Immunogenicity and reactogenicity against the SARS-CoV-2 variants following heterologous primary series involving CoronaVac, ChAdox1 nCov-19 and BNT162b2 plus BNT162b2 booster vaccination: An open-label randomized study in healthy Thai adults.

We evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules involving BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCoV-19 (AstraZeneca) and CoronaVac (Sinovac) in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. Participants were randomized to one of seven groups that received two-dose homologous BNT162b2 or heterologous combinations of CoronaVac, ChAdOx1 nCoV-19 and BNT162b2, with 4 weeks interval. A total of 210 participants were enrolled, 30 in each group. Median age of participants was 38 (19-60) years, and 108/210 (51.43%) were female. Overall adverse events after the second dose were mild to moderate. We found that groups that received BNT162b2 as second dose induced the highest anti-receptor binding domain IgG response against the ancestral strain [BNT162b2: geometric mean concentration (GMC) 2133-2249 BAU/mL; ChAdOx1 nCoV-19: 851-1201; CoronaVac: 137-225 BAU/mL], neutralizing antibodies (NAb) against Beta and Delta, and interferon gamma response. All groups induced low to negligible NAb against Omicron after second dose. A BNT162b2 booster (third dose) following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens induced >140-fold increase in NAb titers against Omicron. Our findings indicate that heterologous regimens using BNT162b2 as the second dose may be an alternative schedule to maximize immune response. While heterologous two-dose schedules induced low NAb against Omicron, the use of an mRNA vaccine booster dose substantially increased the Omicron response. These findings are relevant for low-income countries considering heterologous primary and booster COVID-19 vaccine schedules.

The STING Ligand and Delivery System Synergistically Enhance the Immunogenicity of an Intranasal Spike SARS-CoV-2 Vaccine Candidate.

The respiratory organ serves as a primary target site for SARS-CoV-2. Thus, the vaccine-stimulating immune response of the respiratory tract is significant in controlling SARS-CoV-2 transmission and disease development. In this study, mucoadhesive nanoparticles were used to deliver SARS-CoV-2 spike proteins (S-NPs) into the nasal tracts of mice. The responses in the respiratory organ and the systemic responses were monitored. The administration of S-NPs along with cGAMP conferred a robust stimulation of antibody responses in the respiratory tract, as demonstrated by an increase of IgA and IgG antibodies toward the spike proteins in bronchoalveolar lavages (BALs) and the lungs. Interestingly, the elicited antibodies were able to neutralize both the wild-type and Delta variant strains of SARS-CoV-2. Significantly, the intranasal immunization also stimulated systemic responses. This is evidenced by the increased production of circulating IgG and IgA, which were able to neutralize and bind specifically to the SARS-CoV-2 virion and spike protein. Additionally, this intranasal administration potently activated a splenic T cell response and the production of Th-1 cytokines, suggesting that this vaccine may well activate a cellular response in the respiratory tract. The results demonstrate that STING agonist strongly acts as an adjuvant to the immunogenicity of S-NPs. This platform may be an ideal vaccine against SARS-CoV-2.

The Pilot Study of Immunogenicity and Adverse Events of a COVID-19 Vaccine Regimen: Priming with Inactivated Whole SARS-CoV-2 Vaccine (CoronaVac) and Boosting with the Adenoviral Vector (ChAdOx1 nCoV-19) Vaccine.

In response to the SARS-CoV-2 Delta variant, which partially escaped the vaccine-induced immunity provided by two doses of vaccination with CoronaVac (Sinovac), the National Vaccine Committee recommended the heterologous CoronaVac-ChAdOx1 (Oxford-AstraZeneca), a prime-boost vaccine regimen. This pilot study aimed to describe the immunogenicity and adverse events of the heterologous CoronaVac-ChAdOx1 regimen, in comparison with homologous CoronaVac, and homologous ChAdOx1. Between May and August 2021, we recruited a total of 354 participants from four vaccination groups: the CoronaVac-ChAdOx1 vaccinee (n = 155), the homologous CoronaVac vaccinee (n = 32), the homologous ChAdOx1 vaccinee (n = 47), and control group of COVID-19 patients (n = 120). Immunogenicity was evaluated by measuring the level of IgG antibodies against the receptor-binding domain (anti-SRBD) of the SARS-CoV-2 spike protein S1 subunit and the level of neutralizing antibodies (NAbs) against variants of concern (VOCs) using the plaque reduction neutralization test (PRNT) and pseudovirus neutralization test (pVNT). The safety profile was recorded by interviewing at the 1-month visit after vaccination. The anti-SRBD level after the second booster dose of the CoronaVac-ChAdOx1 group at 2 weeks was higher than 4 weeks. At 4 weeks after the second booster dose, the anti-SRBD level in the CoronaVac-ChAdOx1 group was significantly higher than either homologous CoronaVac, the homologous ChAdOx1 group, and Control group (p < 0.001). In the CoronaVac-ChAdOx1 group, the PRNT50 level against the wild-type (434.5 BAU/mL) was the highest; followed by Alpha variant (80.4), Delta variant (67.4), and Beta variant (19.8). The PVNT50 level was also found to be at its highest against the wild-type (432.1); followed by Delta variants (178.3), Alpha variants (163.9), and Beta variant (42.2), respectively. The AEs in the CoronaVac-ChAdOx1 group were well tolerated and generally unremarkable. The CoronaVac-ChAdOx1 heterologous regimen induced higher immunogenicity and a tolerable safety profile. In a situation when only CoronaVac-ChAdOx1 vaccines are available, they should be considered for use in responding to the Delta variant.

