Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study.

BACKGROUND: This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B. METHODS: In this first-in-human, phase 1, observer-blind study, subjects aged 18-45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50-70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose. RESULTS: Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation. CONCLUSIONS: The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile. CLINICAL TRIAL REGISTRATION: NCT04026009.

Bacterial infection with Clostridioides difficile can be severe or life threatening. A vaccine candidate to prevent C. difficile infection is being developed, containing a protein (F2 antigen) that stimulates the immune system to neutralize 2 C. difficile toxins. This is the first study investigating this vaccine candidate in people. Healthy people aged 18­45 years were given 2 doses of placebo or F2 antigen. People aged 50­70 years were given 2 doses of placebo, F2 antigen, or F2 antigen with an additional component (adjuvant) that helps stimulate the immune response. Some also received a third dose of F2 antigen or F2 antigen with adjuvant. The vaccine candidate was well tolerated with an acceptable safety profile. Injection site pain, tiredness, and headache were the most common side effects. The effects were mostly mild to moderate and transient, and were more frequently reported in the adjuvanted group, as expected. No serious safety events were considered related to the vaccine candidate. The vaccine candidate induced neutralization activity against both toxins, especially when given with adjuvant. In people with no measurable neutralization activity at the study start, a third dose increased the response. These findings offer potentially valuable insights for C. difficile vaccine development.

Safety and Immunogenicity of a Second Dose of an Investigational Maternal Trivalent Group B Streptococcus Vaccine in Nonpregnant Women 4-6 Years After a First Dose: Results From a Phase 2 Trial.

BACKGROUND: Maternal immunization against group B streptococcus (GBS) could protect infants from invasive GBS disease. Additional doses in subsequent pregnancies may be needed. We evaluated the safety and immunogenicity of a second dose of an investigational trivalent CRM197-glycoconjugate GBS vaccine (targeting serotypes Ia/Ib/III), administered to nonpregnant women 4-6 years postdose 1. METHODS: Healthy women either previously vaccinated with 1 dose of trivalent GBS vaccine 4-6 years before enrollment (n = 53) or never GBS vaccinated (n = 27) received a single trivalent GBS vaccine injection. Adverse events (AEs) were recorded. Serotype-specific (Ia/Ib/III) anti-GBS antibodies were measured by multiplex immunoassay prevaccination and 30/60 days postvaccination. RESULTS: AEs were reported with similar rates after a first or second dose; none were serious. Of previously GBS-vaccinated women, 92%-98% had anti-GBS concentrations that exceeded an arbitrary threshold (8 µg/mL) for each serotype 60 days postdose 2 vs 36%-56% postdose 1 in previously non-GBS-vaccinated women. Of previously GBS-vaccinated women with undetectable baseline (predose 1) anti-GBS levels, 90%-98% reached this threshold postdose 2. For each serotype, anti-GBS geometric mean concentrations (GMCs) 30/60 days postdose 2 in previously GBS-vaccinated women were ≥200-fold higher than baseline GMCs. Among women with undetectable baseline anti-GBS levels, postdose 2 GMCs in previously GBS-vaccinated women exceeded postdose 1 GMCs in previously non-GBS-vaccinated women (≥7-fold). CONCLUSIONS: A second trivalent GBS vaccine dose administered 4-6 years postdose 1 was immunogenic with a favorable safety profile. Women with undetectable preexisting anti-GBS concentrations may benefit from a sufficiently spaced second vaccine dose. CLINICAL TRIALS REGISTRATION: NCT02690181.

Safety and Immunogenicity of a Carbohydrate Fatty Acid Monosulphate Ester Adjuvant Combined with a Low-Dose Quadrivalent Split-Virion Inactivated Influenza Vaccine: A Randomised, Observer-Blind, Active-Controlled, First-in-Human, Phase 1 Study.

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.

Safety and immunogenicity of the live-attenuated hRVFV-4s vaccine against Rift Valley fever in healthy adults: a dose-escalation, placebo-controlled, first-in-human, phase 1 randomised clinical trial.

BACKGROUND: Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans. METHODS: A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00. FINDINGS: Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months. INTERPRETATION: The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use. FUNDING: The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.

Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: OVX836, a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1) and the oligomerisation domain OVX313, has displayed a good safety profile and elicited dose-dependent humoral and cellular immune responses at 90 µg or 180 µg (intramuscularly) in previous clinical trials. The aim of this study was to explore higher doses, since no maximum tolerated dose had been reached. METHODS: In this phase 2a, randomised, double-blind, placebo-controlled study, we recruited 137 healthy adults aged 18-55 years in a single centre in Belgium. Participants were randomly assigned (interactive web response system; block size=4) using SAS (version 9.4) to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 µg [n=33], 300 µg [n=35], and 480 µg [n=36]) or placebo (n=33). The two primary endpoints were the safety and the cell-mediated immune response to OVX836 at the three doses in terms of change of nucleoprotein-specific IFNγ spot forming cell (SFC) frequencies in the peripheral blood mononuclear cell (PBMC) population, measured by IFNγ ELISpot, at day 8 versus pre-injection baseline (day 1). The population used for the safety analysis is the modified intention-to-treat cohort. The population used for the immunogenicity analysis is the per-protocol cohort. This trial is registered with ClinicalTrials.gov, NCT05060887, and EudraCT, 2021-002535-39. FINDINGS: Participants were recruited between Nov 15, 2021, and Feb 1, 2022. OVX836 had a favourable safety profile up to 480 µg without reaching the maximum tolerated dose, and showed a good safety profile at all doses with mild local and systemic reactogenicity. 7 days after vaccination, although no significant differences were observed between the doses, OVX836 increased the frequency of nucleoprotein-specific IFNγ SFCs per million PBMCs from days 1 to 8 (primary endpoint): by 124 SFCs per 106 PMBCs (95% CI 67 to 180; p=0·002) at 180 µg; by 202 SFCs per 106 PMBCs (95% CI 138 to 267; p<0·0001) at 300 µg; by 223 SFCs per 106 PMBCs (95% CI 147 to 299; p<0·0001) at 480 µg; and decreased by 1 SFCs per 106 PMBCs (95% CI -24 to 22] in the placebo group (Kruskal-Wallis test p<0·0001 followed by Mann-Whitney's tests; per-protocol cohort). Dose-dependent and polyfunctional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 µg and 480 µg (secondary endpoints). INTERPRETATION: OVX836 appears to be a safe and well tolerated candidate vaccine that elicits humoral and cellular nucleoprotein-specific immune responses (including CD8 T cells at the highest dose levels) and showed a preliminary signal of protection against influenza. Therefore, OVX836 is a promising vaccine candidate for universal influenza A prevention, that warrants further trials. FUNDING: OSIVAX, Bpifrance, Wallonia Region, and the EUs Horizon 2020 Research and Innovation Program.

Randomized, Double-Blind, Reference-Controlled, Phase 2a Study Evaluating the Immunogenicity and Safety of OVX836, A Nucleoprotein-Based Influenza Vaccine.

OVX836 is a recombinant protein-based vaccine targeting the highly conserved influenza nucleoprotein (NP), which aims to confer a broad-spectrum protection against influenza. In a Phase 1 study, OVX836, administered intramuscularly, has been found safe and immunogenic. The 90µg and 180µg dose levels were selected to be further evaluated in this randomized, monocenter, reference-controlled (Influvac Tetra™: quadrivalent seasonal influenza subunit vaccine), parallel group, double-blind, Phase 2a study in 300 healthy volunteers, aged 18-65 years, during the 2019/2020 flu season. Safety, influenza-like illness episodes (ILI; based on the Flu-PRO® questionnaire) and immunogenicity were assessed up to 180 days post-vaccination. OVX836 was safe and presented a reactogenicity profile similar to Influvac Tetra. It induced a significant increase in terms of NP-specific interferon-gamma (IFNγ) spot forming cells (SFCs), NP-specific CD4+ T-cells (essentially polyfunctional cells) and anti-NP IgG responses. OVX836 was superior to Influvac Tetra for all immunological parameters related to NP, and the 180µg dose was significantly superior to the 90µg dose for SFCs and CD4+ T-cells expressing IFNγ. Both the CD4+ T-cell and the anti-NP IgG responses persisted up to Day 180. An efficacy signal was observed with OVX836 at 180µg through reduction of ILI episodes occurring during the flu season as of 14 days post-vaccination. In conclusion, these results encourage further clinical evaluation of OVX836 in order to confirm the signal of efficacy on ILIs and/or laboratory-confirmed influenza cases. NCT04192500 (https://clinicaltrials.gov/ct2/show/study/NCT04192500).

Safety and immunogenicity of a respiratory syncytial virus fusion glycoprotein F subunit vaccine in healthy adults: Results of a phase 1, randomized, observer-blind, controlled, dosage-escalation study.

