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Despite the declared end of the COVID-19 pandemic, SARS-CoV-2 continues to evolve, with emerging JN.1-derived subvariants (e.g., KP.2, KP.3) compromising the efficacy of current XBB.1.5-based vaccines. To address this, we developed an mRNA vaccine encoding the full-length spike protein of JN.1, incorporating GSAS and 2P mutations and encapsulated in lipid nanoparticles (LNPs). The JN.1-mRNA vaccine elicited robust humoral and cellular immune responses in mice, including high JN.1-specific IgG titers, cross-neutralizing antibodies, and increased T follicular helper (Tfh) cells, germinal center (GC) B cells, and T cell cytokines. Importantly, immunity persisted for up to six months and induced RBD-specific long-lived plasma cells. We also compared the immune responses induced by homologous and heterologous vaccination regimens, and our results demonstrated that the heterologous regimen—combining JN.1-mRNA with a recombinant protein vaccine (RBDJN.1-HR)—induced stronger responses. These findings highlight the JN.1-mRNA vaccine constitutes an effective prophylactic approach against JN.1-related variants, as it induces potent neutralizing antibody responses across all tested lineages. This enhanced immunogenicity is expected to significantly reduce hospitalization rates and mitigate post-COVID complications associated with JN.1 and KP.3 infections. This study emphasizes the need for timely vaccine updates and the adaptability of mRNA vaccines in addressing emerging pathogens, providing a framework for combating future infectious diseases. Collectively, these results offer critical insights for vaccine design and public health strategies in response to emerging SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Abstract Despite the declared end of the COVID-19 pandemic, SARS-CoV-2 continues to evolve, with emerging JN.1-derived subvariants (e.g., KP.2, KP.3) compromising the efficacy of current XBB.1.5-based vaccines. To address this, we developed an mRNA vaccine encoding the full-length spike protein of JN.1, incorporating GSAS and 2P mutations and encapsulated in lipid nanoparticles (LNPs). The JN.1-mRNA vaccine elicited robust humoral and cellular immune responses in mice, including high JN.1-specific IgG titers, cross-neutralizing antibodies, and increased T follicular helper (Tfh) cells, germinal center (GC) B cells, and T cell cytokines. Importantly, immunity persisted for up to six months and induced RBD-specific long-lived plasma cells. We also compared the immune responses induced by homologous and heterologous vaccination regimens, and our results demonstrated that the heterologous regimen—combining JN.1-mRNA with a recombinant protein vaccine (RBDJN.1-HR)—induced stronger responses. These findings highlight the JN.1-mRNA vaccine constitutes an effective prophylactic approach against JN.1-related variants, as it induces potent neutralizing antibody responses across all tested lineages. This enhanced immunogenicity is expected to significantly reduce hospitalization rates and mitigate post-COVID complications associated with JN.1 and KP.3 infections. This study emphasizes the need for timely vaccine updates and the adaptability of mRNA vaccines in addressing emerging pathogens, providing a framework for combating future infectious diseases. Collectively, these results offer critical insights for vaccine design and public health strategies in response to emerging SARS-CoV-2 variants.

The SARS-CoV-2 Omicron variant and its sublineages continue to cause COVID-19-associated pediatric hospitalizations, severe disease, and death globally. BNT162b2 and CoronaVac are the main vaccines used in Chile. Much less is known about the Wuhan-Hu-1 strain-based vaccines in the pediatric population compared to adults. Given the worldwide need for booster vaccinations to stimulate the immune response against new Omicron variants of SARS-CoV-2, we characterized the humoral and cellular immune response against Omicron variant BA.1 in a pediatric cohort aged 10 to 16 years who received heterologous vaccination based on two doses of CoronaVac, two doses of CoronaVac (2x) plus one booster dose of BNT162b2 [CoronaVac(2x) + BNT162b2 (1x)], two doses of CoronaVac plus two booster doses of BNT162b2 [CoronaVac(2x) + BNT162b2 (2x)], and three doses of BNT162b2. We observed that the [CoronaVac(2x) + BNT162b2 (2x)] vaccination showed higher anti-S1 and neutralizing antibody titers and CD4 and CD8 T cell immunity specific to the Omicron variant compared to immunization with two doses of CoronaVac alone. Furthermore, from all groups tested, immunity against Omicron was highest in individuals who received three doses of BNT162b2. We conclude that booster vaccination with BNT162b2, compared to two doses of CoronaVac alone, induces a greater protective immunity. [ABSTRACT FROM AUTHOR]

Background: The ongoing COVID-19 pandemic has seen the emergence of numerous novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In this study, we compared the efficacy of three different forms of immunization against the wild-type, delta, and omicron variants of the virus: two doses of the BNT or AZ vaccine (BNT/BNT or AZ/AZ) as homologous vaccination, three doses of AZ/AZ/BNT as heterologous vaccination, and naturally occurring immunization in severe COVID-19 cases. Methods: We collected serum samples from vaccine recipients (67 receiving BNT/BNT, 111 receiving AZ/AZ, and 18 receiving AZ/AZ/BNT) and 46 patients who were admitted to the hospital with severe COVID-19. Blood samples were taken one month after the last injection and the efficacy of the vaccination was determined using the surrogate virus neutralization test (sVNT), with a positive result defined as an inhibition rate of over 30%. Serum samples from COVID-19 patients were taken at various points during their hospitalization and tested for inhibition rates. Results: Our results indicated that there was no notable difference in the levels of neutralizing antibodies (nAb) in vaccine recipients and patients against the wild-type and delta variants. However, when it came to the omicron variant, the vaccine recipients had significantly lower nAb titers. Among the vaccine recipients, those who received a booster dose of BNT after their first two doses of AZ (AZ/AZ/BNT) demonstrated the highest level of protection against the omicron variant at 44.4%, followed closely by the COVID-19 patients. In analyzing the serial samples taken from hospitalized COVID-19 patients, we observed that their inhibition rates against the wild-type and delta variants improved over time, while the inhibition rate against the omicron variant decreased. Conclusion: In conclusion, our findings suggest that heterologous booster vaccination after primary vaccination produces higher nAb titers and provides a higher level of protection against the omicron variant compared to primary vaccination alone. This protective effect was similar to that observed in patients with severe COVID-19.

We focus on Bayesian inference for survival probabilities in a prime‐boost vaccination regime in the development of an Ebola vaccine. We are interested in the heterologous prime‐boost regimen (unmatched vaccine deliverys using the same antigen) due to its demonstrated durable immunity, well‐tolerated safety profile, and suitability as a population vaccination strategy. Our research is motivated by the need to estimate the survival probability given the administered dosage. To do so, we establish two key relationships. Firstly, we model the connection between the designed dose concentration and the induced antibody count using a Bayesian response surface model. Secondly, we model the association between the antibody count and the probability of survival when experimental subjects are exposed to the Ebola virus in a controlled setting using a Bayesian probability of survival model. Finally, we employ a combination of the two models with dose concentration as the predictor of the survival probability for a future vaccinated population. We implement our two‐level Bayesian model in Stan, and illustrate its use with simulated and real‐world data. Performance of this model is evaluated via simulation. Our work offers a new application of drug synergy models to examine prime‐boost vaccine efficacy, and does so using a hierarchical Bayesian framework that allows us to use dose concentration to predict survival probability. [ABSTRACT FROM AUTHOR]

