Serum anti-Spike antibody titers before and after heterologous booster with mRNA-1273 SARS-CoV-2 vaccine following two doses of inactivated whole-virus CoronaVac vaccine
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Abstract
Background
The inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide. However, data on its immunogenicity and reactogenicity to heterologous boosting with mRNA vaccines are lacking.
Methods
In a cohort of hospital staff in Jakarta, Indonesia, who received two-dose CoronaVac six months prior (median 190 days, IQR165-232), we measured anti-Spike IgG titers on paired serum samples taken before and 28 days after a 100μg mRNA-1273 (Moderna) booster. We performed correlations and multivariable ordinal regressions.
Findings
Among 304 participants, the median age was 31 years (range 21-59), 235 (77.3%) were women, 197 (64.8%) had one or more previous SARS-CoV-2 infections (including 155 [51.0%] who had a post-CoronaVac breakthrough infection. Pre-boost IgG titers correlated negatively with the time since the latest documented “virus exposure” (either by the second CoronaVac or SARS-CoV-2-infection whichever most recent). Previous SARS-CoV-2 infection and a longer time interval between second vaccine and mRNA-1273 boost were associated with a higher pre-boost IgG titer. Post-booster, the median IgG titer increased 9.3-fold, from 250 (IQR32-1389) to 2313 (IQR1226-4324) binding antibody units (BAU/mL) (p<0.001). All participants, including seven whose pre-boost IgG was below assay detection limits, became seropositive and all reached a substantial post-boost titer (≥364 BAU/mL). Post-boost IgG was not associated with pre-boost titer or previous SARS-CoV-2 infection. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living (ADL).
Interpretation
A heterologous, high-dose mRNA-1273 booster after two-dose CoronaVac was highly immunogenic and safe, including in those most in need of improved immunity.
Funding
Wellcome Trust, UK
Research in context
Evidence before this study
The inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide, at around 2 billion doses in 54 countries. Concerns that CoronaVac has lower immunogenicity than virus vector or mRNA vaccines, with pronounced decreases of neutralising antibody titres within a few months, and reduced effectiveness in the older population, highlight the urgent need for immunogenic, safe and well-tolerated booster schedules, especially with Omicron rapidly emerging.
We used the terms “SARS-CoV-2”, “COVID-19”, “vaccine”, “booster” to search PubMed and medRxiv up to Dec 22th, 2021, with no language or date restrictions, to identify clinical trials and real-world studies reporting on the immune responses and reactogenicity to a “third booster” of currently approved COVID-19 vaccines. Previous research reported that neutralising antibody responses elicited by all currently approved vaccines (mRNA, adenovirus-vectored, inactivated, and protein subunit) declined to varying degrees after 6-8 months after full-schedule vaccination. Several clinical trials have evaluated heterologous (“mix and match”) vaccination schedules, demonstrating robust immune responses in adults. After two-dose CoronaVac, BNT162b2 (Pfizer-BioNTech) boost was significantly more immunogenic than a homologous booster against wild-type and Variants of Concern (VOCs) Beta, Gamma and Delta, and AZD1222 boost increased spike RBD-specific IgG 9-10-fold, with high neutralizing activity against the wild type and VOCs. Compared to previous SARS-CoV-2 variants, current vaccine boosters appeared to neutralise Delta to a slightly lesser degree, and Omicron to a substantially lesser degree, although preliminary data from Moderna found that the authorised dose (50μg) of the mRNA-1273 boost increased antibodies 37-fold and the high-dose (100μg) boost 83-fold.
Added value of this study
To our knowledge, this study is the first to provide critical real-world evidence that heterologous boosting with high-dose mRNA-1273 vaccine after CoronaVac is highly immunogenic, safe and well-tolerated in adults. After a primary course of two-dose CoronaVac, we found that a high-dose (100μg) mRNA-1273 booster was immunogenic for all participants in a highly exposed cohort of hospital staff in Jakarta, Indonesia, in the context of Delta predominance, particularly for those with the lowest pre-boost antibody levels. All participants became seropositive and all reached a substantial post-boost titer (≥364 BAU/mL), up to a median 9.3-fold increase. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living
Implications of all the available evidence
The study findings contribute to informing policy makers on flexible options in deploying COVID-19 vaccines in mix-and-match schedules, with particular relevance for countries that are largely dependent on inactivated vaccines. Further trials are warranted that assess clinical endpoints of optimized doses of mRNA-1273 booster, and variant-specific or multivalent vaccines in response to decreased protection against emerging SARS-CoV-2 VOCs.
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SciScore for 10.1101/2021.12.24.21268360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the research ethics committee of Faculty of Medicine Universitas Indonesia (841/UN2.F1.ETIK/PPM.00.02/2021) and Oxford Tropical Research Ethics Committee (22-21).
Consent: All participants provided written informed consent.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Serum was stored at -80°C and transferred to a commercial laboratory, where titers of IgG antibodies against the SARS-CoV-2 spike receptor-binding domain were determined using the chemiluminescent microparticle immunoassay (CMIA) SARS-CoV-2 IgG II Quant assay (Abbott Laboratories, … SciScore for 10.1101/2021.12.24.21268360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the research ethics committee of Faculty of Medicine Universitas Indonesia (841/UN2.F1.ETIK/PPM.00.02/2021) and Oxford Tropical Research Ethics Committee (22-21).
Consent: All participants provided written informed consent.Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Serum was stored at -80°C and transferred to a commercial laboratory, where titers of IgG antibodies against the SARS-CoV-2 spike receptor-binding domain were determined using the chemiluminescent microparticle immunoassay (CMIA) SARS-CoV-2 IgG II Quant assay (Abbott Laboratories, Abbott Park, IL, US) on the Architect i2000sr platform, in accordance with the manufacturer’s package insert. SARS-CoV-2 IgGsuggested: NoneSoftware and Algorithms Sentences Resources Serum was stored at -80°C and transferred to a commercial laboratory, where titers of IgG antibodies against the SARS-CoV-2 spike receptor-binding domain were determined using the chemiluminescent microparticle immunoassay (CMIA) SARS-CoV-2 IgG II Quant assay (Abbott Laboratories, Abbott Park, IL, US) on the Architect i2000sr platform, in accordance with the manufacturer’s package insert. Abbott Laboratoriessuggested: NoneStatistical analysis was performed with Stata/IC 15.1 (StataCorp, College Station, TX, USA). StataCorpsuggested: (Stata, RRID:SCR_012763)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are some limitations to our study. First, although accumulating evidence suggests that anti-Spike IgG response is a correlate of disease protection31,32, it is important to recognise there is not yet an established or well defined correlate of long-term vaccine protection. In this study we did not assess anti-N IgG, neutralizing antibody or cellular immunity33. Second, because subjects had not been under routine surveillance for SARS-CoV-2 infection, we could not fully discern all who had been infected by SARS-CoV-2, and the use of anti-N as a proxy for breakthrough infections was not valid because of the initial immunization with a whole-virus inactivated vaccine. Third, the sample size and follow-up period were not sufficient to identify less common or late adverse events following booster vaccination, and the immunogenicity data were limited to immune responses through study day 28. Fourth, only immunological data were collected and therefore this investigation lacks information regarding the efficacy of a heterologous mRNA-1273 booster vaccination. Lastly, demographics of the volunteers were not representative of the Indonesian population, and elderly were not represented. In conclusion, our study provides evidence that, after a primary course of CoronaVac inactivated virus vaccine, a heterologous, high-dose mRNA-1273 booster was highly immunogenic and safe, even for those with the lowest pre-boost antibody levels.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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