Comparison of the reactogenicity and immunogenicity between two-dose mRNA COVID-19 vaccine and inactivated COVID-19 vaccine followed by an mRNA vaccine in children aged 5-11 years.

To compare the reactogenicity and immunogenicity between the two-dose mRNA COVID-19 vaccine regimen and one or two doses of inactivated vaccine followed by an mRNA vaccine regimen in healthy children between 5 and 11 years of age, a prospective cohort study was performed at King Chulalongkorn Memorial Hospital in Thailand between March to June 2022. Healthy children between 5 and 11 years of age were enrolled and received the two-dose mRNA COVID-19 vaccine (BNT162b2) regimen or the inactivated (CoronaVac) vaccine followed by the BNT162b2 vaccine regimen. In addition, healthy children who received two doses of BBIBP-CorV between 1 and 3 months prior were enrolled to receive a heterologous BNT162b2 as a third dose (booster). Reactogenicity was assessed by a self-reported online questionnaire. Immunogenicity analysis was performed to determine binding antibodies to wild-type SARS-CoV-2. Neutralizing antibodies to Omicron variants (BA.2 and BA.5) were tested using the focus reduction neutralization test. Overall, 166 eligible children were enrolled. Local and systemic adverse events which occurred within 7 days after vaccination were mild to moderate and well-tolerated. The two-dose BNT162b2, CoronaVac followed by BNT162b2, and two-dose BBIBP-CorV followed by BNT162b2 groups elicited similar levels of anti-receptor-binding domain (RBD) IgG. However, the two-dose BNT162b2 and two-dose BBIBP-CorV followed by BNT162b2 groups elicited higher neutralizing activities against the Omicron BA.2 and BA.5 variant than the CoronaVac followed by BNT162b2 group. The CoronaVac followed by BNT162b2 group elicited low neutralizing activities against the Omicron BA.2 and BA.5 variant. A third dose (booster) mRNA vaccine should be prioritized for this group.

The Fourth Dose of mRNA COVID-19 Vaccine Following 12 Different Three-Dose Regimens: Safety and Immunogenicity to Omicron BA.4/BA.5.

The aim of this study is to investigate the reactogenicity and immunogenicity of the fourth dose using monovalent mRNA vaccines after different three-dose regimens and to compare the 30 µg BNT162b2 and 50 µg mRNA-1273 vaccines. This prospective cohort study was conducted between June and October 2022. The self-recorded reactogenicity was evaluated on the subsequent 7 days after a fourth dose. The binding and neutralizing activity of antibodies against the Omicron BA.4/5 variants were determined. Overall, 292 healthy adults were enrolled and received BNT162b2 or mRNA-1273. Reactogenicity was mild to moderate and well tolerated after a few days. Sixty-five individuals were excluded. Thus, 227 eligible individuals received a fourth booster dose of BNT162b2 (n = 109) and mRNA-1273 (n = 118). Most participants, regardless of the type of previous three-dose regimens, elicited a significantly high level of binding antibodies and neutralizing activity against Omicron BA.4/5 28 days after a fourth dose. The neutralizing activity against Omicron BA.4/5 between the BNT162b2 (82.8%) and mRNA-1273 (84.2%) groups was comparable with a median ratio of 1.02. This study found that the BNT162b2 and mRNA-1273 vaccines can be used as a fourth booster dose for individuals who were previously immunized with any prior three-dose mix-and-match COVID-19 vaccine regimens.

Safety and immunogenicity of a third dose of COVID-19 protein subunit vaccine (CovovaxTM) after homologous and heterologous two-dose regimens.

OBJECTIVES: To report the safety and immunogenicity profile of a protein subunit vaccine (CovovaxTM) given as a third (booster) dose to individuals primed with different primary vaccine regimens. METHODS: A third dose was administered to individuals with an interval range of 3-10 months after the second dose. The four groups were classified according to their primary vaccine regimens, including two-dose BBIBP-CorV, AZD1222, BNT162b2, and CoronaVac/AZD1222. Immunogenicity analysis was performed to determine binding antibodies, neutralizing activity, and the T-cell responses. RESULTS: Overall, 210 individuals were enrolled and boosted with the CovovaxTM vaccine. The reactogenicity was mild to moderate. Most participants elicited a high level of binding and neutralizing antibody against Wild-type and Omicron variants after the booster dose. In participants who were antinucleocapsid immunoglobulin G-negative from all groups, a booster dose could elicit neutralizing activity to Wild-type and Omicron variants by more than 95% and 70% inhibition at 28 days, respectively. The CovovaxTM vaccine could elicit a cell-mediated immune response. CONCLUSION: The protein subunit vaccine (CovovaxTM) can be proposed as a booster dose after two different priming dose regimens. It has strong immunogenicity and good safety profiles.