• The third dose of the BNT162b2 vaccine increases the risk of myocarditis, particularly in adolescent males. • The risk of myocarditis from BNT162b2, whether as an initial or booster dose following the BBIBP-CorV series, is close. • The risk of myocarditis after vaccination is less marked in children aged 5–11. Due to the data scarcity in low- and middle-income countries, we aimed to examine the incidence rate of myocarditis and pericarditis within 30 days after each dose of homologous (3 × BNT162b2) and heterologous prime-boost (2 × BBIBP-CorV/BNT162b2) vaccine regimen among individuals younger than 40 years. We conducted a historical control cohort using routinely recorded data from Thai national vaccine and insurance claims databases. Sex-specific incidence rate ratios (IRRs) for myocarditis and pericarditis were calculated for each vaccination strategy and contrasted with incidence rates among the non-immunised population in the pre-COVID-19 period. From August 2021 to September 2022, we tracked the incidence of myocarditis and pericarditis within 30 days after vaccinations using < 40-year-old national population databases. Our reference was the average monthly incidence of these conditions in the non-immunised population from August to October 2019. The exposure of interest was immunisation against the SARS-CoV-2 virus, incorporating the following vaccination strategies: three-dose 3 × BNT162b2 regimen, three-dose 2 × BBIBP-CorV/BNT162b2 regimen, and non-immunisation. For myocarditis, a total of 215 cases were identified among 7,594,965 individuals in the 3 × BNT162b2 cohort, 5 cases among 2,914,643 individuals in the 2 × BBIBP-CorV/BNT162b2 cohort, and 115 cases among 32,424,780 non-immunised individuals. The sex-specific IRRs (95 % confidence intervals) of myocarditis and pericarditis after the homologous vaccination were 3.09 (1.61, 5.93) and 1.84 (0.72, 4.73) for females and 7.43 (3.11, 17.73) and 10.48 (3.90, 28.15) for males, respectively. Conversely, the IRRs of myocarditis after the heterologous vaccination were not significant (females: 2.24 (0.70, 7.17); males: 1.99 (0.48, 8.21)). IRRs could not be obtained for pericarditis after the heterologous vaccination because of the small number of observed events. The study observed a significantly increased risk of myocarditis and pericarditis following homologous 3 × BNT162b2 vaccination but had insufficient power to confirm an increased risk for myocarditis following the heterologous prime-boost 2 × BBIBP-CorV/BNT162b2 vaccination. The incidence of pericarditis following the heterologous vaccination was too rare to evaluate. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 Omicron variant and its sublineages continue to cause COVID-19-associated pediatric hospitalizations, severe disease, and death globally. BNT162b2 and CoronaVac are the main vaccines used in Chile. Much less is known about the Wuhan-Hu-1 strain-based vaccines in the pediatric population compared to adults. Given the worldwide need for booster vaccinations to stimulate the immune response against new Omicron variants of SARS-CoV-2, we characterized the humoral and cellular immune response against Omicron variant BA.1 in a pediatric cohort aged 10 to 16 years who received heterologous vaccination based on two doses of CoronaVac, two doses of CoronaVac (2x) plus one booster dose of BNT162b2 [CoronaVac(2x) + BNT162b2 (1x)], two doses of CoronaVac plus two booster doses of BNT162b2 [CoronaVac(2x) + BNT162b2 (2x)], and three doses of BNT162b2. We observed that the [CoronaVac(2x) + BNT162b2 (2x)] vaccination showed higher anti-S1 and neutralizing antibody titers and CD4 and CD8 T cell immunity specific to the Omicron variant compared to immunization with two doses of CoronaVac alone. Furthermore, from all groups tested, immunity against Omicron was highest in individuals who received three doses of BNT162b2. We conclude that booster vaccination with BNT162b2, compared to two doses of CoronaVac alone, induces a greater protective immunity.

The ongoing COVID-19 pandemic has seen the emergence of numerous novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In this study, we compared the efficacy of three different forms of immunization against the wild-type, delta, and omicron variants of the virus: two doses of the BNT or AZ vaccine (BNT/BNT or AZ/AZ) as homologous vaccination, three doses of AZ/AZ/BNT as heterologous vaccination, and naturally occurring immunization in severe COVID-19 cases. We collected serum samples from vaccine recipients (67 receiving BNT/BNT, 111 receiving AZ/AZ, and 18 receiving AZ/AZ/BNT) and 46 patients who were admitted to the hospital with severe COVID-19. Blood samples were taken one month after the last injection and the efficacy of the vaccination was determined using the surrogate virus neutralization test (sVNT), with a positive result defined as an inhibition rate of over 30%. Serum samples from COVID-19 patients were taken at various points during their hospitalization and tested for inhibition rates. Our results indicated that there was no notable difference in the levels of neutralizing antibodies (nAb) in vaccine recipients and patients against the wild-type and delta variants. However, when it came to the omicron variant, the vaccine recipients had significantly lower nAb titers. Among the vaccine recipients, those who received a booster dose of BNT after their first two doses of AZ (AZ/AZ/BNT) demonstrated the highest level of protection against the omicron variant at 44.4%, followed closely by the COVID-19 patients. In analyzing the serial samples taken from hospitalized COVID-19 patients, we observed that their inhibition rates against the wild-type and delta variants improved over time, while the inhibition rate against the omicron variant decreased. In conclusion, our findings suggest that heterologous booster vaccination after primary vaccination produces higher nAb titers and provides a higher level of protection against the omicron variant compared to primary vaccination alone. This protective effect was similar to that observed in patients with severe COVID-19. [ABSTRACT FROM AUTHOR]

Over one billion people have received 2–3 dosages of an inactivated COVID-19 vaccine for basic immunization. Whether a booster dose should be delivered to protect against the Omicron variant and its sub-lineages, remains controversial. Here, we tested different vaccine platforms targeting the ancestral or Omicron strain as a secondary booster of the ancestral inactivated vaccine in mice. We found that the Omicron-adapted inactivated viral vaccine promoted a neutralizing antibody response against Omicron in mice. Furthermore, heterologous immunization with COVID-19 vaccines based on different platforms remarkably elevated the levels of cross- neutralizing antibody against Omicron and its sub-lineages. Omicron-adapted vaccines based on heterologous platforms should be prioritized in future vaccination strategies to control COVID-19.

The rapid availability of effective vaccines against SARS-CoV-2 was key during the COVID-19 pandemic. However, vaccine hesitancy and relatively low vaccine coverage rates among the general population and particularly vulnerable populations such as healthcare staff reduced the potential benefits of these vaccines. During the early phase of the pandemic, fear of vaccine-related adverse events was common among individuals who refused vaccination. Between March and May 2021, we comparatively assessed the self-reported reactogenicity of different SARS-CoV-2 prime-boost regimens using mRNA-based (BNT162b2 and mRNA-1273) and vector-based vaccines (ChAdOx1 nCoV-19) in (a) healthcare workers (HCW), and (b) police staff from southwest Germany. The majority of participants (71.8%; 1564/2176) received a homologous vaccination. Among HCW, 75.0% were female, whereas 70.0% of police staff were male. The most frequently reported reactions following the first vaccine administration were pain at the injection site (77.94%; 1696/2176), tiredness (51.75%; 1126/2176), and headache (40.44%; 880/2176), which were more commonly reported by HCW as compared to police staff. In homologous, mRNA-based and heterologous vaccination schedules, more reactions were reported after the second vaccine dose. We conclude that the frequency and intensity of self-perceived vaccine reactogenicity may differ between specific population groups and might be mitigated by tailored communication strategies. [ABSTRACT FROM AUTHOR]

