 2 (p < 0.05), with no significant differences for Salk or Sabin serotypes 3. Responses to sIPV, particularly to Sabin types 1 and 2, were higher in initially seronegative infants, indicating possible interference by maternally-derived antibodies.ConclusionsA novel stand-alone Sabin-based IPV vaccine was well tolerated with an acceptable safety profile, but less immunogenic than reference Salk IPV at 6, 10 and 14 weeks of age for Salk serotypes 1 and 2, with apparent interference by maternal antibodies. Additional preclinical assessments will be made before any further clinical development.     

Immunogenicity and protective efficacy of a tuberculosis DNA vaccine expressing a fusion protein of Ag85B-Esat6-HspX in mice

Tuberculosis remains a major infectious disease worldwide due to the low efficacy of available vaccine of the Mycobacterium bovis Bacillus Calmette-Guérin (BCG). DNA vaccines are especially promising candidates; however, the efficacy of DNA vaccine expressing single antigen of Mycobacterium tuberculosis (MTb) is limited. In this study, a plasmid DNA vaccine, pAEH, was constructed and designed to express a fusion protein of the Ag85B, Esat6, and HspX of MTb. Its immunogenicity and protective efficacy as well as therapeutic effect were assessed in a mouse model of tuberculosis. Vaccination with the pAEH significantly increased the frequency of peripheral blood CD4(+) and CD8(+) T cells, but not γδT cells, similar to that of vaccination with the BCG, and induced significantly higher levels of HspX-specific T cell proliferation, as compared with vaccination with BCG or the pHspX. Furthermore, vaccination with the pAEH increased the frequency of Ag85B, Esat6 and HspX-specific IFNγ-secreting T cells, accompanied by significantly higher levels of IFN-γ and IL-2 production ex vivo, as compared with that of the BCG or pHspX-vaccinated mice. Apparently, vaccination with the pAEH induced potent Th1 responses in mice. More importantly, vaccination with the pAEH inhibited the replication of virulent MTb in the lungs and spleens, even after MTb infection, and related lung inflammation in mice. Potentially, the newly developed pAEH vaccine may be used for the prevention and therapeutic intervention of MTb infection.     

Immunogenicity of pentavalent rotavirus vaccine in Chinese infants

BackgroundA phase III, randomized, double-blind, placebo-controlled clinical study was conducted in China to assess the efficacy, safety, and immunogenicity of the pentavalent rotavirus vaccine (RotaTeq^TM, RV5) among Chinese infants. The efficacy and safety data have been previously reported. This report presents the immunogenicity data of the study.Methods4,040 infants aged 6–12 weeks were randomly assigned in a 1:1 ratio to receive 3 oral doses of RV5 or placebo. Trivalent oral poliovirus vaccine (tOPV) and diphtheria, tetanus, and acellular pertussis vaccine (DTaP) were administered in a staggered-use (N = 3,240) or concomitant-use (N = 800) schedule. Immunogenicity of RV5 was evaluated in 800 participants (400 participants from each staggered- and concomitant-use immunogenicity subgroup). Geometric mean titers (GMTs) and seroresponse rates (≥3-fold rise from baseline to PD3) were measured for anti-rotavirus IgA in the staggered- and concomitant-use subgroups and measured for serum neutralizing antibodies (SNAs) to human rotavirus serotypes G1, G2, G3, G4, P1A[8] in the staggered-use subgroup. Immune responses to tOPV and DTaP co-administered with RV5 were also evaluated in the concomitant-use immunogenicity subgroup. (ClinicalTrials.gov registry: NCT02062385)ResultsThe PD3 GMT and seroresponse rate of anti-rotavirus IgA were higher in the RV5 group (82.42 units/mL, 89.4%) compared to the placebo group (0.33 units/mL, 10.1%). Rotavirus type-specific SNA responses were also higher in the RV5 group compared to the placebo group. In the concomitant-use subgroup, the seroprotection rates of anti-poliovirus type 1, 2, 3 in the participants who received RV5 were non-inferior to those who received placebo, and the antibody responses to DTaP antigens were comparable between the two vaccination groups.ConclusionsRV5 was immunogenic in Chinese infants. Immune responses induced by tOPV and DTaP were not affected by the concomitant use of RV5.     

Immunogenicity and safety of MenACWY-TT,a meningococcal conjugate vaccine,co-administered with routine childhood vaccine in healthy infants: A phase III,randomized study

BackgroundInvasive meningococcal disease has a high burden in young children, particularly during infancy. We investigated the immunogenicity and safety of a quadrivalent meningococcal conjugated vaccine (MenACWY-TT) co-administered with routine vaccines in healthy infants.MethodsIn this phase IIIb study (NCT01340898) conducted in 2 centers in Lebanon and Mexico, 750 infants were randomized (2:1:1) to receive MenACWY-TT according to 3 schedules: 3+1 (at ages 2, 4, 6 and 15–18 months; group ACWY3+1); 1+1 (at 6 and 15–18 months; group ACWY1+1) or single-dose at 15–18 months (group ACWY1). All infants received PHiD-CV and DTPa-IPV/Hib at ages 2, 4, 6, 15–18 months. Immune responses to MenACWY-TT were assessed by rSBA and hSBA at 7 months (groups ACWY3+1, ACWY1+1) and pre- and post-vaccination at 15–18 months of age (all groups). Immune responses to co-administered vaccines, reactogenicity and safety were also evaluated.ResultsImmunogenicity of MenACWY-TT at 1 month post-primary vaccination was demonstrated in group ACWY3+1: the lower limit of the 95% confidence interval for the percentage of infants with rSBA titers ≥8 was >80% for each serogroup. At 7 months of age, ≥93.9% of MenACWY-TT-primed infants had rSBA titers ≥8. Post-MenACWY-TT vaccination at age 15–18 months, ≥96.3% of participants in all groups had rSBA titers ≥8, regardless of the number of doses received previously. The percentage of infants with hSBA titers ≥4 were ≥87.2% and ≥89.7% at post-primary and booster/single-dose vaccination, respectively. Immune responses to PHiD-CV and DTPa-IPV/Hib did not seem impacted by co-administration with MenACWY-TT in infancy. The incidence of all adverse events was similar among groups. Serious adverse events were reported for 63/750 children in all groups; none were considered vaccine-related by investigators.ConclusionPrimary vaccination with 3 or 1 dose(s) of MenACWY-TT when co-administered with routine pediatric vaccines in infants is immunogenic and well-tolerated.     

A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants

This study aimed to evaluate the durability of the immunogenicity of MVA85A beyond infancy. Participants in an immunogenicity study of MVA85A administered at age of 4 months had additional evaluation 14 months after initial vaccination for IFN-γ ELISPOT responses to Ag85A peptide and ESAT6/CFP-10 and tuberculin skin test (TST). 112 children participated in this study. The anthropometry, biochemical and haematological safety profile were similar between the MVA85A recipients and controls. MVA85A recipients still had significantly higher immune responses to Ag85A compared to the controls. The majority of these children had negative responses to the TST as well as the ESAT6/CFP-10 antigens. In summary, MVA85A-vaccinated children had a persistently higher Ag85A immune response 14 months following vaccination than controls. All the children had negligible evidence of latent infection with M. tuberculosis (Mtb), suggesting that deploying a prophylactic vaccine against Mtb infection at this age could still be effective in this setting.