Persistence of immunity against Omicron BA.1 and BA.2 variants following homologous and heterologous COVID-19 booster vaccines in healthy adults after a two-dose AZD1222 vaccination.

OBJECTIVES: The SARS-CoV-2 Omicron variant presents numerous mutations potentially able to evade neutralizing antibodies (NAbs) elicited by COVID-19 vaccines. Therefore, this study aimed to provide evidence on a heterologous booster strategy to overcome the waning immunity against Omicron variants. METHODS: Participants who completed the Oxford/AstraZeneca (hereafter AZD1222) vaccine dose for 5-7 months were enrolled. The reactogenicity and persistence of immunogenicity in both humoral and cellular response after a homologous or heterologous booster with the AZD1222 and messenger RNA (mRNA) vaccines (BNT162b2, full, or half-dose mRNA-1273) administered 6 months after primary vaccination were determined. RESULTS: A total of 229 individuals enrolled, and waning of immunity was observed 5-7 months after the AZD1222-primed vaccinations. Total receptor-binding domain (RBD) immunoglobulin (Ig) levels, anti-RBD IgG, and focus reduction neutralization test against Omicron BA.1 and BA.2 variants and T cell response peaked at 14-28 days after booster vaccination. Both the full and half dose of mRNA-1273 induced the highest response, followed by BNT162b2 and AZD1222. At 90 days, the persistence of immunogenicity was observed among all mRNA-boosted individuals. Adverse events were acceptable for all vaccines. CONCLUSION: A heterologous mRNA booster provided a significantly superior boost of binding and NAbs levels against the Omicron variant compared with a homologous booster in individuals with AZD1222-primed vaccinations.

Comparison of the reactogenicity and immunogenicity of a reduced and standard booster dose of the mRNA COVID-19 vaccine in healthy adults after two doses of inactivated vaccine.

The coronavirus disease 2019 (COVID-19) pandemic has been a serious healthcare problem worldwide since December 2019. The third dose of heterologous vaccine was recently approved by World Health Organization. The present study compared the reactogenicity and immunogenicity of the reduced and standard third booster dose of the BNT162b2 and mRNA-1273 vaccine in adults who previously received the two-dose CoronaVac vaccine. Results showed that headache, joint pain, and diarrhea were more frequent in the 15 µg- than the 30 µg-BNT162b2 groups, whereas joint pain and chilling were more frequent in the 100 µg- than the 50 µg-mRNA-1273 groups. No significant differences in immunogenicity were detected. These findings demonstrate that the reduced dose of the mRNA vaccines elicited antibody responses against the SARS-CoV-2 delta and omicron variants that were comparable to the standard dose. The reduced dose could be used to increase vaccine coverage in situations of limited global vaccine supply.

Safety and Humoral and Cellular Immunogenicity of the BNT162b2 SARS-CoV-2 Vaccine in Liver-Transplanted Adolescents Compared to Healthy Adolescents.

Since BNT162b2 was approved to prevent COVID-19 in children, we aim to compare the safety and immunogenicity of the BNT162b2 vaccine in liver-transplanted (LT) and healthy adolescents. LT and healthy adolescents received two doses of 30 µg of BNT162b2. All were evaluated for total COVID-19 antibodies directed against the receptor-binding domain (RBD) and interferon-γ using the ELISpot at all time points; anti-nucleocapsid immunoglobulin was evaluated at week 8 and the surrogate virus-neutralizing antibody (sVN) to Omicron at day 0 and week 8. Adverse effects were recorded during days 0-7. In total, 16 LT and 27 healthy adolescents were enrolled (aged 14.78 ± 1.70 years). After completion, all LT and healthy adolescents were positive for anti-RBD immunoglobulin, with geometric mean titers of 1511.37 (95% CI 720.22-3171.59) and 6311.90 (95% CI 4955.46-8039.64)) U/mL (p < 0.001). All tested negative for anti-nucleocapsid immunoglobulin, indicating no COVID-19 infection after vaccination. However, the sVNs to Omicron were positive in only nine (33.33%) healthy adolescents and none of the LT adolescents. Interferon-γ-secreting cells were lower in LT adolescents than healthy adolescents. The LT adolescents had a lower immunogenic response to BNT162b2 than the healthy adolescents. Administrating two doses of BNT162b2 was safe, but was less effective against the Omicron variant.

