182fdeb65e6b2f2aab4904275174ca1d vaccines-13-00738.pdf d5acc13aa775ecc99c6bb247135886fc0979e02a vaccines-13-00738.pdf 5f6a96dabffb2b1f0d5f35cf9394fdf9ce796992430abed998e4c10d1025397b vaccines-13-00738.pdf Title: Immune Durability and Breakthrough Infections 15 Months After SARS-CoV-2 Boosters in People over 65: The IMMERSION Study Subject: Background: SARS-CoV-2 booster vaccination remains essential to prevent severe COVID-19, particularly in vulnerable populations such as older adults. This study evaluated the durability and dynamics of immune responses following booster vaccination(s) in >65-year-old individuals and examined their association with protection against new infections. Methods: Immune responses were evaluated at 3, 9, and 15 months post-booster, measuring SARS-CoV-2-specific IgG antibodies against spike [IgG(S)] and nucleocapsid [IgG(N)] proteins, neutralizing activity against the Omicron BA.2 variant, and cellular immunity. A subset of participants was tested before booster administration. Regression analyses examined the influence of clinical and immunological factors—including a bivalent fourth dose—on infection risk over time. Results: Booster vaccination significantly enhanced IgG(S) and neutralizing capacity, peaking at 3 months. Although a decline was observed by 9 months, responses remained above baseline. Individuals with prior SARS-CoV-2 infection exhibited higher IgG(S) levels and neutralizing titers, and significantly lower reinfection rates (15%), compared to uninfected individuals. A fourth vaccine dose further increased IgG(S) levels. While neutralizing capacity was not consistently enhanced by the fourth dose, recipients experienced a lower rate of new infections. Immune trajectory analyses revealed that breakthrough infections elicited strong humoral responses comparable to those seen in previously infected individuals, highlighting the role of hybrid immunity. Conclusions: In older adults, booster vaccination induces durable immune responses, with hybrid immunity offering enhanced protection. A fourth dose boosts antibody levels and reduces infection risk, supporting its use in this high-risk group. Continued monitoring is needed to determine the long-term effectiveness of boosters, particularly against emerging variants. Keywords: SARS-CoV-2; humoral immunity; cohort; ageing; primary health care Author: Concepció Violán, Bibiana Quirant-Sánchez, Maria Palau-Antoja, Dolors Palacin, Edwards Pradenas, Macedonia Trigueros, Guillem Pera, Gemma Molist, Gema Fernández-Rivas, Marc Boigués, Mar Isnard, Nuria Prat, Meritxell Carmona-Cervelló, Noemi Lamonja-Vicente, Brenda Biaani León-Gómez, Eva María Martínez-Cáceres, Pere Joan Cardona, Julià Blanco, Marta Massanella and Pere Torán-Monserrat Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Jul 9 09:51:49 2025 CEST ModDate: Wed Jul 9 09:55:32 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4040597 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WNWTFR+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 AIRHKL+VnURWPalladioL Type 1 Custom yes yes yes 16 0 GJISWJ+URWPalladioL-Roma Type 1 Custom yes yes yes 21 0 LNGZBU+URWPalladioL-Bold Type 1 Custom yes yes yes 27 0 QIYUAC+URWPalladioL-Ital Type 1 Custom yes yes yes 32 0 IKKWKP+CMSY10 Type 1 Builtin yes yes yes 64 0 JMLNIF+PalatinoLinotype TrueType WinAnsi yes yes no 74 0 MKDWFJ+EURM10 Type 1 Builtin yes yes yes 83 0 JMLNHE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 102 0 JMLNIF+PalatinoLinotype TrueType WinAnsi yes yes no 105 0 JMMCEN+TimesNewRoman TrueType WinAnsi yes yes no 108 0 JMLNHE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 151 0 JMLNIE+PalatinoLinotype CID TrueType Identity-H yes yes yes 154 0 JMLNIF+PalatinoLinotype TrueType WinAnsi yes yes no 160 0 JMLNIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 163 0 ANMFCG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 187 0 ANMFCI+PalatinoLinotype TrueType WinAnsi yes yes no 190 0 ANMFCK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 193 0 ANMFEK+CambriaMath CID TrueType Identity-H yes yes yes 196 0 AKNJHA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 207 0 AKNJHC+PalatinoLinotype TrueType WinAnsi yes yes no 210 0 AKNJIE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 213 0 AKNJLE+CambriaMath CID TrueType Identity-H yes yes yes 216 0 BXZYNU+URWPalladioL-BoldItal Type 1 Custom yes yes yes 229 0 MPUDFL+PazoMath Type 1 Builtin yes yes yes 249 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-10-10 03:53:00 CEST RepresentationInformation: vaccines-13-00738.