Immunogenicity and reactogenicity of heterologous and homologous mRNA-1273 and BNT162b2 vaccination: A multicenter non-inferiority randomized trial

Cécile Janssen; Marine Cachanado; Laetitia Ninove; Marie Lachatre; Jocelyn Michon; Olivier Epaulard; Zoha Maakaroun-Vermesse; Christian Chidiac; Bruno Laviolle; Hugues Aumaitre; Ady Assaf; Karine Lacombe; Catherine Schmidt-Mutter; Elisabeth Botelho-Nevers; Magali Briere; Thomas Boisson; Paul Loubet; Boris Bienvenu; Olivier Bouchaud; Amel Touati; Christine Pereira; Alexandra Rousseau; Laurence Berard; Melissa Montil; Xavier de Lamballerie; Tabassome Simon; Odile Launay; ARNCOMBI Study Group

doi:10.1016/j.eclinm.2022.101444

Immunogenicity and reactogenicity of heterologous and homologous mRNA-1273 and BNT162b2 vaccination: A multicenter non-inferiority randomized trial

EClinicalMedicine. 2022 Jun:48:101444. doi: 10.1016/j.eclinm.2022.101444. Epub 2022 May 12.

Authors

Cécile Janssen^{1

2}, Marine Cachanado³, Laetitia Ninove⁴, Marie Lachatre^{5

2}, Jocelyn Michon^{2

6}, Olivier Epaulard^{2

7}, Zoha Maakaroun-Vermesse^{2

8}, Christian Chidiac^{2

9}, Bruno Laviolle^{2

10}, Hugues Aumaitre¹¹, Ady Assaf^{2

12}, Karine Lacombe^{2

13}, Catherine Schmidt-Mutter^{2

14}, Elisabeth Botelho-Nevers^{2

15

16}, Magali Briere¹⁷, Thomas Boisson¹⁸, Paul Loubet^{2

19}, Boris Bienvenu^{2

20}, Olivier Bouchaud²¹, Amel Touati³, Christine Pereira^{5

2}, Alexandra Rousseau³, Laurence Berard³, Melissa Montil³, Xavier de Lamballerie⁴, Tabassome Simon^{3

22}, Odile Launay^{5

2

23}; ARNCOMBI Study Group

Affiliations

¹ Service de Maladies Infectieuses, Centre Hospitalier Annecy Genevois, Annecy 74370, France.
² Inserm, F-CRIN, I REIVAC/COVIREIVAC, France.
³ Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Antoine, Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (Unité de Recherche Clinique (URCEST), Centre de Recherche Clinique (CRCEST), Centre de Ressources Biologiques (CRB.APHP-SU), Paris, France.
⁴ Unité des Virus Emergents, UVE: Aix Marseille Univ, IRD 190, INSERM 1207, Marseille 13005, France.
⁵ Centre d'Investigations Cliniques (CIC 1417) Cochin Pasteur, AP-HP, Hôpital Cochin, Paris, France.
⁶ Service Des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire, Caen 14000, France.
⁷ Service des maladies Infectieuses, CHU Grenoble Alpes, CIC1406 Inserm - CHUGA - Université Grenoble Alpes, Grenoble, France.
⁸ Centre de vaccination, CHU de Tours, CIC 1415 CHU de Tours, France.
⁹ Service des Maladies Infectieuses et Tropicales GHN HCL - CIRI Équipe PH3ID - INSERM - U1111- UCBL Lyon 1 - CNRS - UMR5308 - ENS de Lyon, France.
¹⁰ Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes, Service de Pharmacologie Clinique), Irset (Institut de Recherche en Santé, Environnement et Travail) UMR S 1085, Rennes F-35000, France.
¹¹ SMIT Perpignan - Infectious and Tropical Disease Unit, Perpignan Hospital Center, Perpignan, France.
¹² CHU Lille, Service de Maladies Infectieuses, University Lille, CNRS, Inserm, CHU Lille, Institute Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille F-59000, France.
¹³ IPLESP - AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital St Antoine, Sorbonne Université, Paris, France.
¹⁴ Centre d'Investigation Clinique CIC INSERM 1434, CHU de Strasbourg, France.
¹⁵ Service d'infectiologie, CIC1408, CHU de Saint-Etienne, Saint-Etienne 42055, France.
¹⁶ Team GIMAP, CIRI, Inserm, U1111, CNRS, UMR530, Univ Lyon, Université Jean Monnet, F42023 Saint-Etienne.
¹⁷ Maison de la Médecine Préventive, Service de Médecine interne, Maladies Infectieuses, hématologie, Centre Hospitalier Bretagne Atlantique, 20, boulevard Maurice Guillaudot, Vannes 56000, France.
¹⁸ Service de Médecine Interne, Centre Hospitalier Alpes Léman, Contamine Sur Arve, France.
¹⁹ Department of Tropical and Infectious Diseases, Virulence Bactérienne et Infection Chronique INSERM U1047, University Montpellier, CHU Nîmes, Nîmes, France.
²⁰ Médecine Interne, Hôpital Saint Joseph, CEDEX 08, Marseille 13285, France.
²¹ AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital Avicenne, Université Paris-13, Bobigny, France.
²² Service de Pharmacologie, Sorbonne Université, Paris, France.
²³ Faculté de Médecine, Inserm, CIC 1417, F CRIN I-REIVAC, Université de Paris, Paris, France.

Abstract

Background: Although effective mRNA vaccines for SARS-CoV-2 infection have been deployed worldwide, their interchangeability could facilitate the scale-up of vaccination programs. The objective of the trial was to assess whether the immune response induced by a heterologous SARS-CoV-2 mRNA primo vaccination is non-inferior to that of a homologous mRNA vaccination.

Methods: We conducted a multicenter, randomized, open-label trial in adults 18 years of age and older who received a first dose of SARS-CoV-2 mRNA vaccine. Participants were randomly assigned in a 1:1 ratio to receive a second dose of BNT162b2 or mRNA-1273, 28 to 49 days after the first dose. Randomization was stratified on the vaccine received at the first vaccination. The primary endpoint was the anti-spike IgG antibodies titer measured 28 days after the second vaccine dose. This study is registered with ClinicalTrials.gov, Trial, NCT04900467.

Findings: Of the 414 randomized participants recruited from May 28 to July 2, 2021, 390 were included in the per protocol analysis: 94 participants in group 1 (BNT162b2/BNT162b2), 96 in group 2 (BNT162b2/mRNA-1273), 97 in group 3 (mRNA-1273/mRNA-1273), and 103 in group 4 (mRNA-1273/BNT162b2). The geometric mean titers ratios of anti-spike IgG antibodies for each heterologous regimen relative to the corresponding homologous regimen were 1·37 (two-sided 95% CI, 1·10 to 1·72) in the groups 1 and 2 and 0·67 (two-sided 95% CI, 0·55 to 0·82) in the groups 3 and 4. Levels of neutralizing antibodies to the main circulating SARS-Cov-2 viral strains were higher with the vaccine regimen containing mRNA-1273. Participants who received mRNA-1273 as a second dose experienced a higher rate of local adverse reactions and general symptoms than those who received BNT162b2 (p < 0·0001).

Interpretation: The two SARS-CoV-2 mRNA vaccines could be used with flexibility for the second dose of COVID-19 primo vaccination. Tolerance remains good regardless of vaccine sequence although mRNA-1273 was more reactogenic.

Funding: French Ministries of Solidarity and Health and Research. BNT162b2 was provided by Pfizer/BioNTech. mRNA-1273 was provided by Moderna.

Associated data

ClinicalTrials.gov/NCT04900467