Dear Editor,
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant first emerged in late 2021 and rapidly dominated the world. BA.1 caused the first outbreak of Omicron. In early 2022, two new Omicron sublineages BA.4 and BA.5, harboring identical spike proteins, have been reported in South Africa and gradually become dominant variants in many countries [1]. A study in England demonstrated that vaccine effectiveness against the Omicron variant of two doses of ChAdOx1 nCoV-19 (Vaxzevria, AstraZeneca), BNT162b2 (Comirnaty, Pfizer–BioNTech) or mRNA-1273 (Spikevax, Moderna) vaccine dropped to less than 20% after 6 months of the second vaccination [2]. A booster dose with BNT162b2 or mRNA-1273 increased vaccine effectiveness [2]. The ChAdOx1 nCoV-19 booster conferred less protection against symptomatic SARS-CoV-2 infection caused by the Omicron variant in comparison with BNT162b2 or mRNA-1273 vaccine booster [2]. MVC-COV1901 (Medigen) is an adjuvanted protein subunit vaccine containing recombinant spike protein (S-2P) antigen, CpG 1018 (a Th1-biasing synthetic toll-like receptor 9 agonist), and aluminum hydroxide [3]. An extension to the phase 1 clinical trial found that three doses of 15 μg MVC-COV1901, which was authorized for emergent use in Taiwan and Paraguay, induced detectable neutralizing antibodies against the Omicron variant in 14 out of 15 vaccine recipients [4]. In those who received MVC-COV1901 as a primary vaccine and the mRNA vaccines as a booster, it is unclear whether anti-Omicron antibodies are present. In this study, we reported neutralizing antibody activities from two doses of ChAdOx1 nCoV-19, mRNA-1273 or MVC-COV1901 immunizations followed by a booster dose of mRNA-1273.
Written informed consents were obtained from participants before participation in the study. Inclusion criteria were: (1) healthy volunteers completed two doses of SARS-CoV-2 vaccines, including ChAdOx1 nCoV-19, BNT162b2, or mRNA-1273. (2) Received the third mRNA-1273 vaccine at least 12 weeks after the second vaccination. Exclusion criteria were: (1) age over 100 or less than 20. (2) History of confirmed or suspected COVID-19 infection. (3) Take immunosuppressant drugs after COVID-19 vaccination. The protocols of the cohort were approved by the Changhua Christian Hospital’s IRB committee (IRB no. 201225). SARS-CoV-2 spike pseudotyped viruses containing the wild type (Wuhan-hu-1), Omicron subvariant BA.1 and BA.4/5 were obtained from National RNAi Core Facility (Academia Sinica, Taiwan). Because mutations of BA.4 spike are identical to those of BA.5 spike, we refer to them as BA.4/5. As previously described, neutralizing assays were carried out against pseudotyped viruses [2]. The details of the procedure were described in the supplementary method section. To determine the titers of sera at which half amounts of pseudotyped viruses are inhibited, we calculated 50% inhibitory dilution (ID50) values using the percentage of neutralization at different dilutions. Participants were enrolled in an observational cohort study investigating the immune response to COVID-19 vaccination in health adults. Three groups of 30 healthy volunteers provided serum samples for neutralization assays with wild type and Omicron pseudotyped viruses. Each group of volunteers took two doses of ChAdOx1 nCoV-19, mRNA-1273 or MVC-COV1901 as primary vaccination.
The second dose of ChAdOx1 nCoV-19 vaccine was provided at 10 weeks after the first vaccination. After the first vaccination, mRNA-1273 or MVC-COV1901 was administered a second time 4 weeks later. Sera were collected on a medium of 31 days (range from 30 to 34 days) after a booster dose of mRNA-1273 vaccine (Table 1). The third vaccination with 50 μg mRNA-1273 was provided at least three months apart from the second vaccination. There was no difference in the time between the third COVID-19 vaccination and blood sampling among these three groups (Table 1). There were no significant differences in median age and percentage of gender among the three groups. Sera were collected 1 month after a booster dose of 50 μg mRNA-1273 vaccine. Among the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups, the median period from the second vaccination to the blood sampling was 225, 187, and 293 days, respectively (Table 1). The time between the second dose and blood sampling was significantly longer in participants who received MVC-COV1901 as primary vaccination (p < 0.001 vs. ChAdOx1 nCoV-19 group and p < 0.001 vs. mRNA-1273 group, by Kruskal–Wallis test with Dunn’s multiple comparisons). These differences were caused by the diverse available time for the individual vaccine in Taiwan. The participants did not report severe adverse effects after the primary and booster vaccinations. Most of the participants reported low-grade fever, myalgia, and fatigue after the mRNA-1273 booster.
