key: cord-0936286-oll9e2jq authors: Bae, Seongman; Ko, Jae-Hoon; Choi, Ju-Yeon; Park, Woo-Jung; Lim, So Yun; Ahn, Jin Young; Song, Kyoung-Ho; Lee, Kyoung Hwa; Song, Young Goo; Chan Kim, Yong; Park, Yoon Soo; Choi, Won Suk; Jeong, Hye Won; Kim, Shin-Woo; Kwon, Ki Tae; Kang, Eun-Suk; Kim, Ah-Ra; Jang, Sundong; Kim, Byoungguk; Kim, Sung Soon; Jang, Hee-Chang; Choi, Jun Yong; Kim, Sung-Han; Peck, Kyong Ran title: Heterologous ChAdOx1 and BNT162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity date: 2022-05-19 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2022.04.019 sha: 565738d0fa1fb94a6cbd7298da61adb59c01571d doc_id: 936286 cord_uid: oll9e2jq OBJECTIVES: We assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups. METHODS: We enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or two doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey. RESULTS: We enrolled 499 HCWs (ChAdOx1, n=199; BNT162b2, n=200; heterologous ChAdOx1/BNT162b2, n=100). The geometric mean titer of anti-RBD antibody at 14 days after the booster dose was significantly higher in the heterologous group (11780.55 BAU/mL [95% CI, 10891.52–12742.14]) than in the ChAdOx1 (1561.51 [1415.03–1723.15]) or BNT162b2 (2895.90 [2664.01–3147.98]) groups (both P value<.001). The neutralizing antibody titer of the heterologous group (geometric mean ND(50,) 2367.74 [1970.03–2845.74]) was comparable to that of the BNT162b2 group (2118.63 [1755.88–2556.32], P >.05) but higher than that of the ChAdOx1 group (391.77 [326.16–470.59], P value<.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND(50.) 872.01 [95% CI, 685.33–1109.54]), 4.0-fold in the BNT162b2 group (337.93 [262.78–434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [144.05–296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group. CONCLUSIONS: Heterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2 including the delta variant that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile. Effective vaccination regimens against COVID-19 are crucial for controlling the ongoing 91 pandemic. In response to the instability of vaccine supply and vaccine-related adverse events 92 such as thrombosis with thrombocytopenia syndrome, new immunization programs that 93 combine vaccines from different platforms has been proposed. 1 Boosting with vaccines from 94 the different platforms may become more prevalent if standard homologous vaccination fails 95 to achieve long-lasting immunity or revised vaccines against SARS-CoV-2 variants are 96 required. 2,3 Particularly, repeated vaccination with the same viral vector vaccines may be less 97 effective due to the pre-existing vector-specific immunity. 4, 5 In this regard, it is important to 98 accrue empirical data on the safety and immunogenicity of heterologous prime-boost 99 vaccination regimens in various settings. In this study, we evaluated the reactogenicity and 105 For this prospective observational cohort study, we recruited healthcare workers (HCWs) 106 from 10 domestic hospitals in South Korea who received either 1) homologous prime-boost 107 vaccination with the BNT162b2 mRNA vaccine or the ChAdOx1 adenoviral vector vaccine, 108 or 2) heterologous vaccination with ChAdOx1 followed by BNT162b2 booster. We planned (FDA) toxicity scale. 6 The reactogenicity is presented as a total symptom score, which was 126 calculated as the sum of each symptom during the 7 days after vaccination by assigning a 127 score according to the severity as follows: mild as 1 point, moderate as 2 points, severe as 3 points, and life-threatening as 4 points. Prophylactic use of antipyretics was not 129 recommended but allowed depending on the health conditions. The English version of the 130 questionnaire is provided in the eAppendix in Supplement. Antibody response 133 Antigen-specific humoral immune response was analyzed using the Elecsys AntiSARS- Plaque-reduction neutralization assay (PRNT) 146 To evaluate the functionality of vaccine-induced antibody response, we performed the 147 plaque-reduction neutralization (PRNT) assay by using sera from all 100 participants in the 148 heterologous group and 100 randomly selected participants from each of the homologous 149 groups. In addition, plasmas from ten participants of each vaccination group were randomly 150 selected and neutralizing antibody geometric mean titers determined by PRNT in four SARS- Characteristics of the study