Due to rare but major adverse reactions to the AstraZeneca adenoviral ChAdOx1-S-nCoV-19 vaccine (ChAd), German health authorities recommended adults under 60 who received one dose of ChAd, to receive a second dose of the BioNTech mRNA BNT162b2 vaccine (BNT) as a booster. Studies in the general population suggest an enhanced efficacy of the heterologous (ChAd-BNT) compared to the homologous (BNT-BNT) vaccination regimen. However, an analysis of the efficacy in patient populations with a high risk of severe COVID-19 due to acquired immunodeficiency is still missing. We therefore compared both vaccination regimens in healthy controls, patients with gynecological tumors after chemotherapy, patients on dialysis and patients with rheumatic diseases concerning the humoral and cellular immune response. The humoral and cellular immune response differed substantially in healthy controls compared to patients with acquired immunodeficiency. Overall, the most significant differences between the two immunization regimens were found in neutralizing antibodies. These were always higher after a heterologous immunization. Healthy controls responded well to both vaccination regimens. However, the formation of neutralizing antibodies was more pronounced after a heterologous immunization. Dialysis patients, on the other hand, only developed an adequate humoral and particularly cellular immune response after a heterologous immunization. Tumor and rheumatic patients also - to a weaker extent compared to dialysis patients - benefited from a heterologous immunization. In conclusion, the heterologous COVID-19 vaccination regimens (ChAd-BNT) seem to have an advantage over the homologous vaccination regimens, especially in immunocompromised patients such as patients with end-stage kidney disease treated with hemodialysis. [ABSTRACT FROM AUTHOR]

Since early 2022, various Omicron variants have dominated the SARS-CoV-2 pandemic in most countries. All Omicron variants are B-cell immune escape variants, and antibodies induced by first-generation COVID-19 vaccines or by infection with earlier SARS-CoV-2 variants largely fail to protect individuals from Omicron infection. In the present study, we investigated the effect of Omicron infections in triple-vaccinated and in antigen-naive individuals. We show that Omicron breakthrough infections occurring 2-3.5 months after the third vaccination restore B-cell and T-cell immune responses to levels similar to or higher than those measured 14 days after the third vaccination, including the induction of Omicron-neutralizing antibodies. Antibody responses in breakthrough infection derived mostly from cross-reacting B cells, initially induced by vaccination, whereas Omicron infections in antigen-naive individuals primarily generated B cells binding to the Omicron but not the Wuhan spike protein. Although antigen-naive individuals mounted considerable T-cell responses after infection, B-cell responses were low, and neutralizing antibodies were frequently below the limit of detection. In summary, the detection of Omicron-associated B-cell responses in primed and in antigennaive individuals supports the application of Omicron-adapted COVID-19 vaccines, but calls into question their suitability if they also contain/encode antigens of the original Wuhan virus. [ABSTRACT FROM AUTHOR]

Here, we systematically assessed the safety and immunogenicity of the heterologous ChAd/BNT vaccination regimens. We evaluated the immunogenicity by the geometric mean titers ratio (GMTR) of the neutralizing antibody and anti-spike IgG. The safety of heterologous ChAd/BNT vaccination was evaluated using the pooled risk ratios (RRs) calculated by the random-effects model about the adverse events. Our study was registered with PROSPERO, CRD42021265165. Eleven studies were included in the analyses. Compared to the homologous ChAd/ChAd vaccination, the heterologous ChAd/BNT vaccination showed significantly higher immunogenicity in terms of the neutralizing antibody and GMTR of anti-spike IgG, but at the same time displayed higher incidence of total adverse reactions, especially for the local adverse reactions. Moreover, heterologous ChAd/BNT vaccination showed similar immunogenicity to the homologous BNT/BNT vaccination (GMTR of neutralizing antibody and anti-spike IgG) and similar safety. Heterologous ChAd/BNT vaccination showed robust immunogenicity and tolerable safety. [ABSTRACT FROM AUTHOR]

The humoral response after vaccination was evaluated in 1248 individuals who received different COVID-19 vaccine schedules. The study compared subjects primed with adenoviral ChAdOx1-S (ChAd) and boosted with BNT162b2 (BNT) mRNA vaccines (ChAd/BNT) to homologous dosing with BNT/BNT or ChAd/ChAd vaccines. Serum samples were collected at two, four and six months after vaccination, and anti-Spike IgG responses were determined. The heterologous vaccination induced a more robust immune response than the two homologous vaccinations. ChAd/BNT induced a stronger immune response than ChAd/ChAd at all time points, whereas the differences between ChAd/BNT and BNT/BNT decreased over time and were not significant at six months. Furthermore, the kinetic parameters associated with IgG decay were estimated by applying a first-order kinetics equation. ChAd/BNT vaccination was associated with the longest time of anti-S IgG negativization and with a slow decay of the titer over time. Finally, analyzing factors influencing the immune response by ANCOVA analysis, it was found that the vaccine schedule had a significant impact on both the IgG titer and kinetic parameters, and having a Body Mass Index (BMI) above the overweight threshold was associated with an impaired immune response. Overall, the heterologous ChAd/BNT vaccination may offer longer-lasting protection against SARS-CoV-2 than homologous vaccination strategies. [ABSTRACT FROM AUTHOR]

(1) Background: As the COVID-19 pandemic enters its fourth year, it continues to cause significant morbidity and mortality worldwide. Although various vaccines have been approved and the use of homologous or heterologous boost doses is widely promoted, the impact of vaccine antigen basis, forms, dosages, and administration routes on the duration and spectrum of vaccine-induced immunity against variants remains incompletely understood. (2) Methods: In this study, we investigated the effects of combining a full-length spike mRNA vaccine with a recombinant S1 protein vaccine, using intradermal/intramuscular, homologous/heterologous, and high/low dosage immunization strategies. (3) Results: Over a period of seven months, vaccination with a mutant recombinant S1 protein vaccine based on the full-length spike mRNA vaccine maintained a broadly stable humoral immunity against the wild-type strain, a partially attenuated but broader-spectrum immunity against variant strains, and a comparable level of cellular immunity across all tested strains. Furthermore, intradermal vaccination enhanced the heterologous boosting of the protein vaccine based on the mRNA vaccine. (4) Conclusions: This study provides valuable insights into optimizing vaccination strategies to address the ongoing challenges posed by emerging SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

BA.4 and BA.5 (BA.4/5), the subvariants of Omicron, are more transmissible than BA.1 with more robust immune evasion capability because of its unique spike protein mutations. In light of such situation, the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is in desperate need of the third booster. It has been reported that heterologous boosters might produce more effective immunity against wild‐type SARS‐CoV‐2 and the variants. Additionally, the third heterologous protein subunit booster should be considered potentially. In the present study, we prepared a Delta full‐length spike protein sequence‐based mRNA vaccine as the "priming" shot and developed a recombinant trimeric receptor‐binding domain (RBD) protein vaccine referred to as RBD–HR/trimer as a third heterologous booster. Compared to the homologous mRNA group, the heterologous group (RBD–HR/trimer vaccine primed with two mRNA vaccines) induced higher neutralizing antibody titers against BA.4/5‐included SARS‐CoV‐2 variants. In addition, heterologous vaccination exhibited stronger cellular immune response and long‐lasting memory response than the homologous mRNA vaccine. In conclusion, a third heterologous boosting with RBD–HR/trimer following two‐dose mRNA priming vaccination should be a superior strategy than a third homologous mRNA vaccine. The RBD–HR/trimer vaccine becomes an appropriate candidate for a booster immune injection. [ABSTRACT FROM AUTHOR]

