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Remarkable potency has been demonstrated for mRNA vaccines in reducing the global burden of the ongoing COVID-19 pandemic. This vaccine platform has been extended to encode an alphavirus replicase that self-amplifies the full length mRNA and SARS-CoV-2 spike (S) transgene (self-amplifying mRNA or sa mRNA). However, early phase clinical trials of sa-mRNA COVID-19 vaccine candidates have questioned the potential of this platform to develop potent vaccines. We examined the immune gene response to a candidate sa-mRNA vaccine against COVID-19, and compared our findings to the host response to other forms of vaccines. In blood samples from healthy volunteers that participated in a phase I/II clinical trial, greater induction of transcripts involved in Toll-like receptor (TLR) signalling, antigen presentation and complement activation at 1 day post-vaccination was associated with higher anti-S antibody titers. Conversely, transcripts involved in T-cell maturation at day 7 post-vaccination informed the magnitude of eventual anti-S T-cell responses. The transcriptomic signature for ARCT-021 vaccination strongly correlated with live viral vector vaccines, adjuvanted vaccines and BNT162b2. Correlation with live attenuated vaccines was weaker. Our findings suggest the potential for sa-mRNA to be further developed to be among the most potent forms of vaccines in our arsenal to prevent infectious diseases.

BackgroundThe pandemic of coronavirus disease-19 (Covid-19) continues to afflict the lives and livelihoods of many as global demand for vaccine supply remains unmet.MethodsPhase 1 of this trial (N=42) assessed the safety, tolerability and immunogenicity of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19. Phase 2 (N=64) tested two-doses of ARCT-021 given 28 days apart. Both young and older adults were enrolled. The primary safety outcomes were local and systemic solicited adverse events (AEs) reported immediately and up to 7 days post-inoculation and unsolicited events reported up to 56 days after inoculation. Secondary and exploratory outcomes were antibody and T cell responses to vaccination, respectively.ResultsARCT-021 was well tolerated up to one 7.5 μg dose and two 5.0 μg doses. Local solicited AEs, namely injection-site pain and tenderness, as well as systemic solicited AEs, such as fatigue, headache and myalgia, were more common in ARCT-021 than placebo recipients, and in younger than older adults. Seroconversion rate for anti-S IgG was 100% in all cohorts except for the 1 μg one-dose in younger adults and the 7.5 μg one-dose in older adults, which were each 80%. Neutralizing antibody titers increased with increasing dose although the responses following 5.0 μg and 7.5 μg ARCT-021 were similar. Anti-S IgG titers overlapped with those in Covid-19 convalescent plasma. ARCT-021 also elicited T-cell responses against the S glycoprotein.ConclusionTaken collectively, the favorable safety and immunogenicity profiles support further clinical development of ARCT-021.

Objective: To assess the long-term safety of MF59-adjuvanted trivalent influenza vaccine (aIIV3; Fluad™) in adults ≥65 years of age. Methods: Data from 36 primary vaccination and 7 re-vaccination Phase I through III trials were analyzed; 7532 subjects received aIIV3 and 5198 subjects a nonadjuvanted trivalent inactivated influenza vaccine (IIV3). These trials were evaluated in 2 data poolings: first-dose randomized controlled trials (FD-RCT) and revaccination trials. Spontaneously reported adverse events (AEs) from post-marketing surveillance were also analyzed. Results: The percentages of subjects reporting AEs following vaccination were similar between aIIV3 and IIV3: 24.8% for aIIV3 vs 26.7% for IIV3 (relative risk [RR] 0.94; 95% confidence interval [CI] 0.87–1.01). The percentage of subjects with serious AEs was 6.7% for aIIV3 vs 7.0% for IIV3 (RR 0.95; 95% CI 0.82–1.09). Percentages of subjects with AEs leading to withdrawal, hospitalizations, adverse events of special interest (AESIs), and deaths between vaccination groups were similar. There was no signal of disproportionality for AESIs associated with aIIV3 compared to IIV3 in the post-marketing database. Conclusions: This integrated safety analysis demonstrates an acceptable safety profile for aIIV3 in adults ≥65 years of age. Keywords: Safety, MF59, Adjuvant, Influenza, Vaccine, Elderly

