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 - 26/11/24

Doi : 10.1016/S1473-3099(24)00589-9

Jaya Goswami, MD ^a,⁎ , Jose F Cardona, MD ^b, Denise C Hsu, MD ^a, Alana K Simorellis, PhD ^a, Lauren Wilson, MSN ^a, Rakesh Dhar, MD ^a, Joanne E Tomassini, PhD ^a, Xiaowei Wang, PhD ^a, Archana Kapoor, PhD ^a, Avi Collins, BScN ^a, Vinicius Righi, MBA ^a, Lan Lan, PhD ^a, Jiejun Du, PhD ^a, Honghong Zhou, PhD ^a, Sonia K Stoszek, PhD ^a, Christine A Shaw, PhD ^a, Caroline Reuter, MD ^a, Eleanor Wilson, MD ^a, Jacqueline M Miller, MD ^a, Rituparna Das, MD ^a
on behalf of the
study investigators^{^†}
Study investigators listed in the Supplementary Material)

Adebayo Akinsola ^c, Rachel Anderson ^d, Summer Aymar ^e, John Beckes ^f, Robert Bell ^g, Gary Berman ^h, David Bernard ⁱ, Paul Bradley ^j, Adam Brosz ^k, Jose Cardona ^l, Mark Carlson ^m, Jorge Caso ⁿ, Laurence Chu ^o, Natalie Clarke ^p, Luis De La Cruz ^q, David DeAtkine ^r, Jackson Downey ^s, Donald Eagerton ^t, Bachar Elsaadi ^u, David Ensz ^v, Ivette Espinosa-Fernandez ^w, Brandon Essink ^x, David Fitz-Patrick ^y, Suzanne Fussell ^z, Vicki Kalen ^aa, Christina Kennelly ^ab, Mark Kutner ^ac, Douglas Logan ^ad, Daniel Lorch ^ae, Jay Meyer ^af, Martha Navarro ^ag, Rahul Patel ^ah, Suchet Patel ^ai, Leonel Reyes ^aj, Farhan Siddiqui ^ak, Joseph Soufer ^al, Charles Thompson ^am, Adebayo Akinsola ^an, Faisal Amin ^ao, Rachel Anderson ^ap, Summer Aymar ^aq, John Beckes ^ar, Robert Bell ^as, Gary Berman ^at, Kennet Blad ^au, Paul Bradley ^av, Adam Brosz ^aw, Jose Cardona ^ax, Mark Carlson ^ay, Jorge Caso ^az, Laurence Chu ^ba, Natalie Clarke ^bb, Luis De La Cruz ^bc, Jackson Downey ^bd, Donald Eagerton ^be, David Ensz ^bf, Ivette Espinosa-Fernandez ^bg, Brandon Essink ^bh, Suzanne Fussell ^bi, Charles Harper ^bj, Barry Heller ^bk, Robert Jenders ^bl, Vicki Kalen ^bm, Christina Kennelly ^bn, Mark Kleiner ^bo, Mark Kutner ^bp, Douglas Logan ^bq, Daniel Lorch ^br, Otto Marquez-Mendoza ^bs, Jay Meyer ^bt, Jason Morris ^bu, Banu Myneni ^bv, Martha Navarro ^bw, Hoa Nguyen ^bx, Amit Paliwal ^by, Naresh Parikh ^bz, Rahul Patel ^ca, Suchet Patel ^cb, Katherine Pearce ^cc, Syed Pervaiz ^cd, Bryce Peterson ^ce, Michael Peterson ^cf, Aziz Pirani ^cg, Leone Reyes ^ch, William Sanchez ^ci, Farhan Siddiqui ^cj, Joseph Soufer ^ck, Charles Thompson ^cl, Apinya Vutikullird ^cm, Derrick Ward ^cn

