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In this report regarding an MF59-adjuvanted 2009 H1N1 monovalent vaccine, significant immune responses were elicited by the administration of one or two doses of vaccine (with or without the MF59 adjuvant) in most subjects within 2 to 3 weeks. Higher titers were seen in subjects who received the MF59-adjuvanted vaccine. In this report regarding a monovalent MF59-adjuvanted 2009 H1N1 vaccine, significant immune responses were elicited by the administration of one or two doses of vaccine (with or without the MF59 adjuvant) in most subjects within 2 to 3 weeks. Higher titers were seen in subjects who received the MF59-adjuvanted vaccine. The emergence of the 2009 pandemic influenza A (H1N1) virus demonstrates the unpredictable nature of influenza. 1 The virus has the potential to cause disease, death, and socioeconomic disruption, 2 , 3 and modeling suggests that the effect of the virus can be reduced by immunization. 4 The development of effective vaccines is a public health priority. Traditional seasonal influenza vaccines are produced from reassortant vaccine strains grown in hens' eggs. However, demand for vaccine against the 2009 H1N1 virus will most likely exceed the supply if this method of manufacturing is solely used. Cell culture provides an additional platform for the manufacture of . . .

Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 μg dose (geometric mean titre [GMT] 6400, 95% CI 3683–11 122), with 15 μg dose (7492, 4959–11 319), and the two 45 μg dose cohorts (8770, 5526–13 920 in the two-dose 45 μg cohort; 8793, 5570–13 881 in the single-dose 45 μg cohort); 4 weeks after the second dose (day 57) with two 5 μg doses (102 400, 64 857–161 676), with two 15 μg doses (74 725, 51 300–108 847), with two 45 μg doses (79 586, 55 430–114 268), only a single 45 μg dose (4795, 2858–8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 μg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 μg doses (GMT 228, 95% CI 146–356), two 15 μg doses (230, 170–312), and two 45 μg doses (239, 187–307). This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.

The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients.

Over two influenza seasons, 4707 children were randomly assigned to either control (noninfluenza) vaccines or trivalent influenza vaccines with or without adjuvant MF59. The vaccine with MF59 proved efficacious in this vulnerable population. Children have the highest rates of seasonal influenza infection and illness, with amplification of community viral transmission. Thus, numerous countries recommend routine seasonal vaccination to protect children directly and the entire population indirectly. 1 – 9 Parenteral trivalent inactivated influenza vaccine (TIV) is poorly immunogenic in young children, with an efficacy of only 59.0% in children older than 2 years of age. 10 – 12 Although intranasal live attenuated influenza vaccine has an efficacy of 69.2 to 95.6% in children 2 to 7 years of age, it cannot be used in children under 2 years of age because of the increased risk of hospitalization . . .

We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. We did a randomised trial in 15 countries worldwide during the 2008–09 (year 1) and 2009–10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65–74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12–1·43] of 21 573 vs 310 [1·44%, 1·29–1·61] of 21 482; relative efficacy 12·11%, 95% CI −3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91–1·18] vs 270 [1·26, 1·11–1·41]; relative efficacy 17·53%, 95% CI 1·55–30·92) and influenza A H3N2 (170 [0·79, 0·67–0·92] vs 205 [0·95, 0·83–1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68–35·49). AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. GlaxoSmithKline Biologicals SA.

The annual influenza vaccine is recommended for hematopoietic stem cell transplant (HSCT) patients although studies have shown suboptimal immunogenicity. Influenza vaccine containing an oil-in-water emulsion adjuvant (MF59) may lead to greater immunogenicity in HSCT recipients. We randomized adult allogeneic HSCT patients to receive the 2015–2016 influenza vaccine with or without MF59 adjuvant. Preimmunization and 4-week post-immunization sera underwent strain-specific hemagglutination inhibition assay. We randomized 73 patients and 67 (35 adjuvanted; 32 non-adjuvanted) had paired samples available at follow-up. Median age was 54 years (range 22–74) and time from transplant was 380 days (range 85–8107). Concurrent graft-versus-host disease was seen in 42/73 (57.5%). Geometric mean titers increased significantly after vaccination in both groups. Seroconversion to at least one of three influenza antigens was present in 62.9% vs 53.1% in adjuvanted vs non-adjuvanted vaccine ( P =0.42). Factors associated with lower seroconversion rates were use of calcineurin inhibitors ( P <0.001) and shorter duration from transplantation ( P =0.001). Seroconversion rates were greater in patients who got previous year influenza vaccination (82.6% vs 45.5%, P =0.03). Adjuvanted vaccine demonstrated similar immunogenicity to non-adjuvanted vaccine in the HSCT population and may be an option for some patients.