Comparison of safety and immunogenicity of CoronaVac and ChAdOx1 against the SARS-CoV-2 circulating variants of concern (Alpha, Delta, Beta) in Thai healthcare workers.

Background: Inactivated vaccine (CoronaVac) and chimpanzee adenovirus-vector vaccine (ChAdOx1) have been widely used in resource-limited settings. However, the information on the reactogenicity and immunogenicity of these two vaccines in the same setting are limited. Methods: Healthy health care workers (HCWs) aged 18 years or older were randomly assigned to receive either two doses of CoronaVac at 4 weeks interval or two doses of ChAdOx1 at 10 weeks interval. Self-reported adverse events (AEs) were collected for 7 days following each vaccination. Immunogenicity was determined by IgG antibodies levels against receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S1 subunit) and the 50% plaque reduction neutralization titers against various strains. Results: Of the 360 HCWs, 180 in each vaccine group, the median (interquartile range: IQR) age was 35 (29-44) years old and 84.2% were female. Participants who received ChAdOx1 reported higher frequency of AEs than those received CoronaVac after both the first dose (84.4% vs. 66.1%, P < 0.001) and second dose (75.6% vs. 60.6%, P = 0.002), with more AEs in those younger than 30 years of age for both vaccines. The seroconversion rates were 75.6% and 100% following the first dose of CoronaVac and ChAdOx1, respectively. All participants were seropositive at 2 weeks after the second dose. The anti-SARS-CoV-2 RBD IgG levels induced by CoronaVac was lower than ChAdOX1 with geometric means of 164.4 and 278.5 BAU/mL, respectively (P = 0.0066). Both vaccines induced similar levels of neutralizing antibodies against the Wuhan strain, with the titers of 337.4 and 331.2; however, CoronaVac induced significantly lower GMT against Alpha (23.1 vs. 92.5), Delta (21.2 vs. 69.7), and Beta (10.2 vs. 43.6) variants, respectively. Conclusion: CoronaVac induces lower measurable antibodies against circulating variants but with lower frequency of AEs than ChAdOx1. An earlier boosting to prevent breakthrough infections may be needed.

Immunogenicity and Safety of an Intradermal BNT162b2 mRNA Vaccine Booster after Two Doses of Inactivated SARS-CoV-2 Vaccine in Healthy Population.

Effective vaccine coverage is urgently needed to tackle the COVID-19 pandemic. Inactivated vaccines have been introduced in many countries for emergency usage, but have only provided limited protection. Heterologous vaccination is a promising strategy to maximise vaccine immunogenicity. Here, we conducted a phase I, randomised control trial to observe the safety and immunogenicity after an intradermal boost, using a fractional dosage (1:5) of BNT162b2 mRNA vaccine in healthy participants in Songkhla, Thailand. In total, 91 volunteers who had been administered with two doses of inactivated SARS-CoV-2 (CoronaVac) were recruited into the study, and then randomised (1:1:1) to received different regimens of the third dose. An intramuscular booster with a full dose of BNT162b2 was included as a conventional control, and a half dose group was included as reciprocal comparator. Both, immediate and delayed adverse events following immunisation (AEFI) were monitored. Humoral and cellular immune responses were examined to observe the booster effects. The intradermal booster provided significantly fewer systemic side effects, from 70% down to 19.4% (p < 0.001); however, they were comparable to local reactions with the conventional intramuscular booster. In the intradermal group after receiving only one fifth of the conventional dosage, serum Anti-RBD IgG was halved compared to the full dose of an intramuscular injection. However, the neutralising function against the Delta strain remained intact. T cell responses were also less effective in the intradermal group compared to the intramuscular booster. Together, the intradermal booster, using a fractional dose of BNT162b2, can reduce systemic reactions and provides a good level and function of antibody responses compared to the conventional booster. This favourable intradermal boosting strategy provides a suitable alternative for vaccines and effective vaccine management to increase the coverage during the vaccine shortage.