population 168 A total of 500 HCWs were enrolled in this study, including 200 in the ChAdOx1 Neutralizing antibody titer against the four variants of concern 225 We randomly selected 10 participants from each group to determine the serum level of 226 neutralizing antibodies against the four SARS-CoV-2 variants of concern-B.1.1.7 (alpha), In this prospective observational study including 499 healthcare workers, we found that the We also found that the heterologous vaccination showed higher neutralizing activity than however, because the participants of the Com-Cov study had a median age of 57 years, their 280 results could not be extrapolated to younger age groups. Considering that the reactogenicity is 281 higher in the younger age groups after receiving the ChAdOx1 or BNT126b2 vaccines, 18, 19 282 there is still concern about whether the reactogenicity profile is tolerable in the heterologous 283 regimen, especially in young individuals. Therefore, our data suggest that ChAdOx1 followed 284 by BNT162b2 in young individuals may have some short-term disadvantage in terms of 285 reactogenicity, but the reactogenicity would be largely tolerable without serious or life-286 threatening consequences. This study has several limitations. First, this observational study may be subject to selection bias, particularly in that the heterologous vaccination group was recruited from 289 those who experienced vaccine-related adverse reactions following the priming dose of 290 ChAdOx1. However, this particular selection of participants may allow a different 291 interpretation of our results in that heterologous vaccination can generate a robust antibody 292 response without a significant safety concern in vaccine recipients who experience adverse 293 events following the initial dose. Our cohort was younger and female predominant, which 294 may affect vaccine-induced immune response. 20 However, given the similar age and sex 295 distribution of the three vaccination groups, these factors are unlikely to introduce a 296 significant bias to the results. Second, we did not assess the cellular immunity, which is as One study reported that the 2-dose heterologous vaccination with ChAdOx1/BNT162b2 305 showed slightly higher neutralizing antibody titers than 2-dose homologous vaccination with 306 BNT162b2, while these neutralizing titers against omicron variant were substantially lower 307 than those against other variants. 24 So, a booster shot should be recommended regardless of 308 homologous or heterologous two-shot series until further evidence on this issue is available. In conclusion, we found that heterologous COVID-19 vaccination generated an antibody 310 response to SARS-CoV-2 that was comparable to that of homologous BNT162b2 vaccination Reactogenicity according to sex group. Horizontal bars represent mean, and error bars represent 95% confidence interval. *P<.05, **P<.001, ***P<.0001, ****P<.00001, ns = non-significant P value. Thrombotic between doses Delayed-interval BNT162b2 mRNA COVID-19 379 vaccination enhances humoral immunity and induces robust T cell responses The germinal centre B cell response to SARS-CoV-2 DNA priming and influenza vaccine 384 immunogenicity: two phase 1 open label randomised clinical trials Safety and Immunogenicity of Heterologous and 387 Homologous Two Dose Regimens of Ad26-and MVA-Vectored Ebola Vaccines: A 388 Controlled Phase 1 Study Heterologous 390 prime-boost COVID-19 vaccination: initial reactogenicity data Adverse Reactions Following the First Dose of ChAdOx1 393 nCoV-19 Vaccine and BNT162b2 Vaccine for Healthcare Workers in South Korea Adverse Reactions of the Second Dose of the BNT162b2 396 mRNA COVID-19 Vaccine in Healthcare Workers in Korea COVID-19 mRNA Vaccination Generates 399 Greater Immunoglobulin G Levels in Women Compared to Men Adaptive immunity to SARS-CoV-2 and COVID-19 mRNA-based COVID-19 vaccine 404 boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant Omicron Variant SARS-CoV-2 Omicron Variant Neutralization in 340 All authors have completed the ICMJE uniform disclosure form at 341 www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the 342 submitted work; no financial relationships with any organizations that might have an interest 343 in the submitted work in the previous three years; no other relationships or activities that 344 could appear to have influenced the submitted work.