key: cord-0335818-u13my5e5 authors: Iketani, S.; Liu, L.; Nair, M. S.; Mohri, H.; Wang, M.; Huang, Y.; Ho, D. D. title: A third COVID-19 vaccine shot markedly boosts neutralizing antibody potency and breadth date: 2021-08-18 journal: nan DOI: 10.1101/2021.08.11.21261670 sha: 41c975da4c681ae359725c9b1f00a1f133def99d doc_id: 335818 cord_uid: u13my5e5 COVID-19 (coronavirus disease 2019) vaccines have been rapidly developed and deployed globally as a measure to combat the disease. These vaccines have been demonstrated to confer significant protection, but there have been reports of temporal decay in antibody titer. Furthermore, several variants have been identified with variable degrees of antibody resistance. These two factors suggest that a booster vaccination may be worthy of consideration. While such a booster dose has been studied as a series of three homologous vaccines in healthy individuals, to our knowledge, information on a heterologous regimen remains unreported, despite the practical benefits of such a scheme. Here, in this observational study, we investigated the serological profile of four healthy individuals who received two doses of the BNT162b2 vaccine, followed by a third booster dose with the Ad26.COV2.S vaccine. We found that while all individuals had spike-binding antibodies at each of the timepoints tested, there was an appreciable drop in titer by four months following the second vaccination. The third vaccine dose robustly increased titers beyond that of two vaccinations, and these elicited antibodies had neutralizing capability against all SARS-CoV-2 strains tested in both a recombinant vesicular stomatitis virus-based pseudovirus assay and an authentic SARS-CoV-2 assay, except for one individual against B.1.351 in the latter assay. Thus, a third COVID-19 vaccine dose in healthy individuals promoted not just neutralizing antibody potency, but also induced breadth against dominant SARS-CoV-2 variants. degrees of antibody resistance. These two factors suggest that a booster vaccination 23 may be worthy of consideration. While such a booster dose has been studied as a 24 series of three homologous vaccines in healthy individuals, to our knowledge, 25 information on a heterologous regimen remains unreported, despite the practical 26 benefits of such a scheme. Here, in this observational study, we investigated the 27 serological profile of four healthy individuals who received two doses of the BNT162b2 28 vaccine, followed by a third booster dose with the Ad26.COV2.S vaccine. We found that 29 while all individuals had spike-binding antibodies at each of the timepoints tested, there 30 was an appreciable drop in titer by four months following the second vaccination. The 31 third vaccine dose robustly increased titers beyond that of two vaccinations, and these 32 elicited antibodies had neutralizing capability against all SARS-CoV-2 strains tested in 33 both a recombinant vesicular stomatitis virus-based pseudovirus assay and an authentic 34 SARS-CoV-2 assay, except for one individual against B.1.351 in the latter assay. Thus, 35 a third COVID-19 vaccine dose in healthy individuals promoted not just neutralizing 36 antibody potency, but also induced breadth against dominant SARS-CoV-2 variants. 37 38 Significance 39 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 2). While these vaccines have been promising in reducing symptomatic infections, the 54 decay of neutralizing antibodies has been documented following vaccination (3, 4). 55 Such decay is particularly pertinent due to the emergence of SARS-CoV-2 variants with 56 relative resistance to vaccine-elicited antibodies (5-7). Consequently, losses in vaccine-57 mediated protection against select variants have been observed, and breakthrough 58 infections in vaccinated individuals have been reported (8, 9) . These studies suggest 59 that a booster vaccine may be warranted. Such a concept has been studied in organ 60 transplant patients (10, 11) and in homologous three-dose vaccination courses in 61 healthy individuals (12), but to our knowledge, not as heterologous three-dose 62 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.11.21261670 doi: medRxiv preprint 6 months after the second vaccination). Plasma was collected three weeks after the 108 second vaccination, 16 weeks after the second vaccination, two weeks after the third 109 vaccination, and four weeks after the third vaccination. Enzyme-linked immunosorbent 110 assay (ELISA) to quantify anti-SARS-CoV-2 spike and nucleoprotein antibodies, 111 recombinant vesicular stomatitis virus-based SARS-CoV-2 pseudovirus neutralization 112 assay, and authentic SARS-CoV-2 neutralization assay, were performed as previously 113 described (15). 114 115 Acknowledgements 116 We are grateful to the participants in this study for contributing to SARS-CoV-2 research. 117 There was no applicable funding for this study. 118 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.11.21261670 doi: medRxiv preprint Safety and Efficacy of the BNT162b2 mRNA Covid-19 Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine 123 against Covid-19 Antibody Persistence through 6 Months after the 125 Second Dose of mRNA-1273 Vaccine for Covid-19 Spike-antibody waning after second dose of BNT162b2 or 128 Antibody resistance of SARS-CoV-2 variants B.1 Increased resistance of SARS-CoV-2 variant P.1 to 132 antibody neutralization Reduced sensitivity of SARS-CoV-2 variant Delta to 134 antibody neutralization Vaccine Breakthrough Infections with SARS-CoV-136 Breakthrough SARS-CoV-2 Infections in Prison after Vaccination Three Doses of an mRNA Covid-19 Vaccine in Solid-140 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted August 18, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted August 18, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted August 18, 2021. ; https://doi.org/10.1101/2021.08.11.21261670 doi: medRxiv preprint