Profiling Humoral Immunity After Mixing and Matching COVID-19 Vaccines Using SARS-CoV-2 Variant Protein Microarrays

•Establish CoVariant protein arrays including spike proteins from wild-type to omicron variants.•Concurrently detect neutralizing and binding antibodies against multiple SARS-CoV-2 variants.•Mixing of AZD1222 and mRNA-1273 generates better humoral immunity against omicron than matching. In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130–0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron. In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130–0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron. There are several vaccines available to the population since the first outbreak of SARS-CoV-2 in 2019. Based on the design of the vaccines, they can be classified into four main types, e.g., viral vector, nucleic acid, protein subunit, and whole virus. Until now, more than five billion people have received at least one dose of the COVID-19 vaccine, equal to 68.2% of the world population (acquired from Our World in data). Among different vaccines, the viral vector AZD1222 (ChAdOx1) and the two mRNA (mRNA-1273 and BNT162b2) are the most effective vaccines currently available (1Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2021; 397: 99-111Abstract Full Text Full Text PDF PubMed Scopus (3303) Google Scholar, 2El Sahly H.M. Baden L.R. Essink B. Doblecki-Lewis S. Martin J.M. Anderson E.J. et al.Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase.N. Engl. J. Med. 2021; 385: 1774-1785Crossref PubMed Scopus (343) Google Scholar, 3Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N. Engl. J. Med. 2020; 383: 2603-2615Crossref PubMed Scopus (9627) Google Scholar). However, the performance of vaccines is impacted by inherently high error rates of virus-specific RNA polymerases and deviated from the original wildtype spike antigen (4Thomson E.C. Rosen L.E. Shepherd J.G. Spreafico R. da Silva Filipe A. Wojcechowskyj J.A. et al.Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.Cell. 2021; 184: 1171-1187.e1120Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 5Lou F. Li M. Pang Z. Jiang L. Guan L. Tian L. et al.Understanding the secret of SARS-CoV-2 variants of concern/interest and immune escape.Front. Immunol. 2021; 12744242Crossref Scopus (37) Google Scholar). According to the World Health Organization, five of the SARS-CoV-2 variants of concern (VOCs) have been identified, e.g., alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529). Mutations occur throughout the receptor-binding domain (RBD) and N-terminal domain (NTD) of the spike antigen. Furthermore, multiple subvariants of the SARS-CoV-2 with higher transmissibility and immune escape have emerged from the B.1.1.529 (omicron) variant (6Barouch D.H. Covid-19 vaccines - immunity, variants, boosters.N. Engl. J. Med. 2022; 387: 1011-1020Crossref PubMed Scopus (228) Google Scholar). Thus, understanding humoral immunity against variants is crucial for developing effective vaccination strategies. In the United States, the Centers for Disease Control and Prevention currently advises, wherever possible, completing a primary series of a two-dose vaccine (or three doses for specific immunocompromised people). Interestingly, combining different types of HIV vaccines, e.g., prime with DNA vaccine and boost with envelope protein or viral vector vaccines, has proven to evoke more robust immune responses (7Kardani K. Bolhassani A. Shahbazi S. Prime-boost vaccine strategy against viral infections: mechanisms and benefits.Vaccine. 2016; 34: 413-423Crossref PubMed Scopus (186) Google Scholar, 8Lu S. Heterologous prime-boost vaccination.Curr. Opin. Immunol. 2009; 21: 346-351Crossref PubMed Scopus (371) Google Scholar). Owing to thromboembolic events that occurred following the first dose of the vector-based AZD1222 vaccine against COVID-19, many countries including several European countries and Canada modified their national immunization strategies and reserved the AZD1222 vaccine for older people (9Greinacher A. Thiele T. Warkentin T.E. Weisser K. Kyrle P.A. Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N. Engl. J. Med. 2021; 384: 2092-2101Crossref PubMed Scopus (1564) Google Scholar). Also, a study in France performed a trial to compare 10,609 healthcare workers receiving a matching of BNT162b2 + BNT162b2 with 2512 healthcare workers receiving a mixing of AZD1222 + BNT162b2. Surprisingly, there was almost a 2-fold reduction of the SARS-CoV-2 infection in the mixing group than in the matching group (10Pozzetto B. Legros V. Djebali S. Barateau V. Guibert N. Villard M. et al.Immunogenicity and efficacy of heterologous ChAdOx1-BNT162b2 vaccination.Nature. 