INTRODUCTION: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants. An investigational vaccine using an engineered recombinant RSV fusion glycoprotein in its post-fusion conformation (RSV F subunit vaccine) has been developed to protect young infants via maternal immunization. This first-in-human, phase I, observer-blind study (NCT02298179) evaluated the safety and immunogenicity of different dosages and formulations of RSV F subunit vaccine in healthy non-pregnant women and men aged 18-45 years. METHODS: Participants were enrolled (1:1:1) in a stepwise dosage-escalation manner into three cohorts to receive RSV F subunit vaccine containing 45 µg, 90 µg and 135 µg of RSV F glycoprotein. Within each cohort, participants were randomized (1:1:1:1) to receive two doses of RSV F subunit vaccine with (aluminum hydroxide or MF59) or without adjuvant, or placebo, ≥28 days apart. Safety (until day 365 post-dose 2), anti-RSV neutralizing antibodies (NAbs) and serum total binding antibodies to RSV F protein (until day 181 post-dose 1) were evaluated. RESULTS: All formulations were well-tolerated. No vaccine-related serious adverse events were reported. All participants were seropositive for anti-RSV NAbs at baseline, with geometric mean titers (GMTs) ranging from 184 (95% confidence interval [CI]: 127-266) to 380 (95% CI: 272-531). At 28 days post-dose 1, anti-RSV NAb GMTs in vaccine recipients ranged from 893 (95% CI: 702-1,136) to 1,602 (95% CI: 1,243-2,064). No booster effect was observed, but immune responses were maintained above pre-vaccination levels for six months post-dose 1. Ratios of RSV F total binding antibodies fold changes to NAb fold changes ranged from 2.79 to 4.12 at 28 days post-dose 1. The impact of the adjuvant was limited. CONCLUSIONS: A single dose of each formulation of RSV subunit F vaccine was well-tolerated and enhanced preexisting NAb titers through six months of follow-up.

A randomized, observer-blind Phase Ib study to identify formulations and vaccine schedules of a trivalent Group B Streptococcus vaccine for use in non-pregnant and pregnant women.

BACKGROUND: Group B streptococcus (GBS) is a leading cause of sepsis and meningitis in early infancy. Substantial data demonstrate that women with higher levels of circulating antibody against the capsular polysaccharide (CPS) deliver infants at reduced risk of GBS infection, which serves as the basis for vaccine design. This study evaluates two different dosages, two injection schedules and three formulations of an investigational trivalent (serotypes Ia, Ib and III) CRM197-glycoconjugate GBS vaccine in healthy, non-pregnant women. METHODS: 678 healthy non-pregnant women received one or two injections of one of two dosages (5/5/5 µg or 20/20/20 µg) of the investigational vaccine, formulated with or without aluminum hydroxide (Enrollment Group 1), or with full or half dosages of MF59(®) (Enrollment Group 2); or a placebo (Enrollment Groups 1 and 2). Geometric mean serotype-specific antibody concentrations (GMCs) at Days 61 (Enrollment Group 1) and 361 (both Groups) were analyzed to select a formulation suitable for pregnant or non-pregnant women, respectively. Solicited adverse reactions were recorded up to Day 7 and adverse events (AEs) were recorded throughout the study. RESULTS: Rates of reported AEs were similar across all groups. Higher rates of local reactogenicity were seen in adjuvanted vaccine groups compared with non-adjuvanted vaccine (or placebo) groups. All vaccine groups elicited higher GMCs than placebo; differences between treatments were not statistically significant, indicating no additional potential benefit of higher antigen content, addition of adjuvant, or a second dose. CONCLUSIONS: All GBS vaccine formulations induced a persistent antibody response and showed similar immunogenicity profiles (NCT01150123).

Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: a phase I/II randomized clinical study.

BACKGROUND: New vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults. METHODS: In a phase I double-blind study (www.clinicaltrials.gov: NCT00707798), healthy adults (18-40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23™, Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30 µg), or both dPly and PhtD (10 or 30 µg each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30 µg each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5-9 months after primary vaccination. RESULTS: Of 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, ≤ 8.9% of doses were followed by grade 3 solicited local or general adverse events. No fever >39.5°C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following ≤ 33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides. CONCLUSION: Investigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates.

Improved CD4⁺ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial.

BACKGROUND: The Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 µg of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 µg dose), M72 in saline (40 µg dose) and AS01 alone. METHODS: In this Phase I/II observer-blind controlled trial, 110 participants were randomized (4:4:1:1:1) to receive M72/AS01, M72/AS02, Mtb72F/AS02, M72/saline or AS01, following a 0, 1-month schedule. Subjects receiving the adjuvanted M72 vaccines were followed up until 3 years post vaccination. Evaluation of the immune response and safety/reactogenicity was performed. RESULTS: For all vaccines, solicited adverse events (AEs) were predominantly mild to moderate and transient. No vaccine-related serious AEs occurred and no subject withdrew due to an AE. Immune responses induced by Mtb72F and M72 antigens combined with AS02 were similar. M72/AS01 and M72/AS02 induced robust polyfunctional M72-specific CD4(+) T cell and antibody responses persisting at 3 years, with the highest CD4(+) T cell responses found with M72/AS01. CONCLUSION: This first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.

Randomized trial of the immunogenicity and safety of the Hepatitis B vaccine given in an accelerated schedule coadministered with the human papillomavirus type 16/18 AS04-adjuvanted cervical cancer vaccine.

