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Immune Response and Reactogenicity After Immunization With a Suboptimal Two-Dose mRNA Vaccine Followed by a Full Vaccination With a Standard mRNA Vaccine Compared to a Prime-Boost Regimen of a Standard mRNA Vaccine: A Multicenter Cohort Study

32 Pages Posted: 15 Feb 2022

See all articles by Ana Ascaso

Ana Ascaso

Universidad Complutense de Madrid (UCM) - Servicio de Farmacología Clínica

Javier García-Pérez

Carlos III Institute of Health - CIBER de Epidemiología y Salud Pública (CIBERESP)

Mayte Pérez Olmeda

Instituto de Salud Carlos III- Laboratorio de Serología

Eunate Arana

University of the Basque Country - Biocruces Bizkaia Health Research Institute

Itziar Vergara

affiliation not provided to SSRN

Carla Pérez-Ingidua

Instituto de Investigación Sanitaria San Carlos (IdISSC) - Servicio de Farmacología Clínica

Mercedes Bermejo

Carlos III Institute of Health - National Centre for Microbiology

María Castillo de la Osa

Carlos III Institute of Health

Natale Imaz-Ayo

University of the Basque Country - Biocruces Bizkaia Health Research Institute

Ioana Riaño Fernández

affiliation not provided to SSRN

Oliver Astasio González

Hospital Clinico San Carlos

Francisco Díez-Fuertes

University of Barcelona - AIDS Research Group

Susana Meijide

affiliation not provided to SSRN

Julio Arrizabalaga

affiliation not provided to SSRN

Lourdes Hernández Gutiérrez

Carlos III Institute of Health

Humberto Erick de la Torre-Tarazona

Carlos III Institute of Health

Alberto Mariano Lázaro

Hospital Clinico San Carlos

Emilio Vargas Castrillón

affiliation not provided to SSRN

José Alcamí Pertejo

Carlos III Institute of Health - AIDS Immunopathogenesis Unit

Antonio Portolés

Instituto de Investigación Sanitaria San Carlos (IdISSC) - Servicio de Farmacología Clínica

More...

Abstract

Background: There is no evidence to date on immunogenic response and dynamics in individuals who participated in clinical trials of experimental COVID-19 vaccines, thus being redirected to receive standard courses included in national vaccination programs.

Methods: This multicentre, prospective controlled cohort study included subjects primed with a non-authorised experimental COVID-19 vaccine (test group, TG) and subjects who did not receive any active COVID-19 vaccine earlier (control group, CG), selected among individuals to be vaccinated at study sites according to the Spanish vaccination program. All subjects from TG had received the experimental CVnCoV vaccine previously. All study subjects received BNT162b2 as a standard vaccine of the national program but 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies titres, and neutralising titres (NT50) against G614 (reference), Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed.

Findings: 130 participants (TG: 92; CG: 38) completed standard vaccination. Mean (SD) interval between CVnCoV and BNT162b2 vaccines was 110 (15·4) days (only TG), while interval between BNT162b2 doses was 21 days (SD 2·3 [TG] and 0·9 [CG]). In the TG, median (IQR) titres of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in the CG (p <0·0001). Median NT50 (IQR) of G614 variant was 2674·0 (1865·0-3997·0) in the TG and 63·0 (16·0-123·1) in the CG (p <0·0001). After second BNT162b2 dose, anti-RBD antibody titres increased to ≥12500 BAU/mL (11625·0-12500) in the TG compared to 1859·0 BAU/mL (915·4-3820·0) in the CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific response in the CG showed 8·2-, 5·5-, and 16·8-fold decrease of GM NT50 against Beta, Mu, and Omicron variants, respectively, compared to G614 variant, while in the TG it was 2·6, 2·4, and 4·7 folds, respectively. Most frequent adverse reactions were headache and myalgia (systemic), and pain (local). No severe AEs were reported.

Interpretation: Results suggest that heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than obtained with standard prime-boost BNT162b2 regimen. This apparent benefit was also observed in variant-specific response. No safety concerns arose.

Trial Registration Details: The study is registered with the Spanish Register of Clinical Studies (REEC–code: 0061-2021-OBS).

Funding Information: Partly funded by the Institute of Health Carlos III (Instituto de Salud Carlos III – ISCIII –), (grant numbers PI19CIII/00004 and PI21CIII/00025), and COVID-19 FUND (grants COV20/00679 and COV20/00072) and CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”.