Abstract Background Heterologous prime-boost with ChAdOx1 nCoV-19 vector vaccine (ChAd) and a messenger RNA vaccine (BNT or mRNA-1273) has been widely facilitating mass coronavirus disease 2019 (COVID-19) immunisation. This review aimed to synthesize immunogenicity and reactogenicity of heterologous immunisations with ChAd and BNT (mRNA-1273) vaccine compared with homologous ChAd or BNT (mRNA-1273) immunisation. Methods PubMed, Web of Science, and Embase databases were searched from inception to March 7, 2022. Immunogenicity involving serum antibodies against different SAS-CoV-2 fragments, neutralizing antibody, or spike-specific T cells response were compared. Any, local and systemic reactions were pooled by meta-analysis for comparison. Results Of 14,571 records identified, 13 studies (3024 participants) were included for analysis. Compared with homologous BNT/BNT vaccination, heterologous ChAd/BNT schedule probably induced noninferior anti-spike protein while higher neutralizing antibody and better T cells response. Heterologous ChAd/BNT (mRNA-1273) immunisation induced superior anti-spike protein and higher neutralizing antibody and better T cells response compared with homologous ChAd/ChAd vaccination. Heterologous ChAd/BNT (mRNA-1273) had similar risk of any reaction (RR = 1.30, 95% CI: 0.86−1.96) while higher risk of local reactions (RR = 1.65, 95% CI: 1.27−2.15) and systemic reactions (RR = 1.49, 95% CI: 1.17−1.90) compared with homologous ChAd/ChAd vaccination. There was a higher risk of local reactions (RR = 1.16, 95% CI: 1.03−1.31) in heterologous ChAd/BNT (mRNA-1273) vaccination compare with homologous BNT/BNT but a similar risk of any reaction (RR = 1.03, 95% CI: 0.79−1.34) and systemic reactions (RR = 0.89, 95% CI: 0.60−1.30). Conclusions Heterologous ChAd/BNT schedule induced at least comparable immunogenicity compared with homologous BNT/BNT and better immunogenicity compared with homologous ChAd/ChAd vaccination. The synthetical evidence supported the general application of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Graphical Abstract

Since early 2022, various Omicron variants have dominated the SARS-CoV-2 pandemic in most countries. All Omicron variants are B-cell immune escape variants, and antibodies induced by first-generation COVID-19 vaccines or by infection with earlier SARS-CoV-2 variants largely fail to protect individuals from Omicron infection. In the present study, we investigated the effect of Omicron infections in triple-vaccinated and in antigen-naive individuals. We show that Omicron breakthrough infections occurring 2–3.5 months after the third vaccination restore B-cell and T-cell immune responses to levels similar to or higher than those measured 14 days after the third vaccination, including the induction of Omicron-neutralizing antibodies. Antibody responses in breakthrough infection derived mostly from cross-reacting B cells, initially induced by vaccination, whereas Omicron infections in antigen-naive individuals primarily generated B cells binding to the Omicron but not the Wuhan spike protein. Although antigen-naive individuals mounted considerable T-cell responses after infection, B-cell responses were low, and neutralizing antibodies were frequently below the limit of detection. In summary, the detection of Omicron-associated B-cell responses in primed and in antigen-naive individuals supports the application of Omicron-adapted COVID-19 vaccines, but calls into question their suitability if they also contain/encode antigens of the original Wuhan virus.

Abstract BA.4 and BA.5 (BA.4/5), the subvariants of Omicron, are more transmissible than BA.1 with more robust immune evasion capability because of its unique spike protein mutations. In light of such situation, the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is in desperate need of the third booster. It has been reported that heterologous boosters might produce more effective immunity against wild‐type SARS‐CoV‐2 and the variants. Additionally, the third heterologous protein subunit booster should be considered potentially. In the present study, we prepared a Delta full‐length spike protein sequence‐based mRNA vaccine as the “priming” shot and developed a recombinant trimeric receptor‐binding domain (RBD) protein vaccine referred to as RBD–HR/trimer as a third heterologous booster. Compared to the homologous mRNA group, the heterologous group (RBD–HR/trimer vaccine primed with two mRNA vaccines) induced higher neutralizing antibody titers against BA.4/5‐included SARS‐CoV‐2 variants. In addition, heterologous vaccination exhibited stronger cellular immune response and long‐lasting memory response than the homologous mRNA vaccine. In conclusion, a third heterologous boosting with RBD–HR/trimer following two‐dose mRNA priming vaccination should be a superior strategy than a third homologous mRNA vaccine. The RBD–HR/trimer vaccine becomes an appropriate candidate for a booster immune injection.

Comparative analyses of SARS-CoV-2-specific immune responses elicited by diverse prime-boost regimens are required to establish efficient regimens for the control of COVID-19. In this prospective observational cohort study, spike-specific immunoglobulin G (IgG) and neutralizing antibodies (nAbs) alongside spike-specific T -cell responses in age-matched groups of homologous BNT162b2/BNT162b2 or AZD1222/AZD1222 vaccination, heterologous AZD1222/BNT162b2 vaccination, and prior wild-type SARS-CoV-2 infection/vaccination were evaluated. Peak immune responses were achieved after the second vaccine dose in the naïve vaccinated groups and after the first dose in the prior infection/vaccination group. Peak titers of anti-spike IgG and nAb were significantly higher in the AZD1222/BNT162b2 vaccination and prior infection/vaccination groups than in the BNT162b2/BNT162b2 or AZD1222/AZD1222 groups. However, the frequency of interferon-γ-producing CD4+ T cells was highest in the BNT162b2/BNT162b2 vaccination group. Similar results were observed in the analysis of polyfunctional T cells. When nAb and CD4+ T -cell responses against the Delta variant were analyzed, the prior infection/vaccination group exhibited higher responses than the groups of other homologous or heterologous vaccination regimens. nAbs are efficiently elicited by heterologous AZD1222/BNT162b2 vaccination, as well as prior infection/vaccination, whereas spike-specific CD4+ T -cell responses are efficiently elicited by homologous BNT162b2 vaccination. Variant-recognizing immunity is more efficiently generated by prior infection/vaccination than the other homologous or heterologous vaccination regimens. [ABSTRACT FROM AUTHOR]

The immunogenicity of a heterologous vaccination regimen consisting of ChAdOx1 nCoV-19 (a chimpanzee adenovirus-vectored vaccine) followed by mRNA-1273 (a lipid–nanoparticle-encapsulated mRNA-based vaccine) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the omicron variant (B.1.1.529), is poorly studied. The aim of this study was to evaluate the neutralizing antibody activity and immunogenicity of heterologous ChAdOx1 nCoV-19 and mRNA-1273 prime-boost vaccination against wild-type (BetaCoV/Korea/KCDC03/2020), alpha, beta, gamma, delta, and omicron variants of SARS-CoV-2 in Korea. A 50% neutralizing dilution (ND50) titer was determined in serum samples using the plaque reduction neutralization test. Antibody titer decreased significantly at 3 months compared with that at 2 weeks after the 2nd dose. On comparing the ND50 titers for the above-mentioned variants of concerns, it was observed that the ND50 titer for the omicron variant was the lowest. This study provides insights into cross-vaccination effects and can be useful for further vaccination strategies in Korea. [ABSTRACT FROM AUTHOR]

Currently available COVID-19 vaccines include inactivated virus, live attenuated virus, mRNA-based, viral vectored and adjuvanted protein-subunit-based vaccines. All of them contain the spike glycoprotein as the main immunogen and result in reduced disease severity upon SARS-CoV-2 infection. While we and others have shown that mRNA-based vaccination reactivates pre-existing, crossreactive immunity, the effect of vector vaccines in this regard is unknown. Here, we studied cellular and humoral responses in heterologous adenovirus-vector-based ChAdOx1 nCOV-19 (AZ; Vaxzeria, AstraZeneca) and mRNA-based BNT162b2 (BNT; Comirnaty, BioNTech/Pfizer) vaccination and compared it to a homologous BNT vaccination regimen. AZ primary vaccination did not lead to measurable reactivation of cross-reactive cellular and humoral immunity compared to BNT primary vaccination. Moreover, humoral immunity induced by primary vaccination with AZ displayed differences in linear spike peptide epitope coverage and a lack of anti-S2 IgG antibodies. Contrary to primary AZ vaccination, secondary vaccination with BNT reactivated pre-existing, cross-reactive immunity, comparable to homologous primary and secondary mRNA vaccination. While induced anti-S1 IgG antibody titers were higher after heterologous vaccination, induced CD4+ T cell responses were highest in homologous vaccinated. However, the overall TCR repertoire breadth was comparable between heterologous AZBNT-vaccinated and homologous BNT-BNT-vaccinated individuals, matching TCR repertoire breadths after SARS-CoV-2 infection, too. The reasons why AZ and BNT primary vaccination elicits different immune response patterns to essentially the same antigen, and the associated benefits and risks, need further investigation to inform vaccine and vaccination schedule development. [ABSTRACT FROM AUTHOR]

