Randomised immunogenicity trial comparing 2019-2020 recombinant and egg-based influenza vaccines among frequently vaccinated healthcare personnel in Israel.
Trivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants.
From October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2).
Among 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0).
RIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4.
NCT04523324.
Fowlkes AL
，Peretz A
，Greenberg D
，Hirsch A
，Martin ET
，Levine MZ
，Edwards L
，Radke S
，Lauring AS
，Ferdinands JM
，Zhang C
，Yoo YM
，Dreiher J
，Newes-Adeyi G
，Azziz-Baumgartner E
，Fry AM
，Monto AS
，Balicer R
，Thompson MG
，Katz MA
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Safety and immunogenicity of mRNA-1345 RSV vaccine coadministered with an influenza or COVID-19 vaccine in adults aged 50 years or older: an observer-blinded, placebo-controlled, randomised, phase 3 trial.
Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine.
We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50-59 years, 60-74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than -10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing.
Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was -11·2% (95% CI -17·9 to -4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was -4·4% (95% CI -9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI -6·0 to 6·3) for SARS-CoV-2 ancestral and -0·9% (-6·6 to 4·7) for omicron BA.1.
Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study.
Moderna.
Goswami J
，Cardona JF
，Hsu DC
，Simorellis AK
，Wilson L
，Dhar R
，Tomassini JE
，Wang X
，Kapoor A
，Collins A
，Righi V
，Lan L
，Du J
，Zhou H
，Stoszek SK
，Shaw CA
，Reuter C
，Wilson E
，Miller JM
，Das R
，study investigators
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ResearchGate
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