key: cord-1005267-in04vvur authors: Niyomnaitham, S.; Toh, Z. Q.; Wongprompitak, P.; Jansarikit, L.; Srisutthisamphan, K.; Sapsutthipas, S.; Jantraphakorn, Y.; Mingngamsup, N.; Licciardi, P.; Chokephaibulkit, K. title: Immunogenicity and reactogenicity against the SARS-CoV-2 variants following heterologous primary series involving CoronaVac and ChAdOx1 and BNT162b2 plus heterologous BNT162b2 booster vaccination: An open-label randomized study in healthy Thai adults. date: 2022-03-06 journal: nan DOI: 10.1101/2022.03.03.22271601 sha: 8f1ac1e50338f43863eab58c9a257e30d898637a doc_id: 1005267 cord_uid: in04vvur We evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary series vaccination schedules. Participants were randomized to one of seven groups that received two-dose homologous BNT162b2 or heterologous combinations of CoronaVac, ChAdOx1 and BNT162b2, with 4 weeks interval. Of 210 participants, median age was 38 (19-60) years, 51% were female. The groups that received BNT162b2 as second dose induced the highest virus-specific IgG response against the ancestral strain [BNT162b2: geometric mean concentration (GMC) 2133-2249, 95%CI 1558 to 3055; ChAdOx1: 851-1201, 95%CI 649 to 1522; CoronaVac: 137-225, 95%CI 103-286 BAU/mL], neutralising antibodies (NAb) against Beta and Delta, and interferon gamma response. All groups induced low to negligible NAb against Omicron. A BNT162b2 booster (3rd dose) following heterologous CoronaVac and ChAdOx1 regimens induced >140-fold increase in NAb titres against Omicron. Our findings indicate that heterologous regimens using BNT162b2 as the second dose may be considered an alternative schedule to maximize immune response. As of 22 nd of Feb 2022, the severe acute respiratory syndrome coronavirus-2 (SARS-77 CoV-2) has infected more than 400 million people and caused more than 5 million deaths 78 globally 1 . Vaccination against COVID-19 has been crucial for controlling the pandemic, with CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint The limited supply of COVID-19 vaccines globally has resulted in less than 10% of the 100 eligible population in low-income countries being fully vaccinated 10 ChAdOx1 11 compared to homologous vaccination 12 , limited data is available for heterologous 108 primary vaccination involving inactivated vaccines such as CoronaVac. In Thailand, due to the lack of access to mRNA vaccine in the early phase of the 111 pandemic, and following early reports of better immunogenicity in heterologous primary series 112 than homologous primary series, a CoronaVac-prime and ChAdOx1-boost schedule has been 113 implemented across the country 13 . However, limited data exists for how these vaccine Participant's baseline characteristics 122 Between January 2021-June 2021, a total of 220 participants were screened and 210 123 were enrolled. Participants were assigned to one of the seven groups (30 per group) of either 124 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) CoronaVac groups, 8.18-9.01 (95%CI 6.5 to 11.2), p<0.001) ( Figure 3A and Supplementary 173 Table 1 ). The PRNT50 in the heterologous groups that received BNT162b2 as second dose were 174 . CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. Due to the unavailability of live-virus assay against Omicron, we used pseudovirus-178 based neutralization assay to evaluate neutralizing antibody activity against Omicron and Delta 179 to compare the two variants. There was a strong correlation between the PVNT50 and PRNT50 CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. BNT162b2 are given as second dose, the BNT162b2 given as a third dose was able to induce 309 high level humoral immunity against Omicron. This is the first study to demonstrate that 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint BNT162b2 as the third booster vaccination provided high neutralizing activity against Delta 325 and Omicron, which is likely to provide protection against these two predominant variants. Future studies incorporating mRNA booster to other heterologous primary schedules will be 327 of interest, particularly with other COVID-19 vaccines that have recently received WHO EUL. In conclusion, we found that heterologous COVID-19 primary series using either reported by our study group using the same laboratory method and facility as this study 4 . Unpaired t-test were used to compare IgG GMC between groups at two weeks after 605 second dose vaccination. Numbers on the x-axis represent geometric mean titer (GMT) and error bars represent 613 95% confidence interval (CI). Unpaired t-test were used to compare PRNT50 between 614 each group at two weeks after second dose. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint (orange). (B) Pseudovirus-based neutralizing antibody titres (PVNT50) against Delta (blue) 620 and Omicron (green) variants following a BNT162b2 booster (third dose) at two weeks after 621 second dose and two weeks after the third booster dose. Numbers on the x-axis represent 622 geometric mean titer. The fold change and significance p-value comparing two weeks after the 623 third booster and two weeks after second dose. Accessed on 22 nd February 2022 499 2. The New York Times. 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A pilot study in Health Care Workers SARS-CoV-2 pseudovirus was constructed for pseudotype-based neutralization assays CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint IGRA were performed using the Quantiferon SARS-CoV-2 assay (QIAGEN) 448 according to the manufacturer's instruction. Fresh whole blood samples were collected into 449 tubes containing SARS-CoV-2 S peptide pools for CD4 + T cells (Ag 1), and CD8 + T cells 450 (Ag2), a mitogen tube as the positive control and an unstimulated tube as negative control. The 451 specimen was incubated at 37 ͦ C for 16-24 hours and centrifuged to separate plasma. CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprintThe datasets generated during and/or analyzed during the current study are available 472 from the corresponding author on reasonable request. 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 March 6, 2022. . CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a 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 March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271601 doi: medRxiv preprint Figure 6