Table 1.
Demographics of vaccine recipients
| ChAdOx1 nCoV-19 | mRNA-1273 | MVC-COV1901 | p value | |
|---|---|---|---|---|
| Number | 30 | 30 | 30 | |
| Male (%) | 11 (37%) | 5 (17%) | 7 (23%) | 0.19 |
| Age—median years (IQR; range) | 44 (34–48; 25–62) | 39 (32–46; 24–60) | 45 (39–49; 24–58) | 0.10 |
| Days post 3rd vaccination—median days (IQR; range) | 31 (31–32; 31–34) | 31 (31–32; 31–33) | 31 (31–33; 30–34) | 0.99 |
| Days post 2nd vaccination—median days (IQR; range) | 225 (192–229; 181–281) | 187 (186–188; 185–194) | 293 (279–312;168–333) | < 0.0001 |
Neutralizing antibodies against the wild type and original Omicron variant BA.1 were detected in all vaccine recipients. Neutralizing activities against the Omicron BA.4/5 were not detected in two vaccine recipients in the ChAdOx1 nCoV-19 group with 40 times dilution. The titers of ID50 against different variants are shown in Fig. 1. For the wild type, a range (and the interquartile range, IQR) of ID50 were 1667–26,832 (4495–8200), 2000–29,107 (4816–10,168), and 3333–20,000 (5236–16,122), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1A). For the Omicron BA.1, a range (IQR) of ID50 were 85–833 (190–460), 80–1231 (203–460), and 62–2212 (252–769), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1B). For the Omicron BA.4/BA.5, a range (IQR) of ID50 were 0–1667 (172–381), 40–1111 (110–310), and 62–3759 (254–728), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1C). For the wild type, the GMTs of ID50 were 6104 (95% CI 4806–7753), 6967 (95% CI 5520–8792), and 8132 (95% CI 6684–9864), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1A). There is no significant difference in neutralization efficiency among the three groups against the wild type (p = 0.2 by Kruskal–Wallis test). For the Omicron BA.1, the GMTs of ID50 were 304 (95% CI 242–373), 334 (95% CI 253–423), and 425 (95% CI 309–582), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1B). There is no significant difference in neutralization efficiency among the three groups against the Omicron BA.1 (p = 0.23 by Kruskal–Wallis test). For the Omicron BA.4/5, the GMTs of ID50 were 171 (95% CI 95–307), 184 (95% CI 138–247), and 434 (95% CI 318–592), respectively, in the ChAdOx1 nCoV-19, mRNA-1273, and MVC-COV1901 groups (Fig. 1C). There were significantly higher ID50 levels against the Omicron BA.4/5 in the MVC-COV1901 group compared to ChAdOx1 nCoV-19 group and mRNA-1273 group (Fig. 1C). As compared to the wild type, there is a 20-fold decrease in neutralizing tilters against Omicron variant BA.1 or BA.4/5. (p < 0.001 by Bonferroni’s Multiple Comparison Test). Levels of GMTs against BA.4/5 were decreased in the ChAdOx1 nCoV-19 and mRNA-1273 group as compared to levels of GMTs against BA.1, but a significant difference in ID50 was not observed between the Omicron BA.1 and BA.4/5. (p > 0.05 by Bonferroni's Multiple Comparison Test).
Fig. 1.