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom.Design Open label, randomised, parallel group, phase II study.Setting Five UK centres (Oxford, Southampton, Bristol, Exeter, and London).Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis.Interventions Participants were randomised 1:1 to receive AS03B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose.Main outcome measures Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose).Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38ºC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001).Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group.Trial registration Clinical trials.gov NCT00980850; ISRCTN89141709.

A human cytomegalovirus (HCMV) vaccine is urgently needed to protect against primary infection and enhance existing immunity in HCMV-infected individuals (HCMV⁺). Using sera from HCMV⁺ glycoprotein B/MF59 vaccine recipients prior to transplant, we investigated the composition of the immune response. Vaccination boosted preexisting humoral responses in our HCMV⁺ cohort but did not promote de novo responses against novel linear epitopes. This suggests that prior natural infection has a profound effect on shaping the antibody repertoire and subsequent response to vaccination (“original antigenic sin”). Thus, vaccination of HCMV⁺ may require strategies of epitope presentation distinct from those intended to prevent primary infection.

•aQIV-associated GMTs and seroconversion rates are noninferior to those of aTIV.•aQIV immunogenicity is superior for B strains not included in aTIV.•aQIV was well tolerated in adults aged ≥65 years.•aQIV is suitable for vaccination of adults aged ≥65 years. Evaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65 years. In a multicenter, double-blind, randomized controlled trial, adults ≥65 years were randomized 2:1:1 to vaccination with aQIV (n = 889), aTIV-1 (n = 445), or aTIV-2 (n = 444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21 days after vaccination for homologous influenza strains. aQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1 = 1.27, A/H3N2 = 1.09, B-Yamagata = 1.08, B-Victoria = 1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1 = 7.76%, A/H3N2 = 4.96%, B-Yamagata = 3.27%, B-Victoria = 2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratio = 0.70, SCR difference = −8.81%; B-Victoria GMT ratio = 0.78, SCR difference = −8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65–74 years, 75–84 years, and ≥85 years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. aQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).

•Highest MF59 dose had greatest influenza vaccine immunogenicity in adults ≥ 65 years.•Increased immunogenicity appeared by Day 8 and persisted to Day 181.•Higher local reactogenicity was observed with the highest dosage of MF59.•Increasing MF59 or HA dosage did not increase unsolicited AEs. To assess the safety and immunogenicity of the MF59®-adjuvanted trivalent influenza vaccine (aTIV; Fluad®) compared with modified aTIV formulations. A total of 196 subjects ≥ 65 years were randomized to receive7different formulations of vaccine containing a range of adjuvant and antigen dosesby single injection, or divided into two injections at a single time point. The primary study objective was to compare the serologic response of different formulations of aTIV containing increased amounts of adjuvant and antigen21 days after vaccination. Subjects were followed for immunogenicity and safety for one year. The highest immune response, as measured by hemagglutination inhibition (HI) assay, 3 weeks after vaccination was observed in subjects in Group 6 with GMT 382.2 (95% confidence interval [CI] 237.5 to 615.0), 552.3 (364.8 to 836.1), and 54.1 (36.9 to 79.4) against A/H1N1, A/H3N2, and B respectively. Rates of seroconversion were also generally highest in this treatment group: 75% (95% CI 55.1 to 89.3), 75% (55.1 to 89.3), and 42.9% (24.5 to 62.8), respectively, against A/H1N1, A/H3N2, and B strains. The highest incidence of solicited adverse events (AEs) was reported by subjects who received both the highest dosage of antigen in combination with the highest dosage of adjuvant at the same site: 67.9% and 57.1% in Groups 4 and 6, respectively. The majority of solicited AEs were mild to moderate in severity. The number of unsolicited AEs was similar across the different dosages. In this phase I trial of adults ≥ 65 years of age who received increased adjuvant and antigen dosages relative to the licensed aTIV, increased dosage of MF59 resulted in increased immunogenicity against all 3 components of seasonal influenza vaccine. The increase in immunogenicity was accompanied by an increase in the incidence of local reactogenicity.