2021; 600: 701-706Crossref PubMed Scopus (152) Google Scholar). To investigate the humoral response in the mixing or matching of vaccines, it is important to adopt a high-throughput platform to measure all the VOCs. We recently developed a SARS-CoV-2 Variant (CoVariant) protein array that included the spike proteins from wildtype, alpha, beta, gamma, and delta variants (11Ho T.S. Du P.X. Su W.Y. Santos H.M. Lin Y.L. Chou Y.Y. et al.Development of SARS-CoV-2 variant protein microarray for profiling humoral immunity in vaccinated subjects.Biosens. Bioelectron. 2022; 204114067Crossref Scopus (8) Google Scholar, 12Su W.Y. Du P.X. Santos H.M. Ho T.S. Keskin B.B. Pau C.H. et al.Antibody profiling in COVID-19 patients with different severities by using spike variant protein microarrays.Anal. Chem. 2022; 94: 6529-6539Crossref PubMed Scopus (6) Google Scholar). In this study, we expanded the VOCs collection to include omicron and used it for measuring the humoral immunity in the mixing or matching of AZD1222 and mRNA-1273. The binding antibody and the antibody with surrogate neutralizing activity against spike proteins in all VOCs can be detected simultaneously in a single assay. Although the surrogate neutralizing activity faded with variants, it was more sustained in the mixing than matching, especially in gamma and omicron. This study provided a high-throughput tool for evaluating vaccine strategies to fight against the rapid SARS-CoV-2 mutations. For fabrication of the CoVariant protein microarray, the slides were precoated with aldehyde and stored at 4 °C as described (11Ho T.S. Du P.X. Su W.Y. Santos H.M. Lin Y.L. Chou Y.Y. et al.Development of SARS-CoV-2 variant protein microarray for profiling humoral immunity in vaccinated subjects.Biosens. Bioelectron. 2022; 204114067Crossref Scopus (8) Google Scholar, 13Du P.-X. Chou Y.-Y. Santos H.M. Keskin B.B. Hsieh M.-H. Ho T.-S. et al.Development and application of human Coronavirus protein microarray for specificity analysis.Anal. Chem. 2021; 93: 7690-7698Crossref PubMed Scopus (17) Google Scholar). A contact printer (CapitalBio SmartArrayer 136) was used to print eight variant spike extracellular domains (ECDs), seven spike RBDs, two nucleocapsid proteins, three control, and cell membrane mix with 30% glycerol (supplemental Table S1) in technical triplicate at 4 °C cold room. After printing, the CoVariant arrays were immobilized for 8 h under 4 °C, vacuum sealed, and stored at −80 °C for long-term preservation. The immobilization and functionality of the proteins on the microarrays were assessed by 50 μl of 0.55 μg/ml 647-conjugated rabbit anti-His tag (Jackson ImmunoResearch, #300-605-240), serial dilution of anti-spike antibody (Sino Biological, #40150-D001) with 30 ng/ml Cy3-conjugated anti-human IgG+IgM+IgA (a.k.a. anti-human, Jackson ImmunoResearch, #109-165-064), and 39 ng/ml human biotinylated angiotensin-converting enzyme 2 (ACE2) (Sino Biological, #10108-H08H-B) with 1.8 ug/ml Cy5-conjugated Streptavidin (Jackson ImmunoResearch, #016-170-084). Subjects were healthcare staff of Kaohsiung Chang Gung Memorial Hospital including doctors, nurses, social workers, physician's assistants, patient care technicians, physical therapists, and hospital pharmacists who were free of COVID-19 infection and have been fully vaccinated with two doses of SARS-CoV-2 vaccine for more than 10 days. Plasmas were collected 10 to 90 days after subjects finished two dosages of COVID-19 vaccines, including AZx2, Mx2, or AZ+M. Subjects who had a diagnosis of COVID-19 history or had not received any COVID-19 vaccines were excluded from this study. During the sample collection in late 2021, there were very in with an of since to of the population in including or after the vaccine were for The was to the of and by the Chang Gung Memorial The CoVariant protein arrays stored at −80 °C were to and with with for 10 were with for and with 50 μl of in with for an The CoVariant array was with three and with a 50 μl of 30 ng/ml anti-human + antibodies (Jackson #109-165-064), biotinylated human 39 and Cy5-conjugated 1.8 ug/ml for an After the arrays were and for and with of 30% and The were and as by For the surrogate neutralizing the were on the of binding with For the binding the were on the anti-human by anti-His The were as for or with for and using the 8 For the were by the by multiple For the were by A were and by with The level of was as and Owing to the ongoing of the there were five variants classified as VOCs, including alpha (B.1.1.7), beta gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529). The of the spike proteins was the to infection and with the we the and the of the spike proteins from wildtype and variants to the immune responses after and Table The design of this study was in and were and immobilized on the CoVariant protein the CoVariant arrays were controlled by the anti-His and higher than the (supplemental A and the of two arrays was high with an of (supplemental the spike proteins on the arrays were by with (supplemental the anti-spike antibody showed surrogate neutralizing activity by of the (supplemental the of the CoVariant arrays were for measuring humoral in vaccinated The two of the AZD1222 and mRNA-1273 vaccines