BackgroundThe mass vaccination is a key strategy to prevent and control the coronavirus disease 2019 (COVID-19) pandemic. Today, several different types of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed worldwide. These vaccines are usually administered in a two-dose schedule, and the third dose is currently being administered in most countries. This study aimed to systematically review and meta-analyze the immunogenicity of heterologous vs. homologous vaccination after administration of the third dose of COVID-19 vaccines.MethodsElectronic databases and websites including Scopus, PubMed, Web of Science, and Google scholar were searched for relevant randomized clinical trial (RCT) studies. After applying the inclusion and exclusion criteria, a total of three RCTs were included in the study. These RCTs were included 2,613 healthy adults (18 years or older and without a history of laboratory-confirmed COVID-19) with 15 heterologous and five homologous prime-boost vaccination regimens. Anti-SARS-CoV-2-spike IgG levels at day 28 after administration of the third dose, were compared between the heterologous and homologous regimens.ResultsThe highest antibody responses had been reported for the homologous vaccination regimen of m1273/m1273/m1273 (Moderna), followed by the heterologous regimen of BNT/BNT/m1273. In addition, the immunogenicity of viral vector and inactivated vaccines was remarkably enhanced when they had been boosted by a heterologous vaccine, especially mRNA vaccines.ConclusionThis systematic review suggests that mRNA vaccines in a homologous regimen induce strong antibody responses to SARS-CoV-2 compared to other vaccine platforms. In contrast, viral vector and inactivated vaccines show a satisfactory immunogenicity in a heterologous regimen, especially in combination with mRNA vaccines.

Currently available COVID-19 vaccines include inactivated virus, live attenuated virus, mRNA-based, viral vectored and adjuvanted protein-subunit-based vaccines. All of them contain the spike glycoprotein as the main immunogen and result in reduced disease severity upon SARS-CoV-2 infection. While we and others have shown that mRNA-based vaccination reactivates pre-existing, cross-reactive immunity, the effect of vector vaccines in this regard is unknown. Here, we studied cellular and humoral responses in heterologous adenovirus-vector-based ChAdOx1 nCOV-19 (AZ; Vaxzeria, AstraZeneca) and mRNA-based BNT162b2 (BNT; Comirnaty, BioNTech/Pfizer) vaccination and compared it to a homologous BNT vaccination regimen. AZ primary vaccination did not lead to measurable reactivation of cross-reactive cellular and humoral immunity compared to BNT primary vaccination. Moreover, humoral immunity induced by primary vaccination with AZ displayed differences in linear spike peptide epitope coverage and a lack of anti-S2 IgG antibodies. Contrary to primary AZ vaccination, secondary vaccination with BNT reactivated pre-existing, cross-reactive immunity, comparable to homologous primary and secondary mRNA vaccination. While induced anti-S1 IgG antibody titers were higher after heterologous vaccination, induced CD4+ T cell responses were highest in homologous vaccinated. However, the overall TCR repertoire breadth was comparable between heterologous AZ-BNT-vaccinated and homologous BNT-BNT-vaccinated individuals, matching TCR repertoire breadths after SARS-CoV-2 infection, too. The reasons why AZ and BNT primary vaccination elicits different immune response patterns to essentially the same antigen, and the associated benefits and risks, need further investigation to inform vaccine and vaccination schedule development.

This study aimed to determine the willingness of college students to choose COVID-19 heterologous vaccination and its associated influencing factors in Taizhou, China. A population-based, self-administered online questionnaire was conducted from March 15 to 17, 2022. Of the 2,463 participants who had received the invitation, 1,821 responded to the survey (response rate = 73.9%). Only 14% (86/614) of those willing to receive a booster would chose a heterologous vaccination; the perception of better effectiveness of a COVID-19 heterologous vaccination booster was the significant factor (X2 = 22.671, p

Objective: Vaccination is the most effective way to control the COVID-19 pandemic all over the world. We aimed to evaluate the relationship between antibody titers and vaccine side effects after the BNT162b2 vaccine was administered as a reminder dose in healthcare workers (HCW) who received two doses of inactivated SARS-CoV-2 vaccine name CoronaVac (Sinovac Life Sciences, Beijing, China). Methods: A total of428 HCWs participated in the study. Participants who received the mRNA vaccine as a reminder dose were evaluated with a questionnaire regarding antibody values and vaccine side effects. Three weeks after the first BNT162b2 vaccine, the same questionnaire was applied face-to-face to HCW, and the same questionnaire was applied to those who received a second reminder dose via telephone. Results: Out of428, 373 (87.1%) HCWs preferred one and 55 (12.9%) two doses of the BNT162b2 vaccine as reminder doses after being vaccinated with an inactivated vaccine. It was observed that side effects were more frequent in women aged 18-40 after a single dose of the BNT162b2 vaccine (p<0.001). The most common side effects are redness, swelling, and pain at the injection site, with a rate of 59.6%. Fatigue-weakness was the most common systemic reaction, with a rate of 58.6%. Axillary lymphadenopathy was observed seen in 3 (1.1%) HCWs. The median value of IgG titers in the third week after the reminder dose was found to be higher in HCW with side effects than those without side effects (p<0.001). When the cumulative incidence rate of vaccinated people was evaluated over 389 people, no cases were observed on the 14th and 30th days after the first reminder dose of BNT162b2. However, the first case was observed on the 60th day, and after the second reminder dose, cases were seen on the 14th, 30th, and 60th days. Conclusion: Since the side effects detected after the BNT162b2 reminder dose were mild to moderate and progressed with local symptoms, it was concluded that highly protective mRNA vaccines could be safely preferred for protection from COVID-19. [ABSTRACT FROM AUTHOR]

We investigated antibody titers and avidity after heterologous versus homologous coronavirus disease 2019 vaccination over 6 months after the second dose. We found a significantly higher avidity in regimens including at least 1 dose of the adenoviral vector vaccine ChAdOx1-S compared with 2 doses of the mRNA vaccine BNT162b2. [ABSTRACT FROM AUTHOR]

Heterologous Covid-19 vaccination strategies arose due to interruption of vaccination programs plus delay and shortage of vaccine supplies. We analysed neutralizing response against ancestral SARS-CoV-2 B.1 and P.1, C.37 and B.1.67.2 variants elicited by 16 homologous and heterologous protocols combining Gam-COVID-Vac, ChAdOx1-S, Ad5-nCorV, BBIBP-CorV and mRNA-1273 vaccines. Homologous mRNA-1273 and heterologous schemes of a non-replicative viral vector/inactivated virus-based vaccine combined with mRNA-1273 induced significantly broader and greater neutralizing antibody-response. Moreover, serum from participants vaccinated with combinations of ChAdOx1-S/Ad5-nCorV and BBIBP-CorV/non-replicative viral vector-based vaccines showed higher or equivalent neutralizing response compared to homologous protocols, pointing them as good alternative platforms. BBIBP-CorV used as second dose exhibited significantly lower neutralizing response compared to other protocols, demonstrating that it should not be recommended as second dose. The information provided herein is valuable to redesign vaccination strategies, especially for low-income countries that still struggle with low percentages of immunized populations and vaccine supply shortage. [ABSTRACT FROM AUTHOR]