Effects of boosted mRNA and adenoviral-vectored vaccines on immune responses to omicron BA.1 and BA.2 following the heterologous CoronaVac/AZD1222 vaccination.

The coronavirus 2019 omicron variant has surged rapidly and raises concerns about immune evasion even in individuals with complete vaccination, because it harbors mutations. Here we examine the capability of booster vaccination following CoronaVac/AZD1222 prime to induce neutralizing antibodies (NAbs) against omicron (BA.1 and BA.2) and T-cell responses. A total of 167 participants primed with heterologous CoronaVac/AZD1222 for 4-5 months were enrolled, to receive AZD1222, BNT162b2, or mRNA-1273 as a third dose. Reactogenicity was recorded. Immunogenicity analyses of severe acute respiratory syndrome coronavirus 2-binding antibodies were measured using enzyme-linked immunosorbent assay. The NAb titers against omicron BA.1 and BA.2 were determined using the focus reduction neutralization test (FRNT50) and total interferon-γ responses were measured to observe the T-cell activation. A substantial loss in neutralizing potency to omicron variant was found at 4-5 months after receiving the heterologous CoronaVac/AZD1222. Following booster vaccination, a significant increase in binding antibodies and neutralizing activities toward delta and omicron variants was observed. Neutralization to omicron BA.1 and BA.2 were comparable, showing the highest titers after boosted mRNA-1273 followed by BNT162b2 and AZD1222. In addition, individuals boosted with messenger RNA (mRNA) vaccines develop a T-cell response to spike protein, whereas those boosted with AZD1222 did not. Reactogenicity was mild to moderate without serious adverse events. Our findings demonstrated that mRNA booster vaccination is able to overcome waning immunity to provide antibodies that neutralize omicron BA.1 and BA.2, as well as a T-cell response.

Strong Correlations between the Binding Antibodies against Wild-Type and Neutralizing Antibodies against Omicron BA.1 and BA.2 Variants of SARS-CoV-2 in Individuals Following Booster (Third-Dose) Vaccination.

This study examined the neutralizing activity and receptor-binding domain (RBD) antibody levels against wild-type and omicron BA.1 and BA.2 variants in individuals who received three doses of COVID-19 vaccination. The relationship between the anti-RBD IgG against wild-type and live virus neutralizing antibody titers against omicron BA.1 and BA.2 variants was examined. In total, 310 sera samples from individuals after booster vaccination (third-dose) were tested for specific IgG wild-type SARS-CoV-2 RBD and the omicron BA.1 surrogate virus neutralization test (sVNT). The live virus neutralization assay against omicron BA.1 and BA.2 was performed using the foci-reduction neutralization test (FRNT50). The anti-RBD IgG strongly correlated with FRNT50 titers against BA.1 and BA.2. Non-linear regression showed that anti-RBD IgG at the cut-off value ≥148 BAU/mL and ≥138 BAU/mL were related to the threshold for FRNT50 titers ≥20 against BA.1 and BA.2, respectively. A moderate correlation was observed between the sVNT and FRNT50 titers. At FRNT50 titers ≥20, the predicted sVNT for BA.1 and BA.2 was ≥10.57% and ≥11.52%, respectively. The study identified anti-RBD IgG and sVNT levels that predict detectable neutralizing antibodies against omicron variants. Assessment and monitoring of protective immunity support vaccine policies and will help identify optimal timing for booster vaccination.

Immunogenicity Following Two Doses of the BBIBP-CorV Vaccine and a Third Booster Dose with a Viral Vector and mRNA COVID-19 Vaccines against Delta and Omicron Variants in Prime Immunized Adults with Two Doses of the BBIBP-CorV Vaccine.