Neutralization of SARS-CoV-2 pseudoviruses in sera from recipients of different primary vaccine regimens and mRNA-1273 booster. Each group consists of 30 health volunteers who had received two doses of ChAdOx1 nCoV-19, mRNA-1273, or MVC-COV1901 vaccines. Serum samples were collected 1 month after the 50-μg mRNA-1273 booster dose. Antibody titers against wild-type and Omicron pseudoviruses were measured using pseudovirus neutralization assay. The 50% inhibitory dilution (ID50) was determined using the percentage of neutralization at different dilutions to determine the titers of sera at which half amounts of pseudotyped viruses are inhibited. The GMTs (central horizontal lines) and 95% confidence intervals (upper and lower horizontal lines) are plotted. GMTs of each group are given above each column. Each symbol represents individual vaccine recipients. This assay had a lower limit of detection of 40 (dotted line). A two-sided Kruskal–Wallis test with Dunn’s multiple comparisons was conducted between different types of vaccinated individuals. **P < 0.01, ***p < 0.001
Though individuals who took MVC-COV1901 as primary doses had a longer duration between the second vaccination and blood sampling, the neutralizing titers against the Omicron variant are not inferior to recipients who took ChAdOx1 nCoV-19 or mRNA-1273 as primary doses. A reliable prediction of the vaccine's effectiveness is possible when using data from different studies that have reported neutralization levels and observed levels of protection [5]. A recent study indicated that mRNA-1273 booster increased vaccine effectiveness against Omicron variant up to 66.3–70.1% 2–4 weeks after the booster among those who received ChAdOx1 nCoV-19 or mRNA-1273 as primary courses [2]. Among persons who took MVC-COV1901 as a primary course, we estimated the vaccine effectiveness would be similar.
The current study has some limitations. First, in addition to types of vaccine, age and previous COVID-19 infection may have a great impact on neutralizing tilters. Nevertheless, there is no significant difference in distributions of age in three groups of volunteers in the current study. None of the volunteers had a history of COVID-19 when blood samples were collected. The study was conducted before the outbreak of COVID-19 in Taiwan; therefore, the incidence of asymptomatic COVID-19 infection in the participants is low. Second, we do not report reactogenicity of vaccines. In addition to neutralizing tilters, T-cell response may play role in vaccine effectivenes.
To combat the COVID-19 pandemic, several kinds of SARS-CoV-2 vaccines were developed. The availability of mRNA vaccines is limited in low-income countries due to the requirements for ultracold storage. MVC-COV1901 vaccine (protein vaccine) and ChAdOx1 nCoV-19 vaccine (adenovirus-based vector vaccine) can be stored at 2–8 °C; thus, no cold chain storage is required for mass vaccinations. Two doses of MVC-COV1901 and ChAdOx1 nCoV-19 vaccines, when boosted with mRNA-1273, have favorable immunogenicity and low storage temperature requirement, making them ideal candidates for primary vaccination against the Omicron variant, including BA.4 and BA.5 subvariants.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We acknowledge the National RNAi Core Facility at Academia Sinica in Taiwan for providing SARS-CoV-2 spike-pseudotyped lentiviruses.
Author contributions
Conceptualization, YML, YLL, CEL, and WCS; methodology, YML, YCC and WCS; investigation, YML, YLL, and CEL; resources, NT and WCS; formal analysis, YML and YCC; writing—original draft, YML; writing—review and editing, YLL, CEL, NT, and WCS; funding acquisition, YML and WCS.
Funding
The research described here is supported by the Ministry of Science and Technology (MOST 110-2320-B-039-057 to Wen-Chi Su and MOST 110-2314-B-371-011 to Yuag-Meng Liu), China Medical University (CMU110-MF-25, DMR-111-151 to Wen-Chi Su) and Changhua Christian Hospital (110-CCH-IRP-017 and 110-CCH-MST-128 to Yuag-Meng Liu).
Availability of data and materials
Original data can be made available upon reasonable request.
Code availability
Not applicable.
Declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical approval
All investigations conform to the Declaration of Helsinki. Compliance with ethical standards.
Consent to participate and for publication
Informed consent had been obtained from all participants, which was performed in accordance with institutional and ethics guidelines.
Footnotes
Ni Tien and Wen-Chi Su contributed equally to this letter.
Contributor Information
Ni Tien, Email: t6719@mail.cmuh.org.tw.
Wen-Chi Su, Email: t23514@mail.cmuh.org.tw.
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Associated Data
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Supplementary Materials
Data Availability Statement
Original data can be made available upon reasonable request.
Not applicable.