Objective: To demonstrate the potential of an MF59-adjuvanted inactivated trivalent seasonal influenza vaccine (aIIV3; Fluad™) to improve the immune response in young children, we review the immunogenicity, efficacy, and safety/tolerability of aIIV3 from a comprehensive clinical development program in a pediatric population with a specific need for improved influenza vaccines. Methods: Data were analyzed from a series of 1 phase Ib, 3 phase II, and 2 phase III studies involving 11,942 children aged 6 months through 5 years. Results: The clinical data showed that aIIV3 had statistically significantly greater immunogenicity and efficacy in the prevention of influenza compared to conventional inactivated trivalent seasonal influenza vaccines (IIV3s). The safety profile of aIIV3 was generally similar to that of nonadjuvanted IIV3, apart from an increased frequency of solicited adverse events (AEs) following vaccination. The majority of solicited AEs were mild or moderate in severity and resolved within 1 to 3 days. Conclusions: aIIV3 was well tolerated, with immunogenicity and efficacy exceeding that of conventional IIV3 in children 6 months through 5 years of age. The MF59-adjuvanted vaccine has the potential to fulfill an unmet clinical need in the prevention of seasonal influenza in this age group. Keywords: Children, Influenza, Vaccine, Adjuvant, MF59

Summary Objectives The safety and immunogenicity of mammalian cell-derived quadrivalent influenza vaccine (QIVc) as compared with trivalent influenza vaccines (TIV1c/TIV2c) was evaluated in children aged ≥4 to Methods Two thousand three hundred and thirty-three subjects were randomized 2:1:1 to receive either one or two doses of study vaccine depending on previous vaccination status. Hemagglutination inhibition antibody responses for all four influenza strains were performed 3 weeks after the last dose. Reactogenicity and safety were also assessed (ClinicalTrials.gov: NCT01992107 ). Results QIVc met the non-inferiority criteria against all four vaccine strains and demonstrated superiority for both influenza B strains over the unmatched B lineage included in the comparator vaccines, when geometric mean titers and seroconversion rates were compared at 3 weeks after the last vaccination. Similar percentages of subjects experienced solicited and unsolicited adverse events (AEs) across all subgroups. Unsolicited AEs, serious AEs, medically attended AEs, and new onset chronic disease were reported in comparable percentages of subjects in all study groups. No vaccine-related serious AEs or deaths occurred. Conclusions QIVc demonstrated a similar safety profile and immunogenicity responses against all four vaccine strains without signs of immune interference on addition of an alternate lineage B strain compared with TIV1c/TIV2c and may provide broader protection against both influenza B lineages in children.

Background Adding adjuvants such as MF59 ® to influenza vaccines can enhance the immune response. This analysis evaluated the safety profile of MF59-adjuvanted [(+)MF59] compared with non-adjuvanted [(−)MF59] vaccines in a large clinical database. Methods Safety data were pooled from 64 clinical trials involving (+)MF59 seasonal and pandemic influenza vaccines. Safety outcomes were analysed in the overall population and in subjects aged ≥65 years, in all clinical trials and in controlled trials only. Findings Data from 20,447 (+)MF59 and 7526 (−)MF59 subjects were analysed. Overall, (+)MF59 subjects had lower risks than (−)MF59 subjects of experiencing any unsolicited adverse event (AE) (26.8% vs 39.2%; adjusted risk ratio [ARR] 0.65; 95% CI 0.60–0.70), cardiovascular AEs (1.9% vs 5.6%; ARR 0.44; 95% CI 0.35–0.55), new onset chronic diseases (1.3% vs 1.9%; ARR 0.71; 95% CI 0.57–0.87) and death (0.8% vs 1.2%; ARR 0.67; 95% CI 0.51–0.87). Few AEs of potential autoimmune origin were reported: 0.71 and 0.67 per 1000 with (+)MF59 and (−)MF59, respectively. As expected, (+)MF59 subjects had a higher risk of solicited local or systemic reactions within 3 days of vaccination (58.5% vs 46.9%, weighted RR 1.34; 95% CI 1.28–1.40). Safety outcomes were consistent between total and elderly populations, and between all trials and controlled trials, although statistical significance was lost for some of the outcomes in the subgroups. Interpretation This large-scale analysis supports the good safety profile of (+)MF59 seasonal and pandemic influenza vaccines and suggests a clinical benefit over (−)MF59 influenza vaccines.

MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad (®) (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged ≥ 65 years.A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated with higher doses of MF59 (®) , but there were no MF59- or antigen dose-related increase in the frequency of solicited systemic reactions or unsolicited adverse events and serious adverse events.We report on 357 subjects who received one of eight intramuscular vaccine formulations. Hemagglutination-inhibiting antibodies were assayed on Days 1, 8 and 22; magnitude and functional profile of CD4+ T-cell responses to vaccine antigens were assessed in subsets. Solicited adverse reactions were reported via diary cards for seven days after vaccination and spontaneous adverse events were monitored throughout the study.This study confirms that the current formulation is the optimal one for MF59-adjuvanted influenza vaccine for use in older adults.

Young children are at increased risk for influenza infections and related complications. The protection offered to children by conventional trivalent inactivated influenza vaccines (TIV) is suboptimal, due to poor immunogenicity and a higher exposure to infection and complications in this age group, particularly from influenza B strains. In this dose-ranging, factorial design trial, we report the safety and immunogenicity of different combinations of adjuvanted (ATIV) and non-adjuvanted trivalent (TIV) and quadrivalent (QIV) influenza vaccines in 480 healthy children 6 to

The recent global A/H1N1v pandemic led to major efforts to develop effective vaccines against the novel virus, while global demand and limited production capacity focused attention on dose sparing and schedules.An open-label phase III study of immunogenicity and safety of novel A/H1N1v vaccines included 392 Costa Rican children in two pediatric cohorts (3-8 and 9-17 years). They received two doses, of either an MF59®-adjuvanted formulation containing 7.5 μg antigen or non-adjuvanted formulations containing 15 or 30 μg antigen, three weeks apart. Immunogenicity was assessed as hemagglutination inhibition (HI) titers using the CBER licensure criteria.All three vaccines elicited immune responses in 9-17 year-olds meeting CBER criteria three weeks after one dose; responses were not enhanced by second dose. In 3-8 year-olds only the adjuvanted vaccine met the CBER criteria after one dose, but all three vaccines met criteria after second dose. All vaccines were well tolerated; no related Serious Adverse Events (SAE) and few severe solicited reactions were reported. MF59-adjuvanted vaccine was associated with more reports of injection site pain and tenderness and overall systemic solicited reactions, most notably in older subjects, all of which decreased after the second dose.One dose of non-adjuvanted A/H1N1v vaccine is adequate in 9-17 year-olds, but younger children require either one dose of MF59-adjuvanted vaccine or two doses of non-adjuvanted vaccine to achieve protective titers. Enhanced immunogenicity with MF59 is associated with a small increase in reactogenicity, but no safety issues.

To the Editor: The current 2009 pandemic influenza A (H1N1) virus is associated with substantial morbidity in children, with 45% of hospitalizations occurring in patients under 18 years of age.1 One possible reason for this trend is a lack of preexisting immunity against the 2009 H1N1 virus among children.2 Experience with other pandemic vaccines has suggested that two doses of vaccine for children and adults would be needed to meet the licensure criteria of the Center for Biologics Evaluation and Research (CBER).3 According to these criteria, the lower bound of the two-sided 95% confidence interval should meet or exceed 40% . . .

We evaluated the efficacy and safety of oxybutynin in children with detrusor hyperreflexia due to neurological conditions. Study 1--A prospective, open label trial of 3 formulations of oxybutynin (tablets, syrup and extended release tablets) was conducted for 24 weeks in children 6 to 15 years old with detrusor hyperreflexia who used oxybutynin and clean intermittent catheterization. The effect of treatment on average urine volume per catheterization and on secondary urodynamic outcomes was evaluated. Study 2--The efficacy and safety of oxybutynin syrup were evaluated urodynamically in an open label study of children 1 to 5 years old with detrusor hyperreflexia who used oxybutynin and clean intermittent catheterization. Study 1--Mean urine volume per catheterization (+/- SEM) increased by 25.5 +/- 5.9 ml (p