In this study involving a cohort of employees of the National Airline company in Lebanon, we assessed humoral immunity levels and the effectiveness of two COVID-19 vaccines, Gam-COVID-Vac versus BNT162b2, after two doses and after a homologous and heterologous BNT162b2 booster, in addition to the impact of hybrid immunity. Vaccine effectiveness (VE) was retrospectively determined against laboratory-confirmed SARS-CoV-2 infection during the periods of Delta and Omicron variants' predominance, separately, and was calculated based on a case–control study design. The humoral immune response, measured by a SARS-CoV-2 anti-spike receptor-binding domain (RBD) IgG titer, was prospectively assessed after the aforementioned vaccination schemes at different time points. This study showed higher effectiveness of BNT162b2 after two doses (81%) compared to two doses of Gam-COVID-Vac (41.8%) against the Delta variant of SARS-CoV-2, which correlated with anti-spike antibody levels. Regarding the Omicron variant, protection against infection and antibody levels were severely compromised and the correlation between an anti-spike IgG titer and effectiveness was lost, unlike the situation during the Delta wave. Considering the booster vaccination schemes, a homologous BNT162b2 booster after a BNT162b2 primary vaccination induced a higher humoral immune response when compared to that induced by a heterologous BNT162b2 booster after a Gam-COVID-Vac primary vaccination. However, the VE of both booster regimens against the Omicron variant was almost equal (64% in the homologous regimen and 57% in heterologous regimen). Hybrid immunity evidenced a better humoral response and a greater and longer protection against Delta and Omicron infections compared to vaccination-induced immunity in COVID-19-naïve individuals. Finally, the findings show that VE waned with time during the same wave, highlighting the importance of reinforcing primary and booster COVID-19 vaccination mainly at the beginning of each wave during the surge of a new variant of concern. [ABSTRACT FROM AUTHOR]

Summary: Background: Vaccines are an important means to overcome the SARS-CoV-2 pandemic. They induce specific antibody and T-cell responses but it remains open how well vaccine-induced immunity is preserved over time following homologous and heterologous immunization regimens. Here, we compared the dynamics of humoral and cellular immune responses up to 180 days after homologous or heterologous vaccination with either ChAdOx1-nCoV-19 (ChAd) or BNT162b2 (BNT) or both. Methods: Various tests were used to determine the humoral and cellular immune response. To quantify the antibody levels, we used the surrogate neutralization (sVNT) assay from YHLO, which we augmented with pseudo- and real virus neutralization tests (pVNT and rVNT). Antibody avidity was measured by a modified ELISA. To determine cellular reactivity, we used an IFN-γ Elispot, IFN-γ/IL Flurospot, and intracellular cytokine staining. Findings: Antibody responses significantly waned after vaccination, irrespective of the regimen. The capacity to neutralize SARS-CoV-2 – including variants of concern such as Delta or Omicron – was superior after heterologous compared to homologous BNT vaccination, both of which resulted in longer-lasting humoral immunity than homologous ChAd immunization. All vaccination regimens induced stable, polyfunctional T-cell responses. Interpretation: These findings demonstrate that heterologous vaccination with ChAd and BNT is a potent alternative to induce humoral and cellular immune protection in comparison to the homologous vaccination regimens. Funding: The study was funded by the German Centre for Infection Research (DZIF), the European Union's “Horizon 2020 Research and Innovation Programme'' under grant agreement No. 101037867 (VACCELERATE), the “Bayerisches Staatsministerium für Wissenschaft und Kunst” for the CoVaKo-2021 and the For-COVID projects and the Helmholtz Association via the collaborative research program “CoViPa”. Further support was obtained from the Federal Ministry of Education and Science (BMBF) through the “Netzwerk Universitätsmedizin”, project “B-Fast” and “Cov-Immune”. KS is supported by the German Federal Ministry of Education and Research (BMBF, 01KI2013) and the Else Kröner-Stiftung (2020_EKEA.127).

COVID-19 pandemic continues to challenge the transplant community, given increased morbidity and mortality associated with the disease and poor response to prevention measures such as vaccination. Transplant recipients have a diminished response to both mRNA and vector-based vaccines compared to dialysis and the general population. The currently available assays to measure response to vaccination includes commercially available antibody assays for anti-Spike Ab, or anti- Receptor Binding Domain Ab. Positive antibody testing on the assays does not always correlate with neutralizing antibodies unless the antibody levels are high. Vaccinations help with boosting polyfunctional CD4+ T cell response, which continues to improve with subsequent booster doses. Ongoing efforts to improve vaccine response by using additional booster doses and heterologous vaccine combinations are underway. There is improved antibody response in moderate responders; however, the ones with poor response to initial vaccination doses, continue to have a poor response to sequential boosters. Factors associated with poor vaccine response include diabetes, older age, specific immunosuppressants such as belatacept, and high dose mycophenolate. In poor responders, a decrease in immunosuppression can increase response to vaccination. COVID infection or vaccination has not been associated with an increased risk of rejection. Pre- and Post-exposure monoclonal antibodies are available to provide further protection against COVID infection, especially in poor vaccine responders. However, the efficacy is challenged by the emergence of new viral strains. A recently approved bivalent vaccine offers better protection against the Omicron variant.

ABSTRACT Confronted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as Delta and Omicron, with high infectivity and immune evasion capacity, vaccination remains the most effective tool to prevent infection and severe illness. However, heterologous vaccination of mRNA vaccines primed with protein subunit vaccines had not been evaluated before the current study. Since subunit vaccine MVC-COV1901 (MVC) has been granted emergency use authorization in Taiwan, in this study, we explored the humoral and cellular immune responses to additional third (2× MVC/Mod) and fourth (2× MVC/2× Mod) doses of mRNA-1273 (Mod) after priming with two doses of subunit vaccine MVC against the emerging variants. We found a 12.3- to 16.1-fold increase in antibodies targeting the receptor binding domain (RBD) of the Delta variant with 2× MVC/Mod compared to two doses of MVC (2× MVC) or AZD1222 (2× AZ) regimens and a 26- to 32.2-fold improvement in neutralizing potency against the Omicron variant (BA.1). Besides, the numbers of gamma interferon (IFN-γ)-secreting T cells induced by 2× MVC/Mod were also elevated 3.5-fold and 3.7- to 4.3-fold for the wild type and Delta variant. However, boosting with a fourth dose of Mod (2× MVC/2× Mod) after the 2× MVC/Mod regimen failed to significantly improve the immune responses. Moreover, all vaccination schedules showed reduced neutralizing activity against the Omicron variant. Collectively, our results suggested that the third or fourth dose booster vaccination with mRNA vaccine after priming with two doses of protein subunit vaccine could elicit stronger humoral and cellular immune responses. These findings could provide a future global heterologous boosting strategy against COVID-19. IMPORTANCE Vaccination is the most important strategy to combat the COVID-19 outbreak; however, it remains to be determined whether heterologous prime-boost regimens could induce equal or even stronger immune responses against SARS-CoV-2. Here, we showed that boosting the additional doses of mRNA-1273 (Mod) priming with two doses of MVC-COV1901 (MVC) (2× MVC/Mod) improved humoral and cellular immunity compared to two doses of AZD1222 (2× AZ) or MVC (2× MVC) against SARS-CoV-2 variants. However, the Omicron variant showed strong immune evasion ability for all vaccination schedules. Our findings provided evidence supporting that heterologous vaccination by boosting with mRNA vaccine after priming with two doses of protein subunit vaccine could strongly promote humoral and cellular immune responses against the emerging SARS-CoV-2 variants.