Declaration of Interests: Biocruces Bizkaia HRI and Curevac have a clinical trial contract unrelated to the present study. Biodonostia HRI and Curevac have a clinical trial contract unrelated to the present study. Clinico San Carlos HRI and Curevac have a clinical trial contract unrelated to the present study. JA: Consulting fees from EMA, AEMPS, Almirall, Zeltia; payment for educational events on vaccines 17 from Gilead, Haelix Therapeutics, Merck Sharp & Dohme, Janssen. All other authors declare no competing interests.

Ethics Approval Statement: This study was reviewed and approved by the Ethics Committee of the San Carlos University Hospital (21/528-E) and complied with ethical principles of the Declaration of Helsinki and Good Clinical Practice, as well as the applicable Spanish law. All volunteers signed informed consents to donate their samples and to participate in the study before inclusion.

Keywords: COVID-19 vaccines, m-RNA, vaccines, cohort-study, experimental, vaccines, variants, neutralization, antibodies, omicron, Immunogenicity, vaccine, reactogenicity, CVnCoV vaccine, BNT162b2 vaccine

Suggested Citation

Ascaso, Ana and García-Pérez, Javier and Pérez Olmeda, mayte and Arana, Eunate and Vergara, Itziar and Pérez-Ingidua, Carla and Bermejo, Mercedes and Castillo de la Osa, María and Imaz-Ayo, Natale and Riaño Fernández, Ioana and Astasio González, Oliver and Díez-Fuertes, Francisco and Meijide, Susana and Arrizabalaga, Julio and Hernández Gutiérrez, Lourdes and de la Torre-Tarazona, Humberto Erick and Mariano Lázaro, Alberto and Vargas Castrillón, Emilio and Alcamí Pertejo, José and Portolés, Antonio, Immune Response and Reactogenicity After Immunization With a Suboptimal Two-Dose mRNA Vaccine Followed by a Full Vaccination With a Standard mRNA Vaccine Compared to a Prime-Boost Regimen of a Standard mRNA Vaccine: A Multicenter Cohort Study. Available at SSRN: https://ssrn.com/abstract=4035392 or http://dx.doi.org/10.2139/ssrn.4035392

Ana Ascaso

Universidad Complutense de Madrid (UCM) - Servicio de Farmacología Clínica ( email )

Carretera de Humera s/n
Madrid, Madrid 28223
Spain

Javier García-Pérez

Carlos III Institute of Health - CIBER de Epidemiología y Salud Pública (CIBERESP) ( email )

Monforte de Lemos 5
Madrid
Spain

Mayte Pérez Olmeda

Instituto de Salud Carlos III- Laboratorio de Serología ( email )

Ctra Majadahonda-Pozuelo km2
Majadahonda, Madrid 28220
Spain

Eunate Arana

University of the Basque Country - Biocruces Bizkaia Health Research Institute ( email )

Spain

Itziar Vergara

affiliation not provided to SSRN ( email )

No Address Available

Carla Pérez-Ingidua

Instituto de Investigación Sanitaria San Carlos (IdISSC) - Servicio de Farmacología Clínica ( email )

Madrid
Spain

Mercedes Bermejo

Carlos III Institute of Health - National Centre for Microbiology ( email )

María Castillo de la Osa

Carlos III Institute of Health ( email )

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Natale Imaz-Ayo

University of the Basque Country - Biocruces Bizkaia Health Research Institute ( email )

Spain

Ioana Riaño Fernández

affiliation not provided to SSRN ( email )

No Address Available

Oliver Astasio González

Hospital Clinico San Carlos ( email )

Spain

Francisco Díez-Fuertes

University of Barcelona - AIDS Research Group ( email )

Spain

Susana Meijide

affiliation not provided to SSRN ( email )

No Address Available

Julio Arrizabalaga

affiliation not provided to SSRN ( email )

No Address Available

Lourdes Hernández Gutiérrez

Carlos III Institute of Health ( email )

Humberto Erick De la Torre-Tarazona

Carlos III Institute of Health ( email )

Alberto Mariano Lázaro

Hospital Clinico San Carlos ( email )

Spain

Emilio Vargas Castrillón

affiliation not provided to SSRN ( email )

No Address Available

José Alcamí Pertejo

Carlos III Institute of Health - AIDS Immunopathogenesis Unit ( email )

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Antonio Portolés (Contact Author)

Instituto de Investigación Sanitaria San Carlos (IdISSC) - Servicio de Farmacología Clínica ( email )

Madrid
Spain

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