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-10-09 15:13:20 CEST Size: 4040597 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 424 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Study Design Destination: subsection.2.1 Item: Title: Participant Recruitment, Follow-Up Destination: subsection.2.2 Item: Title: Study Outcomes Destination: subsection.2.3 Item: Title: Covariables Destination: subsection.2.4 Item: Title: Determination of Total Anti-SARS-CoV-2 Antibodies, Neutralization Titers, and T-Cell Responses Destination: subsection.2.5 Item: Title: Determination of Different Trajectories According to Infected or Uninfected Status at Baseline Destination: subsection.2.6 Item: Title: Sample Size and Statistical Power Destination: subsection.2.7 Item: Title: Statistical Analysis Destination: subsection.2.8 Item: Title: Results Destination: section.3 Children: Item: Title: Participant Characteristics Destination: subsection.3.1 Item: Title: Impact of Prior Infection on Immunity After the Third Vaccine Dose Destination: subsection.3.2 Item: Title: Vaccine Dose and Immune Response Dynamics (Trajectories) Destination: subsection.3.3 Item: Title: Risk of Reinfection and Breakthrough Infections Destination: subsection.3.4 Item: Title: Cellular Immune Response Differences by Sex Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: Appendix A Destination: appendix.A. Children: Item: Title: Destination: subsection.A.1 Children: Item: Title: Determination of Anti-SARS-CoV-2 Antibodies Destination: subsubsection.A.1.1 Item: Title: Pseudovirus Neutralization Assay Destination: subsubsection.A.1.2 Item: Title: SARS-CoV-2-Specific Cellular Responses Destination: subsubsection.A.1.3 Item: Title: Determination of Different Trajectories According to Infected or Uninfected Status at Baseline Destination: subsection.A.2 Item: Title: References Destination: appendix.B. Info: Title: Immune Durability and Breakthrough Infections 15 Months After SARS-CoV-2 Boosters in People over 65: The IMMERSION Study Author: Concepció Violán, Bibiana Quirant-Sánchez, Maria Palau-Antoja, Dolors Palacin, Edwards Pradenas, Macedonia Trigueros, Guillem Pera, Gemma Molist, Gema Fernández-Rivas, Marc Boigués, Mar Isnard, Nuria Prat, Meritxell Carmona-Cervelló, Noemi Lamonja-Vicente, Brenda Biaani León-Gómez, Eva María Martínez-Cáceres, Pere Joan Cardona, Julià Blanco, Marta Massanella and Pere Torán-Monserrat Subject: Background: SARS-CoV-2 booster vaccination remains essential to prevent severe COVID-19, particularly in vulnerable populations such as older adults. This study evaluated the durability and dynamics of immune responses following booster vaccination(s) in >65-year-old individuals and examined their association with protection against new infections. Methods: Immune responses were evaluated at 3, 9, and 15 months post-booster, measuring SARS-CoV-2-specific IgG antibodies against spike [IgG(S)] and nucleocapsid [IgG(N)] proteins, neutralizing activity against the Omicron BA.2 variant, and cellular immunity. A subset of participants was tested before booster administration. Regression analyses examined the influence of clinical and immunological factors including a bivalent fourth dose on infection risk over time. Results: Booster vaccination significantly enhanced IgG(S) and neutralizing capacity, peaking at 3 months. Although a decline was observed by 9 months, responses remained above baseline. Individuals with prior SARS-CoV-2 infection exhibited higher IgG(S) levels and neutralizing titers, and significantly lower reinfection rates (15%), compared to uninfected individuals. A fourth vaccine dose further increased IgG(S) levels. While neutralizing capacity was not consistently enhanced by the fourth dose, recipients experienced a lower rate of new infections. Immune trajectory analyses revealed that breakthrough infections elicited strong humoral responses comparable to those seen in previously infected individuals, highlighting the role of hybrid immunity. Conclusions: In older adults, booster vaccination induces durable immune responses, with hybrid immunity offering enhanced protection. A fourth dose boosts antibody levels and reduces infection risk, supporting its use in this high-risk group. Continued monitoring is needed to determine the long-term effectiveness of boosters, particularly against emerging variants. 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