• CoronaVac-BNT162b2 scheme shows significant increase in IgG levels after booster. • IgG levels drop ten weeks after booster but remain higher than those after priming. • Specific IgG levels correlate with neutralizing activity and Fc-mediated functions. Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven to be a successful strategy for prevent severe infections. CoronaVac and BNT162b2 are the most used vaccines worldwide, but their use in heterologous vaccination schedules is still subjected to evaluation. Fifty healthy individuals who received heterologous prime-boost vaccination with CoronaVac and BNT162b2 were enrolled in a post-vaccination serological follow-up longitudinal prospective study. We evaluated specific serum anti-receptor binding domain (RBD) IgG antibody levels, and their capacity to block RBD-ACE2 interaction with a surrogate neutralization assay. In 20 participants, we assessed antibody binding kinetics by surface plasmon resonance, and Fc-mediated functions by ADCC and ADCP reporter assays. Our baseline seronegative cohort, displayed seroconversion after two doses of CoronaVac and an important decrease in serum anti-RBD IgG antibodies levels 80 days post-second dose. These levels increased significantly early after the third dose with BNT162b2, but 73 days after the booster we found a new fall. Immunoglobulin functionalities showed a similar behavior. The heterologous prime-boost vaccination with CoronaVac and BNT162b2 generated an impressive increase in serum anti-RBD specific antibody levels followed by a drop. Nevertheless, these titers remained well above those found in individuals only vaccinated with CoronaVac in the same elapsed time. Serum IgG levels showed high correlation with antibody binding analysis, their capacity to block RBD-ACE2 interaction, and Fc-effectors mechanisms. Our work sheds light on the humoral immune response to heterologous vaccination with CoronaVac and BNT162b2, to define a post-vaccination correlate of protection against SARS-CoV-2 infection and to discuss the scheduling of future vaccine boosters in general population. [ABSTRACT FROM AUTHOR]

This prospective cohort study aimed to evaluate the efficacy of COVID-19 vaccine schemes, homologous versus heterologous vaccine strategies, and vaccine-induced anti-S-RBD-IgG antibody response in preventing COVID-19 among 942 healthcare workers 1 year after vaccination with the inactivated and/or mRNA vaccines. All participants received the first two primary doses of vaccines, 13.6% of them lacked dose 3, 50.5% dose 4, and 90.3% dose 5. Antibody levels increased with the increase in number of vaccine doses and also in heterologous vaccine regimens. In both inactive, mRNA vaccines and mixed vaccination, infection rates were significantly higher in two-dose-receivers, but lower in four- or five-dose receivers and increasing the total number of vaccine doses resulted in more protection against infection: the three-dose regimen yielded 3.67 times more protection, the four-dose 8 times, and five-dose 27.77 times more protection from COVID-19 infection, compared to any two-dose vaccination regimens. Antibody levels at the end of the first year of four- or five-dose-receivers were significantly higher than two- or three-dose receivers. To conclude, an increased number of total vaccine doses and anti-S-RBD antibody levels increased the protection from COVID-19 infection. Therefore, four or more doses are recommended in 1 year for effective protection, especially in risk groups. [ABSTRACT FROM AUTHOR]

(1) Background: High immunosuppressive regimen in lung transplant recipients (LTRs) hampers the immune response to vaccination. We prospectively investigated the immunogenicity of heterologous ChAdOx1 nCoV-19-BNT162b2 mRNA vaccination in an LTR cohort. (2) Methods: Forty-nine COVID-19 naïve LTRs received a two-dose regimen ChAdOx1 nCoV-19 vaccine. A subset of 32 patients received a booster dose of BNT162b2 mRNA vaccine 18 weeks after the second dose. (3) Results: Two-doses of ChAdOx1 nCoV-19 induced poor immunogenicity with 7.2% seropositivity at day 180 and low neutralizing capacities. The BNT162b2 mRNA vaccine induced significant increases in IgG titers with means of 197.8 binding antibody units per milliliter (BAU/mL) (95% CI 0–491.4) and neutralizing antibodies, with means of 76.6 AU/mL (95% CI 0–159.6). At day 238, 32.2% of LTRs seroconverted after the booster dose. Seroneutralization capacities against Delta and Omicron variants were found in only 13 and 9 LTRs, respectively. Mycophenolate mofetil and high-dose corticosteroids were associated with a weak serological response. (4) Conclusions: The immunogenicity of a two-dose ChAdOx1 nCoV-19 vaccine regimen was very poor in LTRs, but was significantly enhanced after the booster dose in one-third of LTRs. In immunocompromised individuals, the administration of a fourth dose may be considered to increase the immune response against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Summary: Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p

Summary: Background: The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180. Methods: Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739). Findings: In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49–5956·71) in the IG and 7298·22 BAU/mL (6739·41–7903·37) in the CG (p 1:100 at day 180 (19% and 22%, respectively). Interpretation: Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180. Funding: Funded by Instituto de Salud Carlos III (ISCIII).

Response to SARS-CoV-2-vaccines in kidney-transplant recipients (KTR) is severely reduced. Heterologous3rd vaccination combining mRNA and vector vaccines did not increase seroconversion at 4 weeks after vaccination, but evolution of antibody levels beyond the first month remains unknown. We have recently completed a randomized-controlled trial on heterologous (Ad26COVS1) vs. homologous (BNT162b2 or mRNA-1273) 3rd vaccination in 201 KTR not developing SARS-CoV-2-spike-protein antibodies following two doses of mRNA vaccine (EurdraCT: 2021-002927-39). Here, we report seroconversion at the second follow-up at 3 months after the 3rd vaccination (prespecified secondary endpoint). In addition, higher cut-off levels associated with neutralizing capacity and protective immunity were applied (i.e., > 15, > 100, > 141, and > 264 BAU/ml). A total of 169 patients were available for the 3-month follow-up. Overall, seroconversion at 3 months was similar between both groups (45 vs. 50% for mRNA and the vector group, respectively; p = 0.539). However, when applying higher cut-off levels, a significantly larger number of individuals in the vector group reached antibody levels > 141 and > 264 BAU/ml at the 3-month follow-up (141 BAU/ml: 4 vs. 15%, p = 0.009 and 264 BAU/ml: 1 vs. 10%, p = 0.018 for mRNA vs. the vector vaccine group, respectively). In line, antibody levels in seroconverted patients further increased from month 1 to month 3 in the vector group while remaining unchanged in the mRNA group (median increase: mRNA = 1.35 U/ml and vector = 27.6 U/ml, p = 0.004). Despite a similar overall seroconversion rate at 3 months following 3rd vaccination in KTR, a heterologous 3rd booster vaccination with Ad26COVS1 resulted in significantly higher antibody levels in responders.

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response. [ABSTRACT FROM AUTHOR]

At present, the global COVID‐19 epidemic has not been completely controlled, and epidemic prevention and control still face severe challenges. As there is no specific treatment for COVID‐19, promoting roll‐out vaccinations and building herd immunity are still the most effective and economic measures to control the COVID‐19 pandemic. However, the neutralizing antibody level in the recipients decreases with time, and the vaccine's protective efficacy gradually weakens. It is still inconclusive whether it is necessary to carry out booster vaccination to strengthen the immune barrier to infection. In this paper, we combined the existing data on the effectiveness and persistence of COVID‐19 vaccines. We found that it is necessary to carry out a booster vaccination strategy. However, not all subjects need to receive one more dose of vaccine 6 months after the initial immunization. Priority should be given to the high‐risk groups, such as the elderly and people with immunodeficiency. A heterologous booster can induce higher immune responses and enhance immune protection than homologous vaccinations. However, more scientific data and clinical studies are needed to verify the safety of heterologous vaccination strategies. Highlights: At present, the global COVID‐19 epidemic still faces severe challenges.It is necessary to carry out a booster vaccination strategy, especially for the high‐risk groups.A heterologous booster can induce higher immune responses than homologous vaccinations. [ABSTRACT FROM AUTHOR]