Coronavirus disease 2019 (COVID-19) booster vaccination is being comprehensively evaluated globally due to waning immunity and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Therefore, this study aimed to evaluate antibody responses in individuals vaccinated with two doses of the BBIBP-CorV vaccine and to explore the boosting effect of the different vaccine platforms in BBIBP-CorV-primed healthy adults, including a viral vector vaccine (AZD122) and mRNA vaccines (BNT162b2 and mRNA-1273). The results showed that in the BBIBP-CorV prime group, the total receptor-binding domain (RBD) immunoglobulin (Ig) and anti-RBD IgG levels waned significantly at three months after receiving the second dose. However, after the booster, RBD-specific binding antibody levels increased. Neutralizing antibody measured by a surrogate neutralization test showed inhibition over 90% against the SARS-CoV-2 delta variant but less than 70% against the omicron variant after the third dose on day 28. All booster vaccines could induce the total IFN-É£ T-cell response. The reactogenicity was acceptable and well-tolerated without serious adverse events. This study supports the administration of the third dose with either a viral vector or mRNA vaccine for BBIBP-CorV-primed individuals to stimulate antibody and T-cell responses.

Immunogenicity of heterologous inactivated and adenoviral-vectored COVID-19 vaccine: Real-world data.

Limited data are available on the responses to heterologous vaccine regimens for SARS-CoV-2, especially among countries using inactivated and adenoviral-vectored vaccines. A total of 77 participants who received heterologous inactivated COVID-19 vaccine (CoronaVac) and adenoviral-vectored vaccine (AZD1222) were enrolled in our study. There were two comparison groups vaccinated with the homologous CoronaVac (N = 79) and AZD1222 (N = 78) regimen. All sera samples were tested for anti-receptor-binding-domain IgG (anti-RBD IgG) using a chemiluminescent microparticle immunoassay (CMIA). The neutralizing activity in a subset of serum samples was tested against the original Wuhan strain and variants of concern, B.1.1.7, B.1.617.2 and B.1.351, using an enzyme-linked immunosorbent assay (ELISA)-based surrogate virus neutralization test (sVNT). The heterologous CoronaVac/AZD1222 vaccine induced higher levels of anti-RBD IgG than that of two-dose homologous CoronaVac or AZD1222 vaccines (p < 0.001). Sera samples of the CoronaVac/AZD1222 vaccine recipients elicited higher neutralizing antibody activity against the original Wuhan and all variants of concern than in the recipients of the two-dose CoronaVac. The heterologous CoronaVac followed by AZD1222 is an alternative regimen to combat with the SARS-CoV-2 variants in case of vaccine shortage with improved immunogenicity compared to the homologous CoronaVac regimen.

Neutralizing Activities Against the Omicron Variant After a Heterologous Booster in Healthy Adults Receiving Two Doses of CoronaVac Vaccination.

BACKGROUND: The use of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (CoronaVac) against SARS-CoV-2 is implemented worldwide. However, waning immunity and breakthrough infections have been observed. Therefore, we hypothesized that the heterologous booster might improve the protection against the delta and omicron variants. METHODS: A total of 224 individuals who completed the 2-dose CoronaVac for 6 months were included. We studied reactogenicity and immunogenicity after a heterologous booster with the inactivated vaccine (BBIBP), the viral vector vaccine (AZD1222), and the messenger ribonucleic acid (mRNA) vaccine (both BNT162B2 and mRNA-1273). We also determined immunogenicity at 3- and 6-month boosting intervals. RESULTS: The solicited adverse events were mild to moderate and well tolerated. Total receptor binding domain (RBD) immunoglobulin (Ig), anti-RBD IgG, focus reduction neutralization test (FRNT50) against delta and omicron variants, and T-cell response were highest in the mRNA-1273 group followed by the BNT162b2, AZD1222, and BBIBP groups, respectively. We also witnessed a higher total Ig anti-RBD in the long-interval than in the short-interval group. CONCLUSIONS: All 4 booster vaccines significantly increased binding and neutralizing antibodies in individuals immunized with 2 doses of CoronaVac. The present evidence may benefit vaccine strategies to thwart variants of concern, including the omicron variant.

