Safety and immunogenicity of an investigational mRNA-lipid nanoparticle-based monovalent influenza vaccine: Results from a phase 1, randomized, dose-escalation study

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This first-in-human, randomized, controlled, phase 1 proof-of-principle study evaluated the safety, reactogenicity, and immunogenicity of an investigational mRNA-based monovalent influenza vaccine encoding influenza A/H1N1 hemagglutinin (FLUmHA). Younger adults (YA) aged 18–45 y received one dose of FLUmHA at one of 10 dose levels (0.5–100 µg, n = 24/25 per group) or licensed Flu Dresden-quadrivalent seasonal influenza vaccine (Flu D-QIV, n = 35) on day (D)1. Older adults (OA) aged 60–80 y received FLUmHA (18 µg, n = 32) or Flu D-QIV (n = 16). Reporting rates for solicited adverse events (AEs) occurring within 7 d post-vaccination generally increased with increasing FLUmHA dose levels, and were 62.5%-100% (severe: 0.0%-20.8%) in YA across FLUmHA dose levels versus 88.6% (severe: 2.9%) in Flu D-QIV-vaccinated YA, and 62.5% (severe: 0.0%) (FLUmHA) versus 56.3% (severe: 0.0%) (Flu D-QIV) in OA. Unsolicited AEs within 28 d post-vaccination were reported by 50.0%–70.8% of YA across FLUmHA dose levels versus 68.6% of Flu D-QIV-vaccinated YA, and by 43.8% (FLUmHA) versus 50.0% (Flu D-QIV) of OA. No safety concerns were identified. A/H1N1 hemagglutination inhibition titers increased from pre-vaccination to D22, with adjusted geometric mean increases (GMIs) of 6.2–36.7 across YA and OA groups; the observed response was dose-dependent and higher in FLUmHA (for doses > 1 µg) versus Flu D-QIV recipients. Titers decreased but remained above pre-vaccination levels at D183 (GMI: 2.9–14.0). Additionally, FLUmHA elicited a numerically higher hemagglutinin-specific CD4+ T-cell response (predominantly Th1 profile) than Flu D-QIV, both in YA and OA. These results support the progression to clinical development of a multivalent mRNA Flu vaccine candidate. Trial registration: NCT05446740. What is the context? Seasonal flu is a common respiratory illness caused by influenza viruses. Most people only have mild symptoms, but flu can also be serious and lead to hospitalization and death.Flu vaccines are updated each year to match the most common influenza virus strains expected to be present that year. Because influenza viruses change easily, some years the vaccines do not work as well when strains chosen for the vaccine are a poor match with the circulating strains. Moreover, flu vaccines do not always work well in older adults.Investigational flu vaccines that use messenger RNA (mRNA) technology have been shown to cause a robust and durable immune response, also in older adults. In addition, the production of mRNA vaccines is flexible and scalable, and the vaccines contain the virus’s exact genetic code, avoiding the changes that can occur in traditional vaccines grown in eggs. This may lead to a better match between the vaccine and the influenza viruses circulating during the season. Seasonal flu is a common respiratory illness caused by influenza viruses. Most people only have mild symptoms, but flu can also be serious and lead to hospitalization and death. Flu vaccines are updated each year to match the most common influenza virus strains expected to be present that year. Because influenza viruses change easily, some years the vaccines do not work as well when strains chosen for the vaccine are a poor match with the circulating strains. Moreover, flu vaccines do not always work well in older adults. Investigational flu vaccines that use messenger RNA (mRNA) technology have been shown to cause a robust and durable immune response, also in older adults. In addition, the production of mRNA vaccines is flexible and scalable, and the vaccines contain the virus’s exact genetic code, avoiding the changes that can occur in traditional vaccines grown in eggs. This may lead to a better match between the vaccine and the influenza viruses circulating during the season. What is new? We did a study to collect data on the safety and immune response of an investigational mRNA Flu vaccine targeting one flu strain.The study included 276 adults aged 18–45 y and 48 adults aged 60–80 y. Participants received either the mRNA Flu vaccine or a licensed flu vaccine as control. The younger participants receiving mRNA Flu were divided in 10 groups, each getting a different dose of the vaccine. The older participants received one specific dose.We found that side effects after mRNA Flu vaccination were mostly mild or moderate and were short-lived, even at the highest vaccine doses. Only a few serious adverse events occurred, and these were not related to the vaccine.The mRNA Flu vaccine induced an immune response against the flu strain targeted by the vaccine. The immune response was higher than with the control vaccine for most doses and increased with higher doses. We did a study to collect data on the safety and immune response of an investigational mRNA Flu vaccine targeting one flu strain. The study included 276 adults aged 18–45 y and 48 adults aged 60–80 y. Participants received either the mRNA Flu vaccine or a licensed flu vaccine as control. The younger participants receiving mRNA Flu were divided in 10 groups, each getting a different dose of the vaccine. The older participants received one specific dose. We found that side effects after mRNA Flu vaccination were mostly mild or moderate and were short-lived, even at the highest vaccine doses. Only a few serious adverse events occurred, and these were not related to the vaccine. The mRNA Flu vaccine induced an immune response against the flu strain targeted by the vaccine. The immune response was higher than with the control vaccine for most doses and increased with higher doses. What is the impact? The safety data and robust and durable immune response of the tested vaccine support further clinical development of an mRNA Flu vaccine targeting multiple flu strains. The safety data and robust and durable immune response of the tested vaccine support further clinical development of an mRNA Flu vaccine targeting multiple flu strains.

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