different immune we subjects who two doses of AZD1222 (AZx2), two doses of mRNA-1273 and one dose of AZD1222 by one dose of mRNA-1273 (AZ+M). The of subjects in AZx2, Mx2, and AZ+M was and There were in and However, there were significant in with the in AZ+M and days with the in Mx2 and from the spike proteins, we included nucleocapsid protein on the CoVariant protein array for The were included in Table with group The from the subjects were with CoVariant protein microarrays and with the anti-human which is the single three and human the human the the low immune response to the higher The in AZx2 were more than in Mx2 and which can be into high and low responses of subjects who mixing or matching of AZD1222 and after vaccination in this study include and were by the by multiple or by compared with AZx2 and compared with Mx2. in a The in this study include and were by the by multiple or by compared with AZx2 and compared with Mx2. we developed CoVariant protein microarrays for profiling the humoral in subjects after mixing or matching two doses of vaccines. measuring the and with the surrogate neutralizing can be as with with Mx2 and AZx2 showed the surrogate neutralizing against wildtype alpha beta gamma delta and omicron Interestingly, AZ+M exhibited the surrogate neutralizing against alpha beta gamma and omicron and the is the for the surrogate neutralizing against the is the to the vaccine with the spike the spike contained more and to AZx2 showed the surrogate neutralizing against wildtype alpha beta gamma delta and omicron the AZ+M the surrogate neutralizing against gamma and omicron and AZD1222 and mRNA-1273 were to wildtype it is to investigate the surrogate neutralizing against In AZx2, the surrogate neutralizing antibodies against the were in alpha, beta, gamma, delta, and omicron (supplemental In Mx2, the surrogate neutralizing against the were in VOCs (supplemental In the surrogate neutralizing antibodies against the were at a similar level as wildtype for beta and omicron (supplemental than the may with the human L. J. M. et neutralizing antibodies against multiple on SARS-CoV-2 2020; PubMed Scopus Google Scholar, J. T. et and immune by the spike protein of SARS-CoV-2 2021; PubMed Scopus Google Scholar). In study, the surrogate neutralizing against were more the variants than In AZx2, the surrogate neutralizing antibodies against the were in alpha, gamma, and omicron (supplemental In Mx2, the surrogate neutralizing against the were in beta, gamma, and omicron (supplemental In the surrogate neutralizing antibodies against the were at a similar level as wildtype for gamma and omicron (supplemental the surrogate neutralizing the mixing of AZ+M more surrogate neutralizing against variants than matching AZx2 and Mx2. To the of antibodies after we human antibodies in AZx2, Mx2, and AZ+M using CoVariant protein The were used to the protein on the CoVariant protein with Mx2 and AZx2 showed the binding antibodies to wildtype alpha beta gamma delta and omicron There were in binding antibodies Mx2 and AZ+M in the of any VOCs. The design of the AZD1222 and mRNA-1273 vaccines was on the wildtype SARS-CoV-2 the antibodies not the but of the spike with Mx2 and AZx2 showed the binding antibodies against wildtype alpha beta gamma delta and omicron There were in binding antibodies Mx2 and AZ+M in the of any VOCs. In AZx2, the binding antibodies against were variants, including beta, gamma, delta, and omicron (supplemental In Mx2 and the binding antibodies against were in alpha but in beta gamma delta and omicron The of binding antibodies against was In AZx2, the binding antibodies were in beta gamma and omicron (supplemental In Mx2, the binding antibodies in beta and omicron (supplemental Surprisingly, the mixing of AZ+M showed binding antibodies the of variants (supplemental the binding antibody the mixing of AZ+M may more antibodies against variants than matching AZx2 and Mx2. To the of the binding antibody and the surrogate neutralizing antibody after we and all the surrogate neutralizing (supplemental binding antibodies (supplemental surrogate neutralizing (supplemental and binding antibodies (supplemental the the higher surrogate neutralizing were not by higher binding we the surrogate neutralizing antibodies with binding antibodies against The results showed significant low e.g., in wildtype in alpha in beta in gamma in delta and in omicron (supplemental the surrogate neutralizing antibodies and binding antibodies against were significant but with low The were in wildtype in alpha in beta in gamma in delta and in omicron (supplemental The surrogate neutralizing antibodies and binding especially in the to the antibody and After two and of the COVID-19 several VOCs are by the World Health Organization, including alpha, beta, gamma, delta, and omicron. have a decrease in vaccine against VOCs B. J. et antibodies against SARS-CoV-2 variants of concern by the COVID-19 vaccine in 2022; PubMed Scopus Google Scholar, M. A. M. R. et of neutralizing by three COVID-19 vaccines against variants of Immunol. 