COVID-19 Breakthrough Infection after Inactivated Vaccine Induced Robust Antibody Responses and Cross-Neutralization of SARS-CoV-2 Variants, but Less Immunity against Omicron.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the waning of immunity in vaccinated individuals is resulting in increased numbers of SARS-CoV-2 breakthrough infections. This study investigated binding antibody responses and neutralizing activities against SARS-CoV-2 variants, in patients with COVID-19 who had been fully vaccinated with CoronaVac (n = 77), individuals who had been fully vaccinated with CoronaVac but had not contracted COVID-19 (n = 170), and individuals who had received AZD1222 as a third vaccination (n = 210). Breakthrough infection was generally detected approximately 88 days after the second CoronaVac vaccination (interquartile range 68-100 days). Blood samples were collected at a median of 34 days after infection. Binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AZD1222 as a third vaccination. However, neutralizing activities against wild-type and variants, including alpha (B.1.1.7), beta (B.1.351), and delta (B.1.617.2), were comparable in patients with breakthrough infections and individuals who received a third vaccination with AZD1222, which exceeds 90%. Omicron (B.1.1.529) was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants. The study suggests that breakthrough infection after two doses of an inactivated vaccine can induce neutralizing antibodies against omicron. Further investigation is needed to assess the long-term persistence of antibodies against the omicron variant.

Safety and immunogenicity of heterologous and homologous inactivated and adenoviral-vectored COVID-19 vaccine regimens in healthy adults: a prospective cohort study.

In light of intermittent supply shortages of individual vaccines and evidence of rare but serious adverse events after vaccination, heterologous regimens for COVID-19 vaccines have gained significant interest. This study aims to assess the reactogenicity and immunogenicity of the heterologous adenoviral vector (ChAdOx1-S, AstraZeneca; hereafter referred to as AZ) and the inactivated vaccine regimen (CoronaVac; hereafter referred to as CV) in healthy Thai adults immunized between June and September 2021. Our study showed that adverse events following homologous CV-CV and AZ-AZ, and heterologous CV-AZ and AZ-CV combinations, were mild and well tolerated overall. Receptor-binding domain (RBD)-specific antibody responses and neutralizing activities against wild-type and variants of concern after two-dose vaccination were higher in the heterologous CV-AZ and homologous AZ-AZ groups compared to the CV-CV and AZ-CV groups. Conversely, the spike-specific IgA response was detected only in the CV-AZ group after two doses of vaccination. The total interferon gamma response was detected in both the CV-AZ and AZ-CV groups after the two-dose vaccination. Given the shorter completion time of two doses, heterologous CoronaVac followed by ChAdOx1-S can be considered as an alternative regimen to homologous efficacy-proven ChAdOx1-S in countries with circulating variants. Additional studies on the efficacy and durability of immune responses induced by heterologous vaccine regimens are warranted.

Safety and Immunogenicity of the Third Booster Dose with Inactivated, Viral Vector, and mRNA COVID-19 Vaccines in Fully Immunized Healthy Adults with Inactivated Vaccine.

The coronavirus disease 2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2), in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7-alpha, B.1.351-beta, and B.1.617.2-delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of IFN-É£ secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.

Immunogenicity of a third dose viral-vectored COVID-19 vaccine after receiving two-dose inactivated vaccines in healthy adults.

In June 2021, Thailand was hit by the delta variant of SARS-CoV-2 resulting in the biggest wave of COVID-19. Due to the widespread delta variant, more than 600 healthcare workers had COVID-19 despite completion of two-dose CoronaVac. The Ministry of Public Health recommended that healthcare workers received a third dose of AZD1222 to increase level of protection against SARS-CoV-2. However, immune response after the AZD1222 booster in individuals who completed the two-dose CoronaVac vaccine are limited. In this study, sera from those who received a booster of AZD1222 in June-July 2021 were tested for SARS-CoV-2 spike receptor-binding-domain (RBD) IgG, anti-RBD total immunoglobulins and anti-spike protein 1 (S1) IgA. The neutralizing activities in a subset of serum samples were tested against the wild type and variants of concern (B.1.1.7, B.1.617.2, and B.1.351) using an enzyme-linked immunosorbent assay-based surrogate virus neutralization test. Participants who received the booster of AZD1222 possessed higher levels of spike RBD-specific IgG, total immunoglobulins, and anti-S1 IgA than the two-dose vaccinees (p < 0.001). They also elicited higher neutralizing activity against the wild type and all variants of concern than the recipients of the two-dose vaccines. This study demonstrated a high immunogenicity of the AZD1222 booster in individuals who completed the two-dose inactivated vaccines.