The human papillomavirus type 16/18 (HPV-16/18) AS04-adjuvanted cervical cancer vaccine is licensed for females aged 10 years and above and is therefore likely to be coadministered with other licensed vaccines, such as hepatitis B. In this randomized, open-label study, we compared the immunogenicity of the hepatitis B vaccine administered alone (HepB group) or with the HPV-16/18 AS04-adjuvanted vaccine (HepB+HPV group) in healthy women aged 20 to 25 years (clinical trial NCT00637195). The hepatitis B vaccine was given at 0, 1, 2, and 12 months (an accelerated schedule which may be required by women at high risk), and the HPV-16/18 vaccine was given at 0, 1, and 6 months. One month after the third dose of hepatitis B vaccine, in the according-to-protocol cohort (n = 72 HepB+HPV; n = 76 HepB), hepatitis B seroprotection rates (titer of ≥10 mIU/ml) were 96.4% (95% confidence interval [CI], 87.5 to 99.6) and 96.9% (CI, 89.2 to 99.6) in the HepB+HPV and HepB groups, respectively, in women initially seronegative for anti-hepatitis B surface antigen (HBs) and anti-hepatitis B core antigen (HBc). Corresponding geometric mean titers of anti-HBs antibodies were 60.2 mIU/ml (CI, 40.0 to 90.5) and 71.3 mIU/ml (CI, 53.9 to 94.3). Anti-HBs antibody titers rose substantially after the fourth dose of hepatitis B vaccine. All women initially seronegative for anti-HPV-16 and anti-HPV-18 antibodies seroconverted after the second HPV-16/18 vaccine dose and remained seropositive up to 1 month after the third dose. Both vaccines were generally well tolerated, with no difference in reactogenicity between groups. In conclusion, coadministration of the HPV-16/18 AS04-adjuvanted vaccine did not affect the immunogenicity or safety of the hepatitis B vaccine administered in an accelerated schedule in young women.

Effect on cellular and humoral immune responses of the AS03 adjuvant system in an A/H1N1/2009 influenza virus vaccine administered to adults during two randomized controlled trials.

The influence of AS03(A), a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03(A)-adjuvanted H1N1 vaccine containing 3.75 µg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 µg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03(A)-adjuvanted vaccine (3.75 µg HA) or nonadjuvanted vaccine (15 µg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥ 40). A lower response following 3.75 µg HA without adjuvant was observed (73% with titers of ≥ 40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03(A)-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 µg HA and 150 for 3.75 µg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4⁺ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4⁺ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4⁺ T-cell frequencies and day 42 HI titers. AS03(A) adjuvant enhanced the humoral and CD4⁺ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4⁺ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4⁺ T-cell frequencies and post-dose 2 antibody responses.

Priming with AS03 A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: an open non-randomised extension of a double-blind randomised primary study.

An influenza vaccine with cross-immunogenic potential could play a key role in pandemic mitigation by promoting a rapid immune response to infection and/or subsequent vaccination with strains drifted from the primary vaccine strain. Here we assess the role of AS03(A) (an oil-in-water emulsion based Adjuvant System containing tocopherol) in this prime-boost concept using H5N1 as a model shift influenza antigen. In this open, non-randomised study (NCT00506350; an extension of an earlier randomised study) we assessed immunogenicity in nine groups of 35-50 volunteers aged 19-61 years following administration of AS03(A)-adjuvanted split-virion H5N1 vaccine containing 3.75mug of haemagglutinin (HA) from the A/Indonesia/5/2005(IBCDC-RG2) clade 2.1 strain. A single booster dose of vaccine was administered to four groups primed 14 months previously with different HA levels of AS03(A)-adjuvanted clade 1 A/Vietnam/1194/2004 H5N1 vaccine. Two booster doses (given 21 days apart) were administered to four groups primed 14 months previously with different HA levels of non-adjuvanted A/Vietnam/1194/2004 H5N1 vaccine and also to a control group of un-primed subjects. In individuals primed 14 months earlier with AS03(A)-adjuvanted A/Vietnam/1194/2004 vaccines, a single booster dose of AS03(A)-adjuvanted A/Indonesia/5/2005 induced rapid immune responses (licensure criteria met in 7-14 days) comparable to that observed in the un-primed control group following two doses of adjuvanted vaccine. In contrast, individuals primed with non-adjuvanted formulations exhibited minimal immune responses which, even after two doses, were unexpectedly much lower than that observed in un-primed subjects. AS03(A) enhances the initial priming effect of pandemic influenza vaccination enabling a rapid humoral response to single dose boosting with a heterologous strain at 14 months. In contrast, priming without adjuvant appears to inhibit the response to subsequent vaccination with a heterologous strain. These findings should guide the development of vaccines to combat the present influenza A/H1N1 pandemic.