2022; Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of different vaccine strategies, neutralizing antibodies against VOCs, and binding antibodies against VOCs are we developed CoVariant protein microarrays for profiling the humoral in subjects after mixing or matching two doses of vaccines. In the matching we a decrease in surrogate neutralizing antibodies and binding antibodies in most VOCs, especially in omicron. The results were by using reduction et antibody responses by SARS-CoV-2 mRNA vaccination and are by Med. 2022; PubMed Scopus Google Scholar, A. M. J. J. et of SARS-CoV-2 by BNT162b2 mRNA human 2022; PubMed Scopus Google Scholar). reduction is the most to quantify neutralizing in and is to to the and days of have developed surrogate to the by the reduction but can on one variant at a et SARS-CoV-2 surrogate on antibody-mediated of 2020; PubMed Scopus Google Scholar). Until now, we developed the high-throughput platform to quantify the surrogate neutralizing antibodies in all VOCs with the binding there is similar high-throughput we on the wildtype SARS-CoV-2 and with reduction and surrogate In study, we that the were from to and the of this high-throughput platform (11Ho T.S. Du P.X. Su W.Y. Santos H.M. Lin Y.L. Chou Y.Y. et al.Development of SARS-CoV-2 variant protein microarray for profiling humoral immunity in vaccinated subjects.Biosens. Bioelectron. 2022; 204114067Crossref Scopus (8) Google Scholar). membrane from human cell has been used for and the results not any significant not The of the platform to include protein to monitor The low level of in the with the low infection in late 2021, the in which have been for the study. In we and surrogate which with the or that COVID-19 immunity with the dose to 4 from the first trials and of vaccination that vaccines can of against and (1Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2021; 397: 99-111Abstract Full Text Full Text PDF PubMed Scopus (3303) Google Scholar, N. N. S. et mRNA Covid-19 vaccine in a vaccination Engl. J. Med. 2021; 384: PubMed Scopus Google Scholar). Furthermore, an dose strategy is to be effective against infection and R. A. R. M. 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A to detect SARS-CoV-2 antibodies in collected 2020; Scopus Google Scholar). neutralizing antibodies are described by et in and in with the SARS-CoV-2 spike or T. J. M. M. et SARS-CoV-2 neutralizing antibodies against spike N-terminal domain a single 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). Also, et that are than in the K. M. A. F. et of neutralizing antibodies against multiple SARS-CoV-2 in using 2022; PubMed Scopus (8) Google Scholar). This be by the that by to a on the protein of the but binding to to the the surrogate neutralizing or binding antibodies against or of VOCs were better in mixing AZ+M than matching AZx2 and Mx2. It is worth noting that mixing AZ+M higher surrogate but similar binding antibodies in VOCs than Mx2. better antibody of in mixing AZ+M. The mechanisms for this are not in the While the mRNA-1273 vaccine generates antibody responses to the the AZD1222 vaccine mixing vaccines boost immune 2021; PubMed Scopus Google Scholar). The of by in mixing AZ+M may provide a better of the antibodies against VOCs. There are of this study, including a of and the vaccine in V. S. F. A. A. et against SARS-CoV-2 after Covid-19 vaccination and Engl. J. Med. 2022; PubMed Scopus Google this study on different vaccine strategies from 10 to 90 days During that there was significant correlation surrogate and days after are for the in mixing and matching. Although this study on humoral immunity, more and more showed the humoral immunity and study showed that better humoral immunity is with a higher of virus-specific Z. Z. Li et are with long-term of neutralizing 2022; PubMed Scopus Google Scholar). of the study is that the of the are developing and are two of the (B.1.1.529). was first in in South Africa, and as of 2022, and the most variants in In several a of with two and in the spike has in Although were not the of this study, it is to include on the CoVariant protein microarrays in the In this study, we CoVariant protein microarrays for profiling surrogate neutralizing antibodies and binding CoVariant protein we that mixing of AZD1222 and mRNA-1273 better humoral responses against omicron than matching of AZD1222 or mRNA-1273. The high-throughput tool and the vaccine strategy that we may on SARS-CoV-2 mutations. The in this study are available from the The proteins on the CoVariant microarrays were in Table This with and The The study was in by the of the of Health and and of to the of at We are for the from the for and This was in by Chang Gung Memorial Hospital and We for the microarray The had in study collection and to or of the This was in by the and - T.-S.

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