Bhutan – a landlocked least developed country in the Himalayas – vaccinated 94% of its adults with the first dose of COVID-19 vaccine in March-April 2021, 90.2% with second dose in July 2021, and 89.1% with booster (third) dose by March 2022. The country used COVISHIELD (Oxford-Astrazeneca) vaccine for the first dose but decided to pursue a heterologous prime-boost strategy ("mix-and-match") for the second dose using Moderna's mRNA vaccine for adults. Bhutan rapidly rolled out Pfizer and Moderna vaccines for 12 to 17-year-olds through a school-based vaccination strategy followed by booster doses: 78.6% of adolescents aged 12–17 years were vaccinated with the first dose by August 2021, 92.8% with second dose by November 2021, and 79.7% with booster (third) dose by March 2022. More than 97% of children aged 5 to 11 years have received Pfizer's Comirnaty vaccine for their first dose. Bhutan is steadily vaccinating its population and might soon become one of the few least developed countries to achieve herd immunity-level vaccination coverage with more than 80% of its population fully vaccinated. [ABSTRACT FROM AUTHOR]

Limited data are available on the short‐ to midterm levels of antibodies to the CoronaVac vaccine and quantitative change in humoral response after homologous or heterologous booster doses. In this prospective cohort study, we evaluated the anti‐receptor‐binding domain (RBD) immunoglobulin G (IgG) levels after two doses of CoronaVac and heterologous/homologous booster administration among healthcare workers in a university hospital in Turkey. Quantitative anti‐RBD IgG antibody levels were measured at first and fourth months in 560 healthcare workers who had completed two doses of CoronaVac vaccine, and within 2 months after the third dose of CoronaVac or BNT162b2. Participants were asked to complete a questionnaire during the first blood draw. The seropositivity rate was 98.9% and 89.1%, and the median antibody level was 469.2 AU/ml and 166.5 AU/ml at first and fourth month, respectively. In the fourth month, a mean reduction of 61.4% ± 20% in antibody levels was observed in 79.8% of the participants. The presence of chronic disease (odds ratio [OR]: 1.76, 95% confidence interval [CI]: 1.15–2.69) and being in the 36–50 age group (OR: 2.11, 95% CI: 1.39–3.19) were identified as independent predictors for low antibody response. The antibody level increased 104.8‐fold (median: 17 609.4 vs. 168 AU/ml) and 8.7‐fold (median: 1237.9 vs. 141.4 AU/ml) in the participants who received BNT162b2 and CoronaVac, respectively. During the follow‐up, 25 healthcare workers (4.5%) were infected with severe acute respiratory syndrome coronavirus 2. Considering the waning immunity and circulating variants, a single booster dose of messenger RNA vaccine seems reasonable after the inactivated vaccine especially in risk groups. Highlights: The seropositivity rate was quite high with two doses of inactivated CoronaVac vaccine.Chronic disease and preobesity caused lower antibody response.There was a significant decrease in the antibody levels at the fourth month after the second dose of CoronaVac.An increase in antibody levels was detected with both homologous and heterologous booster (messenger RNA vaccine BNT162b2) administration approximately 5 months after the second dose of CoronaVac.A Heterologous booster with BNT162b2 provided a marked increase in antibody response compared to a homologous booster (104.8‐ vs. 8.7‐fold, respectively). [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the mixed and homogeneous application of the inactivated SARS-CoV-2 vaccine CoronaVac (CV) and the mRNA vaccine BNT162b2 (BNT). This prospective cohort study included 235 health care workers who had received two prime shots with CoronaVac. They were divided into three cohorts after the third month: Cohort-I (CV/CV); Cohort-II (CV/CV/CV); and Cohort-III (CV/CV/BNT). Anti-S-RBD-IgG and total anti-spike/anti-nucleocapsid-IgG antibody concentrations were examined in vaccinated health workers at the 1st, 3rd, and 6th months following the second dose of the vaccination. The mean age of 235 health care workers who participated in the project was 39.51 ± 10.39 (min-max: 22–64). At the end of the 6th month, no antibodies were detected in 16.7% of Cohort-I participants, and anti-S-RDB IgG levels showed a decrease of 60% compared to the levels of the 3rd month. The antibody concentrations of the 6th month were found to have increased by an average of 5.13 times compared to the 3rd-month levels in Cohort-II and 20.4 times in Cohort-III. The heterologous vaccination strategy "CoronaVac and BNT162b2 regimen" is able to induce a stronger humoral immune response and it will help remove inequalities in the developing world where CoronaVac was the initial prime. [ABSTRACT FROM AUTHOR]

Immune responses against different variants of SARS-CoV-2 including Omicron following 6 months of administration of heterologous prime-boost COVID-19 vaccine Keywords: SARS-CoV-2; heterologous vaccination; Covaxin; Covishield; neutralization; Omicron EN SARS-CoV-2 heterologous vaccination Covaxin Covishield neutralization Omicron 1 4 4 06/08/22 20220401 NES 220401 Within a short span of time severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines developed through usage of different platforms have been approved across the globe. It is very clear from the geometric mean titre of the heterologous group at 1, 6 months and their ratio compared with homologous vaccination groups that the heterologous CS and CV vaccination is immunogenically superior to homologous vaccination. [Extracted from the article]

COVID-19 has swept across the globe since 2019 and repeated waves of infection have been caused by different variants of the original SARS-CoV-2 (wild type), with the Omicron and Delta variants having dominated recently. Vaccination is among the most important measures in the absence of widespread use of antivirals for prevention of morbidity and mortality. Inactivated virus vaccine has been abundantly used in many countries as the primary two-dose regimen. We aim to study the safety and immunogenicity of CoronaVac (three-dose inactivated virus vaccine) and the BNT162b2 (two-dose inactivated virus vaccine followed by an mRNA vaccine) booster. Both CoronaVac and BNT162b2 boosters are generally safe and have good immunogenicity against the wild type SARS-CoV-2 and the Delta variant with the majority having neutralizing antibodies (NAb) on day 30 and day 90. However, the BNT162b2 booster is associated with a much higher proportion of positive NAb against the Omicron variant. Only 8% of day 30 and day 90 samples post CoronaVac booster have NAb against the Omicron variant. In addition, more BNT162b2 booster recipients are having positive T-cell responses using interferon gamma release assay. In places using inactivated virus vaccine as the primary two-dose scheme, the heterologous mRNA vaccine booster is safe and more immunogenic against the Omicron variant and should be considered as a preferred option during the current outbreak. [ABSTRACT FROM AUTHOR]

We evaluated the post-vaccination humoral response of three real-world cohorts. Vaccinated subjects primed with ChAdOx1-S and boosted with BNT162b2 mRNA vaccine were compared to homologous dosing (BNT162b2/BNT162b2 and ChAdOx1-S/ChAdOx1-S). Serum samples were collected two months after vaccination from a total of 1248 subjects. The results showed that the heterologous vaccine schedule induced a significantly higher humoral response followed by homologous BNT162b2/BNT162b2 and ChAdOx1-S/ChAdOx1-S vaccines (p < 0.0001). Moreover, analyzing factors (i.e., vaccine schedule, sex, age, BMI, smoking, diabetes, cardiovascular diseases, respiratory tract diseases, COVID-19 diagnosis, vaccine side effects) influencing the IgG anti-S response, we found that only the type of vaccine affected the antibody titer (p < 0.0001). Only mild vaccine reactions resolved within few days (40% of subjects) and no severe side effects for either homologous groups or the heterologous group were reported. Our data support the use of heterologous vaccination as an effective and safe alternative to increase humoral immunity against COVID-19. [ABSTRACT FROM AUTHOR]

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response.