Peritoneal Administration of a Subunit Vaccine Encapsulated in a Nanodelivery System Not Only Augments Systemic Responses against SARS-CoV-2 but Also Stimulates Responses in the Respiratory Tract.

The COVID-19 pandemic has currently created an unprecedented threat to human society and global health. A rapid mass vaccination to create herd immunity against SARS-CoV-2 is a crucial measure to ease the spread of this disease. Here, we investigated the immunogenicity of a SARS-CoV-2 subunit vaccine candidate, a SARS-CoV-2 spike glycoprotein encapsulated in N,N,N-trimethyl chitosan particles or S-TMC NPs. Upon intraperitoneal immunization, S-TMC NP-immunized mice elicited a stronger systemic antibody response, with neutralizing capacity against SARS-CoV-2, than mice receiving the soluble form of S-glycoprotein. S-TMC NPs were able to stimulate the circulating IgG and IgA as found in SARS-CoV-2-infected patients. In addition, spike-specific T cell responses were drastically activated in S-TMC NP-immunized mice. Surprisingly, administration of S-TMC NPs via the intraperitoneal route also stimulated SARS-CoV-2-specific immune responses in the respiratory tract, which were demonstrated by the presence of high levels of SARS-CoV-2-specific IgG and IgA in the lung homogenates and bronchoalveolar lavages of the immunized mice. We found that peritoneal immunization with spike nanospheres stimulates both systemic and respiratory mucosal immunity.

Intranasal Administration of RBD Nanoparticles Confers Induction of Mucosal and Systemic Immunity against SARS-CoV-2.

Mucosal immunity plays a significant role in host defense against viruses in the respiratory tract. Because the upper respiratory airway is a primary site of SARS-CoV-2 entry, immunization at the mucosa via the intranasal route could potentially lead to induction of local sterilizing immunity that protects against SARS-CoV-2 infection. In this study, we evaluated the immunogenicity of a receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein loaded into N,N,N-trimethyl chitosan nanoparticles (RBD-TMC NPs). We showed that intranasal delivery of RBD-TMC NPs into mice induced robust local mucosal immunity, as evidenced by the presence of IgG and IgA responses in BALs and the lungs of immunized mice. Furthermore, mice intranasally administered with this platform of immunogens developed robust systemic antibody responses including serum IgG, IgG1, IgG2a, IgA and neutralizing antibodies. In addition, these immunized mice had significantly higher levels of activated splenic CD4+ and CD8+ cells compared with those that were administered with soluble RBD immunogen. Collectively, these findings shed light on an alternative route of vaccination that mimics the natural route of SARS-CoV-2 infection. This route of administration stimulated not only local mucosal responses but also the systemic compartment of the immune system.

Plant-Produced Receptor-Binding Domain of SARS-CoV-2 Elicits Potent Neutralizing Responses in Mice and Non-human Primates.

The emergence of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected global public health and economy. Despite the substantial efforts, only few vaccines are currently approved and some are in the different stages of clinical trials. As the disease rapidly spreads, an affordable and effective vaccine is urgently needed. In this study, we investigated the immunogenicity of plant-produced receptor-binding domain (RBD) of SARS-CoV-2 in order to use as a subunit vaccine. In this regard, RBD of SARS-CoV-2 was fused with Fc fragment of human IgG1 and transiently expressed in Nicotiana benthamiana by agroinfiltration. The plant-produced RBD-Fc fusion protein was purified from the crude extract by using protein A affinity column chromatography. Two intramuscular administration of plant-produced RBD-Fc protein formulated with alum as an adjuvant have elicited high neutralization titers in immunized mice and cynomolgus monkeys. Further it has induced a mixed Th1/Th2 immune responses and vaccine-specific T-lymphocyte responses which was confirmed by interferon-gamma (IFN-γ) enzyme-linked immunospot assay. Altogether, our results demonstrated that the plant-produced SARS-CoV-2 RBD has the potential to be used as an effective vaccine candidate against SARS-CoV-2. To our knowledge, this is the first report demonstrating the immunogenicity of plant-produced SARS-CoV-2 RBD protein in mice and non-human primates.