^c Tekton Research, Chamblee, Georgia, USA

^d Tekton Research, Moore, Oklahoma, USA

^e Medical Center For Clinical Research, San Diego, Californina, USA

^f Acclaim Clinical Research, San Diego, California, USA

^g Tekton Research, Beaumont, Texas, USA

^h Clinical Research Institute, Inc., Minneapolis, Minnesota, USA

ⁱ CHEAR Center LLC - ClinEdge, Bronx, New York, USA

^j Meridian Clinical Research, Savannah, Georgia, USA

^k Meridian Clinical Research, Grand Island, Nebraska, USA

^l Indago Research and Health Center, Hialeah, Florida, USA

^m Be Well Clinical Studies, LLC, Lincoln, Nebraska, USA

ⁿ Suncoast Research Associates LLC, Miami, Florida, USA

^o Benchmark Research, Austin, Texas, USA

^p New Phase Research & Development, Knoxville, Tennessee, USA

^q Velocity Clinical Research, Greenville, South Carolina, USA

^r Central Research Associates Inc, Birmingham, Alabama, USA

^s Westside Center for Clinical Research, Jacksonville, Florida, USA

^t Trial Management Associates LLC, Myrtle Beach, South Carolina, USA

^u Zenos Clinical Research, Dallas, Texas, USA

^v Meridian Clinical Research, Sioux City, Iowa, USA

^w Revival Research Corporation, Doral, Florida, USA

^x Meridian Clinical Research, Omaha, Nebraska, USA

^y East West Medical Research Institute, Honolulu, Hawaii, USA

^z Long Beach Clinical Services, INC., Long Beach, California, USA

^aa Del Sol Research Management, Tucson, Arizona, USA

^ab Javara Research Inc., Charlotte, North Carolina, USA

^ac Suncoast Research Group LLC, Miami, Florida, USA

^ad Meridian Clinical Research, Cincinnati, Ohio, USA

^ae Teradan Clinical Trials, Brandon, Florida, USA

^af Meridian Clinical Research, LLC, Lincoln, Nebraska, USA

^ag Ark Clinical Research, Long Beach, CA, USA

^ah Meridian Clinical Research, Rockville, Maryland, USA

^ai Velocity Clinical Research, Vestal, New York, USA

^aj Sun Research Institute, San Antonio, Texas, USA

^ak Velocity Clinical Research, Spartanburg, South Carolina, USA

^al Chase Medical Research LLC, Waterbury, Connecticut, USA

^am Velocity Clinical Research, Anderson, South Carolina, USA

^an Tekton Research, Chamblee, Georgia, USA

^ao Central Valley Research, LLC, Modesto, California, USA

^ap Tekton Research, Moore, Oklahoma, USA

^aq Medical Center For Clinical Research, San Diego, Californina, USA

^ar Acclaim Clinical Research, San Diego, California, USA

^as Tekton Research, Beaumont, Texas, USA

^at Clinical Research Institute, Inc, Minneapolis, Minnesota, USA

^au Midwest Regional Health Services - CCT Research, Omaha, Nebraska, USA

^av Meridian Clinical Research, Savannah, Georgia, USA

^aw Meridian Clinical Research, Grand Island, Nebraska, USA

^ax Indago Research and Health Center, Hialeah, Florida, USA

^ay Be Well Clinical Studies, LLC, Lincoln, Nebraska, USA

^az Suncoast Research Associates LLC, Miami, Florida, USA

^ba Benchmark Research, Austin, Texas, USA

^bb New Phase Research & Development, Knoxville, Tennessee, USA

^bc Velocity Clinical Research, Greenville, South Carolina, USA

^bd Westside Center for Clinical Research, Jacksonville, Florida, USA

^be Trial Management Associates LLC, Myrtle Beach, South Carolina, USA

^bf Meridian Clinical Research, Sioux City, Iowa, USA

^bg Revival Research Corporation, Doral, Florida, USA

^bh Meridian Clinical Research, Omaha, Nebraska, USA

^bi Long Beach Clinical Services, Inc., Long Beach, California, USA

^bj Meridian Clinical Research, Norfolk, Nebraska, USA

^bk Long Beach Clinical Trials, LLC, Long Beach, California, USA

^bl Velocity Clinical Research, Panorama City, California, USA

^bm Del Sol Research Management, Tucson, Arizona, USA

^bn Javara Research Inc., Charlotte, North Carolina, USA

^bo Javara Inc./Privia Medical Group INC, Forest, Virginia, USA

^bp Suncoast Research Group LLC, Miami, Florida, USA

^bq Meridian Clinical Research, Cincinnati, Ohio, USA

^br Teradan Clinical Trials, Brandon, Florida, USA

^bs Dolphin Medical Research, Doral, Florida, USA

^bt Meridian Clinical Research, LLC, Lincoln, Nebraska, USA

^bu Clinical Trials of SWLA, LLC, Lake Charles, Louisiana, USA

^bv Meridian Clinical Research, Portsmouth, Virginia, USA

^bw Ark Clinical Research, Long Beach, CA, USA

^bx Paragon Rx Clinical, Inc, Garden Grove, California, USA

^by Empire Clinical Research, Pomona, California, USA

^bz Georgia Clinic / CCT Research, Norcross, Georgia, USA

^ca Meridian Clinical Research, Rockville, Maryland, USA

^cb Velocity Clinical Research, Vestal, New York, USA

^cc Meridian Clinical Research, Baton Rouge, Louisiana, USA

^cd Santa Rosa Medical Centers of Nevada - CCT Research, Las Vegas, Nevada, USA

^ce Cope Family Medicine, Bountiful, Utah, USA

^cf CCT Research at Springville Dermatology, Springville, Utah, USA

^cg Lifeline Primary Care / CCT Research, Lilburn, Georgia, USA

^ch Sun Research Institute, San Antonio, Texas, USA

^ci Floridian Clinical Research, Miami Lakes, Florida, USA

^cj Velocity Clinical Research, Spartanburg, South Carolina, USA

^ck Chase Medical Research LLC, Waterbury, Connecticut, USA

^cl Velocity Clinical Research, Anderson, South Carolina, USA

^cm Ark Clinical Research, Tustin, California, USA

^cn Meridian Clinical Research, LLC, Overland Park, Kansas, USA

^a Moderna, Cambridge, MA, USA

^b Indago Research and Health Center, Hialeah, FL, USA

^* Correspondence to: Jaya Goswami, Moderna, Cambridge, MA 02139, USA Moderna Cambridge MA 02139 USA

connectez-vous ou créez un compte

Bienvenue sur EM-consulte, la référence des professionnels de santé.
Article gratuit.

Connectez-vous pour en bénéficier!

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 26 November 2024

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.